Health Technology Assessment 2000; Vol. 4: No. 37 Review

Systematic review of treatments for atopic eczema

C Hoare A Li Wan Po H Williams

Health Technology Assessment NHS R&D HTA Programme HTA HTA

How to obtain copies of this and other HTA Programme reports. An electronic version of this publication, in Adobe Acrobat format, is available for downloading free of charge for personal use from the HTA website (http://www.hta.ac.uk). A fully searchable CD-ROM is also available (see below). Printed copies of HTA monographs cost £20 each (post and packing free in the UK) to both public and private sector purchasers from our Despatch Agents. Non-UK purchasers will have to pay a small fee for post and packing. For European countries the cost is £2 per monograph and for the rest of the world £3 per monograph. You can order HTA monographs from our Despatch Agents: – fax (with credit card or official purchase order) – post (with credit card or official purchase order or cheque) – phone during office hours (credit card only). Additionally the HTA website allows you either to pay securely by credit card or to print out your order and then post or fax it.

Contact details are as follows: HTA Despatch Email: [email protected] c/o Direct Mail Works Ltd Tel: 02392 492 000 4 Oakwood Business Centre Fax: 02392 478 555 Downley, HAVANT PO9 2NP, UK Fax from outside the UK: +44 2392 478 555 NHS libraries can subscribe free of charge. Public libraries can subscribe at a very reduced cost of £100 for each volume (normally comprising 30–40 titles). The commercial subscription rate is £300 per volume. Please see our website for details. Subscriptions can only be purchased for the current or forthcoming volume.

Payment methods Paying by cheque If you pay by cheque, the cheque must be in pounds sterling, made payable to Direct Mail Works Ltd and drawn on a bank with a UK address. Paying by credit card The following cards are accepted by phone, fax, post or via the website ordering pages: Delta, Eurocard, Mastercard, Solo, Switch and Visa. We advise against sending credit card details in a plain email. Paying by official purchase order You can post or fax these, but they must be from public bodies (i.e. NHS or universities) within the UK. We cannot at present accept purchase orders from commercial companies or from outside the UK.

How do I get a copy of HTA on CD? Please use the form on the HTA website (www.hta.ac.uk/htacd.htm). Or contact Direct Mail Works (see contact details above) by email, post, fax or phone. HTA on CD is currently free of charge worldwide.

The website also provides information about the HTA Programme and lists the membership of the various committees. Systematic review of treatments for atopic eczema C Hoare1 A Li Wan Po2 H Williams1*

1 Centre of Evidence-Based Dermatology, University of Nottingham, Queens Medical Centre NHS Trust, Nottingham, UK 2 Centre of Evidence-Based Pharmacotherapy,Aston University, Birmingham, UK

* Corresponding author

Competing interests: Colette Hoare has been funded by the NHS Health Technology Assessment (HTA) R&D programme. Professor Hywel Williams: four of Hywel Williams’ staff are currently employed on NHS HTA or Regional Research and Development grants.Two other Cochrane Skin Group staff members receive NHS R&D core support. He is a paid editor for the Drugs and Therapeutics Bulletin. He is also a life member of the National Eczema Society. He does not work as a consultant to any Pharmaceutical Company although he has received payment from Novartis for lectures on the epidemiology of atopic eczema in 1999. One of his research staff was previously funded by Crookes Healthcare International to conduct a pilot study into the role of nurses in running dermatology follow-up clinics. Professor Alain Li Wan Po has acted as occasional lecturer or consultant for Boots HealthCare Ltd, Novartis, Zyma, SmithKline Beecham,Yamanouchi and Warner Lambert.

Published December 2000

This report should be referenced as follows:

Hoare C, Li Wan Po A,Williams H. Systematic review of treatments of atopic eczema. Health Technol Assess 2000;4(37).

Health Technology Assessment is indexed in Index Medicus/MEDLINE and Excerpta Medica/ EMBASE. Copies of the Executive Summaries are available from the NCCHTA website (see opposite). NHS R&D HTA Programme

he NHS R&D Health Technology Assessment (HTA) Programme was set up in 1993 to ensure T that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. Initially, six HTA panels (pharmaceuticals, acute sector, primary and community care, diagnostics and imaging, population screening, methodology) helped to set the research priorities for the HTA Programme. However, during the past few years there have been a number of changes in and around NHS R&D, such as the establishment of the National Institute for Clinical Excellence (NICE) and the creation of three new research programmes: Service Delivery and Organisation (SDO); New and Emerging Applications of Technology (NEAT); and the Methodology Programme. This has meant that the HTA panels can now focus more explicitly on health technologies (‘health technologies’ are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care) rather than settings of care. Therefore the panel structure has been redefined and replaced by three new panels: Pharmaceuticals; Therapeutic Procedures (including devices and operations); and Diagnostic Technologies and Screening. The HTA Programme will continue to commission both primary and secondary research. The HTA Commissioning Board, supported by the National Coordinating Centre for Health Technology Assessment (NCCHTA), will consider and advise the Programme Director on the best research projects to pursue in order to address the research priorities identified by the three HTA panels. The research reported in this monograph was funded as project number 96/17/01. The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health. The editors wish to emphasise that funding and publication of this research by the NHS should not be taken as implicit support for any recommendations made by the authors.

Criteria for inclusion in the HTA monograph series Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors. Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

HTA Programme Director: Professor Kent Woods Series Editors: Professor Andrew Stevens, Dr Ken Stein and Professor John Gabbay Monograph Editorial Manager: Melanie Corris

The editors and publisher have tried to ensure the accuracy of this report but do not accept liability for damages or losses arising from material published in this report. They would like to thank the referees for their constructive comments on the draft document.

ISSN 1366-5278 © Queen’s Printer and Controller of HMSO 2000 This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to HMSO,The Copyright Unit, St Clements House, 2–16 Colegate, Norwich, NR3 1BQ. Published by Core Research,Alton, on behalf of the NCCHTA. Printed on acid-free paper in the UK by The Basingstoke Press, Basingstoke. G Health Technology Assessment 2000; Vol. 4: No. 37

Contents

List of abbreviations and glossary ...... i 5 Other topical agents ...... 31 Topical coal tar ...... 31 Executive summary ...... iii Emollients ...... 31 1 Background and aims ...... 1 Lithium succinate ointment ...... 34 The problem of atopic eczema ...... 1 Tacrolimus ...... 34 The prevalence of atopic eczema ...... 2 Ascomycin derivatives ...... 36 How does atopic eczema affect people? ...... 2 Summary of other topical agents ...... 36 What causes atopic eczema?...... 3 6 Antimicrobial and antiseptic agents ...... 39 Pathophysiology ...... 3 Summary of antimicrobial and Does atopic eczema clear with time? ...... 4 antiseptic agents ...... 39 How is atopic eczema treated?...... 4 How are the effects of atopic eczema 7 Antihistamines and mast cell stabilisers 45 captured in clinical trials?...... 5 Antihistamines ...... 45 Why is a systematic review needed?...... 5 Sodium cromoglycate...... 46 Summary of the problem of atopic eczema .. 6 Nedrocromil sodium...... 46 Research questions asked in this review ...... 6 Ketotifen ...... 47 Topical doxepin cream ...... 47 2 Methods ...... 9 Tiacrilast ...... 48 General methods structure...... 9 Summary of antihistamines and Search strategy...... 10 mast cell stabilisers ...... 49 Data assessment ...... 11 Methods of presenting qualitative results .... 12 8 Dietary interventions ...... 65 Separating trial data from Dietary restriction in established authors’ opinions ...... 12 atopic eczema ...... 65 Identifying treatments with no RCTs Summary of dietary restriction in and future research priorities ...... 12 established atopic eczema ...... 65 Supplementation with essential fatty acids... 66 3 Results ...... 15 Pyridoxine...... 67 Included studies ...... 15 Vitamin E and multivitamins...... 67 Excluded studies ...... 15 Zinc supplementation ...... 68 Prevention of atopic eczema ...... 16 Summary of dietary interventions ...... 69

4 Topical corticosteroids ...... 25 9 Non-pharmacological treatments ...... 81 Topical corticosteroids versus placebo ...... 25 House dust mite reduction...... 81 Topical corticosteroids versus other House dust mite hyposensitisation...... 82 topical corticosteroids ...... 25 Avoidance of enzyme-enriched detergents .. 83 Topical corticosteroids versus other Benefit from specialised clothing ...... 84 topical preparations ...... 26 Salt baths...... 85 Topical corticosteroids plus Nurse education ...... 85 additional agents ...... 26 Bioresonance ...... 86 Different formulations of the same Psychological approaches ...... 87 topical corticosteroid ...... 26 Ultraviolet light ...... 88 Once-daily versus more frequent use Summary of non-pharmacological of the same topical corticosteroids ...... 26 treatments ...... 89 Prevention of relapse using topical corticosteroids ...... 27 10 Systemic immunomodulatory agents ...... 93 Trials that have specifically examined Allergen–antibody complexes of adverse effects of topical corticosteroids ...... 28 house dust mite ...... 93 Trials that evaluated oral steroids ...... 28 Cyclosporin ...... 93 Additional unanswered questions ...... 28 Levamisole ...... 97 Summary of topical corticosteroids ...... 28 Platelet-activating factor antagonist ...... 97 Contents

Interferon-gamma ...... 99 13 Discussion ...... 113 Thymic extracts and their Treatments with no RCT evidence...... 113 synthetic derivatives ...... 101 Validity and robustness of results ...... 114 Immunoglobulin ...... 103 14 Summary and conclusions...... 117 Transfer factor ...... 103 Research included in the review ...... 117 Summary of systemic Future research priorities ...... 119 immunomodulatory agents ...... 103 Implications for healthcare ...... 121 Summary ...... 121 11 Complementary therapies ...... 105 Chinese herbal medicine...... 105 Acknowledgements ...... 123 Massage therapy...... 106 References ...... 125 Hypnotherapy/biofeedback ...... 106 Homeopathy and aromatherapy ...... 107 Appendix 1 Search strategies ...... 141 Summary of complementary therapies ...... 107 Appendix 2 Excluded studies...... 143 Appendix 3 Studies of steroid therapy ...... 151 12 Other interventions ...... 109 Nitrazepan ...... 109 Appendix 4 Duplicate and triplicate Ranitidine ...... 109 publications ...... 181 Theophylline ...... 110 Health Technology Assessment Salbutamol ...... 110 reports published to date ...... 183 Papaverine ...... 110 Suplatast tosilate ...... 111 Health Technology Assessment Summary of other interventions ...... 111 Programme ...... 189

d Health Technology Assessment 2000; Vol. 4: No. 37

List of abbreviations and glossary

Technical terms and abbreviations are used throughout this report. The meaning is usually clear from the context but a glossary is provided for the non-specialist reader. In some cases usage differs in the literature but the term has a constant meaning throughout this review.

List of abbreviations

ADASI Atopic Dermatitis Area Severity Index NS not significant b.d. twice daily* o.d. once daily* BIT biophysical information therapy PAF platelet-activating factor CCT controlled clinical trial* PP per protocol* CCTR Cochrane Controlled Trials Register PUVA psoralen plus UVA CI confidence interval q.d.s. four times daily* DSCG disodium cromoglycate RCT randomised controlled trial EDEN European Dermato-Epidemiology RoNAA Rule of Nines area assessment* Network SCG sodium cromoglycate ETAC Early Treatment of the Atopic SCORAD Severity Scoring of Atopic Dermatitis Child (study) SEM standard error of the mean* GLA gamma-linoleic acid t.d.s. three times daily* IgE immunoglobulin E UVR ultraviolet radiation ISAAC International Study of Asthma and Allergies in Childhood VAS visual analogue scale* * ITT intention-to-treat *Used only in tables

Glossary

Atopic dermatitis Synonymous with atopic Demarcated Lacks boundary. eczema. Erythema Redness. Bayesian approach An approach to data analysis first developed by Thomas Bayes, Inverse proportion A relation between two which tests the likelihood of something quantities such that one increases in proportion occuring in the light of prior knowledge as the other decreases. and belief about what is likely to happen. This is different from traditional ‘frequentist’ ITT analysis A method of analysis for RCTs statistics, which seeks to disprove the null whereby all patients randomly allocated to hypothesis of no difference between the oneof the treatments in a trial are analysed things being compared. continued i List of abbreviations and glossary

continued

together irrespective of whether or not they Spongiosis Excess fluid between the cells completed or received that treatment. in the epidermis.

Lichenification Thickening of the skin as a Tracker studies A type of experimental result of chronic scratching. design suggested by Lillford for testing technologies that are rapidly changing, for Morphology Form. example prosthetic devices. In the duration of a 3-year trial, the types of devices that were Pruritus Itching. originally tested might have already been improved upon, thereby limiting the extent Rebound phenomenon The tendency for atopic to which one could generalise from the eczema to flare up immediately on stopping a findings. Tracker studies are more flexible treatment that suppresses the disease process. by permitting the use of the technology as it evolves within the trial. Recombinant Reformed by recombination. Wiskott–Aldrich Syndrome A genetic Rule of Nines A method for estimating extent defect affecting a gene on the x chromo- of eczema based on dividing the body into some. Generally passed from mother to multiples of 9%. son. Main symptoms are proneness to infections, thrombocytopenia (low Serological (serology) The scientitic study of platelet counts) and eczema of blood sera and their effects. differing severity.

ii Health Technology Assessment 2000; Vol. 4: No. 37

Executive summary

Background Inclusion/exclusion criteria Only RCTs of therapeutic agents used in the Atopic eczema is the commonest inflammatory prevention and treatment of people with atopic skin disease of childhood, affecting 15–20% of eczema of any age were considered for inclusion. children in the UK at any one time. Adults Only studies where a physician diagnosed atopic make up about one-third of all community cases. eczema or atopic dermatitis were included. Moderate-to-severe atopic eczema can have a profound effect on the quality of life for both Data extraction sufferers and their families. In addition to the Data extraction was conducted by two observers effects of intractable itching, skin damage, sore- onto abstraction forms, with discrepancies resolved ness, sleep loss and the social stigma of a visible by discussion. skin disease, other factors such as frequent visits to doctors, special clothing and the need to Quality assessment constantly apply messy topical applications all The quality assessment of retrieved RCTs included add to the burden of disease. The cause of atopic an assessment of: eczema is unknown, though a genetic pre- disposition and a combination of allergic and • a clear description of method and concealment non-allergic factors appear to be important in of allocation of randomisation determining disease expression. Treatment of • the degree to which assessors and participants atopic eczema in the UK is characterised by a were blinded to the study interventions, and profusion of treatments aimed at disease control. • whether all those originally randomised were The evidential basis of these treatments is often included in the final main analysis. unclear. Most people with atopic eczema are managed in primary care where the least research Data synthesis has been done. Where possible, quantitative pooling of similar RCTs was conducted using the Cochrane Collab- oration’s methods. Where statistical heterogeneity Objectives was found, sources of heterogeneity in terms of study participants, formulation or posology of The objectives of this scoping review are two-fold. intervention, and use of co-treatments were • To produce an up-to-date coverage ‘map’ of explored. Where pooling was not deemed to be randomised controlled trials (RCTs) of appropriate, detailed descriptions of the study treatments of atopic eczema. characteristics and main reported results were • To assist in making treatment recommend- presented along with comments on study quality. ations by summarising the available RCT evidence using qualitative and quantitative methods. Results

A total of 1165 possible RCTs were retrieved in hard Methods copy form for further scrutiny. Of these, 893 were excluded from further analysis because of lack of Data sources appropriate data. The 272 remaining RCTs of Data sources included electronic searching of atopic eczema covered at least 47 different MEDLINE, EMBASE, the Cochrane Controlled interventions, which could be broadly categorised Clinical Trials Register, the Cochrane Skin Group into ten main groups. specialised register of trials, handsearching of atopic eczema conference proceedings, follow-up Quality of reporting was generally poor, and of references in retrieved articles, contact with limited statistical pooling was possible only for leading researchers and requests to relevant oral cyclosporin, and only then after considerable pharmaceutical companies. data transformation. iii Executive summary

There was reasonable RCT evidence to support commonly used treatments compared with each the use of oral cyclosporin, topical cortico- other or in combination. This mismatch is probably steroids, psychological approaches and ultra- due to a combination of the questions not being violet light therapy. asked coupled with a lack of independent investment in primary atopic eczema research. There was insufficient evidence to make recom- mendations on maternal allergen avoidance for Recommendations for research disease prevention, oral antihistamines, Chinese Urgent primary research priorities include RCTs herbs, dietary restriction in established atopic of wet-wrap treatments, the clinical benefit of eczema, homeopathy, house dust mite reduction, allergy testing, the use of water softeners, the massage therapy, hypnotherapy, evening primrose role of specialist nurses, comparisons of tacrolimus oil, emollients, topical coal tar and topical doxepin. and ascomycin against topical corticosteroids, studies of disease prevention, and the use of There was no RCT evidence to support any emollients in preventing disease relapse. Such clear clinical benefit on the use of avoidance RCTs should ideally be pragmatic and simple in of enzyme washing powders, cotton clothing as design, with a few outcome measures that doctors opposed to soft-weave synthetics, biofeedback, and patients find easy to understand. They should twice-daily as opposed to once-daily topical ideally be of 4 months’ or more duration in order corticosteroids, topical antibiotic/steroid to capture the chronicity of disease as well as short- combinations versus topical steroids alone term effects. If such trials are intended to inform and antiseptic bath additives. primary care, where patients may have milder disease, then they should be conducted in a There was complete absence of RCT evidence on primary care setting. short bursts of potent versus longer-term weaker topical steroids, dilution of topical corticosteroids, This review suggests that there is some scope oral prednisolone and azathioprine, salt baths, for further secondary research by systematically impregnated bandages, wet-wrap bandages, water reviewing some of the major treatment groups softening devices, allergy testing, and different such as antihistamines and essential fatty acids approaches to organisation of care. in more detail, and some of these are already underway within the Cochrane Skin Group.

Conclusions Future methodological research is needed to increase the clinical relevance and reliability of Coverage outcome measures for atopic eczema. The RCT The evidence base for the prevention and treat- database contained within this report also provides ment of atopic eczema has many limitations. a good opportunity to conduct some general It is characterised by a profusion of short-term research into the relationship between study trials of ‘me too’ products, a lack of common quality and treatment benefit. There is much outcome measures which measure things that are scope for improving the standard of clinical trial important to patients, poor standards of clinical reporting in atopic eczema by dermatology trial reporting, and a lack of data on questions journals adopting rigorous checks on clinical that physicians and people with atopic eczema trial reporting and by registering ongoing trials deem to be important. Little research has evaluated with the Cochrane Skin Group.

iv Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 1 Background and aims

The problem of atopic eczema are highly variable. This variability can be in the skin rash morphology (e.g. it can be dry What is atopic eczema? and thickened or weeping and eroded), in Atopic eczema is a chronic inflammatory skin place (e.g. it commonly affects the cheeks in condition characterised by an itchy red rash that infants and skin creases in older children) favours the skin creases such as folds of elbows or and time (it can be bright red one day and behind the knees. The eczema lesions themselves apparently gone in a couple of days). There vary in appearance from collections of fluid in is no specific diagnostic test that encompasses the skin (vesicles) to gross thickening of the skin all people with typical eczema and which can (lichenification) on a background of poorly serve as a reference standard. Diagnosis is demarcated redness. Other features such as therefore essentially a clinical one. crusting, scaling, cracking and swelling of the skin can occur.1 Atopic eczema is associated Up until the late 1970s, at least 12 synonyms with other atopic diseases such as hay fever and for atopic eczema were in common usage in asthma. People with atopic eczema also have a the dermatological literature, and it is not dry skin tendency, which makes them vulnerable certain if physicians were all referring to the to the drying effects of soaps. Atopic eczema same disease when using these terms. A major typically starts in early life, with about 80% of milestone in describing the main clinical features cases starting before the age of 5 years.2 of atopic eczema was the Hanifin and Rajka diagnostic criteria of 1980.4 These are frequently Is atopic eczema ‘atopic’? cited in clinical trial articles, and they at least Although the word ‘atopic’ is used when provide some degree of confidence that describing atopic eczema, it should be noted researchers are referring to a similar disease that around 20% of people with otherwise typical when using these features. It should be borne atopic eczema are not atopic as defined by the in mind however that these criteria were presence of positive skin prick test reactions to developed on the basis of consensus, and their common environmental allergens, or through validity and repeatability is unknown in relation blood tests, which detect specific circulating to physician’s diagnosis.3 Some of the 30 or so immunoglobulin E (IgE) antibodies.3 The minor features have since been shown not to be word ‘atopic’ in the term atopic eczema is simply associated with atopic eczema, and many of the an indicator of the frequent association with terms, which are poorly defined, probably mean atopy and the need to separate this clinical something only to dermatologists. Scientifically phenotype from the ten or so other forms of developed refinements of the Hanifin and Rajka eczema such as irritant, allergic contact, discoid, diagnostic criteria, mainly for epidemiological venous, seborrhoeic and photosensitive eczema, studies, have been developed by a UK working which have other causes and distinct patterns. party, and these criteria have been widely used The terms atopic eczema and atopic dermatitis throughout the world.5 According the these are synonymous. The term atopic eczema or just criteria,6 in order to qualify as a case of atopic eczema is frequently used in the UK, whereas eczema, the person must have: atopic dermatitis is used more in North America. Much scientific energy has been wasted in • an itchy skin condition debating which term should be used. plus three or more of: • past involvement of the skin creases, such as How is atopic eczema defined the bends of elbows or behind the knees in clinical studies? • personal or immediate family history of asthma Very often, no definition of atopic eczema is or hay fever given in clinical studies such as clinical trials. • tendency towards a generally dry skin This leaves the reader guessing as to what sort • onset under the age of 2 years of people were studied. Atopic eczema is a • visible flexural dermatitis as defined by a difficult disease to define as the clinical features photographic protocol. 1 Background and aims

Binary or continuous disease? Severity distribution It is unclear whether atopic eczema is an ‘entity’ Most cases of childhood eczema in any given com- in itself or whether it is part of a continuum when munity are mild. One recent study by Emerson and considered at a population level. Some studies colleagues found that 84% of 1760 children aged have suggested that atopic dermatitis score is 1–5 years from four urban and semi-urban general distributed as part of a continuum.3 Although it practices in Nottingham were mild, as defined may be appropriate to ask the question: “How globally by the examining physician, with 14% much atopic eczema does he/she have?” as opposed of cases in the moderate category and 2% in the to “Does he/she have atopic eczema – yes or no?”, severe category.11 Disease severity was not the most population and clinical studies require a only determinant of referral for secondary care, categorical cut-off point and tend to include well- however. This severity distribution was very similar defined and typical cases. to another recent population survey in Norway.12

Is it all one disease? It is quite possible that there are distinct subsets of How does atopic eczema atopic eczema, for example those cases associated affect people? with atopy and those who have severe disease with recurrent infections. Until the exact genetic and Direct morbidity has been estimated in several causative agents are known, it is wiser to consider studies using generic dermatology quality-of-life the clinical disease as one condition. Perhaps scales. It has been found that atopic eczema usually sensitivity analyses can be done for those who are accounts for the highest scores when compared with thought to represent distinct subsets (e.g. those other dermatological disease. Specific aspects of a who are definitely atopic with raised circulating child’s life that are affected by atopic eczema are: IgE to allergens, or those with severe disease and associated asthma).3 • itch and associated sleep disturbance (Figure 1) • ostracism by other children and parents • the need for special clothing and bedding The prevalence of atopic eczema • avoidance of activities such as swimming, which other children can enjoy, and Atopic eczema is a very common problem. • the need for frequent applications of greasy Prevalence studies in the last decade in Northern ointments and visits to the doctor. Europe suggest an overall prevalence of 15–20% in children aged 7–18 years.7 Standardised Family disturbance is also considerable with sleep questionnaire data from 486,623 children aged loss and the need to take time off work for visits to 13–14 years in the International Study of Asthma healthcare professionals.7 and Allergies in Childhood (ISAAC) suggest that atopic eczema is not just a problem confined Economic costs to Western Europe, with high prevalence found In financial terms, the cost of atopic eczema is in many developing cities undergoing rapid potentially very large. One recent study of an demographic change.8 There is reasonable entire community in Scotland estimated the evidence to suggest that the prevalence of atopic mean personal cost to the patient at £25.90 eczema has increased two- to three-fold over the over a 2-month period with the mean cost to past 30 years, the reasons of which are unclear.9 the health service of £16.20.13 If these results No reliable incidence estimates are available for were extrapolated to the UK population, the atopic eczema. annual personal costs to patients with atopic eczema based on lower prevalence estimates Age than recent studies suggest would be £297 Atopic eczema is commoner in childhood, partic- million. The cost to the health service would ularly in the first 5 years of life. One study of 2365 be £125 million and the annual cost to society patients who were examined by a dermatologist for through lost working days would be £43 million atopic eczema in the town of Livingston, Scotland, making the total expenditure on atopic eczema suggested that atopic eczema is relatively rare over £465 million per year (1995 prices). Another the age of 40, with a 1-year period prevalence of recent study from Australia found that the 0.2%.10 Nevertheless, adults over 16 years made up annual personal financial cost of managing mild, 38% of all atopic eczema cases in that community. moderate and severe eczema was Aus$330,818 Adults also tend to represent a more persistent and and $1255, respectively, which was greater than the 2 severe subset of cases. costs associated with asthma in that study.14 Health Technology Assessment 2000; Vol. 4: No. 37

FIGURE 1 Despite the public’s tendency to trivialise skin that atopic eczema is commoner in wealthier disease, the suffering associated with the intractable itching of families.17 It is unclear whether this positive social atopic eczema can be greater than other illnesses such as class gradient is a reflection of indoor allergen 7 asthma and heart disease. exposures or whether it reflects a whole constel- lation of other factors associated with ‘develop- ment’. Other studies have shown an inverse association between eczema prevalence and family size.18 This observation led to the ‘hygiene hypo- thesis’, that is that children in larger families were protected from expressing atopy because of frequent exposure to infections.19 Some evidence for this protective effect of infections on atopic eczema has been shown in relation to measles infection in Guinea Bissau.20

Migrant studies also point strongly to the role of environmental factors in atopic eczema. It has been shown that 14.9% of black Caribbean children living in London develop atopic eczema (according to the UK diagnostic criteria) comp- ared with only 5.6% for similar children living in Kingston, Jamaica.21 Other migrant studies reviewed elsewhere have consistently recorded large differences in ethnic groups migrating from warmer climates to more prosperous cooler countries.

Further work has suggested that the tendency to atopy may be programmed at birth and could be related to factors such as maternal age.22 The observation that many cases of atopic eczema improve spontaneously around puberty is also difficult to explain in genetic terms alone.2 Specific risk factors for eczema expression in What causes atopic eczema? the environment are still not fully elucidated. Allergic factors such as exposure to house dust Genetics mite may be important but non-allergic factors There is strong evidence to suggest that genetic such as exposure to irritants, bacteria and hard factors are important in the predisposition to water may also be important.23 atopic eczema. In addition to family studies, twin studies have shown a much higher concord- ance for monozygotic (85%) when compared with Pathophysiology dizygotic twins (21%).15 Preliminary work has suggested that a marker for IgE hyper-responsive- A number of mechanisms and cells are thought ness might be located on chromosome 11q, but to be important in atopic eczema and these are this has not been consistent. It is possible that the reviewed in detail elsewhere.1,24 Microscopically, tendency to atopic eczema might be inherited the characteristic appearance of eczema is that independently from atopy. of excess fluid between the cells in the epidermis (spongiosis). When severe, this fluid eventually Environment disrupts the adjacent cells in the epidermis to While genetic factors are probably a very important form small collections of fluid, which are visible factor for disease predisposition, there are numerous to the naked eye as vesicles. In the chronic phase, general and specific clues that point strongly to the atopic eczema is characterised by gross thickening crucial role of the environment on disease expres- of the epidermis (acanthosis) and an infiltrate of sion.16 It is difficult to explain the large increase in lymphocytes in the dermis. The theory that atopic eczema prevalence over the past 30 years, unifies the various abnormalities of atopic eczema for instance, in genetic terms.9 It has been shown suggest that blood stem cells carrying abnormal 3 Background and aims

genetic expression of atopy cause clinical disease of treatment, though care regarding the duration as they infiltrate and remain in the mucosal of treatment, site and age of the person treated surfaces and skin. There appears to be a failure was emphasised. Antihistamines were only to switch off the natural predominance of Th2 recommended for their sedative action. Cognitive helper lymphocytes, which normally occurs in behavioural techniques were also mentioned infancy, and this leads to an abnormal response as being important to some families. Allergen of chemical messengers called cytokines to a avoidance, for example the reduction of house variety of stimuli. The underlying mechanism dust mite or dietary intervention, was described of disease may be either abnormalities of cyclic as a second-line treatment, as was treatment with nucleotide regulation of marrow-derived cells or ultraviolet light under specialist care. Third-line allergenic over-stimulation that causes secondary treatment (always under the care of a specialist) abnormalities. Some studies have suggested a included such treatments as short bursts of defect in lipid composition and barrier function systemic corticosteroids, cyclosporin A, evening of people with atopic eczema – a defect that primrose oil and Chinese herbal medicines. is thought to underlie the dry skin tendency and possibly enhanced penetration of environ- These recommendations were made on the mental allergens and irritants, leading to basis of consensus from a wide range of pract- chronic inflammation. itioners and patient advocates. Although some recommendations were based on RCTs, many were not. It is unclear, therefore, how many of Does atopic eczema clear these recommendations are truly beneficial to with time? patients. New developments since the publication of these recommendations include increased use Although the tendency towards a dry and irritable of a double layer of protective bandages (‘wet- skin is probably lifelong, the majority of children wraps’) with or without topical steroids, ‘newer’ with atopic eczema appear to ‘grow out’ of their once-daily topical corticosteroids such as momet- disease, at least to the point where the condition asone and fluticasone, and possibly some increased no longer becomes a problem in need of medical use of potent systemic agents such as cyclosporin A. care. A detailed review of studies that have deter- Other new potent topical preparations such as mined the prognosis of atopic eczema has been tacrolimus and ascomycin derivatives are probably reported elsewhere.2 This review suggested that going to become available in the near future.26 most large studies of well-defined and represen- tative cases suggest that about 60% of childhood How is care organised in the UK? cases are clear or free of symptoms from disease Most children with atopic eczema in the UK are in early adolescence. Many such apparently clear probably managed by the primary care team. This cases are likely to recur in adulthood, often as includes advice from pharmacists, health visitors, hand eczema. The strongest and most consistent practice nurses and family practitioners. About factors that appear to predict more persistent 4% of children with atopic eczema are referred atopic eczema are early onset, severe widespread to a dermatologist for further advice.11 disease in infancy, concomitant asthma or hay fever and a family history of atopic eczema. The quality of service provided by secondary care for eczema sufferers has recently been audited by the British Association of Dermatologists. How is atopic eczema treated? Although most departments provided a high- quality service, some aspects of care, such as the The management of atopic eczema in the UK administration of simple standardised record was summarised in a paper jointly produced by forms could be improved.27,28 a British Association of Dermatology and Royal College of Physicians Working Party in 1995.25 Compliance (or more correctly, concordance) The article described the management of atopic seems to be a major cause of apparent treatment eczema in three stages. The first line of treat- failures and a recent study suggested that this was ment involved providing an adequate explanation often due to a poor understanding of the chronic of the nature of disease as well as advice on nature of the disease, a fear of topical cortico- avoiding irritants. The role of emollients in steroids and the belief that all atopic eczema is adequate quantities was emphasised, as well caused by a specific allergy. A survey in Notting- as prompt treatment of secondary infections. ham has found that most mothers worry that 4 Topical steroids were highlighted as the mainstay topical steroids cause adverse effects, though Health Technology Assessment 2000; Vol. 4: No. 37

many were not able to distinguish between weak Why is a systematic review needed? and strong ones.29 The authors suspect that little research has been The National Eczema Society is the UK’s self-help done into primary and secondary prevention of organisation for atopic eczema sufferers and people atopic eczema. Research is also probably very with other forms of eczema. It has a well-organised limited in non-pharmacological areas of treatment information service and national network of activities such as psychological approaches to disease geared to help eczema sufferers and their families. management. Even for traditional pharmaceutical Sources of alternative care for atopic eczema sufferers preparations, the choice of treatments for atopic abound in the community ranging from the highly eczema by patients or their practitioners is professional to elaborate expensive diagnostic and complicated by a profusion of preparations whose therapeutic measures of dubious value. comparative efficacy is unknown.5 Thus, the current British National Formulary lists 19 classes of topical corticosteroids available for treating atopic How are the effects of atopic eczema and a total of 63 preparations that eczema captured in clinical trials? combine corticosteroids with other agents such as antibiotics, antiseptics, antifungals and keratolytic Outcome measures used in trials have recently agents.34 How can a family practitioner make a been reviewed by Finlay.30 Most outcome rational choice between so many preparations?35 measures have incorporated some measure of itch as assessed by a doctor at periodic reviews Systemic treatments for severe atopic eczema have or patient self-completed diaries. Other more only been partially evaluated. There are plenty of sophisticated methods of objectively recording trials, for instance on expensive drugs such as itch have been tried. Finlay drew attention to cyclosporin A (which may have serious long-term the profusion of composite scales used in adverse effects), yet to the best of our knowledge, evaluating atopic eczema outcomes. These there is not a single controlled trial on oral usually incorporate measures of extent of atopic azathioprine – a much cheaper and possibly safer eczema and several physical signs such as redness, and more effective treatment that is currently scratch marks, thickening of the skin, scaling widely used by British dermatologists.36 In other and dryness. Such signs are typically mixed with areas, there is a profusion of small studies, which symptoms of sleep loss and itching and variable do not have the power to adequately answer the weighting systems are used. It has been shown therapeutic questions posed. that measuring surface area involvement in atopic eczema is fraught with difficulties,31 which The authors are also aware that many clinical trials is not surprising considering that eczema is, by have not asked patients enough of what they think definition, ‘poorly-defined erythema’. Charman about the various treatments under test. There is and colleagues recently performed a systematic an opportunity in a systematic review, therefore, to review of named outcome measure scales for redress the balance of outcome measures used in atopic eczema and found that of the 13 named clinical trials towards the sort of measures that are scales in current use, only one (Severity Scoring clinically meaningful to patients and their carers. of Atopic Dermatitis, SCORAD) had been fully tested for validity, repeatability and responsive- Public concern over long-term adverse effects such ness.32 Quality-of-life measures specific to as skin thinning and growth retardation from use dermatology include the Dermatology Quality of topical corticosteroid preparations has not been of Life Index30 and SKINDEX.33 The Children’s matched by long-term studies on atopic eczema Dermatology Life Quality index has been used sufferers. Individuals with atopic eczema often in atopic eczema trials in children. resort to self-prescribed diets, which can be nutri- tionally harmful, or they may turn to ‘alternative’ The authors are aware that most clinical trials of tests and treatments which may turn out to be atopic eczema have been short term, that is about beneficial or expensive and harmful. 6 weeks. This seems inappropriate in a chronic relapsing condition. Very few studies have consid- Thus, there is considerable uncertainty about the ered measuring number and duration of disease- effectiveness of the prevention and treatment of free relapse periods. It is impossible to say whether atopic eczema. This combination of high disease modern treatments have increased chronicity at prevalence, chronic disability, high financial costs, the expense of short-term control in the absence public concerns regarding adverse effects, lack of of such long-term studies. evaluation of non-pharmacological treatments, 5 Background and aims

concern regarding the clinical relevance of trial • Most people with atopic eczema are managed by outcome measures and the profusion of treatments the primary care team. and care settings of unknown effectiveness is why a • Some people with atopic eczema seek alternative scoping systematic review of atopic eczema treatments. treatments is needed. It is hoped that the review • A systematic review is needed to map out where will form the basis for identifying, prioritising and high quality research has been conducted to generating further primary, secondary and date with the aim of resolving some areas of methodological research. uncertainty and in order to identify knowledge gaps to be addressed by further primary research. Summary of the problem of atopic eczema Research questions asked • The terms atopic eczema and atopic dermatitis in this review are synonymous. • The definition of atopic eczema is a clinical one The remit of this project is to provide a summary based on itching, redness and involvement of of RCTs of atopic eczema with the main aim of the skin creases. informing the NHS R&D Office and other research • About 20% of people with clinically typical commissioners of possible research gaps for atopic eczema are not ‘atopic’. further primary, secondary or methodological • The word ‘atopic’ in atopic eczema serves to research. It is also hoped that the review will be distinguish it from the ten or so other types of some use to healthcare providers, physicians of ‘eczema’. involved in the care of people with atopic eczema • Atopic eczema affects about 15–20 % of UK and also to atopic eczema sufferers and their schoolchildren. families by placing current treatments in context • About 80% of cases in the community are mild. with their evidence base. The main research • Adults form about one-third of all cases in a questions asked in this review are therefore: given community. • Disease prevalence is increasing for unknown • What therapeutic interventions have the RCTs reasons. of atopic eczema covered so far? The main • The constant itch and resultant skin damage in output of this coverage question is a summary atopic eczema can lead to a poor quality of life of research gaps for further research, with for sufferers and their families. research commissioners, charities and • The economic costs of atopic eczema to both researchers as the main target audience. State and patient are high. • What treatment recommendations can be • Genetic and environmental factors are both made by summarising the available RCT critical for disease expression. evidence using qualitative and quantitative • Non-allergic factors may be just as important methods? The main output for this question as allergic factors in determining disease are detailed summaries of available RCT expression and persistence. evidence for different interventions for atopic • Imbalances of T-lymphocytes and skin barrier eczema along with the authors’ interpretation abnormalities are both important in explaining of the data based on the quality, magnitude the pathological processes of atopic eczema. of treatment effect, and clinical relevance of • About 60% of children with atopic eczema that evidence. are apparently clear or free of symptoms by adolescence. An impossible task? • Early onset, severe disease in childhood and It is unrealistic to attempt to summarise the entire associated asthma/hay fever are predictors of a ‘treatments of atopic eczema’ into a single worse prognosis. Cochrane-style systematic review, as such a task • Current first-line treatment in the UK includes would take years and cover several volumes. emollients, topical corticosteroids, and sedative Atopic eczema is a complex disease with at least antihistamines. 40 different treatment approaches and specific • Second-line treatments include allergen questions that can be asked of each treatment avoidance and ultraviolet light. group. What is more realistic is to produce a • Third-line treatments include systemic ‘sketch’ or ‘map’ of RCTs of atopic eczema, to immunomodulatory treatments such as quantitatively summarise a few areas of conflicting 6 cyclosporin A and azathioprine. studies where possible, and to qualitatively review Health Technology Assessment 2000; Vol. 4: No. 37

the others in a form that would be helpful to • Does the early introduction of solids bring on clinicians and patients. Such an approach could atopic eczema? also act as ‘seed reviews’ for subsequent, more detailed Cochrane systematic reviews. Trying to answer similar questions for each of the 40 or so interventions used for the treatment A question or data-driven review? of atopic eczema would be impossible in one The very broad-ranging scoping nature of this short report. review implies that it cannot be hypothesis-driven. Even in just one area of atopic eczema manage- This review is therefore unashamedly a data- ment such as dietary prevention, there are at least driven one. It is a review that aims to map out six separate systematic reviews that can be asked what has been done in terms of RCTs in atopic of the available data: eczema to date and to reflect and comment on the coverage of already researched areas in • Does maternal avoidance of certain potentially relation to questions that are commonly asked allergenic foods prevent atopic eczema and if by physicians and their patients. so, by how much in offspring at high risk (i.e. family history of atopy) versus those at The authors are aware that there is a danger normal risk? that a data-driven review can serve to amplify • Does dietary manipulation in pregnancy reduce and perpetuate current trends in evaluating the severity of atopic eczema in offspring? minor differences between a profusion of similar • Does exposing infants to allergens at an early pharmacological products. The authors have stage of their immune development help by mitigated against this inevitable hazard by making them tolerant to substances that they drawing attention to gaps that have not been will inevitably encounter in later life? addressed when summarising the reported • Does exclusive breastfeeding protect against studies, and also by including a comprehensive atopic eczema? section on ‘unanswered questions’ in chapter 14 • Does prolonged breastfeeding with supplemen- of this report, based on the views of contemporary tation protect against atopic eczema? researchers, physicians and patients.

7

Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 2 Methods

General methods structure with non-atopic people were also excluded. Studies also had to include at least one clinical outcome. This review has been prepared along the guide- Therefore, studies that only reported changes in lines developed by the University of York37 and those blood tests or cellular mechanisms were excluded. issued by the NHS Health Technology Assessment (HTA) programme38 and uses methods developed Study participants by the Cochrane Collaboration39 where possible. Studies were included if participants were babies, children or adults who have atopic eczema (syn. Types of studies included in the review atopic dermatitis) according to Hanifin and Rajka Only RCTs of treatments for atopic eczema were diagnostic criteria,4 or as diagnosed by a physician. included in the data summaries as other forms of Terms used to identify trial participants with evidence are associated with higher risks of bias. definite, possible and definitely not atopic eczema In order to be included as an RCT, a random- are shown in Table 1. Those studies using terms in isation procedure was described, the study compared the ‘definitely not atopic eczema’ category such as two or more treatments in human beings, and the allergic contact eczema were excluded. Those study was prospective. In addition, the RCTs had to studies using terms in the ‘possible atopic eczema’ be concerned with therapeutic issues in relation to category, such as ‘childhood eczema’ were scru- the prevention or treatment of atopic eczema. tinised by one of the authors and only included if Thus, RCTs that involved evaluating cellular or bio- the description of the participants clearly indicated chemical responses of patients with atopic eczema atopic eczema (i.e. itching and flexural involvement). after testing or injecting them with substances such as histamine were not included. Although they might Main outcome measures inform future therapy, they were not therapeutic Changes in patient-rated symptoms of atopic trials. Studies of possible increased incidence of eczema such as itching (pruritus) or sleep loss drug adverse effects in atopic people compared were used where possible. Global severity as rated

TABLE 1 Terms used to identify trial participants with definite, possible and definitely not atopic eczema

Definite atopic eczema Possible atopic eczema Not atopic eczema (include if study was an RCT) (implies original paper must be obtained and (implies that the authors did not accept read before a judgement is made to include this term as representing atopic eczema) or exclude by one of the authors based on additional features such as a good clinical description of atopic eczema with atopy) Atopic eczema Periorbital eczema Seborrheic eczema Atopic dermatitis Childhood eczema Contact eczema Besnier’s prurigo Infantile eczema Allergic contact eczema Neurodermatitis atopica (German) ‘Eczema’ unspecified Irritant contact eczema Flexural eczema/dermatitis Constitutional eczema Discoid/nummular eczema Endogenous eczema Asteatotic eczema Chronic eczema Varicose/stasis eczema Neurodermatitis Photo-/light-sensitive eczema Neurodermatis (German) Chronic actinic dermatitis Dishydrotic eczema Pompholyx eczema Hand eczema Frictional lichenoid dermatitis Lichen simplex Occupational dermatitis Prurigo 9 Methods

by patients or their physician were also sought. Possible trials were identified from each of the If these were not available, then global changes in four databases by: composite rating scales using a published named scale, or where not possible, the author’s modifi- • MEDLINE (Index Medicus online): the Cochrane cation of existing scales or new scales developed Collaboration ‘highly sensitive electronic search within the study were summarised. Adverse events string’ for RCTs was used (appendix 1). Years were also included if reported. The selection of 1966–December 1999 were searched and yielded outcome measures was explored in more detail over 3000 references using the disease search in a focus group of consumers held by one of terms in appendix 1. An iterative approach was the authors. used with retrieved papers. Once trials on specific drug types were obtained, an additional MEDLINE Secondary outcome measures search was carried out employing these specific Secondary outcomes measures were changes in drug terms (e.g. tacrolimus) or their developmen- individual signs of atopic eczema as assessed by a tal names (e.g. FK506) combined with a general physician, for example: skin search (appendix 1). References were checked for possible additional RCTs of atopic eczema. • erythema (redness) Review articles were also retrieved in hard copy • purulence (pus formation) form and references were checked for further RCTs. • excoriation (scratch marks) • EMBASE (Excerpta Medica online): due to the • xerosis (skin dryness) different format of this database, an alternative • scaling search strategy was employed which was • lichenification (thickening of the skin) developed by the BMJ Publishing Group for its • fissuring (cracks) Clinical Evidence series (appendix 1).44 Years • exudation (weeping serum from the skin surface) 1980–December 1999, (the only years fully • pustules (pus spots) searchable on OVID), were searched. This • papules (spots that protrude from the skin yielded over 1000 references using the same surface) eczema terms as for MEDLINE in Table 1. Trials • vesicles (clear fluid or ‘water blisters’ in the skin) that might have been on the EMBASE database • crusts (dried serum on skin surface) from 1974 to 1979 would have been picked up • infiltration/oedema (swelling of the skin), and by CCTR (see below), which has compiled its • induration (a thickened feel to the skin). search of the entire EMBASE database since its inception in 1974. • CCTR: the Cochrane Library, Issue 4, 1999 was Search strategy searched for controlled trials within the CCTR section by exploding the disease-specific search Electronic searching terms separated by the boolean ‘AND’ with the In order to retrieve all RCTs on atopic eczema advanced search option. These include clinical treatments in accordance with inclusion criteria, controlled trials (quasi randomisation) and a systematic and mainly electronic search strategy RCTs (randomisation). was carried out. The Cochrane Collaboration • Cochrane Skin Group Specialised Register: this Handbook39 and the Centre for Reviews and was searched with the disease-specific terms and Dissemination guidelines for systematic reviews37 kind help of the Cochrane Skin Group Trials were used as templates. Search Coordinator.

The following electronic databases have been Handsearching searched: As there are over 200 specialist dermatology journals and none specific to atopic eczema, separate hand- • MEDLINE40 (1966 to end of 1999) searching was not done for this report. Some trials • EMBASE41 with its higher yield of published in journals not listed in the main biblio- non-English reports (1980 to end of 1999) graphic databases or published within the body of a • The Cochrane Controlled Trials Register letter to the editor might therefore have been missed. (CCTR)42 and However, results of handsearching of specialist • The Cochrane Skin Group Specialised dermatology journals by the Cochrane Skin Group Trials Register.43 are kept on the Cochrane Skin Group Specialised Register of trials, which was searched. This included Disease terms for atopic eczema (as a textword and results of handsearching the following dermatology 10 MeSH term) are shown in appendix 1. journals as at July 2000: Health Technology Assessment 2000; Vol. 4: No. 37

• Acta Dermato-Venereologica Supplementum 1970–91 Non-English studies • Archives of Dermatology 1976–98 Studies published in non-English languages were • British Journal of Dermatology 1991–97 screened by international colleagues (listed in the • Clinical & Experimental Dermatology 1976–99 acknowledgement section) to see if they were • Cutis 1967–99 possible RCTs with full data abstraction if this • International Journal of Dermatology 1985–98 proved to be the case. • Journal of Investigative Dermatology 1991–97 • Journal of the American Academy of Dermatology 1987–99. Data assessment

In addition, conference proceedings of previous After assessment of retrieved papers for inclusion/ symposia such as the Atopic Dermatitis Sympos- exclusion criteria, the final list of included RCTs ium, held every 3 years (initially set up by Professor were subject to data abstraction with view to Georg Rajka), and all meeting abstracts for the pooling or qualitative summary. Data abstraction annual meetings of the Society of Investigative forms were developed and used for those treat- Dermatology, European Academy of Dermatology ment groups where pooling appeared likely. Data and British Association of Dermatologists have for pooling were abstracted by two authors with been handsearched by one of the authors and the discrepancies checked by a third if required. Data results made available to the Skin Group Special- for qualitative summary were abstracted by one ised Register. Furthermore, one of the authors author and checked by a second. has been prospectively handsearching five derma- tology journals (Clinical Experimental Dermatology, Study quality British Journal of Dermatology, Journal of the American Methodological quality of each study was assessed Academy of Dermatology, Journal of Investigative using a previously described scheme where the three Dermatology and Paediatric Dermatology) since January potential sources of bias were evaluated,46 namely: 1998, and any possible atopic eczema trials were accessed further by the team. • the quality of the randomisation procedure • the extent to which the primary analysis Other trial source included all participants initially randomised In addition to checking citations in retrieved RCTs (i.e. an intention-to-treat analysis) and review articles, additional trials were sought by • the extent to which those assessing the personal contact with atopic eczema researchers, outcomes were aware of the treatments of those and by writing to 37 pharmaceutical companies being assessed (blinding). with a product or developing product in the area of atopic eczema. These three factors have been consistently shown to predict possible bias in effect estimates.47 Filtering A descriptive component, rather than a score-based With the 3899 references yielded from the initial system, was used to quality rate the studies so that searches of MEDLINE, EMBASE and CCTR a readers can see which aspects of the study report- filtering process began. This was carried out ing were deficient. Due to the sheer size of this manually to assess whether the reference fitted scoping review, report authors were not blinded the preliminary labels of ‘trial’ and ‘atopic to the identity of the RCT authors when quality eczema’. rating or data abstracting. Such blinding would have needed to be very thorough (to the point Not all references had abstracts; therefore, ‘titles of having to conceal the interventions) as many only’ had to be included as possible trials to avoid of the RCTs are well known to one of the premature judgement. Where doubt existed from abstracting authors. the abstract or title, the full paper was requested and scrutinised further by two of the authors. Quantitative data synthesis Papers labelled as ‘rejects’ were categorised with Where pooling made sense clinically in terms of another label to specify why they were not suitable the interventions, study participants and common for inclusion. This was carried out by one reviewer clinical outcomes, a meta-analysis was performed and checked by a second reviewer in any cases of using both a fixed- and random-effects model possible uncertainty. depending on whether there was evidence of statistical heterogeneity. Odds ratios of improve- All papers were catalogued on a specialised ProCite ment compared with the comparison intervention database.45 was used in the pooling exercises. The inverse of 11 Methods

the variance of the outcome measures was used as • global severity score based on several skin signs, or weights for pooling the data from different trials. • individual skin sign scores, Sources of heterogeneity, such as differences in patients or formulation of interventions, were in that order of preference. In many studies eval- explored within the meta-analysis. uating multiple clinical signs of atopic eczema, only those that were statistically significant (post-hoc) were highlighted in the paper’s conclusions or abstract. Methods of presenting The authors have mitigated against this post hoc bias qualitative results by reporting results relating to excoriations, erythema, extent or lichenification (in order of preference) Summarising the evidence of treatment and harm if global or other more clinically meaningful from 283 RCTs covering at least 47 different inter- summary measures were not reported. ventions in a way that would be helpful to health- care commissioners, providers, physicians and If pre-existing systematic reviews were identified users is challenging. There is always a conflict in for any of the interventions, these were highlighted such a situation of providing too much information at the beginning of the results sections and described resulting in loss of the general picture or of omit- in more detail. Help in deciding which outcomes ting important details in some specific areas. Readers were important to patients was obtained by running are therefore encouraged to read the original a focus group of four participants recruited through studies for themselves where doubt occurs as to the the Cochrane Skin Group Consumer Network. reported data or author’s conclusions in this paper.

For qualitative data summaries, the authors have Separating trial data from adopted two systems. authors’ opinions • Where six or more RCTs are identified, these Throughout the report, the authors of the current are summarised in tabular form, noting the review have been careful to make a clear distinc- interventions and comparator plus any other tion between the facts abstracted from individual treatments permitted concurrently during the studies and the respective author’s interpretation study (co-treatments), study population and of what those results or lack of results mean. Thus, sample size, study design and duration, outcome actual data on efficacy and possible harms have measures used in the study, main reported results, been clearly separated from the author’s ‘comment’ quality of reporting and specific comments section. In the comment sections of the tables, the relating to the study. The table is introduced authors have commented on issues such as clinical with a brief summary of the rationale for use of relevance, quality of reporting, possible sources of the drug and the way it is used, and appended bias, generalisability of the study, clinical implica- by any additional general comments and a tions and research gaps. summary of key points. • Interventions with five or fewer RCTs have been summarised in text form in a way similar to that Identifying treatments with used in the BMJ Publishing Group’s Clinical no RCTs and future research Evidence series.44 After a brief introduction, the evidence of benefits from included RCTs is priorities presented for each study, followed by a section Given the inescapable fact that a data-driven review on harms of treatment, followed by a section on can only identify treatments for which some evidence author’s interpretation of the data. exists, the authors sought to list those other treat- ments that are currently used throughout the world In many of the studies, over ten outcome measures in atopic eczema which are not necessarily suppor- have been reported, and it would have been im- ted by RCTs. This was done by mailing colleagues practical to document every one when presenting through professional networks, requesting them to the reported results in the above two formats. In add any interventions that were missing from a list deciding which results to highlight in the ‘main of treatments supported by RCTs drawn up by the reported results’ sections therefore, the authors authors. Eighteen out of 23 physicians from six have adopted a systematic approach of: different countries responded to this request.

• patient-rated global improvement or itch or In order to help the authors identify future 12 sleep loss, then research priorities, another sample of colleagues Health Technology Assessment 2000; Vol. 4: No. 37

was approached asking them to indicate the top England, Wales, Scotland and Ireland working in five ‘unanswered’ questions in atopic eczema district general hospitals who did not have a therapy today. Three purposive samples were sent declared special interest in atopic eczema, six this question on a personal letter: 12 colleagues consumer members of the Cochrane Skin Group internationally renowned for clinical atopic eczema and the seven Steering Group members of the research in the UK and abroad, four general European Dermato-Epidemiology Network (EDEN). practitioner colleagues with a known interest in Responses were collated by the authors and new skin disease, eight consultant dermatologists in themes were added as they became apparent.

13

Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 3 Results

Included studies Excluded studies A total of 283 trials were finally included. In order Details of excluded studies are shown in Figure 2. to help summarise the interventions, groupings Further details on the 146 RCTs that included were constructed on the basis of: whether treatments atopic eczema participants and which were dealt with prevention of new disease or treatment excluded in the final stages are shown in of established disease, and similar pharmacological appendix 2. The commonest reasons for exclusion drug type (e.g. topical steroids), similar intervention were ‘eczema’ unspecified and combining the type (e.g. dietary measures) or convenience results of atopic eczema patients with patients (e.g. non-pharmacological treatments) (Table 2). who had other dermatoses.

TABLE 2 Summary of study groupings

Intervention groupings No. of studies References Intervention groupings No. of studies References

A. Prevention of atopic eczema 20 Non-pharmacological contd. Prevention by allergen avoidance Avoidance of enzyme- during pregnancy 8 48–55 enriched detergents 1 268 Prevention by allergen avoidance Specialised clothing 3 269–271 after birth 12 56–67 Salt baths 1 272 Nurse education 1 273 B. Established atopic eczema 254 Bioresonance 1 274 Topical corticosteroids 83* 68–150 Psychological approaches 3 106,275,276 Ultraviolet light 7 277–283 Other topicals 12 Coal tar 1 151 Systemic immunomodulatory agents 30 Emollients 6 152–157 Allergen–antibody complexes * Lithium succinate 1 158 of house dust mite 2 284,285 Tacrolimus 3 159–161 Cyclosporin A 13* 286–298 Ascomycin 1 162 Levamisole 1 299 Platelet activating factor antagonist 1 300 Antimicrobial/antiseptics 10 163–172 Interferon-gamma 3 301–303 Antihistamines and mast Thymodulin 2 304,305 cell stabilisers 51 Thymostimulin 2 306,307 Antihistamines 21 173–193 Thymopentin 4 308–311 Chromone compound/ Immunoglobulin 1 312 sodium cromoglycate 20 84, 194–121 Transfer factor 1 313 Nedocromil sodium 3 213–215 Complementary therapies 8 Ketotifen 2 216,217 Chinese herbs 4 314–317 Doxepin 4 218–221 Homeopathy 1 318 Tiacrilast 1 222 Aromatherapy 1 319 Dietary interventions 37 Hypnotherapy/biofeedback 1 320 Dietary restriction in Massage therapy 1 321 established atopic eczema 9 223–231 Miscellaneous 7 Evening Primrose Oil 14* 232–245 Nitrazepam 1 322 Borage oil 5 246–250 Ranitidine 1 323 Fish oils 4 251–254 Theophylline 1 324 Pyridoxine 1 255 Salbutamol 1 325 Vitamin E and multivitamins 3 256–258 Papaverine 2 326,327 Zinc supplementation 1 259 Suplatast tosilate 1 328 Non-pharmacological 18 House dust mite reduction 8* 260–267 Total RCTs 283

*Includes duplicate publications 15 Results

FIGURE 2 Details of excluded studies and process involved

Electronic search for RCTs on MEDLINE, EMBASE, and CCTR using the trial filter and atopic eczema search terms n = 3800

Is the reference a trial? Is the reference a trial? YES/NOT SURE NO n = 1165 n = 2593*

Is it a trial related to eczema? Is it a trial related to eczema? YES/NOT SURE NO n = 940 n = 225*

Electronic database update search for year 2000 n = 172

CCTs of atopic eczema RCTs of atopic eczema Non-English Excluded papers treatments treatments n = 71† n = 564§ n = 202‡ n = 283

* Available from authors on request.Aetiology, biological laboratory tests, case reports, clinical evaluations, diagnostics, miscellaneous epidemiology, morphological studies, non-human studies, pathogenesis, retrospective studies, severity scores, observational studies, treatment studies, treatment investigations, surveys, adverse effects, non-atopic eczema, treatment commentaries, case series † Non-English: 17 non-English RCTs already included (nine Japanese, six Spanish, two French), ten non-English RCTs require data abstraction (one Finnish, eight German and one Danish), ten non-English awaiting translation to see if RCT of atopic dermatitis (nine Italian, one Polish), Russian papers translated no RCTs found.The remaining 45 papers consisted of 32 CCTs, 13 excluded RCTs and seven excluded non-RCTs ‡ Non-randomised CCTs: available from authors on request § 162 excluded RCTs see appendix 2, the rest excluded for same reason as * CCT, controlled clinical trial Note: numbers are close approximates as duplicates of the same paper were deleted when identified and references located from other sources were added to the database

Prevention of atopic eczema When considering disease prevention, it is important to be clear about whether a high-risk Given the high and rising prevalence of atopic approach (i.e. intervening with parents who have eczema, prevention of atopic eczema has to be atopic disease) or a low-risk population-based a desirable goal. It seems to be a far more logical approach is being used in order to try and prevent one than treating sick individuals who present atopic eczema developing in their offspring. themselves after a long chain of pathological effects Although it may sound an obvious strategy to with potentially toxic and expensive medicines, simply target children known to be at high risk of which at best only ameliorate disease symptoms. developing atopic eczema, it has been previously Disease prevention can be considered at several suggested that a high-risk approach would prevent levels: that of preventing allergen sensitisation at about 31% of children from developing atopic birth (which may or may not lead to atopic eczema compared with about 50% if the entire disease), prevention of manifest atopic eczema in population was targeted.5 It is also important that childhood, the prevention of severe disease (with- studies that purport to prevent atopic eczema out necessarily altering the total prevalence of follow-up children for a long time (i.e. 4 years or disease) and the prevention of other atopic diseases more), to ensure that the programme does not just 16 such as asthma, which may follow atopic eczema. simply delay the onset of disease to a time when it Health Technology Assessment 2000; Vol. 4: No. 37

could have an even more damaging effect on the Many questions can be asked in relation to such child’s development. prevention, for example:

Most prevention studies have focused on the role • Does avoidance of certain potentially allergenic of allergen avoidance (mainly dietary) in early life, foods prevent atopic eczema and if so by how and these are summarised in the next sections. much in offspring at high risk (i.e. family The authors were not able to find any RCT history of atopy) versus those at normal risk? evidence of other forms of disease prevention such • Does exposing infants to allergens at an early as avoidance of soaps, regular use of emollients or stage of their immune system development deliberate exposure to allergens at a critical time help by making them tolerant to such sub- of thymic development during infancy to try to stance, which they will inevitably encounter induce tolerance to allergens. in later life? • Does such a programme simply delay the onset One small study62 on 40 pregnant Venezuelan of disease and does it decrease disease severity? women with a history of atopic disease, randomised • Do the benefits to children outweigh the 20 mothers to an educational and nutritional rigorous long-term measures needed to programme (which was not clearly defined) and undertake such dietary exclusions? 20 to no intervention in an open fashion, and • Does exclusive breastfeeding protect against followed the offspring to evaluate the efficacy of atopic eczema or does prolonged breastfeeding the programme in preventing atopic disease. protect against atopic eczema? No cases of atopic eczema (definition based on • Does the early introduction of solids bring on the Hanifin and Rajka guide) were noted in the atopic eczema? 20 intervention children aged 4 years, whereas ten out of 20 children in the non-intervention group All of these questions require different studies. had developed atopic eczema by this time. Similar Most have been observational in nature. This is beneficial differences were noted for bronchial understandable for breastfeeding, as the decision hyper-reactivity and rhinitis. Randomisation was to breastfeed is not something that can be easily not described, and the study was unblinded. subject to an RCT. The decision to breastfeed can also be inextricably linked to possible confounding One ambitious RCT of a cohort of 817 infants factors such as social class and family history of aged 1–2 years with atopic eczema, the Early atopy, rendering observational studies of such Treatment of the Atopic Child (ETAC) study,329 issues difficult to interpret. These have been tested the hypothesis that long-term treatment reviewed by Kramer.330 with the non-sedating antihistamine cetirizine, at a dose of 0.25 mg/kg twice daily, could prevent A Cochrane systematic review331 has evaluated the development of asthma. Although there was three trials of maternal antigen avoidance during no overall difference in the incidence of asthma pregnancy for preventing atopic disease in general between the cetirizine and placebo intention-to- in infants of women at high risk of atopy.48,52,53 treat populations, there was a reduced risk for Kramer’s review331 of 504 women showed that the developing asthma in subgroups who were combined evidence did not suggest a strong sensitised to grass pollen and house dust mite, protective effect or maternal antigen avoidance who made up 20% of the study population. Data during pregnancy on the development of atopic on the severity of atopic eczema in the two treat- eczema and other allergic diseases in the first year ment groups have not been published to date. of life of their children and some evidence that such avoidance could lead to lower birth weight. Atopic eczema prevention by allergen The trials also suggested a non-significant increase avoidance during pregnancy in pre-term birth in the intervention groups. Cord Dietary prevention blood IgE levels were similar in both groups. The idea of trying to prevent atopic eczema by avoiding potentially allergenic foods and other Seven RCTs48–50,52–55 that have looked at dietary allergens such as house dust mite during manipulation during and after pregnancy are pregnancy and early life is an attractive one. summarised in Table 3. All included studies have Parents often believe that foods are an important involved children at high risk of developing atopic cause of atopic eczema and expectant mothers are eczema because of atopic disease in close family often highly motivated to do what they can to members. Although some of the interventions are prevent illness in their offspring, particularly if broadly similar, pooling is probably not justified in there is a strong family history of atopic disease. view of the differences in foods avoided, duration 17 Results continued Unclear if reported benefit was sustained after age 1 year Lack of blinding serious threat to validity of study findings mothers in the control More formula-fed,group which could eczema explain increased High-quality study that tested milk in that cows’ hypothesis risk of increase life early no allergic disease and found to supportevidence this Definition of atopic eczema vague Marked differences differences Marked (64% vs 46%) in mothers with personal history of atopic vs high ‘reduced’ eczema in the at baseline dairy groups intake No definition of atopic eczema given Concealment of allocation unclear Unblinded study (12/121 No ITT analysis some of whom drop-outs undisclosed for withdrew reasons) Clear description of method of randomisation and concealment in sealed envelopes examining Physician reported to be children of allocation unaware status Clear description of flow of study participants out carried ITT analysis Method and concealment of allocation unclear Study assessors reported of diet to be unaware allocation No ITT analysis > 0.05) p = 0.069) p Of 109 mothers who completed study, 17 out of 55 (30.9%) children born to the dietary had group restriction 1 year eczema by with compared in 24/54 (44.4%) children group the control ( in lower scores Severity intervention group Eczema during first year in 41% of intervention vs 34% in control group ( group wheeze and Similar for nasal discharge Of 163 evaluable children, in no difference of asthma, prevalence rhinitis, urticaria or atopic eczema of obvious, Proportion and possible probable cases of atopic eczema was group in reduced with 28% 33% compared in other group Proportion of infants who Proportion atopic eczema developed of and severity/extent atopic eczema Atopic eczema, wheeze, nasal discharge and skin- prick tests Proportion developing Proportion atopic diseases and positive skin-prick tests follow-up Prospective RCT with Prospective infants followed-up until age 1 year Prospective RCT with Prospective infants followed-up until age 1 year Prospective randomised study with followed-up children to age 18 months of age 121 women with a 121 women history of a previous child with atopic eczema 487 mothers with at member least one family atopic from suffering disease (238 intervention, 249 control) 162 mothers with respiratory allergy to animal dander and/or pollens giving birth to 166 infants and sample size description and results reporting Dietary antigen avoidance of Dietary antigen avoidance milk, dairy products, egg, fish, throughout beef and peanuts and lactation vs no pregnancy dietary restriction Pregnant mothers restricting Pregnant to half a milk intake their daily and pint during pregnancy of during lactation and addition milk if needed vs no soya-based such restrictions Maternal diet low in hens’ egg Maternal diet low diet’) milk (‘reduced and cows’ egg and vs diet with one hen’s 1 l of milk in last 3 months pregnancy RCTs of dietary in offspring manipulation during atopic eczema and after pregnancy aimed at preventing et al., et al., 53 54 48 et al., Study Interventions Study population design, Trial Outcome measures Main reported Quality of Comment Chandra (Canada) 1986 Lilja 1989 Miskelly Miskelly 1988 Sweden 18 Wales TABLE 3 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 Very large drop-out from large drop-out Very original randomisation Bias mis-classification of outcome cannot be ruled out due to unblinding the Some changes between at apparent that were 2 groups allergy (food and age 2 years no milk sensitisation) were at age 7 years longer present in eczema Differences not recorded treatment Promising and persistent Promising in atopic eczema difference in intervention prevalence group Unclear if reported benefit was diet,die to prenatal feeding practices after birth or in house dust mite reduction Similar limitation of unblinding to other studies, though similar with objective proportion argues against bias by atopy observers based on Atopic eczema mainly history with some physical examination rate high follow-up Remarkably such a long study (95%) for Concealment of allocation unclear Study patients were unblinded due to nature of intervention recording Investigators atopic eczema also not blinded probably No ITT analysis Method and concealment of allocation unclear Study participants unblinded but some attempt at blinding study assessor No ITT analysis Method and concealment of allocation unclear Study unblinded No ITT (hough very few drop-outs) > 0.05) p Of 165 children at age 7 years, evaluable in atopic no differences eczema prevalence, allergic rhinitis, asthma, serum IgE noted for of prevalence Period atopic eczema in at intervention group (estimated age 7 years = 7%, graph) from identical to control group At age 2 years, 13.8% in and the prophylactic 24.2% in the control had examined group atopic eczema At age 4 years, this persists difference (8% and 15% with atopic eczema, respectively) in No differences eczema severity also significantly Atopy less common in intervention group Of 209 evaluable at age 5 years, children in the 29% of children dietary vs 24% in group had group the control reported atopic eczema ( with asthma, Proportion and objective fever hay very similar in atopy both groups Proportion developing Proportion atopic eczema and other atopic diseases, allergy food and skin-prick tests Atopic eczema (prevalence and severity), asthma, rhinitis and skin-prick tests Prevalence of allergic Prevalence disease including atopic eczema, skin-prick testing, and IgE follow-up Prospective randomised study with followed-up children to age 7 years Prospective randomised study with followed-up children to age 4 years Prospective randomised study with followed-up children to age 5 years 288 children born to 288 children at high risk of parents atopic disease 120 children identified 120 children birth as being at before atopy high risk for 209 pregnant mothers 209 pregnant families with at from least one allergic family member and sample size description and results reporting RCTs of dietary in offspring manipulation during atopic eczema and after pregnancy aimed at preventing Mothers who avoided cows’ Mothers who avoided milk, during eggs and peanuts and last trimester of pregnancy lactation and whose children milk until 1 year, cows’ avoided and fish until egg until 2 years vs mothers and their 3 years standard who followed children practices feeding Mothers during last trimester of and during lactation pregnancy excluded dairy products, egg, milk or soy-based fish and nuts house to reduce plus measures dust mite at home vs mothers fed whose infants were with no control conventionally of house dust mite Total abstinence of cows’ milk abstinence of cows’ Total 28 of week and eggs from until delivery vs pregnancy throughout normal food pregnancy 51 55 1993 1996 49 et al., 50 52 Study Interventions Study population design, Trial Outcome measures Main reported Quality of Comment ITT, intention-to-treat Zeiger & Heller, 1995, USA England Hide 1994, Sweden Falth-Magnusson & Kjellman, 1992 19 TABLE 3 contd TABLE Results

of avoidance after birth and whether the mother eczema have been given. These studies share similar continued to avoid the foods during lactation. methodological concerns regarding disease Some key points emerging from these five studies definition and unmasking of blinding. are as follows. Other summary points are as follows. • Lack of blinding seriously threatens the validity of the studies. Even if assessors were reported • The Moore and colleagues63 study illustrates to be blind to the dietary allocation, it is possible the difficulty of trying to randomise mothers that unblinded parents revealed their allocation to breastfeed. to assessors. Independent assessment of disease • There is no evidence to support the use of soya status (e.g. by using coded photographic records) milk as opposed to cows’ milk supplementation is one way of reducing such a possibility. to children as a means of preventing or delaying • Disease definition is often quite vague or non- onset of atopic eczema. existent in these studies. Disease definition is • There is some evidence to support the use of particularly important in the first year of life to extensively hydrolysed cows’ milk formulae over separate atopic eczema from simple irritant regular cows’ milk formulae in preventing atopic eczema and seborrhoeic dermatitis of infancy. eczema in high-risk families, though the extent • Studies that have examined avoidance of to which these unpalatable formulations can be potentially allergenic foods during pregnancy taken up in practice is unclear. produce conflicting results with two suggesting • There is some evidence that maternal avoidance benefit and four no benefit. The highest of allergenic foods during lactation may reduce quality reported study54 found no benefit. the incidence of subsequent atopic eczema and • Methodological difficulties such as failure other allergic disease. to comply with protocols, lack of blinding • Some studies (e.g. Chandra et al.,61 Marini and complex interventions can probably be et al.,65 and Porch et al.,57) mix up results of overcome by closer involvement with observational data with randomised participants consumers and by use of more objective in such a way as to render it difficult to make outcome measures. valid comparisons. • Most of the studies refer to children born to Prevention of atopic eczema through families with atopic disease. allergen avoidance and dietary manipulation after birth House dust mite One Cochrane systematic review331 of maternal No RCTs evaluating the sole use of anti-house antigen avoidance during lactation pooled three dust mite measures to prevent atopic eczema studies53,61,332 and found some benefit on the were identified. The study by Hide and colleagues55 prevention of atopic disease in offspring from evaluated the combined effect of dietary allergen maternal avoidance of allergenic foods while reduction and house dust mite reduction during breastfeeding. Methodological shortcomings in all pregnancy and after birth, but it is impossible to three trials (mainly loss of blinding) argue for say from this study whether it was the diet, house caution in interpreting the results. RCTs that have dust mite reduction or both that was responsible examined the usefulness of manipulating the diet for the observed benefit. Future studies evaluating of lactating mothers and their infants after birth a combination of interventions simultaneously with a view to preventing atopic eczema56–61,63–67 should consider factorial designs in order to tease are summarised in Table 4. A further trial332 has out which components of the intervention have been excluded because no separate data on atopic been beneficial.

20 Health Technology Assessment 2000; Vol. 4: No. 37 continued Small study, which did not to evidence any provide supplements suggest that soy a range benefit for had any of allergic diseases over milk cows’ Unclear if all four groups were groups Unclear if all four randomised and at what point Description I methods suggest breast-fed that the exclusive not randomised were group at all Atopic eczema notoriously difficult to separate from eczema at up to seborrhoeic age 6 months An ambitious large study that illustrates the difficulty in randomising mothers to breastfeed Method of randomisation and concealment not specified single-blind Probably with no drop-outs Two ITT analysis No details on randomisation procedure or concealment thereafter examining physicians Two reported to be blind status of child formula No ITT analysis Method of randomisation and concealment of allocation unclear skin recording Person lesions reported to be group of feeding unaware No ITT analysis < 0.005) p a 13/25 infants in the soy with compared group milk 11/25 in the cows’ obvious developed group atopic or probable dermatitis (NS) No significant differences in other allergic diseases groups the two between Of 263 evaluable children, 7.4% in the group, hydrolysate 29.9% in the milk group, conventional group 27.9% in the soya and 18.3% in the breast-fed exclusive had atopic eczema group statistical (not tested for significance in paper) score Eczema severity all between did not differ groups four disease Incidence of any of allergic atopic eczematiology was in hydrolysate lowest ( group Because only 26% of Because only mothers in experimental groups and control breast-fed exclusively their infants, were results as a not analysed randomised study but as an observational one Obvious and probable atopic disease (atopic dermatitis, asthma, allergy, gastrointestinal urticaria and rhinitis) Atopic eczema development, eczema severity, wheezing illness, nasal discharge Prevalence of eczema at Prevalence 3, 6 and 12 months follow-up Parallel study with followed-up children 4 years for Prospective RCT with Prospective up for infants followed 6 months Prospective RCT with Prospective infants followed-up until aged 1 year 48 children whose 48 children both had atopic parents disease 288 ‘high-risk’ infants historywith family of atopic disease among relatives. first-degree in each of the 72 children interventionfour groups 525 mothers (250 in experimental and 275 in group) control and sample size description and results reporting Supplementing breastfeeding milk or cows’ with either soy to age 9 months weaning from Four different infant feeding different Four formulae: milk cows’ hydrolysate vs formula vs soy-based formula milk vs cows’ conventional for breastfeeding exclusive 4 months or more Breastfeeding for at least 3 for Breastfeeding of solids months and avoidance this time with soya-based for vs supplementation if required milk advice plus cows’ standard if needed formula 67 , Studies looking at dietary manipulation of mothers or infants, diet after birth onset of atopic eczem with the aim of preventing et al. et al., 56 63 Study Interventions Study population design, Trial Outcome measures Main reported Quality of Comment Kjellman & Johansson 1979 Sweden 1989a Canada Moore Moore 1985 Chandra England 21 TABLE 4 TABLE Results and continued post hoc Unclear if blinding of assessors was successful definition of atopic Vague eczema, be which could easily confused with seborrhoeic eczema of infancy each exclusion from Several after randomisation group Large study with high-quality reporting Description of atopic eczema ‘characteristic based on distribution’ unclear risk in Finding of increased atopic families needs testing in other studies to non- of results Validity infants unclear preterm Unblinded study No definition of eczema given Despite randomisation, 58% in vs 33% in group hydrolysate chose to milk group cows’ breastfeed, which could results confound Method of concealment allocation unclear No blinding of eczema in groups breast-fed Blinding of observers formula-fed reported for babies No ITT analysis Randomisation and concealment described Observers reported to be blind to infants’ initial diet ITT analysis No details on randomisation procedure or concealment thereafter No mention of blinding in study with a No ITT analysis rate at age 30% drop-out 4 years < 0.05) p a < 0.001) p Eczema less common in and milder in severity breast- babies who were and whose mothers fed diet on a restricted were (11/49 (22%) vs 21/48 (48%)) In infants fed hydrolysate, or cows’ soy milk, 9/43 (21%), 26/41 (63%) and 28/40 (70%), respectively eczema developed Eczema significantly common at more 4 months, age 2 and age 4 years At age years, 7.1% (5/70) had eczema of children group in the hydrolysate with 25.9% in compared milk group the cows’ ( of No evidence of effect protective asthma for hydrolysate No difference in the No difference incidence of allergic dietarydisease between in either trial at groups 18 months after term with a family In subgroup history of atopy, early milk to cows’ exposure risk of increased eczema (odds developing ratio 3.6 in those with a historyfamily vs 0.7 in those without; Development of atopic Development eczema and severity Atopic eczema occurrence and severity, asthma, food intolerance and objective (total IgE) tests of atopy Development of eczema, Development asthma or wheezing, and reactions allergic food follow-up Prospective RCT with Prospective for infants followed-up 18 months Prospective RCT with Prospective for infants followed-up 18 months after term Prospective RCT with Prospective for infants followed-up until aged 4 years 97 mothers who chose and 124 to breastfeed who did not 777 preterm infants 777 preterm (birth < 1850 g) weight at no born to parents of atopic increased disease 177 infants (92 in and group hydrolysate formula 85 in adapted a selected from group) birth cohort whose had a immediate family history of allergic disease medical confirmed by records and sample size description and results reporting Studies looking at dietary manipulation of mothers or infants, diet after birth onset of atopic eczem with the aim of preventing Two studies: Two i) mothers who planned to allocated to either breastfeed (milk,diet restricted dairy products, eggs, fish, and peanuts or normal diet while soybeans) breastfeeding ii) mothers who did not plan to allocated to one of breastfeed feeds formula three (hydrolysate, milk or soy milk) cows’ conventional Infants assigned to hydrolysate milk cows’ vs adapted formula formula either Both interventions were for alone or with breastfeeding 4 months Two trials: Two donor milk vs i) evaluated as sole diet or formula preterm randomised) as a (separately supplement to mother’s milk expressed ii) infants allocated term vs formula preterm 59 et al., et al., 61 60 Study Interventions Study population design, Trial Outcome measures Main reported Quality of Comment Chandra Canada 1989b Lucas 1990 Mallett & Henocq, 1992 France 22 England TABLE 4 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued No description of atopic eczema definition Due to the obvious taste to hydrolysate, difference likely unblinding highly Small underpowered randomised study occurring within a large case control study results difficult to relate Very to original randomisation groups schedule as so many the observationalfrom part of together the study mixed Small study where there is loss there Small study where randomised groups of originally due to mothers’ preferences Authors point out the difficulties in randomising such “we and conclude that a group high atopy-risk can spare extra families this (hydrolysate) burden” No details on randomisation procedure or concealment thereafter Some attempt at blinding of mothers and observers with a No ITT analysis rate at age 23% drop-out 5 years Randomisation procedure or concealment thereafter unclear Mothers unblinded; reported to be physicians of dietary unaware allocation with a No ITT analysis rate at age 22% drop-out 3 years Method of randomisation described Study not blinded No ITT analysis a Of 58 evaluable children Of 58 evaluable at age 5 years, 7/28 had on whey children eczema vs developed milk (NS) 8/30 on cows’ in eczema No difference severity atopic Cumulative type was disease of any 29% vs 60% in the whey milk group vs cows’ Unclear which results to the randomised refer groups Of the 25 evaluable on hydrolysate children milk,plus breast three (12%) had eczema at 3 vs 3/22 (13.6%) years in the children evaluable plus cows’ breastfeeding (NS) milk group Of the 82 randomised infants, 11 mothers chose exclusive to continue and these breastfeeding joined nine other a non- to form children randomised comparison of 20 children group atopic eczema Data for 32 in the remaining randomised to children and 39 to hydrolysate ordinary formula, cows’ not given,were but reported as not significant statistically Cows’ milk protein Cows’ sensitivity, atopic eczema and severity, prevalence allergic rhinitis and asthma Atopic eczema, recurrent wheeze, rhinitis, urticaria and gut symptoms Atopic eczema occurrence, asthma, rhinitis and food allergy Also skin-prick tests and IgE analysis follow-up Prospective RCT with Prospective for infants followed-up until aged 5 years Prospective RCT with Prospective for infants followed-up until aged 3 years Prospective RCT with Prospective for infants followed-up until aged 18 months = 279) = 32) and n n = 28) n 75 infants with atopic disease in at least two and relatives first-degree whose mothers chose not to breastfeed Children born to Children mothers with high atopic risk participating in an allergen avoidance ( programme whose mothers had milk insufficient breast These mothers randomised to plus breastfeeding ( hydrolysate milk plus cows’ breast ( 82 infants with at least atopic family two members or one atopic whose mothers parent for breast-fed exclusively 9 months Lactating mothers and their infants also avoided milk egg and fish until 12 months and sample size description and results reporting Studies looking at dietary manipulation of mothers or infants, diet after birth onset of atopic eczem with the aim of preventing Assignment to partial whey- vs regular formula hydrolysate milk during first 6 months cows’ of life Hydrolysed milk formula vs milk formula Hydrolysed milk formula cows’ conventional Hydrolysed cows’ milk formula cows’ Hydrolysed vs ordinary milk formula cows’ et et al., 66 et al., 65 64 1995 Study Interventions Study population design, Trial Outcome measures Main reported Quality of Comment Vandenplas Vandenplas al., Belgium Odelram 1996 Italy Finland and Sweden Marini 1996 23 TABLE 4 contd TABLE Results Atopic eczema definition unclear of success blinding Degree unclear Another study evaluating quite Another study evaluating of motivated a select group with atopic disease parents who chose not to breastfeed their infants in No statistical differences noted atopic dermatitis were randomised the three across groups,feeding and the rate of atopic dermatitis (12%) was similar in the non-randomised group breastfed Randomisation procedure or concealment thereafter unclear Mothers unblinded to but milk formula cows’ some attempt at blinding hydrolysate between formulae reported to be Physicians of formula unaware No ITT analysis Clear description of method of randomisation and blinding: parents, hospital staff, physicians reported and investigators of to be unaware allocation status carried No ITT analysis out a In the 55 children randomised to hydrolysed extensively formula, 17% had 18 eczema by developed months vs 44% of the 51 in the partially children and group hydrolysed in the 41% of 49 children milk group cows’ regular Of the 130 infants who completed the 1-year study, out of 40 two formula, (5%) on soy out of 42 (12%) five on partially hydrolysed and three formula whey out of 31 (10%) on the hydrolysed extensively developed formula atopic dermatitis by 1 year were These differences different not statistically Symptoms of food similar intolerance were in all groups Cumulative prevalence of prevalence Cumulative asthma, atopic eczema and rhinitis and IgE antibodies Development of atopic Development dermatitis in infants based a on examination by and/or paediatrician nurse physician, or chronic and vomiting recurrent of in first year diarrhoea persisting longer than life over or recurring 3 weeks 2 months or more follow-up Prospective RCT with Prospective for infants followed-up until aged 18 months Prospective, randomised, double- blind parallel study of 12 months duration Observational group of infants who were breast-fed 155 infants with a family history of allergy who milk for cows’ avoided first 9 months and no eggs or fish until 12 months mothers Breastfeeding same foods avoided 181 infants recruited birth if one or before had a both parents history of allergy those infants whose Only mothers decided not to were breastfeed assigned to randomly feeding one of three groups and sample size description and results reporting Studies looking at dietary manipulation of mothers or infants, diet after birth onset of atopic eczem with the aim of preventing Extensively hydrolysed vs hydrolysed Extensively vs regular partially hydrolysed in infants at milk formula cows’ stage weaning Three different infant feeding different Three formulae: hydrolysed extensively casein formula, partially and formula whey hydrolysed formula soy et al., et al., 58 57 Study Interventions Study population design, Trial Outcome measures Main reported Quality of Comment Oldaeus 1997 Sweden Porch Porch 1998 USA 24 NS, not significant TABLE 4 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 4 Topical corticosteroids

opical corticosteroids have been one of the of the benefit. Those studies that do report T cornerstones of treatment of atopic eczema magnitude of benefit suggest a large treatment for almost 40 years. Hydrocortisone was first effect. We could not find one RCT comparing developed in 1952 and improved various eczem- betamethasone 17-valerate and placebo, which is atous dermatoses when applied topically.333 Since worrying as this is used as the ‘standard’ compar- then, another 30 or so compounds have been ator for most new topical corticosteroids developed developed, each in different formulations such subsequently. Nearly all studies were less than as creams, oily creams or ointments, and often in 1 months’ duration. combination with other ingredients such as antibiotics. They vary in strength (as measured by ability to constrict blood vessels rather than clinical Topical corticosteroids versus anti-inflammatory or skin thinning effect) from other topical corticosteroids very mild (e.g. hydrocortisone), to very strong fluorinated products (e.g. clobetasone pro- This group of RCTs represents the largest in this pionate). Systemic adverse effects are rare and section (n = 40). Most trials are again of poor include suppression of the pituitary–adrenal axis quality, and have tended to mix atopic eczema and Cushing’s syndrome. Local adverse effects patients with a whole range of other patients. include spread of untreated fungal infection, In these studies, responses to the same topical irreversible striae (stretch marks) and prominent corticosteroids for different conditions are in many fine blood vessels, contact dermatitis, perioral cases quite different, though it is unclear how dermatitis and worsening of acne and mild loss many of these observations are due to different of pigmentation. The adverse effect that sample sizes in the different groups. It is difficult undoubtedly causes the most concern is that of to make any summary statement on this group of skin thinning.334 trials as there are no trials that compare all of the contenders for the most effective and safest topical We located 83 RCTs on the use of topical steroids corticosteroid together. Thus drug A has been in atopic eczema.68–150 Sixty-five other RCTs on use compared with drug C, drug C against drug D, of topical steroids, summarised in appendix 2, had drug D against drug A, Drug B against drug C, to be excluded as they did not give a sufficiently but never all together. It is difficult therefore to clear description of the patients, or the results of make any ranking conclusions. Some batches of patients with atopic eczema and other inflammatory RCTs introducing a ‘new’ topical corticosteroid dermatoses were mixed up together. Due to the are oddly country-specific despite being marketed large number of studies, the 83 included RCTs are by international companies. Many of the RCTs summarised in appendix 3 and separated into introducing a ‘me too’ product claim equivalence groups according to the sort of questions they against a standard preparation, erroneously address (though some RCTs straddle more than making the assumption that no evidence of these categories). These groups will be commented statistical difference is the same as evidence on in turn. Some quantitative pooling of data was of equivalence. attempted for the question of once- versus twice- daily corticosteroid usage in view of the importance Two newer topical corticosteroids (fluticasone of this question to the NHS and patients. propionate and mometasone furoate) have been introduced in the UK over the past 10 years and claim to have less systemic absorption and an Topical corticosteroids efficacy profile that permits them to be used 335 versus placebo once as opposed to twice daily. The RCTs that have compared these two substances have Quality of reporting of studies in the 1960s to invariably compared the ‘new’ agents against 1980s was generally poor, and methodological twice-daily older agents and demonstrated details scant. Studies that only report patient reasonable equivalence. They have subsequently preference data give us little idea of the magnitude and rightly been marketed as ‘once-daily’ 25 Topical corticosteroids

treatments for atopic eczema, possibly giving Different formulations of the the impression that once-daily application of same topical corticosteroids other topical corticosteroids is not as effective as twice daily. The RCTs evaluating these newer Two points are worthy of note in this section. The agents have been careful therefore to only include first is that there is some evidence that composition a once-daily comparison of their product against of vehicle can affect efficacy,130 though long-term a twice-daily comparator. This has occasionally studies are needed to see whether these benefits introduced problems with patient masking. are at the expense of adverse effects. The second The absence of a once-daily comparator point is that cosmetic preference may be very (e.g. beta-methasone 17-valerate) is thus a pity important even when equivalence is suggested in a in these RCTs as it is possible that most of the comparison of two different formulations of the ‘older’ established topical steroids can also be same preparation,144 though this is not consistent used once daily. This point becomes important between studies even in the same countries.143 when one considers that the cost of 100 g of cream is £3.95, £14.05 and £13.90 for beta- methasone, mometasone and fluticasone Once-daily versus more creams, respectively. frequent use of the same topical corticosteroids Topical corticosteroids versus Several trials have investigated whether single daily other topical preparations topical application of corticosteroid is as effective as more frequent applications. The question being Only four RCTs are described in detail in this addressed is important from several perspectives: section, but probably many more described in other result sections could have been included • the patient’s perspective because this would as topical betamethasone and hydrocortisone make therapy much less burdensome and are used as standard comparators. It is difficult potentially safer because of the reduced risk of to evaluate treatment efficacy in those studies adverse effects of corticosteroid, and without a placebo arm (e.g. the tar versus hydro- • the NHS perspective because of reduced cost cortisone study). There is one useful and well- of therapy. described study, which does not provide any evidence of benefit of hamamelis above placebo, Results whereas some benefit for hydrocortisone was Unfortunately few trials met our inclusion criteria present. Blinding can be a problem for other and of the three that did, the methods of assess- topicals such as tar. ment were disparate. The response rate, defined as the proportion of patients who obtained at least a good response with treatment, allowed us to Topical corticosteroids plus assess comparative efficacy. However, because of additional active agents the disparate study designs, the estimates from the individual trials were not pooled. Several RCTs have evaluated the possible benefit of adding in various antimicrobial/antiseptics to Table 5 is a contingency table of the data from the topical corticosteroids. Despite their widespread three eligible trials. The estimated differences in use, we located only one RCT comparing plain response rates with once-daily versus more frequent betamethasone 17-valerate against a combination applications, are also shown in Table 5 and Figure 3. of betamethasone 17-valerate plus fusidic acid,111 It is clear that in none of the studies were more which provided no evidence of improved efficacy frequent applications superior to once-daily applic- of the combination product in patients with ation. While the point estimates suggest that a small infected atopic eczema. Similarly, we found only difference in favour of more frequent applications one RCT that compared 1% hydrocortisone with cannot be excluded, it is doubtful whether this is fusidic acid against 1% hydrocortisone alone.128 practically meaningful. This was also the conclusion That study did not find any evidence to support a of a recent review that considered this question in benefit of the combination product above plain relation to all inflammatory dermatoses.336 hydrocortisone in patients with moderately severe atopic eczema. Another study90 failed to demon- Koopmans and colleagues69 concluded that the strate any additional benefit of adding in genta- proportion of patients who were cleared of eczema 26 micin to betamethasone. in the twice-daily group was higher than that in the Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 5 Estimate of difference in response rate for topical corticosteroids

Study and analysis Stratum Contingency table Risk 95% CI difference (near exact) ab cd

Bleehen et al., 199587 1 110 113 27 20 –0.047 –0.138 to 0.045 ITT Bleehen et al., 199587 2 108 110 29 27 –0.015 –0.111 to 0.082 PP Koopmans et al., 199569* 3 71 74 4 1 –0.040‡ –0.118 to 0.025‡ Koopmans et al., 199569† 4 70 74 5 1 –0.053§ –0.136 to 0.013§ Sudilovsky et al., 198195 5 99 100 17 16 –0.009 –0.101 to 0.084 o.d. vs t.d.s. a = number who obtained at least a good response in the once-daily group; b = number who obtained at least a good response with more frequent application; c = number who did not obtain at least a good response in the once-daily group; d = number who did not obtain at least a good response in the more frequent application group * ITT; † PP (per protocol); ‡ Physician-assessed; § Patient-assessed

FIGURE 3 Estimated risk difference for topical steroids

Bleehen et al., 199587 ITT

Bleehen et al., 199587 PP

Koopmans et al., 199569 Physician-assessed

Koopmans et al., 199569 Patient-assessed

Sudilovsky et al., 198195 o.d. vs t.d.s.

– +

0.18 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 0.02 0.04 0.06 0.08 Twice-daily treatment Once-daily treatment better better once-daily group. Re-analysis of their data shows just trying to demonstrate short-term efficacy. The that this is the case, using doctors’ assessment of study’s methodological deficiencies and missing clearance (rate difference –0.21; 95% confidence data discussed elsewhere337 made it difficult to say interval (CI) –0.36 to –0.06) but not the patients’ whether prevention of relapse was due to application assessments (rate difference 0.13; 95% CI –0.28 to of steroids to previously healed sites or due to 0.02). While the results of their trial do not exclude application to ‘new’ areas, in which case, the study the possibility that Koopman and colleagues’ claim has become a straightforward vehicle-controlled may be true, theirs was the only trial that reported comparison. The study did however suggest a benefit results in sufficient detail to test their claim. of using intermittent topical corticosteroid to prevent relapse. Generalising from the 37.5% subsample of original study participants is also problematic. Prevention of relapse using Nevertheless, this is one of the first studies to topical corticosteroids look at long-term outcomes of this chronic disease in a pragmatic way. The study also provided useful One RCT has broken new ground by trying to detailed data suggesting that topical corticosteroids evaluate the usefulness of topical corticosteroids in do not produce any skin thinning when used in preventing relapse rather than the usual trend of short bursts over a long period. 27 Topical corticosteroids

Trials that have specifically stability, purity and compatibility. The possibility of examined adverse effects of compromising on stability, compatibility and micro- biological purity following extemporaneous dilution topical corticosteroids of topical corticosteroids seems unnecessary with RCTs are not the best studies to evaluate adverse the current range of products of different effects. A more detailed search for other surveil- strength.339–341 It is recognised that widespread lance and case-control data is needed, which is use of diluted topical corticosteroids reflects a beyond the scope of this review. Those RCTs that perceived increased safety margin compared have specifically gathered data on skin thinning with undiluted products by prescribers and their and suppression of the pituitary–adrenal axis have patients, though such a belief may be a false failed to find any evidence of harm, though these reassurance unless there are clear data to say studies are very short term. The study on preven- otherwise. Use of diluted products by prescribers tion of relapse104 also found no evidence of skin may also indicate the need for a wider range of thinning after 4 months, intermittent use of a products towards the less potent end of the spectrum, potent topical corticosteroid. Four other RCT particularly for the very young. studies of topical corticosteroid use in healthy volunteers reviewed elsewhere334 show skin thinning What is the most effective and safest at 6 weeks, which reversed within 4 weeks of way of using topical corticosteroids? stopping. While there are undoubtedly occasional Atopic eczema is most commonly a condition that horror stories of individuals developing Cushing’s comes and goes, and constant use of topical syndrome, permanent skin thinning and striae corticosteroids is unnecessary and indeed undesir- after long-term use of potent topical corticosteroids able in view of long-term local and systemic adverse in large areas, there is no evidence to suggest that effects. Thus, most practitioners probably use they are a problem for typical clinical use topical corticosteroids in short bursts followed characterised by bursts of 1–2 weeks’ treatment by ‘holiday’ periods of emollients only.342 Others followed by ‘holiday’ periods with emollients only. may start with a potent preparation and then Nevertheless, steroid ‘phobia’ is now firmly established decrease to a lower potency preparation as the in the UK among both patients and doctors.29 condition improves (the step-down approach). We could find no RCT evidence to throw light on these important issues. A pragmatic RCT set up Trials that evaluated oral steroids to compare short bursts of a potent steroid versus longer-term use of a weak preparation is currently Large treatment effects are observed in studies that being conducted in Nottingham with support from compare systemic steroids versus placebo in terms Trent Regional R&D. of short-term disease response. We could not identify any longer-term studies evaluating the usefulness of oral prednisolone (continuous or intermittent) Summary of topical against other systemic agents such as cyclosporin in corticosteroids the treatment of severe atopic eczema. • RCTs of topical corticosteroids versus placebo are few, but suggest a large treatment effect. Additional unanswered questions • It is difficult to make recommendations about the ‘best’ topical corticosteroid as most trials Dilution of topical corticosteroids have only compared one against another one, This is widely practised in the UK on the basis that but seldom against the same one and never dilution might reduce adverse effects but maintain all together. the same degree of efficacy.338 We could find no RCT • The market is currently saturated with many evidence to demonstrate this in patients with atopic different strengths and formulations of eczema. The largest manufacturer of topical cortico- topical corticosteroids. steroids does not recommend dilution as there is • Many older studies confuse absence of statistical a wide range of preparations currently available evidence of superiority of one compound over covering a wide range of potencies (Glaxo Wellcome, another with evidence supporting therapeutic personal written communication, May 1998). equivalence. Nevertheless, such a practice occurs with sufficient • Three RCTs have compared antibiotic/topical frequency to stimulate companies such as Glaxo corticosteroid combinations versus cortico- Wellcome to provide ready diluted preparations steroids alone in infected and non-infected 28 such as Betnovate RD™ 1:4 ointment of known atopic eczema. Health Technology Assessment 2000; Vol. 4: No. 37

• None have demonstrated superior clinical • There is no RCT evidence to suggest that skin efficacy of the combination antibiotic/cortico- thinning is a problem for correct use of topical steroid above corticosteroid alone despite their corticosteroids, though other non-RCT evidence frequent use in clinical practice. should be considered before making firm • There is some evidence to suggest that the type conclusions. of vehicle used for a topical corticosteroid may • No RCTs have compared oral steroids with enhance its efficacy. other systemic agents in patients with severe • Patient preference on the basis of cosmetic atopic eczema. acceptability may be important for long-term use • There is no RCT evidence to support the notion even when equivalent effects are demonstrated that diluting topical corticosteroids reduces between two treatments. adverse effects while maintaining efficacy in • There is no clear RCT evidence to support the people with atopic eczema. use of twice-daily over once-daily topical cortico- • There are some concerns that extemporaneous steroid administration. dilution of topical corticosteroids could affect • Based on this evidence, it would be justifiable stability, compatibility and microbiological purity. to use once-daily corticosteroids as a first step • Such a practice, although firmly established with in all patients with atopic eczema. some practitioners, seems unnecessary given the • Such a policy could halve the drug bill for wide range of different preparations of different topical corticosteroids overnight, and possibly potencies currently available. increase compliance and reduce adverse effects, • We could find no RCT evidence to support though changing well-engrained practice may different approaches to using topical cortico- be challenging. steroids such as comparing shorter bursts of • There is need for a cost-effectiveness study strong preparations versus longer-term comparing betamethasone 17-valerate once treatment with weaker preparations. daily with once-daily mometasone furoate and • A pragmatic RCT is currently underway by this fluticasone propionate ointments. research team which addresses this last question.

29

Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 5 Other topical agents

Topical coal tar vehicle alone and versus other common topical treatments such as topical steroids. There is a Although less commonly used today in Northern theoretical risk that tar is a possible carcinogen Europe, coal tar was used to treat chronic atopic based on observational studies of occupational eczema for many decades. We have located one RCT groups working with tar components. conducted by Niordson and Stahl,151 which compared one type of coal tar preparation (Clinitar™, CHS, UK) versus conventional 1% crude coal tar in the Emollients same cream, in 27 patients (mainly children) with atopic eczema in a right/left comparison study of Skin dryness is a very common feature of atopic 4 weeks’ duration. As the preparations were designed eczema, so much so that it is a diagnostic criterion.3 to be cosmetically different, only investigator blinding Skin dryness can lead to inflammation, and vice was possible. The title of the RCT is ‘Treatment of versa, and which event occurs first has been debated Psoriasis…’, which is clearly a misprint as the entire over the years.343 There is considerable biochemical article refers to atopic eczema. evidence to suggest that there are specific abnorm- alities in skin lipids (ceramides) of atopic eczema Benefits skin. A dry skin is less supple than normal skin, Of the 23 evaluable patients after 4 weeks, infiltration, and this can lead to painful cracks, particularly redness, skin thickening, scratch marks and dryness overlying joints. Another consequence of the reduced by about 50% in both treatment groups. atopic dry skin is impaired barrier function, both None of the differences were statistically significant. in terms of keeping undesirable things out (such No statistically significant differences in parents as bacteria) and retaining useful things, such as preference for treatment was found. There was a water. Staphylococcus aureus, a common secondary statistically significant (p < 0.001) preference by pathogen in atopic eczema, is also known to patients or their parents for Clinitar cream exhibit enhanced adherence to the dry surface compared with the crude coal tar cream, however, skin cells in atopic eczema. at the end of the study. Few would dispute that a dry skin is an important Harms feature of atopic eczema, but the rationale for Four patients complained of stinging and itching, reversing this dryness with moisturisers one on the site treated with Clinitar cream, two with (emollients) is less clear. One rationale is simply coal tar cream and one with both. All were shown to relieve the feeling and appearance of ‘dryness’, with patch testing to be an allergic reaction. which many eczema sufferers choose to do. Another rationale is that emollients may have a Comment soothing effect on itching and soreness. Emollients Although coal tar has been used for many years in are often purported to have a topical steroid- atopic eczema, it is a pity not to discover any RCTs sparing effect. Another question to pose is whether demonstrating its efficacy compared with vehicle emollients have any low grade anti-inflammatory alone. It is difficult to say from this study comparing activity without the use of additional topical steroids. two different preparations of coal tar whether Some have even advocated a form of ‘total emollient both were vehicle effects or whether two active therapy’ for children with atopic eczema.344 It is treatments were being compared. Both treatment possible that emollients might play a role in groups improved equally during the study. Although decreasing the incidence and severity of secondary cosmetic acceptability was higher for the Clinitar infections. It is also possible that emollients may group, this was an unblinded assessment in patients prevent allergen sensitisation if used from a very who might have been eager to please the investi- young age in high-risk infants, or the opposite is gators. Method of randomisation was not described possible (i.e. enhanced allergen penetration and no intention-to-treat analysis was performed. because of alteration of the skin barrier fat Further RCTs should compare the most cosmeti- solubility characteristics). It is also possible that cally acceptable form of coal tar treatment versus regular emollient use may reduce relapses. 31 Other topical agents

There are thus many questions that need to be and Moisturel lotion groups, respectively (n = 22). answered by RCTs in terms of the use of emollients. Although differences from baseline were Emollients are almost universally recommended as statistically significant, there were no significant first-line therapy for atopic eczema treatment in differences between the two emollients. the UK.25 Currently there are at least 30 different types of emollients listed in the British National The Hanifin and colleagues study156 compared the Formulary, and this excludes different formulations effects of adding an emollient called Cetaphil™ (e.g. lotion, cream or ointment). A further group (manufactured by the study sponsor) applied three of ten bath additives are also available.34 Emollients times daily to twice-daily application of 0.05% mainly act by either occluding water loss from the desonide lotion (a topical steroid) versus twice- outer layers of the skin (e.g. white soft paraffin), by daily topical desonide alone in 80 patients with improving water binding of the skin (e.g. urea) or atopic eczema for a 3-week period. The study was by directly adding water to the dry outer layers of investigator-blinded only. Efficacy variables included the skin (e.g. aqueous cream). seven symptoms and signs measured on a scale of 0–9, with a maximum score of 63. Global assess- Some are used as bath additives, and most are ment by investigators was also recorded. At the applied directly to the skin. It is often recommended end of 3 weeks, there was a 70% and 80% relative to apply emollients after a bath so that water is reduction in total score from a baseline of 24.23 retained in the skin. Some have advocated using and 24.13 for the desonide alone compared emollients under damp cotton bandages at night with the desonide/moisturiser side, respectively in the ‘wet-wrap’ technique. (p < 0.01). The sides treated by desonide alone showed complete clearing according to physician Despite our rigorous searching efforts, only five global evaluation in about 10% of people compared published RCTs152,154–157 could be included in this with 11% in the side treated with combination section. Many other possible trials were excluded (data estimated from graph). because they were not randomised (or randomisation was unclear), many included a range of skin The Wilhelm and colleagues157 and Andersson conditions with no separate results for atopic and colleagues155 studies both evaluated the benefit eczema (e.g. Newbold345), and some (e.g. Pigatto of emollients containing urea preparations et al.153) did not present any actual clinical data – a substance intended to improve water-binding but instead concentrated on a host of biometric capacity of the outer layer of skin. In the Wilhelm measurements, the clinical significance of which study, 80 patients with subacute atopic eczema and was unclear. The use of emollients with added associated dry skin were randomised to apply a antiseptics is discussed elsewhere in chapter 9 topical formulation containing 10% urea (Non-pharmacological treatments), where it was (manufactured by the study sponsors) versus the concluded that the addition of antiseptics did not vehicle base as ‘placebo’ in a right/left forearm show any benefit. comparison for 4 weeks. Skin redness was improved in 70% of patients at the site of the 10% urea Benefits preparation compared with 30% on the vehicle The Kantor and colleagues study154 compared the site. Similar differences were noted for induration, use of an oil-in-water emollient (Moisturel™, not but not for summary score. Measurement of outer available in the UK) versus a water-in-oil emollient skin moisture using a capacitance meter showed (Eucerin™, Beiersdorf, UK) in 50 patients of all statistically increased hydration in the 10% urea ages with symmetrical atopic eczema using a left/ group when compared with vehicle alone. right comparison design for a period of 3 weeks. The study was split into two RCTs, which compared The Andersson and colleagues study155 compared the two preparations in either a cream (Study 1) a ‘new’ cream containing 5% urea as the active or lotion (Study 2). Test limbs affected by atopic substance with an established licensed cream eczema were treated once daily with the designated containing 4% urea and 4% sodium chloride in emollients and once daily with 2.5% hydrocortisone a parallel double-blind study of 48 adults with cream, and were assessed by an independent atopic eczema in Sweden. Patients were asked to physician for redness, scaling/crusting, itching, apply the creams at least once daily for 30 days to burning/stinging and a global eczema severity dry, eczematous areas. Clinical disease severity on a scale of 0–3. Global severity reduced from measured by a physician on scale with a maximum 1.28 to 1.00 and 1.92 to 0.96 in the Eucerin and score of 1600, showed a significant benefit for both Moisturel cream groups. respectively (n = 25) and creams, but with no statistical differences between 32 from 1.91 to 0.68 and 1.91 to 0.91 in the Eucerin the preparations. Actual data were not given and Health Technology Assessment 2000; Vol. 4: No. 37

data were difficult to read from the figure as most Comment data points were scrunched up towards the lower The first two studies were of extremely short range of the large scale. Patient evaluation on a duration and quality of reporting was generally visual analogue scale (maximum of 14 meaning poor with little description of randomisation ‘no dry skin’) changed from 7.5 at baseline to 10 method, limited blinding and no intention-to-treat at Day 31 for those on the ‘new’ cream compared analysis. The Kantor study failed to show any with a change from 7 at baseline to 9 at the end of benefit of one emollient preparation over another treat-ment for the established cream (estimated (in the presence of a moderate potency topical from graph). There was no statistical difference steroid), and the Hanifin study suggested that between the two groups in terms of biometric regular use of an emollient with a topical steroid measure-ments of water content or water loss may result in a small increase in treatment through the outer layer of the skin. response compared with a topical steroid alone. Very few physicians prescribe a course of topical Ammonium lactate is another substance thought steroids without an emollient, but it was good to to improve the water-binding capacity of the outer see some RCT evidence that such a policy is layer of the skin. This was the subject of Larregue justified. Neither study was designed to show a and colleagues’ study,153 comparing 6% ammonium steroid-sparing effect for emollients. lactate with its cream base only, in 46 children aged 6 months to 12 years with atopic dermatitis. The two studies on urea preparations showed a The study was a within-person comparison of two possible benefit of a urea-containing preparation symmetrical sites on patients recruited from France compared with vehicle, and the other (which and Italy. Outcome measure included pruritus, compared two preparations both containing and clinical objective measures included redness, urea in different concentrations) failed to show dryness (xerosis), desquamation, lichenification, any benefit of a new preparation containing the hyperkeratosis, and presence of papules. These higher concentration of urea. Quality of reporting were graded on a scale of 0–3. Intensity items were on randomisation, blinding and intention-to-treat only partially reported in the results section, and analysis was poor in both studies. Similar findings suggested a reduction in lichenification, hyper- were present in the Larregue lactate study. keratosis and dryness in both groups but slightly more in the ammonium lactate group. This was It is extremely disappointing, particularly in reported to be statistically significant at Day 15 relation to the questions posed at the beginning for lichenification and for erythema at Day 30 of this section, to see a virtual absence of clinically (the final evaluation point of the study). useful RCT data on the use of emollients in atopic Tolerance, as evaluated by the patients, was very eczema. Many studies have been performed with similar in both groups. Results for itching symptoms emollients, but these have concentrated on were not given. ‘objective’ measurements such as transepidermal water loss and surface profilimetry. Despite their Harms scientific ring, such measurements are often No adverse effects were reported in the first two highly variable in terms of measurement reliability studies with the exception of one patient in the and more importantly, their clinical significance Kantor and colleagues study154 experiencing a to a child with chronic atopic eczema is often burning sensation when the oil-in-water emollient completely unclear. In addition to measuring was applied. In the Hanifin and colleagues study,156 efficacy of emollients in treating mild atopic 14% of the patients reported stinging or burning eczema lesions or the dry skin associated with on the side treated with desonide compared with atopic eczema, it is essential that future RCTs 12% on the side treated with a combination at of emollients measure long-term tolerability, week 1. Most patients (96% versus 4%) preferred patient preferences and cosmetic acceptability the combination treatment. Transient burning was as these are probably key determinants for noticed in four and five patients when treated with successful long-term use. urea and vehicle creams, respectively in the Wilhelm and Scholermann study.157 No adverse The history of emollient use in atopic eczema is effects were described in the Andersson and a good example of the inverse research law in colleagues study.155 Other adverse effects of dermatology, whereby the quality and quantity emollients include an occlusion folliculitis on hair- of evidence is inversely proportional to their bearing skin and accidents from slipping while frequency of use.346 Emollients have become climbing into the bath due to the use of emollient consecrated through usage and are firmly bath additives. implanted in the treatment regimens of most 33 Other topical agents

European healthcare practitioners. Although Lithium succinate ointment emollients many have many beneficial actions,347 there is an urgent need to answer several basic Based on observation for the possible benefit for questions about their use, preferably through lithium succinate ointment for the treatment of industry-independent RCTs. Although other seborrhoeic dermatitis, Anstey and Wilkinson158 clinical and laboratory studies may continue to conducted a small RCT of 8% lithium succinate shed some light on the use of emollients in versus inactive placebo ointment in a right/left atopic eczema, RCTs are needed to address the comparison of flexural arm eczema for 2 weeks. unanswered clinical questions of most relevance to eczema sufferers and their carers. The top ten Benefits questions that need answering through RCTs with Fourteen patients (mean age 16 years) with regard to use of emollients are as follows. mild-to-moderate atopic eczema and symmetrical lesions were enrolled and three dropped out. • Do some emollients have a useful therapeutic One developed redness on both arms and subse- effect (with or without wet-wraps) for treating quent patch testing confirmed a contact allergy minor flares of atopic eczema when compared to wool alcohol present in the ointment. At the with other emollients or very mild topical end of 2 weeks, there was slight improvement steroids? for overall impression and global score compared • Are some emollients effective in reducing itch with baseline and changes were virtually identical and soreness associated with dry skin in atopic in the active and placebo group. None of the eczema compared with no emollients or other changes were statistically significant between emollients? the two groups. • Do emollients have a topical steroid-sparing effect without loss of efficacy in the long-term Harms management of atopic eczema? No adverse effects were reported within this study • Does the regular use of emollients in between apart from the contact allergy to wool alcohol. eczema flares treated by topical steroids help Patients given topical lithium should be monitored to reduce relapse rates? for lithium toxicity if large quantities are applied. • Does the use of emollients in children born to atopic parents reduce the incidence of allergen Comment sensitisation and subsequent clinical disease? Although this was a very small study published • Does the regular use of emollients prevent in correspondence form only, the detailed results painful cracks (fissures) on the hands of atopic section is particularly informative as CIs around eczema sufferers? the treatment differences are presented. Because • Which emollients do children and adults prefer of the small standard deviations within patient at different sites of their body? differences, the study excluded moderate and • Does the pouring of an expensive emollient into large treatment effects. Method of randomisation a bath provide any additional benefit to having and concealment of allocation and blinding an ordinary bath and then applying an was unclear and no intention-to-treat analysis emollient directly to the skin afterwards? was performed. • Does the use of regular emollients reduce the incidence and severity of secondary infection in atopic eczema? Tacrolimus • How common is clinically relevant sensitisation to emollient constituents such as lanolin? Tacrolimus or FK506 is a macrolide lactone isolated from the bacterium Streptomyces tsukubaensis. It is It might be argued that because clinical opinion an effective immunosuppressant drug used for the on the use of emollients is so deeply engrained prevention of rejection after kidney and liver organ that the position of clinical equipoise348 for testing transplantation. Because of its lower molecular emollients passed some 20 years ago. On the weight and higher potency compared with cyclo- other hand, patients and the NHS spend a vast sporin, it was proposed as an effective topical agent amount on emollients and trials would be justified for inflammatory skin conditions such as atopic on the basis of potential economic savings alone. eczema. Its use in dermatology has been reviewed It is understandable that it is not in the interests elsewhere.349 Two RCTs have been published on of the pharmaceutical industry to invest much the use of tacrolimus ointment in atopic eczema – into RCTs of the comparative efficacy of estab- one in adults161 and in children.159 A further open 34 lished emollients. study was published by Nakagawa and colleagues350 Health Technology Assessment 2000; Vol. 4: No. 37

in 1994. We are aware of at least four other ongoing reported in the children’s study, though again trials sponsored by the manufacturer, comparing burning and increased itching at the site of tacrolimus with vehicle and hydrocortisone. application during the first 4 days of the study were reported in about a quarter of the patients. Only Benefits seven of the 254 blood samples evaluated contained In the adult study,161 215 patients with moderate- more than 1 ng/ml of tacrolimus. To put this into to-severe atopic eczema aged 13–60 years were context, increased toxicity in transplant patients randomised to a parallel group study of either has been associated with concentrations of greater 0.03%, 0.1% or 0.3% tacrolimus ointment or than 20 ng/ml. vehicle alone. No concurrent treatment except emollients were allowed and the study duration Another study of potential skin thinning of was 3 weeks. Compared with baseline, the percen- tacrolimus has been reported by Reitamo and tage of patients with completely resolved or colleagues,160 whereby the authors evaluated the markedly improved skin lesions at the treatment site potential of 0.1% tacrolimus ointment versus according to an overall assessment by a physician vehicle control versus betamethasone valerate were 60%, 82%, 72% and 8% (data estimated from (a potent topical corticosteroid) applied in a graphs) in the 0.03%, 0.1%, 0.3% tacrolimus oint- randomised order to apparently normal areas of ment and vehicle groups, respectively. Results were skin on the abdomen under occlusion for 7 days. similar for patients’ overall assessments, though the They found no evidence of skin thinning as data were not shown. Median percentage decrease measured by ultrasound in the tacrolimus group in a summary score for redness, swelling and itch (compared with 8.8% median decrease in skin was markedly greater in the tacrolimus groups thickness relative to a vehicle control for compared with vehicle (66%:83%) when compared betamethasone). They did not find any increase in with placebo (22.5%). All of the changes were chemical markers for collagen breakdown in the statistically significant for comparisons of placebo tacrolimus group whereas these were present in versus the three tacrolimus concentrations, but the steroid group. there were no statistical differences between the three tacrolimus concentrations. Comment Both of these RCTs were well reported with a The tacrolimus ointment for children with atopic good description of randomisation, blinding and eczema study had the same four comparison both with intention-to-treat analyses. The flow groups as the adult study with 180 children of diagram of the trial profile in the Boguniewicz moderate-to-severe atopic eczema aged 7–16 years and colleagues159 trial was particularly refreshing. recruited from 18 study centres in North America. Magnitude of the clinical benefit measured in a For the patients’ (or parents’) assessment of itching, number of ways was moderately large in tacro- the median percentage improvement from baseline limus in both adults and children when compared to the end of the 3-week trial was 50.5% for vehicle, with placebo, and little difference was observed 88.7% for 0.03% tacrolimus, 73.6% for 0.1% tacro- between the different concentrations of tacro- limus, and 77.1% for 0.3% tacrolimus. Only the limus. Although no more serious adverse effects differences between vehicle and the different have been reported to date, much larger numbers tacrolimus concentrations were statistically significant. and experience with the drug is needed before Similar percentage improvements were seen for topical tacrolimus can be declared safe for the physician’s global evaluation. The mean percentage widespread use of atopic eczema in the community. improvement for a modified eczema area and severity Both of the trials were of extremely short duration index at the end of the treatment for each of the and longer-term trials are needed to evaluate the three tacrolimus groups (72% for the 0.03% prep- benefit of tacrolimus in managing the chronicity of aration, 77% for the 0.1%, and 81% for the 0.3% atopic eczema. Both trials are placebo-controlled preparation) was significantly better than the and therefore lack the crucial comparisons against vehicle group (26%; p < 0.001). short bursts of moderate-to-potent topical cortico- steroids and also against the newly developed and Harms very similar topical ascomycin derivatives. Such There was a significantly higher sensation of comparative trials should include cost-effectiveness, burning at the site of application in the adult and they should also be pragmatic in order to tacrolimus patients. Itching and redness were also capture the tolerability of the topical agents in reported in the adult study. Blood concentrations the community, where transient burning may result of tacrolimus remained very low throughout the in lower compliance than that in organised clinical adult study. No serious adverse effects were trials. The lack of skin thinning is a potential 35 Other topical agents

advantage of tacrolimus, along with ascomycin, Harms though the evidence that serious skin thinning None of the patients in the van Leent study were occurs with correct use of topical corticosteroids shown to have any skin irritation or other local in the community is lacking. Both of these RCTs adverse effects. Blood values of ascomycin remained were sponsored by the manufacturer, Fugisawa low throughout the study. In another study USA Inc. published in abstract form only,352 ascomycin 1% cream did not cause any thinning of the skin in 16 healthy volunteers who applied the cream Ascomycin derivatives to their forearm for 4 weeks.

Topical ascomycin (SDZ ASM 981, Novartis Comment Pharma AG) is a cytokine inhibitor. It inhibits This was a well-reported study, though the method activation of T-lymphocyte cells by inhibiting T-cell of randomisation and concealment of allocation proliferation antigen-specific activation. Based on in randomisation was not described. Blinding was some success in psoriasis, it has been tried on well described and intention-to-treat analysis was atopic dermatitis. Two RCTs on ascomycin have performed. The study showed large treatment been found, one of which was published in full at effects when presented in terms of relative treat- the time of writing this report.162 ment difference of a composite severity system when compared with placebo. The magnitude Benefits of the benefit was almost twice as large in the The van Leent and colleagues study of 1998162 twice-daily group compared with the once-daily randomised 34 patients with moderate atopic group, though the percentages are not directly eczema to a double-blind placebo-controlled comparable as they were not derived from the right/left comparison study. Topical 1% asco- same randomised population. Although the atopic mycin cream was applied twice daily (n = 16) dermatitis severity index scores were unequivocally or once daily (n = 18) and compared with a beneficial in the active group, it was disappointing corresponding placebo cream base for symmetrical not to see any patients’ views on efficacy for pruritus lesions on the arm on one or other side. The trial incorporated in the main outcome measures. The duration was 21 days, and all participants were small placebo effect of the cream is also unusual adults. At the end of 21 days, those in the twice- for atopic eczema trials, and possibly points to daily group showed a 71.9% decrease in baseline unblinding of the interventions. The fact that only severity score compared with 10.3% in the placebo three out of 16 patients showed total clearing of group (p < 0.001). Changes were also beneficial in their eczema lesion on the arm after twice-daily the once-daily ascomycin group, but the magnitude continual application for 3 weeks is also slightly was not so impressive with a 37.7% reduction in disappointing, bearing in mind the clearance atopic dermatitis severity index in the active versus potential of moderately potent topical steroids. a 6.2% reduction of score in the placebo group Nevertheless, this study suggests that topical (p = 0.002). Three out of 15 patients showed total ascomycin derivatives are effective in moderately clearance of their lesion in the twice-daily asco- severe atopic eczema in adults, and is a welcome mycin group compared with none in the placebo addition to the treatment modalities available. group. None of the patients in the once-daily More comparative trials are needed, particularly group (neither active nor placebo) showed any against intermittent use of potent topical steroids clearance of their lesions. and tacrolimus ointment in order to evaluate the place of ascomycin therapy in atopic eczema. The other study has been published in abstract Longer-term safety studies are also needed to form only351 and preliminary results were shown ascertain rare but serious adverse effects from at a recent satellite symposium sponsored by the systemic absorption. manufacturers. The study randomised patients to one of four different concentrations of ascomycin, vehicle, or betamethasone 17-valerate cream. Summary of other topical agents Results presented at the meeting suggested that the ascomycin cream was significantly more Coal tar effective than the vehicle alone in a dose- • One small RCT has suggested no difference in dependent manner, but not as effective as the efficacy between Clinitar cream and 1% crude topical corticosteroid. Full publication of the coal tar, though parents preferred the Clinitar study is awaited before further comments can preparation. It is difficult to say whether the 36 be made. efficacy changes reported from baseline were Health Technology Assessment 2000; Vol. 4: No. 37

due to the vehicle or active drug. Further RCTs Lithium succinate ointment comparing the most cosmetically acceptable coal • One small RCT failed to show any benefit of tar preparation versus other topical treatments lithium succinate ointment when compared with and vehicle alone are needed. placebo for the treatment of flexural eczema on the upper arms. Emollients • Although the use of emollients has become Tacrolimus established as one of the firmest rituals of atopic • Topical tacrolimus has been shown to be an eczema treatment, the RCT evidence for its effective short-term treatment for atopic eczema efficacy is very sparse. in children and adults. • There is a reasonable rationale for using • Transient burning and redness at the site of emollients in atopic eczema in terms of their application is a common adverse effect. steroid-sparing effect providing this is not • Future trials of tacrolimus should compare it accompanied by loss of efficacy. against short bursts of topical corticosteroids and • There is little RCT evidence to form a rationale against ascomycin derivatives in a cost-effective- for choosing between different emollients. ness analysis. Such studies should be of long • As emollients vary tremendously between duration (i.e. 4 months or more), in order to themselves in terms of greasiness and water capture the effect on chronicity of disease. content, and because they need to be used long term, patient preference is a crucial factor. Ascomycins • The correct emollient is therefore the one • Topical ascomycin derivatives have shown to that the patient will use regularly. be markedly effective in moderate atopic • There is little RCT evidence to support the use eczema when compared with placebo in the of emollients in atopic eczema. trial of 3 weeks of twice-daily applications.

37

Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 6 Antimicrobial and antiseptic agents

he relationship between secondary infection or eczema. This has led to the use of many anti- T skin colonisation with the bacterium S. aureus microbial compounds such as oral antibiotics and atopic eczema disease activity has been debated active against S. aureus given in short or prolonged for many years, and is still far from clear. People courses, topically applied antibiotics, and anti- with atopic eczema carry S. aureus in about 90% septic agents applied directly or by mixing with of clinically involved areas and about 75% of emollients applied directly to the skin or within clinically uninvolved areas.353 S. aureus represents bath additives. Topical corticosteroid/antibiotic about 90% of the total aerobic bacterial flora of contributions have already been discussed in such individuals compared with 30% in normal chapter 5 (Other topical agents). skin.354 The density of S. aureus tends to increase with the clinical severity of the atopic eczema A total of ten RCTs163–172 evaluating the possible lesions. It has been suggested that the dry skin benefit of antmicrobial or antiseptic agents in of atopic eczema is deficient in certain inhibitory atopic eczema were located and these are pre- fatty acids, which may encourage growth of the sented in Table 6. Three of the studies evaluated organism, and the organism may also show the use of oral antibiotics, one evaluated topical enhanced adherence properties to skin cells antibiotics, and five evaluated antiseptic agents. obtained from atopic eczema sufferers compared Another study evaluated the use of an anti-yeast with normal controls.355 preparation and this has also been included in this section for completeness. In view of the differences Few clinicians would dispute that grossly infected in the types of interventions (e.g. topical or oral) atopic eczema with oozing and sore pus spots and different patient populations (e.g. those requires treatment with some form of antibiotic or with clinically infected as opposed to uninfected antiseptic, and that the bacteria are contributing at eczema), it did not make sense to pool the least in part to that particular flare-up. The role of studies quantitatively. S. aureus in non-clinically infected atopic eczema skin or for borderline infection (e.g. with just Comment redness and oozing) is far from clear however,356 Table 6 shows quality of reporting was generally and the reliability of physicians to diagnose ‘clinically disappointing in the studies. Missing data and infected atopic eczema’ is probably poor. Skin swabs small sample sizes rendered interpretation difficult. taken for bacteriological culture are of little use The RCT results suggest that the potential role of due to the almost universal colonisation of atopic S. aureus in atopic eczema may have been over- eczema skin with S. aureus, though such swabs may stated in the past, and this combined with concerns reveal additional bacteria such as Streptococci spp. of selecting resistant strains argue against the general use of antiseptics and antimicrobials in clinically If S. aureus does play a pathogenic role in atopic uninfected atopic eczema. Normalisation of the eczema, then this could be due to a direct affected eczematous skin by treatment with a chemical irritation, a non-specific reaction of the topical steroid alone decreases S. aureus colonisation protein A component of the bacterium with dramatically,164 suggesting that topical steroids alone immune cells, and by the production of specific are an effective means of decreasing bacterial skin exotoxins called superantigens, which are capable colonisation in atopic eczema. of large populations of T-lymphocytes distant from the site of colonisation, giving rise to widespread activation of eczematous lesions.357 Summary of antimicrobial and antiseptic agents Although in many cases of non-clinically infected atopic eczema, the presence of S. aureus could be • Some patients with atopic eczema develop overt considered as an ‘innocent bystander’, which has signs of clinical infection which is usually due to simply colonised a dry and broken skin surface, the bacterium S. aureus. there is at least thus some rationale for considering • Most atopic eczema patients’ skins are colonised a role of S. aureus in more acute forms of atopic with S. aureus. 39 Antimicrobial and antiseptic agents

• There is no RCT evidence that oral antibiotics benefit in atopic eczema when applied directly are of any benefit in clinically uninfected to the skin or in the bath. atopic eczema. • One small study of 1-week duration in Japan • There is some evidence that a short course of suggested that spraying an acidic solution on cefadroxil is of benefit in clinically infected babies with atopic eczema might result in an atopic eczema. improvement of disease activity. • There is some evidence from a short-term study • A study of head and neck atopic eczema failed that topical mupirocin may improve atopic to show any benefit of antifungal creams and eczema activity as well as reduce bacterial counts, shampoos directed against the yeast though there is concern regarding the emerg- Pityrosporum ovale. ence of resistant strains with such an approach. • Topical steroids alone are an effective way of • There is no evidence that antiseptics are of reducing skin colonisation by S. aureus.

40 Health Technology Assessment 2000; Vol. 4: No. 37 continued Difficult to evaluate as two Difficult to evaluate being compared were ‘actives’ of inpatient in the presence and potent co-treatment care patients The fact that seven eczema infected with clinically had no bacteriological evidence confirms the of infection difficulty understanding the link disease and bacteria between Results clearly in favour of in favour Results clearly these children for cefadroxil atopic eczema with infected quality of reporting Poor An important study that did to evidence not find any use of anti- support prolonged antibiotics in staphylococcal uninfected those with clinically atopic eczema temporarily only Flucloxacillin changed skin colonisation by S. aureus Method of randomisation and concealment unclear No ITT analysis Method of randomisation and concealment unclear No description of blinding No ITT analysis Good description of randomisation, blinding, (five but no ITT analysis 4) week by drop-outs = 0.32) p counts t has also been included completeness) for S. aureus Mean duration of treatment was 7.7 Mean duration of treatment in the EA and ES and 7.5 days days groups, respectively At the end of treatment, 75% and 83% of those in the EA and ES groups, ‘good’ respectively, noted to show were improvement ‘very effective’ or to patients according Similar results similar effects adverse Gastrointestinal in both groups Of 30 evaluable patients,Of 30 evaluable all 13 in the no longer had clinical group cefadroxil at the end of superinfection evidence with six out of of the study compared 15 in the placebo group Number of patients with positive and from 13 to four from isolates fell and placebo 17 to nine in the cefadroxil groups, respectively global improvement Physician-rated or moderate marked recorded in 84 of cefadroxil improvement with 53% of placebo- compared patients treated Although mean in those treated significantly decreased with flucloxacillin, clinical efficacy scores the two did not change between systematic way in any groups in bacteriological counts The difference after stopping treatment at 14 days no longer significant ( were strains were Methicillin-resistant commoner in those on flucloxacillin , patient S. aureus Investigator and Investigator patient assessment of efficacy on treatment Likert a five-point scale and adverse effects Clearance of superinfection (assessed clinically), eczema severity, of patients number cultures with positive and global improvement compliance, and composite eczema scores severity Change in baceteriological count of Parallel group randomised double- 5 to blind study for 12 days Parallel group randomised double- blind study for 2 weeks Parallel group randomised double- blind study for 1 month with an follow-up 8-week period and or mixed infection infection S. aureus S. aureus follow-up four had combined four Staph/Strep 42 patients (aged 15 to admitted with 66 years) atopic infected clinically eczema Most had bacteriological isolates of 33 patients aged 6 with months to 12 years bacteriologically confirmed superinfected atopic eczema caused by either Staph/Strep 50 children aged 1–16 50 children who did not have years of signs suggestive any bacterial infection (co-treatments) and sample size description and measures results reporting Oral cefadroxil Oral cefadroxil equal in two 50 mg/kg/day doses vs placebo for (no mention of 2 weeks co-treatments) Oral erythromycin acistrate (EA) 400 mg vs oral times daily three stearate erythromycin times (ES) 500 mg three 5 to 12 days for daily and (topical steroids emollients) Oral flucloxacillin 250 mg Oral flucloxacillin or matched placebo daily 4 for times daily four (topical steroids, weeks emollients and antihistamines) RCTs that have evaluated antimicrobial or antiseptic agent in atopic eczema. or antiseptic agent antimicrobial RCTs that have evaluated (An additional RCT of the use an antifungal agen et al., et al., 170 169 et al., 163 Study Interventions Study population design, Trial Outcome Main reported Quality of Comment Weinberg Weinberg 1992 South Africa Salo 1988 Finland England Ewing 1998 41 TABLE 6 TABLE Antimicrobial and antiseptic agents continued Crossover design not ideally Crossover suited to a study of antibiotics actions on the with delayed skin of atopic Some evidence in the eczema improvement of first study period in favour mupirocin selection of Concern for strains resistant Difficult to interpret with such Difficult to interpret study and the a tiny active comparison of two treatments Scanty methodological detail The clinical tolerance data the most useful were Method of randomisation and concealment unclear No ITT analysis; no of period or carryanalysis effect over Results suggest a significant carry-over 1st and between effect 2nd periods Poor quality of reporting Poor with very few methodological details t has also been included completeness) for = 0.63) < 0.002); p = 0.37) p p Bacterial count for 45 evaluable Bacterial count for in reduced patients was significantly but topical mupirocin those receiving not in the placebo group, although in the 4-week occurred recolonisation period (17% of whom had follow-up strain that had not ‘new’ a developed isolated) been previously period, the first treatment For total a mean from fell score skin severity of 69.9 to 68 in the placebo group 59.5 to 37.6 with a fall from compared ( group in the mupirocin not were surface area changes for so marked in statistically Patient assessments were the first for of the mupirocin favour period treatment Total severity score fell from 8.8 at day from fell score severity Total for 0 to 5.7 at the end of 7 days 11.1 to 8.8 for chlorhexidine and from ( the permanganate group sites of affected Intensity and number very little difference also showed groups the two between substantially Bacterial counts feel not were but they in both groups significant ( statistically groups in the two and baseline scores quite different were in both ‘good’ Clinical tolerance was groups Type and counts of Type bacterial isolates, composite clinical and score severity by extent involved disease Patients’ assessment of appearance, itch and sleep Bacterial counts, composite clinical and score severity patient reported tolerance Double-blind randomised period crossover with a 2-week run-in, 2-week two periods crossover and a further follow-up 4-week Parallel double- blind randomised study of 1 week duration follow-up 49 patients aged 2–56 with relapsing years atopic eczema without secondaryovert skin infection 20 children aged 5 20 children months to 9 years if they No details given infected clinically were RCTs that have evaluated antimicrobial or antiseptic agent in atopic eczema. or antiseptic agent antimicrobial RCTs that have evaluated (An additional RCT of the use an antifungal agen (co-treatments) and sample size description and measures results reporting Topical mupirocin Topical 2 ointment vs placebo for (topical steroids weeks and emollients) Proprietary brand of chlorhexidine solution against 1:20,000 compared dilution of potassium permanganate solution for to in addition 7 days topical desonide (a steroid) et al., et al., 167 164 Study Interventions Study population design, Trial Outcome Main reported Quality of Comment Stalder 1992 Lever Lever 1988 Scotland 42 France TABLE 6 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Difficult to interpret the clinical Difficult to interpret statistical data as the correct comparison has not been done and because of the short duration of the study Some serious concerns about the study quality an acid The ethics of spraying infants is also a onto young concern cause for Both this study and the published in Holland study are table’ discussion ‘round a the by document sponsored manufacturer of in view Difficult to interpret statistical tests being the wrong used and missing patient- reported data of data comparing Re-analysis between the change in score at 4 weeks treatments the two superiority did not confirm any of the antiseptic emollient Although the study was described as randomised, is serious cause to there challenge this in the methods section whereby the authors state that 22 patients were a divided by ‘arbitrarily into two physician referee of 11’;groups blinding also due to the seems unlikely acidic taste and sensation of the acid Method of randomisation was described, but no ITT analysis statistical tests of Only from change in scores each baseline for separately treatment rather than the test of the appropriate in score difference the two changes between treatments t has also been included completeness) for Colony counts decreased by around by counts decreased Colony but not in the water 50% in the active were (though baseline scores group quite different) 9 to 5 from fell scores Global severity with a compared group in the active 7 to 8 in the water group; rise from itching and sleep also for scores but not group in the active decreased in the water group a Although the authors found significant change in all of statistically group the active for these measures with baseline,compared did not they test of difference do the appropriate groups the two between Based on 26 evaluable patients,Based on 26 evaluable the (baselines baseline score change from those was 9.0 for not given) scores using the antiseptic emollient compared those with regular with 2.7 for emollient at 4 weeks any did not show Patient rated scores the two between significant differences (data not shown) treatments S. , composite Colony counts of Colony aureus grading score, and itching and for scores sleep disturbance Composite sign and (max. symptom score 100), patient recorded global overall and global impression change scales Parallel randomised double blind study duration of 1 week Randomised study of crossover 4 week two periods treatment with a 2-week washout period in between follow-up 22 children aged 2 to 56 22 children months with mild-to- moderate atopic eczema 30 children aged 1–9 30 children with recurrent years and/or infections exacerbation frequent ) vs the same ™ ) used daily at a dose ) used daily ™ RCTs that have evaluated antimicrobial or antiseptic agent in atopic eczema. or antiseptic agent antimicrobial RCTs that have evaluated (An additional RCT of the use an antifungal agen Comparison of spraying infants with water twice a or an acid 1 week for day water (pH < electrolytic gun (no 2.7) using a spray in allowed co-treatment this period) of 15 ml to the bath for 4 of 15 ml to the bath for (topical steroids) weeks Comparison of a standard proprietary bath emollient (Oilatum with the two added with the two antiseptics 6% w/w chloride benzalkonium and 2% triclosan (Oilatum Plus (co-treatments) and sample size description and measures results reporting 166 171 1997 Sasai-Takedatsu et al., Japan Harper, 1995 England Study Interventions Study population design, Trial Outcome Main reported Quality of Comment 43 TABLE 6 contd TABLE Antimicrobial and antiseptic agents may be a may P. ovale Despite widespread use of Despite widespread atopic eczema antifungals for the head and neck, affecting this RCT does not suggest that benefit additional is any there treatment conventional over the and that colonisation by yeast secondary phenomenon Worth pursuing in a larger Worth double-blind study as is a cheap povidone-iodine anti- antiseptic with good properties staphylococcal in This is study inconclusive of unblinding, of threat view short duration, to and failure the appropriate perform statistical tests Difficult to interpret the lack of Difficult to interpret demonstration of efficacy in study with high such a tiny drop-outs S. aureus No description of randomisation method, allocation concealment and no ITT analysis Unclear method and concealment of randomisation masking Investigator suspect as iodine stains the skin No description of or randomisation process ITT analysis Although described as a parallel study, patients matching for paired were pre-treatment population densities t has also been included completeness) for < 0.01), but p counts between S. aureus colonisation rates fell Of 53 evaluable patients,Of 53 evaluable score severity 58.6 at baseline to 33.2 after 4 from fell in the antifungal group weeks with 60.1 at baseline to 22.9 compared (NS) group in the standard P. ovale but in the antifungal group significantly group treatment not in the standard Of 15 evaluable patients,Of 15 evaluable physicians in the reported an improvement sites ( povidone-treated sites not on the control Bacterial colonisation was significantly but not on the treated reduced site untreated No summary data of differences reported treatments between At the end of 4 weeks’ treatments, At the end of 4 weeks’ in the clinical scores had fallen emollient/antiseptic group than those in the emollient only more group, statistically but these were significant significant was no statistically There in difference at the end of groups the two period treatment in the emollient only drop-outs Five group P. ovale Modified SCORAD (a composite sign and and symptom score) in reduction counts Physician-assessed and after before and photographs counts of colony S. aureus Clinical scores of Clinical scores signs, symptoms and extent and bacterial counts Parallel randomised double-blind trial of duration 6 weeks’ Right/left investigator- blinded comparison study of 1 week duration Parallel randomised double-blind study of 4 weeks’ duration on on their P. ovale S. aureus 60 patients aged 14–53 with atopic eczema years the head and affecting neck of whom 83% were for positive at startculture follow-up 16 volunteers with atopic 16 volunteers eczema aged 12–29 years with similar eczema lesions in each elbow fold skin 15 patients aged 4–34 with moderate-to- years atopic eczema severe with Pityrosporum , Stiefel, UK ™ RCTs that have evaluated antimicrobial or antiseptic agent in atopic eczema. or antiseptic agent antimicrobial RCTs that have evaluated (An additional RCT of the use an antifungal agen After a course of antibiotics, patients were allocated to a combination against active yeasts (a cream containing (a cream yeasts the antifungal miconazole plus hydrocortisone to the twice daily applied head and neck shampoo ketoconazole vs plain twice weekly) and cream hydrocortisone shampoo base (emollients) Daily povidone-iodine Daily solution to one arm vs nil else on opposite side (emollients only) Comparison of a standard proprietary bath emollient (Oilatum) vs the same added with the two antiseptics 6% w/w chloride benzalkonium and 2% triclosan (Oilatum 4 for Plus) used daily not (co-treatments weeks mentioned) (co-treatments) and sample size description and measures results reporting and Olatum Plus et al., et al., ™ 168 172 165 Oilatum Broberg & Broberg Faergemann, 1995 Sweden Hizawa Hizawa 1998 Japan England Holland 1995 44 Study Interventions Study population design, Trial Outcome Main reported Quality of Comment TABLE 6 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 7 Antihistamines and mast cell stabilisers

Antihistamines Ongoing systematic review No statistical pooling has been attempted in this Itching is the central and often most distressing review as there is an ongoing, more detailed feature of atopic eczema. Antihistamines have long Cochrane Skin Group systematic review of anti- been prescribed for atopic eczema in the belief that histamines in atopic eczema which includes the they reduce itching by blocking the action of hista- authors of this report.360 This is likely to be published mine on its receptors in the skin. The role of hista- later in 2000. Although the outcome data in mine in the itch of atopic eczema is unclear, and it Table 8 suggests that some pooling for itch might may only play a small part. Histamine receptors are be possible for most studies, the ongoing Cochrane of two types, named H1 and H2, respectively. Both Skin Group review of antihistamines in atopic eczema types are found in the skin. Most antihistamines that is already encountering difficulty in pooling due to have been tried in atopic eczema are of the H1 type. missing vital information such as baseline data, These H1 antihistamines can be further subdivided type of scale used, and standard errors. into those with a sedating (e.g. chlorpheniramine) and those with a less-sedating action (e.g. cetirizine). Sedative antihistamines Although lack of sedation may be desirable in the Those studies that have evaluated sedating anti- daytime, it is often stated that oral antihistamines histamines against placebo176,182,184,185 do not are only effective in atopic eczema if they are show any evidence of a clear benefit for itch or sedative.25 It is suggested that sedating antihista- global improvements. All the studies are quite mines are effective because of their central sedating small however. effect rather than any action on peripheral hista- 178 mine blockade. H2 antihistamines Similarly, those studies182,184 that have evaluated

Regardless of how antihistamines might work in the benefit of the H2 antihistamine, cimetidine, atopic eczema, it is useful to consider the evidence alone or in combination with H1 drugs have not of whether they help at all. We located 21 RCTs of shown any benefit of the H2 agents, though both antihistamines of various types in the treatment of studies were under-powered to detect even a atopic eczema,173–193 and these are summarised in modest improvement. Tables 7–9. A further study358 was excluded as data on atopic eczema patients were not separated from Less-sedative antihistamines patients with urticaria. Those studies that have included comparative data on less-sedating antihistamines versus Comment placebo177–179,187–190,192 show mixed results. The Quality of studies largest study of 817 children followed-up for Generally, the quality of study reporting was very poor, 18 months as part of the ETAC study,329 has only with some (e.g. Hjorth186 and Foulds & MacKie184) published safety data to date, but the authors are not containing any clinical effective-ness data at all. aware that preliminary data presented at a previous At least eight of the studies used a crossover study meeting (Diepgen T, oral communication, 1999) design, which, as others have noted,359 is perhaps not on SCORAD scores361 between the placebo and the best design in view of potential carry-over and cetirizine groups did not show any differences. period effects. Such effects were only formally tested The full publication of the ETAC atopic eczema for in one study,178 and in the absence of such testing, outcome data is eagerly awaited. The second only comparisons for the first treatment period can largest (n = 187) and relatively well-reported study be evaluated with confidence. Atopic eczema is also by Hanuksela and colleagues190 compared three a very unstable disease, with flares occurring within different doses of cetirizine with placebo. They 24 hours, making it an unsuitable condition for eval- showed a possible benefit with cetirizine, but only uation by crossover design. The clinical usefulness at four times the normal recommended dose and of small but statistically significant changes in mean at the expense of some sedation. The remaining itch scores between treatment groups is also very studies show a mixture of no effect and some difficult to judge from the papers. effect, but need to be interpreted cautiously in 45 Antihistamines and mast cell stabilisers

the absence of baseline data and other missing may also have had an effect. One of the Kimata important data in the reports. studies201 also included oxatomide in both the control and treatment arms so that treatment Studies that have compared different antihistam- effects from his two studies cannot be quanti- ines or doses against each other are very difficult tatively compared. The other two studies provide to interpret in the absence of a clear demonstration estimates which suggest that at 2 weeks, the itch of benefit in placebo-controlled studies. scores decreased to a comparable extent with both DSCG and beclomethasone dipropionate Other systematic reviews (Table 18). The magnitude of change in itch One systematic review on the use of antihistamines scores obtained with those two drugs were some- in atopic eczema has recently been published.362 what higher than the difference seen between That study missed nine of the RCTs identified in DSCG and placebo. this report173–175,180,185–187,192,193 and also evaluated non-randomised studies in their qualitative analysis The study by Moore and colleagues198 also suggests based on study quality. The authors suggested that that SCG was effective in atopic eczema with severity the best-quality evidence did not support a useful scores substantially reduced within 1 month of initia- effect of antihistamines in relieving the itch of tion of therapy. However, the individual symptom atopic eczema. scores are not reported so that quantitative compar- ison with the Kimata studies is not possible. Sodium cromoglycate Nedocromil sodium Sodium cromoglycate (SCG) is used widely in the management of bronchial asthma and allergic Nedocromil sodium, a mast cell stabiliser, is the rhinitis. Its effectiveness is thought to be at least disodium salt of pyranoqiunoline dicarboxylic partly due to inhibition of release of inflammatory acid and is similar to SCG in pharamcological mediators from mast cells following antigen action. Its mode of action prevents the release of encounter.203 The drug has an impressive safety inflammatory mediators from mucosal mast cells, record and as immunological mechanisms are blocking the late cutaneous reactions in mast known to be important in atopic eczema, several cell-dependent allergic reactions. investigators have evaluated its use for this condition. In addition, increased intestinal permeability to Three RCTs213–215 that evaluated nedocromil sodium macromolecules is thought to be one of the pre- in atopic eczema were identified. Two studies213,214 disposing factors to food allergy in children with evaluated nedocromil cream versus placebo cream atopic dermatitis, and orally administered SCG is and the other215 evaluated oral nedocromil thought to reduce intestinal permeability.211 Opinions versus placebo. remain divided over the value of SCG in atopic eczema. We therefore undertook a systematic review Benefits of relevant RCTs.84,194–212 The study by Kemmett and Barnetson213 (abstract only) evaluated topical 4% nedocromil sodium Results and discussion cream versus matching placebo, in 32 atopic A summary of the studies retrieved, their character- eczema patients over a 4-week period. There were istics and the outcomes used are presented in no significant differences between treatment and Tables 10–17. The studies using oral SCG generally control groups as determined by clinical assessment reported little or no beneficial effect for the drug and IgE levels (no data given). Patient-assessed compared with placebo. From those results it is relief of itch, redness and weeping was recorded probably safe to conclude that orally administered but no data were given. SCG is of little value in atopic eczema. The paper by van Bever and Stevens214 evaluated The results of trials of topical disodium cromo- topical 4% nedocromil sodium cream versus glycate (DSCG) are conflicting. Most of the studies vehicle only, in 26 adults and children with that have reported positive effects were from the atopic eczema over a 4-week period. Patients same laboratory84,194,201 and have used solutions of and clinicians could not detect any difference the drug rather than semi-solid formulations. between the two treatments as determined by While differences in product formulation may daily score card for itch, sleep and overall have accounted for the differences in observed severity of skin lesions and clinical examination 46 responses, it is possible that the study populations for severity of skin lesions. Health Technology Assessment 2000; Vol. 4: No. 37

The study by Benton and colleagues215 evaluated period. The eczema was assessed for itch, sleep loss, oral nedocromil sodium 100 mg three times daily erythema, lichenification and overall efficacy of treat- versus placebo, in 22 adults with moderate-to-severe ment. Improvement of itch over baseline on a scale atopic eczema over a 4-week period. Patient diary of 1–3 was 2.40 reduced to 1.20 for ketotifen (p < 0.01) cards for itch, redness and weeping and clinician’s versus 2.30 reduced to 1.60 for placebo (p < 0.05). overall opinion showed no significant differences between active treatment and placebo. Harms Apart from slight drowsiness no other adverse Harms effects were reported. Benton and colleagues performed full blood counts and tests of renal and hepatic function each month Comment to determine any drug toxicity. The authors report no The White and colleagues study217 was prim- abnormalities were found in the laboratory data, and arily evaluating ketotifen for asthma; however, the drug was well tolerated apart from one patient 15 of the children also had eczema. Being who developed persistent diarrhoea, which ceased on a small sub-group the authors conclude the withdrawal of the drug. Van Bever and Stevens report number of patients with eczema was too small 17 episodes of flaring of symptoms, nine were in for meaningful analysis. The method and the nedocromil sodium group. One other patient concealment of randomisation were unclear, reported dryness of skin and another furunculosis. though the study was described as double-blind. Withdrawals or drop-outs were not mentioned. Comment All three studies were randomised but method The Falk study216 showed no appropriate test of and concealment of randomisation was unclear, differences between the two treatments and no all described as double blind. The Kemmett and standard errors were given, therefore the results colleagues study was in abstract form only so little are difficult to interpret. The method and information was available and no data were given concealment of randomisation were unclear, for results. The van Bever and Stevens study did though the study was described as double-blind. not specify whether daily score card was patient- Four dropped out, and there was no intention-to- or doctor-assessed, and no actual data were given. treat analysis. It was unclear how many people were enrolled in the Benton and colleagues study. The results do not show any evidence to support benefit of Topical doxepin cream nedocromil sodium, though the studies were relatively small and over short periods of time. Doxepin is a tricyclic antidepressant drug, which also has powerful antihistamine properties by antagonising both H1 and H2 histamine receptors. Ketotifen On the basis of the putative role of histamine in the itch of atopic eczema and potent antihistamine Ketotifen is a benzocycloheptathiophene with antagonising effects of doxepin, topical preparations antihistaminic and anti-anaphylactic properties. of doxepin have been tried in people with atopic Its action is said to resemble SCG. eczema and other itchy skin conditions.

Benefits Benefits We located two RCTs reporting the use of ketotifen Four RCTs218–221 that evaluated topical doxepin in for atopic eczema216,217 one on adults and one on atopic eczema patients were identified. A further children. The study in children217 evaluated study of weal response in atopic eczema patients ketotifen 1–2 mg twice daily versus placebo on 42 was excluded because no atopic eczema outcomes atopic children with asthma and allergic rhinitis were reported.363 One trial364 was excluded as it was (15 had eczema) for a period of 4 months. Parent- only published in abstract form with few data. assessed diary cards of asthma symptom scores plus Of the remaining four RCTs, two evaluated topical night itch, day itch and redness of skin were the doxepin versus vehicle cream218,219 and the other primary outcome measures. No statistically significant two evaluated the possible additional benefit of beneficial effect of ketotifen was shown in asthma, topical doxepin to treatment with topical corti- allergic rhinitis or eczema. costeroids.220,221 Statistical pooling of the Breneman and colleagues219 and Drake and colleagues221 Falk216 evaluated ketotifen 1 mg twice daily versus plac- studies was not possible because separate data on ebo in 60 adults with atopic eczema over a 3-month atopic eczema were not given in the latter study. 47 Antihistamines and mast cell stabilisers

Pooling was not attempted in the Berberian and stated that there were no significant differences in colleagues220 and Drake and colleagues221 studies severity of atopic eczema between the two treatments because different strengths of topical triamcin- at any point throughout the course of treatment. olone were used. Pruritus severity scores (one of six itching assess- ment methods used in this study) demonstrated The study by Drake and colleagues218 evaluated statistically significant greater improvement in the topical 5% doxepin cream versus vehicle only, doxepin/triamcinolone group at 8 days (p = 0.001), applied four times daily, in 270 patients with though actual data for this and the other pruritus atopic eczema over a 7-day period. Relief of itch outcomes were not given. (as recorded by a physician) was reported in 85% of doxepin and 57% of vehicle-treated patients by Day 7. Harms A statistically significant relief in itch as recorded Transient stinging or burning was commoner in by patients on a 100 mm visual analogue scale doxepin-treated patients (e.g. 16 versus three in (where 0 = no relief and 100 = complete relief) the Drake study). Drowsiness was also a problem was also noted in the doxepin versus vehicle groups (37 for doxepin versus three in the vehicle-treated (68.6 versus 54.6, respectively after 7 days with patients in the Drake study), resulting in 16 drop- baseline of 0 for both groups). Physician-reported outs from the doxepin arm versus three in the eczema severity was also reported to be better in vehicle arm. Somnolence was also noted in four the doxepin group, though no data were given. out of 22 participants in the Drake study.221

The paper by Breneman and colleagues219 is more Comment difficult to asses as the RCT reported within this The quality of reporting in the studies was quite paper included a mixture of 47 patients with atopic good – methods of randomisation (though not eczema and 49 with lichen simplex (another form subsequent concealment of allocation), a description of localised eczema), and results were not presented of blinding and an intention-to-treat analysis were separately. There was no clinically or statistically present in all three studies above. The fact that significant difference in patient-assessed itch relief many patients developed drowsiness and stinging at the end of the 7-day RCT. resulting in differential drop-outs in study arms raises concerns regarding the success of blinding The study by Berberian and colleagues220 evaluated in these studies. All four RCTs were sponsored by the possible additional benefit of adding 5% doxepin the manufacturer and were conducted by the same to commonly used topical steroids in an 8-day study group of US investigators. Two of the above studies of 349 patients with atopic eczema. Four groups suggest that there is some evidence that topical doxe- were randomly allocated to 2.5% hydrocortisone, pin produces some additional relief for itching in 0.1% triamcinolone acetonide, 2.5% hydrocort- the short term (24–48 hours) when compared with isone plus 5% doxepin or 0.1% triamcinolone vehicle. Whether this initial relief is clinically useful acetonide plus 5% doxepin, applied four times daily. is doubtful, particularly when problems of drowsi- At the end of 8 days, the mean visual analogue scale ness are taken into account. These short-term effects value for patient-recorded itch in the doxepin/ on itch become clinically insignificant over a 1- hydrocortisone group versus hydrocortisone group week period. None of the studies have demonstrated was 77.8 and 68.3, respectively (where 100 = complete a clinically useful benefit of doxepin on atopic relief from itching). For the doxepin/triamcino- eczema severity or control even over the very short lone versus triamcinolone groups, the relief scores 1-week assessment periods. The studies have also were 94.9 versus 90.5, respectively (p < 0.05). used outcome measures scales that include itch as Baseline scores were not reported. Statistically a prominent feature, or they have used several significant effects were noted in the groups methods to assess itch, thereby increasing the like- containing the doxepin from Day 1 onwards, but lihood of demonstrating a significant difference the magnitude of these effects diminished with between the groups for itch. Longer-term indepen- each consecutive day. Physicians’ global evaluation dent studies (i.e. at least 6 months) evaluating of eczema severity at the end of the 8 days was not combinations of doxepin plus other commonly clinically or statistically significantly different. used topical agents in atopic eczema are needed.

The Drake and colleagues study221 was mainly a pharmacokinetic study comparing doxepin hydro- Tiacrilast chloride 5% cream alone with doxepin plus 0.025% triamcinolone acetonide in 24 adults for 7 days. Tiacrilast is an important mast cell degranulation 48 Only limited efficacy data were given. The paper inhibitor in in vitro and in animal studies. As mast Health Technology Assessment 2000; Vol. 4: No. 37

cells and their mediators are possibly involved in • There is limited and conflicting RCT evidence atopic eczema, it has been tried in a topical prepar- that less-sedating oral antihistamines have a ation in atopic eczema. One RCT222 compared 3% clinically useful benefit in atopic eczema. tiacrilast in the hydrogel formulation with vehicle • It is possible that any benefit can only be alone in a multicentre study of 37 adults. achieved with doses much higher than is currently recommended. Benefits • The largest and highest quality study of In this right/left comparison study of 28 days, a antihistamines in 817 children followed lesion of atopic eczema was rated as responding for 18 months has yet to report its outcome if the sum of its rating (a composite scale of signs data on atopic eczema severity. and itching) decreased by at least 33% from • The current RCT evidence does not support baseline to the end of treatment. Of 32 evaluable the routine use of antihistamines in atopic patients, 78% were noted to respond on the active eczema. drug versus 75% compared with a vehicle (p = 0.614). • There is no evidence to support the use of oral Median changes of efficacy parameters from baseline SCG in atopic eczema. to end of treatment were also very similar between • The results of trials of topical DSCG are the two groups. conflicting. • Most of the studies that reported positive results Harms are from the same study laboratory and need to Treatment was well tolerated except for one patient be repeated elsewhere. who experienced burning at the site of drug appli- • There is no RCT evidence to support the cation (site not specified). use of nedocromil sodium treatment in atopic eczema. Comment • There is no RCT evidence that shows any This is one of the few RCTs in atopic eczema to benefit to oral ketotifen in atopic eczema. pre-specify a measure of ‘success’ of its complex • Two RCTs suggest that topical doxepin might efficacy ratings scale. Method of randomisation produce some additional relief of itching was unclear and no intention-to-treat analysis was compared with vehicle alone in the first 48 hours. performed. Although this study was under-powered, • None of the studies of topical doxepin have the complete lack of difference between active and demonstrated a clinically useful benefit on vehicle argues against a large treatment effect. eczema severity. • Drowsiness may occur with topical doxepin. • All of the studies of topical doxepin have Summary of antihistamines been conducted by the same research team – and mast cell stabilisers sponsored by the manufacturer. • Longer-term independent RCTs of topical • There is no RCT evidence to suggest that doxepin are needed. sedating oral antihistamines have a clinically • There is no evidence to support the benefit of useful benefit in atopic eczema. topical tiacrilast in atopic eczema.

49 Antihistamines and mast cell stabilisers continued One loss to follow-up Two personal reasons Two * Five Four active,Four one placebo 51 total effects, 20 adverse 19 non- compliers 37 total but unclear how in atopic many eczemagroup drop-outs Emollients * None butyrate and aqueous cream 1% hydrocortisone Ichthammol + emulsifier + Ichthammol + emulsifier 25 mg promethazine hydrochloride * 0.1% betamethasone 1 Placebo steroid Topical Placebo Betamethasone valerate 0.1% b.d. Placebo 0.05% clobetasone daily Twice Placebo Emollients Placebo Placebo H Placebo Placebo ointment Bland greasy 1 + placebo 1 Terfenadine 60 mg b.d. Terfenadine alclometasone propionate (0.1%) ointment b.d. Acrivastine 8 mg t.d.s. vs 60 mg t.d.s. Terfenadine Three different doses of different Three cetirizine 10 mg, 20 mg and 40 mg daily vs Cimetidine + H Azelastine 4 mg vs Cetirizine 10 mg Cimetidine + placebo vs H Sedative Cimetidine + chlorpheniramine vs Chlorpheniramine + Placebo vs Placebo + placebo with history of contact urticaria diagnosis of atopic eczema severe severe pruritus severe eczema of atopic eczema 2 weeks Atopic eczema * 17–67 2 weeks Moderate to 28 11–67 1 week Stable 120 mg b.d. Terfenadine Four: to comply failure 30 64 7–? 6 weeks Mild to severe 60 mg b.d. Terfenadine + 49 16–58 2 weeks Clinical 178 18+ 4 weeks Moderate to 74 with atopic eczema 244 total including urticaria 21 14–2918 3 x 2 weeks atopic Life-long 14–43 3 x 4 weeks history 3-year patients (years) Crossover RCT Crossover RCT Parallel RCT Parallel RCT Parallel RCT Parallel RCT Multiple crossover RCT Multiple crossover RCT 186 et al., Patient characteristics and interventionsPatient of included studies of antihistamines et al., et al., et al., et al., 178 192 179 190 187 184 182 Study Design No. of Age Duration Severity Treatment Comparator Co-treatments and Withdrawals Berth-Jones & Graham-Brown, 1989 Hjorth, 1988 (Japanese translation) Hamada 1996 1989 Doherty 1993 Hannuksela Hannuksela Frosch Frosch 1984 Henz 1998 50 & MacKie,Foulds 1981 TABLE 7 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued * None * * * 11 One One voluntary withdrawal to meet entry failure Ten criteria or report for follow-up Unclear 15 11 Nine drop-outs White vaseline and topical hydrocortisone * * * specified Lubriderm lubricating cream Mild topical steroid not specified White vaseline Placebo t.d.s. but not treatment Topical Ketotifen 2mg/day Placebo but not specified Yes Cyproheptadine 0.25 mg/kg/day Placebo Emollients Placebo but Routine topical treatment Placebo Cetirizine 10 mg/day Hydroxyzine 0.7 mg/kg 0.07mg/kg/day and 0.13mg/kg/day azelastine hydrochloride Trimeprazine tartrate 20 mg Trimeprazine maleate 50 mg Trimipramine LN2974 15 mg 10 mg loratadine o.d. placebo b.d. t.d.s. 25 mg hydroxyzine hydrochloride) 4 mg/day and 4 mg/day hydrochloride) 2 mg/day Hydroxyzine 1.25 mg/kg/day Hydroxyzine Loratadine 10 mg 30 for Cetirizine 5 mg/day kg and under 30 kg over for 10 mg/day loratadine 10 mg/day 1.4 mg/kg Hydroxyzine hydrochloride) 0.017 /kg/day 0.017 /kg/day hydrochloride) Severe atopic Severe eczema atopic eczema * exacerbations of atopic eczema severe Rajka moderate severity widespread 4 weeks 10 days Long standing * 6–? 4 weeks Mild to severe E-0659 (azelastine 18–65 1 week 1–15 4 weeks Mild to severe E-0659 (azelastine * * 169 GIR/ GUR 179 OSR 41 out of 59 20 2–1616 1 week 19–3723 Acute 12 weeks 6–12 Moderate- 8 weeks118 Hanifin and 12–6512 2 weeks 23–38 At least 3 nights over 12 1–14 4 days Severe 10 157 GIR 168 OSR 159 GUR patients (years) Parallel RCT Parallel RCT Parallel RCT Six consecutive crossover RCTs Parallel RCT Parallel RCT Unclear if parallel or crossover RCT Crossover RCT Multiple crossover RCT Parallel RCT Patient characteristics and interventionsPatient of included studies of antihistamines 183 et al., et al., et al., et al., 193 174 et al., et al., et al., 188 189 176 185 191 180 181 Klein & Galant, 1980 (Japanese translation) Monroe, 1992 Savin 1979 Patel 1997 Savin Savin 1986 Ishibashi 1989(b) Langeland 1994 La Rosa 1994 Simons, 1984 Study Design No. of Age Duration Severity Treatment Comparator Co-treatments and Withdrawals Ishibashi 1989(a) (Japanese translation) 51 TABLE 7 contd TABLE Antihistamines and mast cell stabilisers Eight total (six on on and two hydroxyzine Astemizole treatment) None 99 drop-outs Emollients only Three active Three treatments Placebo 1% hydrocortisone Placebo but no details given Yes three divided doses three in 10 mg daily Terfenadine divided doses two vs in one Astemizole 5 mg daily dose Terfenadine 60 mg b.d. Terfenadine Clemastine 2 mg b.d. Cetirizine 0.25 mg/kg b.d. atopic eczema with family history 52 2–6 4 weeks Not specified in 25 mg daily Hydroxyzine 25 17–42 3 days Persistent 817 12–24 18 months Atopic eczema patients (years) Parallel RCT Crossover RCT Parallel RCT Patient characteristics and interventionsPatient of included studies of antihistamines 175 et al., et al., 173 177 No data GIR, rating; improvement general OSR, rating; safety overall GUR, usefulness rating general b.d., twice daily t.d.s., times daily three * Study Design No. of Age Duration Severity Treatment Comparator Co-treatments and Withdrawals (Colombia translated) Zuluaga de Cadena 1989 Wahlgren Wahlgren 1990 52 Simons, 1999 TABLE 7 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 % body surface area scratching; 181 et al., global global assessment named (if severity severity (method modified Physician Patient Area Scale assesssment assessment used) specify) scratching; Savin 185

Patient sleep loss et al.,

Doctor itch Patient itch

Induration

Infiltration

Crusts

Inflammation

Oedema number and size of hives or lesions;number and size Savin

Oozing/weeping 176

Pustules/papules

Vesiculation

Exudation

Fissuring hives, macules, plaques; Monroe, Cracking 191

Lichenification

Scaling

Xerosis

Dryness whealing; Klein & Galant, 187

Excoriation et al., Purulence Safety study:Safety and serious events drop-outs Erythema also desquamation and extent of eczema 173 184 190 178 188 177 impetiginisation; Henz 191 et al., 179 192 189 et al., 183 182 1993 182 187 185 181 1994 180 1990 1989 1989(a) 1989(b) 1996 1994 176 1984 175 1984 186 et al., et al., 1998 Outcome measures signs and symptoms of antihistamines Outcome measures 1979 1986 1997 et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., 173 Study Foulds & MacKie,Foulds 1981 Zuluaga de Cadena Berth-Jones & Graham-Brown, 1989 Doherty Frosch Hamada Hannuksela Henz Hjorth, 1988 Ishibashi Ishibashi Klein & Galant, 1980 Langeland La Rosa Monroe, 1992 Patel Savin Savin Simons Simons, 1999 Wahlgren 1989 Note: Frosch Zuluaga de Cadena 53 TABLE 8 TABLE Antihistamines and mast cell stabilisers continued -value for statistical comparisons -value for p Method and concealment of randomisation unclear, study described as double-blind.Visual for given analogue data only 7.Day active, (four drop-outs Five one placebo), no ITT analysis. Unclear what was being assessed and examination of the skin’ ‘careful meant by described as double-blind. to failure for withdrawals Four comply, not clear at which point and in initial arm. No ITT analysis. in effect to detect carry-over power Low 20 patients.only form. No data in graphical First and last double separately.Terfenadine period data not presented normal dose Randomisation was conducted according to a Latin square, Randomisation was conducted according study described as double-blind. Baseline itch not given, unable to calculate change.therefore errors No standard given. drop-outs, Missing baseline data.Two no ITT analysis out carried Method and concealment of randomisation unclear.A high rate of 51,drop-out sedation) and (mainly side-effects 20 for 19 non-compliers, specify drug group. doesn’t No ITT out. carried analysis benefit of cetirizine when used Possible times normal dose,at four but at the expense of sedation than placebo. more itching significantly Neither drug reduced atopic eczema patients, for Statistics not given no description of what constituted a response, placebo looks very impressive, in atopic eczema patients. no difference clearly rate of 37,High drop-out out carried no ITT analysis Used different topical steroids in each intervention and no topical steroids Used different oral placebo. No ITT Method and concealment of randomisation unclear, study described as double-blind. one loss to follow-up, Only no out. carried ITT analysis clinical for No actual data given outcomes – only No outcome data given and no information whatsoever on whatsoever and no information No outcome data given placebo response. and concealment of random- Method isation unclear, study described as double-blind. Unclear if or withdrawals.Author drop-outs any since deceased 2 and H 1 receptor antagonist receptor 2 receptor antagonist commonly used in commonly antagonist receptor 1 Acrivastine and terfenadine can partiallyAcrivastine and terfenadine relieve itching in atopic eczema There was no benefit from terfenadine was no benefit from There Method and concealment of randomisation unclear, study young adults with severe chronic atopic eczema chronic adults with severe young to the H receptor antagonists is of no benefit in the antagonists receptor of atopic eczema treatment The combined administration of H was partly The sedation observed probably pruritus relief, for responsible authors suggest responsible that cetirizine has other properties skin lesion healing for efficacy of The data underline the low antihistamines in atopic eczema is if value in some patients with Terfenadine atopic eczema and a history of contact urticaria Combination of terfenadine ingestion and Combination of terfenadine is more topical alclometasone application only than betamethasone application effective This study does not demonstrate any significant This study does not demonstrate any an H advantage in adding p = 0.005).This p = 0.026) and p < 0.001) and night pruritus (0.01 p = 0.021). Both acrivastine ( p = 0.037) improved the patient’s condition significantly more than more condition significantly the patient’s = 0.037) improved p Acrivastine significantly reduced itching when compared with placebo according itching when compared reduced Acrivastine significantly assessment ( to the doctor’s ( terfenadine placebo according to the patient’s assessment of the degree of benefit obtained. assessment of the degree to the patient’s placebo according treatments active the two between found were No significant differences There was no evidence of any difference between terfenadine and placebo.The terfenadine between difference of any was no evidence There of errors (and standard of treatment the last 4 days itch over for mean scores the phase and 25.13 (±5.1) for the terfenadine 23.95 (±4.9) for the means) were placebo phase.There when or period-effect of carry-over was no evidence assessed were pruritus scores improvement was significantly more pronounced for cetirizine 40 mg compared for pronounced more was significantly improvement with placebo Analysis of cimetidine plus chlorpheniramine results for weeks 2, weeks for of cimetidine plus chlorpheniramine results Analysis 3 and 4 for with chlorpheniramine and night-time patient-assessed itch compared both day- significant difference any and placebo failed to show in patient-assessed groups between was a non-significant difference There pruritus intensity at baseline.All ( significantly improved groups was 36.4%, global score rate based on physician’s % response Mean overall 25.0% and 27.3% in the azelastine, cetirizine and placebo groups, respectively. Baseline not were of atopic eczema patients in each group data and exact numbers stated. and 2.2 to 1.4 in the cetirizine group from dropped Mean itching score graphs) (estimated from 2.2 to 1.2 in both azelastine and placebo groups from 52% of patients, of itch in approximately severity reduced 34% Terfenadine of itch. severity reported no change and 14% reported increased No data given placebo for Although it was found that there was a significant difference between individual between was a significant difference that there Although it was found pruritus ( patient-assessed day patients for ‘improved’ significantly. improved and scratch marks were Itching score Physician compared group was 89.3% in antihistamine and steroid improved’ ‘markedly and group only with 50% in the topical steroid < 0.025) there was no difference between the treatment periods the treatment between was no difference < 0.025) there 190 184 179 192 182 1993 187 1989 1996 1984 186 178 et al., 1998 Results et al., et al., et al., et al., Study Main reported results Authors’ conclusions Comment and quality Doherty Berth-Jones & Graham- Brown, 1989 Hamada Henz Hjorth, 1988 Hannuksela Hannuksela Frosch Frosch 54 & MacKie,Foulds 1981 TABLE 9 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Study excludes non-responders before study started but before Study excludes non-responders report suggests ITT but fails to many.The not told how carry it out. Unclear if either drug is of benefit in absence of placebo group. Method and concealment of randomisation unclear, study described as double-blind Complex design, crossovers. six consecutive Changes in all small differences.VAS period or No data for pruritus on shown. effects carry over Method and concealment of randomisation unclear, study described as double-blind (block randomised) to antihistamines. Patients excluded if unresponsive No baseline values given. Method and concealment of randomisation unclear, study described as double-blind. short study at 1 week Very Method and concealment of randomisation unclear, study described as double-blind. (voluntary one drop-out Only withdrawal). in those on active Higher baseline scores to the means could suggest that regression treatments partly results amount for study.Unclear if parallel or crossover Length of study unclear. and concealment of randomisation unclear, Method study described as double-blind.Withdrawals or drop-outs not mentioned in this study. Unclear if the changes in sleep eczema pattern helped the patient’s Unstable data shown on a graph with inflationary on a graph Unstable data shown % scale but no actual data given. Method and concealment of randomisation unclear, study described as double-blind. Not or withdrawals drop-outs clear if any In the management of symptoms atopic eczema, as loratadine is as effective cetirizine and is less sedating Loratadine may be tried as an adjuvant therapy Loratadine may and moderate in the management of severe atopic eczema, in patients complaining of pruritus Loratadine demonstrates a significant in atopic eczema antipruritic effect The results of this preliminary study suggest that The results pruritus and control cetirizine can effectively suffering other cutaneous symptoms in children atopic eczema without noticeable adverse from effects Both trimeprazine and trimipramine sleep becomes less broken, with a lessening of the and in stage 1 sleep,time awake and that these actions, be helpful to some patients, which may in the associated with a modest reduction were and length of scratching bouts number No translated data available No translated data available This study suggests that hydroxyzine is more This study suggests that hydroxyzine the for than cyproheptadine effective management of pruritus associated with atopic eczema in children No translated data available No translated data available < 0.001) than the percentage improvement for improvement < 0.001) than the percentage p > 0.05) after 8 weeks treatment (estimated from graph) (estimated from treatment > 0.05) after 8 weeks p Loratadine reduced patients perceived severity of their overall condition of their overall severity patients perceived Loratadine reduced 20.8% at endpoint.by Incidence of somnolence was 9% with cetirizine and 3% with loratadine The study detected a significant effect of loratadine,The study detected a significant effect with placebo, as compared of rash and night severity on patient-assessed pruritus during the day with 57% in the 14 patients treated decreased pruritus score The daily loratadine, with hydroxyzine, 38% in the 14 patients treated and 33% in the 13 placebo patients Patient diary card scores showed a statistically significant decrease in erythema significant decrease a statistically showed Patient diary scores card and other cutaneous symptoms such as lichenification, in the cetirizine group. cetirizine reduced of 230 for baseline total mean global score over Improvement treatment,to 155 after 8 weeks to 180 placebo reduced and 205 baseline for ( of scratching bout beginning in the likelihood Neither of the drugs altered stage of sleep. or in any wakefulness However, both drugs, especially trimeprazine, made sleep less broken, time spent in stage 1 of and the reduced amount of scratching in the overall a modest reduction sleep accounted for during the night No difference in final general improvement rating or general usefulness in final general improvement No difference groups.The of among the three and usefulness in the treatment effectiveness groups.There the three similar for was a considered atopic eczema were and 2 mg/day the 4 mg/day rating between safety in overall significant difference than in the 4 mg/day groups.The group rating was higher in the 2 mg/day safety the between no significant difference rating showed safety group.The overall groups and ketotifen or the 2 mg/day groups and ketotifen 4 mg/day The group receiving hydroxyzine had a daytime percentage improvement of improvement percentage had a daytime hydroxyzine receiving The group 32.14 ± 4.98 (mean ± week, the entire their baseline pruritus for SEM) over ( greater which is significantly of 6.21 ± group the cyproheptadine 4.90 No significant difference in general improvement rating, in general improvement No significant difference rating severity overall dose groups.Aand general usefulness rating among the three significant in the signs dose group among three ratio was found in improvement difference if itch, papules, erythema and lichenification 193 174 188 191 Results 189 180 1994 185 1989(b) 1989(a) 1994 176 1997 1979 et al., et al., et al., et al., et al., et al., Patel Monroe, 1992 Langeland Savin La Rosa Study Main reported results Authors’ conclusions Comment and quality Ishibashi Klein & Galant, 1980 (Japanese translation) (Japanese Ishibashi translation) (Japanese 55 TABLE 9 contd TABLE Antihistamines and mast cell stabilisers Outcome measures and their combination were quite and their combination were Outcome measures complex. Method and concealment of randomisation unclear. Study described as single (investigative)-blind. No ITT analysis. and no placebo group Small numbers Very short 3 days. trial of only Very Method and concealment of randomisation unclear, study described as double blind. No or drop-outs.withdrawals Underpowered No actual data given. Method and concealment of randomisation unclear, study described as double-blind. or drop-outs withdrawals Unclear if any Good description of randomisation and blinding.Well reported study. 99 drop-outs, out. carried no ITT analysis awaited. Clinical efficacy outcome data eagerly This trial was buried in the middle of a case-series.This trial was buried in the middle Only rather than at end of treatment mean score presented mean change in score. not Itch data and baseline scores given. Sample size unclear. of randomisation was after Point the single dose study. Method and concealment of randomisation unclear, study described as double blind. or drop-outs. withdrawals Unclear of any Far too small a study to establish equivalence effects antagonist 1 antagonist ever antagonist 1 Antihistamines may be beneficial in atopic Antihistamines may a prolonged eczema with astemizole conferring benefit The antipruritic effect of 3 days of treatment of 3 days The antipruritic effect and clemastine (non-sedative) with terfenadine with that found from did not differ (sedative) placebo No significant suppression of scratching,No significant suppression as meters, limb movement by measured or of itching,VASs, could be on recorded demonstrated conducted in children and the longest of conducted in children H study of any safety prospective Hydroxyzine 0.7 mg/kg three times daily was as times daily 0.7 mg/kg three Hydroxyzine times 1.4 mg/kg three as hydroxyzine effective pruritus and promoting in relieving daily of the skin lesions resolution conducted in any age group conducted in any The safety of cetirizine has been confirmed in The safety study,this prospective the largest and longest randomised, double-blind, placebo-controlled, H of any investigation safety 0.05) ≤ = 0.737); of these, only p p = 0.421). (9.3%) receiving reported in 37 children were Serious events = 0.189). slightly, Fatigue and insomnia were significantly, but not statistically p p At the end of the 4-week evaluation period, evaluation At the end of 4-week eight out of 15 patients on with eight out of 17 patients on astemizole and six compared terfenadine in itch. had improvement 8 patients on hydroxyzine was Global improvement noticed in 14 out of 15 cases on terfenadine, 15 out of 17 cases on astemizole out eight cases on hydroxyzine.and seven in other outcome Improvements groups. all three was similar between measures Other laboratory were measures also recorded No significant difference in itch intensity between the three treatment periods treatment the three in itch intensity between No significant difference was detected with Pain-Track, in time awake difference any nor was there without pruritus. during each No significant changes in itch magnitude appeared 0–3) period (Days No significant difference was detected between the limb movement times on the limb movement was detected between No significant difference with LN2974.The treatment the mean placebo and on active between difference of the visual analogue assessment itching on placebo and LN2974 scores LN2974 statistical significance although tending to favour did not reach The scores for atopic eczema severity and distribution were significantly reduced significantly and distribution were atopic eczema severity for The scores ( both doses of hydroxyzine for at the end of treatment During the 18 month long study, with cetirizine and treated 48 children only ( reason’ any ‘for out with placebo dropped 51 treated 11 and 15 children, respectively, out because of symptoms or events dropped ( placebo. (13.6%) receiving cetirizine and in 54 children Hospitalisations were placebo cetirizine and in 47 receiving receiving reported in 36 children ( raised in cetirizine group. cetirizine and in somnolence between difference No placebo. No efficacy data given 177 et al., Results 183 181 1990 1984 175 1986 et al., et al., et al., 173 Zuluaga de Cadena 1989 (Colombia) translated Wahlgren Wahlgren Savin Savin Study Main reported results Authors’ conclusions Comment and quality SEM, of the mean;VAS, error standard scale visual analogue Simons 56 Simons, 1999 TABLE 9 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 * * None 18 Eight None Six Three (one due to adverse Three effects) * One due to systemic cortico-steroids drop-outs hydrocortisone butyrate hydrocortisone * antihistamines Antibiotics if infected minimum, allowed no steroids hydrocortisone butyrate) hydrocortisone emollients antihistamines Placebo Placebo 1% hydrocortisone Placebo All stopped Placebo and Hydrocortisone Placebo 1% hydrocortisone Placebo cream, Moisture oil bath and Placebo to a kept Other treatment Placebo 1% hydrocortisone Placebo (Locoidon, Corticosteroids Placebo Emollients, corticosteroids, Oral DSCG 6 mg q.d.s. 30–40 Oral cromolyn mg/kg/day FPL 57787 (chromone acid) 18 mg q.d.s. carboxylic FPL 57787 6 mg q.d.s. 3 weeks 200 mg q.d.s. 3 weeks for Oral DSCG 200 mg q.d.s (adults) 100 mg q.d.s. (children) Oral aqueous solution SCG FPL 57787 18 mg q.d.s. Oral DSCG 100–120 q.d.s. mg/kg/day * * * * widespread to require continuous treatment * * 14 18+ 6 weeks 28 19–48 6 weeks 29 3–1235 6 weeks 15–42 Chronic 2 weeks Oral SCG 100 mg q.d.s. for 10 3–15 1 week 24 4–37 6 weeks Severe 31 0.5–10 8 weeks enough Severe 23 18–41 6 weeks 83 0.1–1.5 4 weeks 29 2–10 4 weeks severity Varying Oral SCG 100 mg q.d.s. patients (years) Parallel, double-blind, randomised Parallel, double- blind, randomised Crossover, double-blind, randomised, no ITT Crossover, double-blind, randomised, no ITT Crossover, double- blind, randomised Crossover, double-blind, randomised Crossover, double-blind, randomised, ITT Crossover, double-blind, randomised Parallel, double-blind, randomised Crossover, double- blind, randomised ,Yamanouchi, UK ™ 195 210 Design, patient characteristics and interventions of included studies: SCG oral = Locoid et al., et al., et al., ™ et al., et al., 208 206 197 204 207 205 211 203 Graham 1984 Lindskov & Lindskov Knedsen, 1983 Larsen & Larsen, 1979 Birkeland Birkeland 1981 Burks & Sampson, 1988 Kavli & Larsen, Kavli 1981 Study Design No. of Age Duration Severity Treatment Comparator Co-treatments and Withdrawals Locoidon q.d.s., times daily four Businco 1986 Larsen & Jacobsen, 1980 Ventura Ventura 1996 Atherton 1982 57 TABLE 10 TABLE Antihistamines and mast cell stabilisers Five drop-outs no data drop-outs Five given * Seven withdrew:Seven three SCG, placebo four 20: ineffective treatment Five * Three: SCG one from lack of compliance group placebo group from two deterioration of eczema Four: placebo from two group: from two ineffective group:active use incorrect of treatment None drop-outs * Terfenadine (adults) Terfenadine Clemastine (children) hydrocortisone antihistamines emollients and potent topical steroids Oxatomide Placebo None Betnovate None Placebo 1% Hydrocortisone Placebo None Placebo 0.1% triamcinolone, 1% Vehicle Antihistamines if required Placebo 1% hydrocortisone Placebo (water solution plus oxatomide) Placebo None DSCG 10% in white soft paraffin SCG oil in water cream Placebo Topical SCG (concentration Topical not given 4% SCG paraffin Cromolyn sodium inhalation Cromolyn solution 0.21% 10% SCG w/w in white soft paraffin SCG 4% oil in water SCG nebulizer plus oxatomide (1.5 mg/kg/day) Cromolyn nebulizer solution Cromolyn severe * * * severe severe * severe severe 11 1–1.5 4 weeks Moderate to 36 1–14 12 weeks 43 5.2–14.6 2 weeks 46 16–65 12 weeks 44 0.42–14 12 weeks Chronic 10% SCG in white soft 26 0.5–18 4 weeks Moderate to 22 2–16 6 weeks Moderate to 53 4.1–14.2 4 weeks Moderate to 40 1–18 12 weeks 45 0.8–3 4 weeks Moderate to patients (years) Right/left comparison, double-blind, randomised Parallel, double- blind, randomised Parallel, double- blind, randomised Parallel, double- blind, randomised Parallel, double- blind, randomised Crossover, randomised, not blinded Parallel, double- blind, randomised Parallel, double- blind, randomised Parallel, double- blind, randomised Parallel, double- blind, randomised 201 199 Design, patient characteristics and interventions of included studies: topical SCG 196 202 et al., et al., et al., 1985 212 84 198 200 209 194 Thirumoorthy & Thirumoorthy Greaves, 1978 Pike & Atherton, & Pike 1988 Study Design No. of Age Duration Severity Treatment Comparator Co-treatments and Withdrawals Hiratsuka 1996 Ariyanayagum Ariyanayagum et al., Haider, 1977 Moore Moore 1998 Croner Croner 1981 Kimata & Hiratsuka, 1994 Kjellman & Gustafsson, 1986 58 Kimata & Igarashi, 1990 TABLE 11 TABLE Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 12 Outcome measures: oral SCG

Study Outcome measure Scale

Atherton et al., Parent diary card for day-time itch and night-time sleep loss 0–3 scale 1982203 Clinical evaluations 20 areas of skin surface for erythema, vesiculation and/or crusting, excoriation and lichenification At end of study general well-being and severity of eczema +2 to –2 (very much better to very much worse)

Birkeland et al., Clinical assessments of 14 regions for colour, scaling, infiltration, itching of the three most active 1–3 scale (1 = none, 2 = slight, 1981208 eczematous regions 3 = marked) Total serum IgE and reduction in disease activity

Burks & Parent symptom diary cards: rash distribution, pruritus, urticaria 0–3 scale Sampson, 1988207

Businco et al., Clinician-assessed body divided into ten areas for redness, weeping, vesiculation, crusting, 0–3 score total body score 60, 1986205 excoriations, lichenification max score for all parameters 240 Parent-assessed diary card for itching and sleep disturbance due to itching, weeping, redness of skin 0–3 scale max score 12

Graham et al., Patient diary card for pruritus, sleeplessness, severity and area of eczema 0–4 scale 1984197 Clinical assessment on a homunculus for severity and area. 0–4 scale Dryness and excoriation also noted

Kavli & Larsen, Clinician-assessed disease extent and severity. 1981204 Patient diary cards for itching and sleep loss and severity for lichenification, excoriation, redness 0–3 scale (none-severe)

Larsen & Larsen, Scaling, colour, lichenification, general assessment of the eczema and severity of itch * 1979206

Larsen & Clinician-assessed dryness, lichenification, excoriation 0–3 scale Jacobsen, 1980195

Lindskov & Clinician-assessed lichenification, eczema, and overall disease Scales 0–2, 0–3 and 0–4, Knudsen, 1983210 respectively Patient- or parent-assessed day- and night-time itching and general severity of eczema 0–5mm VAS

Ventura et al., Clinician-assessed erythema, exudation, lichenification, eczema extension and itch * 1996211 * No scale

59 Antihistamines and mast cell stabilisers

TABLE 13 Outcome measures: topical SCG

Study Outcome measure Scale

Ariyanayagam Patient diary card for pruritus, sleeplessness, severity of eczema and use of concomitant 0–3 point scale patient-assessed et al., 1985202 therapy signs and symptoms Severity assessed on erythema, lichenification, vesiculation, dryness and excoriation over four 0–6 point scale physician-assessed main areas over four main areas for signs

Croner et al., Patient diary cards for itching (day and night), sleep disturbance and severity of eczema on face, 0–3 score where 0 = no 1981200 trunk, arms and legs symptoms and 3 = severe symptoms

Haider, 1977196 Physician-assessed inflammation, lichenification and cracking of the arms and legs 0–2 point scale physician-assessed signs over two areas Patient diary card for severity of itching (day and night) and sleep disturbance 0–3 point scale patient-assessed itch and sleep loss

Hiratsuka et al., Physician-assessed inflammation, lichenification, cracking on 15 body areas 0–2 point scale in ascending order 199684 of severity Patient diary cards for itching and sleep disturbance 0–3 point scale patient-assessed diary cards

Kimata & Signs: inflammation, lichenification and cracking assessed on four body areas max score 24, 0–8 0–2 point scale in ascending order Igarashi, 1990194 mild, 9–16 moderate, 17–24 severe (only scores > 9 entered) of severity Symptoms: sleep and itching patient-assessed record card 0–3 scale

Kimata & Physician-assessed signs lichenification, inflammation and cracking on 15 body areas, 0–2 scale Hiratsuka, 1994201 max. score = 30 Patient-assessed symptoms itch and sleep loss on a diary card 0–3 scale

Kjellman & Patient diary cards for itch, sleep disturbance and overall severity (redness, vesiculation and 0–3 scale Gustafsson, crusting, excoriation, lichenification) 1986209

Moore et al., Physician-assessed erythema, vesiculation, crusting and cracking, scaling, and lichenification in 0–3 scale (none to severe) 1998198 12 body areas, (Rule of Nines) max. per area = 15

Pike & Atherton, Diary charts recording pruritus, sleep disturbance by physician Body score chart 1988212

Thirumoorthy & Patient diary card for itching * Greaves, 1978199 Clinical responses of the two sides assessed weekly by clinician and patient *

* No scale

60 Health Technology Assessment 2000; Vol. 4: No. 37 VAS RoNAA RoNAA global global assessment named (if global global assessment named (if severity severity (method modified severity severity (method modified Physician Patient Area Scale Physician Patient Area Scale assesssment assessment used) specify) assesssment assessment used) specify)

Sleep loss Sleep loss Itch Itch

Induration Induration

Infiltration Infiltration

Crusts Crusts

Inflammation Inflammation Eczema extention;Eczema RoNNA, assessment Rule of Nines area ¶ Oozing Oozing

Pustules/papules Eczema; Pustules/papules § Vesiculation Vesiculation Colour; Exudation ‡ Exudation/weeping

Fissuring Fissuring

Cracking Cracking Lichenification Lichenification

Scaling Scaling

Xerosis Xerosis

Dryness Dryness

Excoriation Excoriation

Purulence Purulence Lumps, redness, weeping, vesiculation and crusting together;

Erythema Erythema † 199 209 210 210§ 202 195 207* 194 206‡ 84 203 208 204 1985 197 205† 211¶ 200 198 1996 1982 1981 1984 1986 et al., 1996 1981 1998 Outcome measures: SCG – signs and symptoms oral Outcome measures: topical SCG – signs and symptoms 196 et al., et al., et al., et al., et al., et al., et al., et al., Rash distribution and urticaria; Study Study Atherton Birkeland Burks & Sampson, 1988 Businco Graham & Larsen,Kavli 1981 Larsen & Larsen, 1979 Larsen & Jacobsen, 1980 & Knudsen,Lindskov 1983 Ventura * Ariyanayagam Croner Haider, 1977 Hiratsuka Kimata & Igarashi, 1990 Kimata & Hiratsuka, 1994 Kjellman & Gustafsson, 1986 Moore & Greaves,Thirumoorthy 1978 61 TABLE 14 TABLE 15 TABLE Antihistamines and mast cell stabilisers

TABLE 16 Results of studies of oral treatments

Study Main reported results Authors’ conclusions Quality

Atherton et al., No difference detected at 4 weeks The results do not confirm previous Small and short-term study. Randomisation, 1982203 between the effects of DSCG and placebo anecdotal reports of effectiveness of blinding and 4-week washout period appear SCG in children with atopic eczema adequate

Birkeland et al., No significant changes were found No benefit could be proven for the drug Method and concealment of randomisation 1981208 between the severe and mild atopic in the clinical investigation or any change unclear, study described as double-blind. eczema for number of regions involved in the immunological tests during the trial. Unclear whether any drop-outs at the first visit and reduction in disease There was no demonstrable differences activity during the trial. Serum IgE in in the applied immunoparameters between relation to T and B cells shows non- mild and severe atopic dermatitis significant differences in the figures in the severe and mild atopic dermatitis for T cells and B cells.

Burks & SCG (40 mg/kg/day) did not protect Oral SCG is of no benefit in the treatment Only ten children were studied and eight Sampson, 1988207 against food-induced symptoms in of children with atopic eczema and reacted to food challenge in this crossover patients with atopic eczema and food hypersensitivity study egg hypersensitivity

Businco et al., Increase in symptom score higher when SCG seems to have reduced exacerbations Randomisation, blinding and 2-week 1986205 patients were given DSCG than placebo of atopic eczema caused by food allergens washout period appear adequate. Small and short-term study. Patients had history of food hypersensitivity

Graham et al., Mean eczema scores for severity and area Tailored diets were of value but SCG did Randomisation, blinding and 2-week 1984197 not different between groups receiving not produce a significant additional effect washout period appear adequate. Small and DSCG and placebo short-term study. Patients had history of food hypersensitivity

Kavli & Larsen, A significant reduction in patient-assessed Systemic chromone derivatives relieve Method and concealment of randomisation 1981204 itch was found for chromone carboxylic certain symptoms in patients with atopic unclear, study described as double-blind. acid in the placebo, washout, chromone dermatitis. However, statistically significant Over half enrolled patients dropped out group (p < 0.05) after 6 weeks’ treatment. results in favour of chromone carboxylic (n = 18) mainly due to increased severity of Significant differences were found for acid were obtained only in the group that atopic eczema or ineffective treatment, no lichenification, excoriation and redness in started on placebo and only after the first ITT analysis carried out the placebo, washout, chromone group for 3 weeks of treatment.This may be due in clinically assessed signs (p = 0.05). No part to the reduced sample at 6 weeks, and significant differences were found between possibly also to an increasing awareness chromone followed by placebo groups at during the trial on the part of the patients 3 weeks treatment of antigen avoidance

Larsen & Larsen, No statistically significant differences in the Unable to prove the new chromone drug Method and concealment of randomisation 1979206 clinician’s scores for any parameter to be effective in systemic treatment of unclear, study described as double-blind. atopic dermatitis No drop-outs. No results data given. Small sample over a short period of time

Larsen & There were no statistically significant This trial could not demonstrate any effect Method and concealment of randomisation Jacobsen, 1980195 differences in the clinical assessments, in of chromone compound in systemic unclear, study described as double-blind. the patients’ diary cards, or in the use of treatment of atopic eczema. Furthermore, Three drop-outs, no ITT. No results data hydrocortisone cream. Eleven patients the applied dose resulted in some given. Small sample over a short period of preferred the active period, while nine dyspeptic adverse effects time.Authors conclude:“Our first study patients preferred the placebo period [Larsen & Larsen206] gave some evidence that FPL 57787 might be effective in the treatment of [atopic eczema]”. However, it gave no evidence of benefit.The later study used three times (18 mg t.d.s.) the earlier dose of 6 mg t.d.s.

Lindskov & No significant differences between the two Unable to confirm the favourable results Crossover trial with no washout period. Knudsen, 1983210 treatments in the patients’ assessments of DSCG in atopic eczema reported Small study of 14 adults and ten children by others

Ventura et al., No difference in eczema score in the The usefulness of dietary treatment is Parallel group trial. Randomisation and 1996211 DSCG and placebo groups confirmed. Orally given DSCG does not blinding adequate seem capable of preventing a secondary sensitisation in patients with cows’ milk protein allergy

62 Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 17 Results of studies using topical SCG

Study Main reported results Authors’ conclusions Quality

Ariyanayagam Mean eczema severity score reduced Topical SCG as a long-term measure may Double-blind parallel group with et al., 1985202 significantly at 12 weeks compared with be useful randomisation. Short-term study of 3 weeks in patients on DSCG but not on 12 weeks with an open label follow-up placebo.The same effects were seen with of 1 year daytime itch and night-time itch

Croner et al., No significant group differences found Topical DSCG did not add to the drug’s Small short-term study. Parallel group 1981200 except for less frequent use of steroids success in bronchial asthma and atopic randomised double-blind trial eczema. Steroid-sparing effect could be worthwhile

Haider, Significantly more withdrew for lack of Safe alternative to topical steroids in the Small short-term study. Parallel group 1977196 effect from the placebo than the DSCG treatment of atopic eczema in children randomised double-blind trial arms (16/21 vs 4/21)

Hiratsuka et al., Equivalent to beclomethasone Both DSCG and beclomethasone 199684 dipropionate in reducing eczema scores diproprionate produced remarkable at 2 weeks eczema improvement

Kimata & Itch scores, eczema scores and sleep Topical cromolyn solution was found to be Double-blind randomisation appeared Igarashi, 1990194 scores all improved by week 2 very effective adequate

Kimata & Itch scores, eczema scores and sleep DSCG adds to the effect of oxatomide Double-blind randomisation appeared Hiratsuka, 1994201 scores all improved with DSCG but not adequate with placebo

Kjellman & No significant change in itch scores or Topical DSCG did not relieve the patients’ Double-blind randomisation appeared Gustafsson, sleep disturbance reported eczema adequate 1986209 Moore et al., At 1-month crossover period, the Topical DSCG has a significant anti- Crossover study with satisfactory blinding 1998198 group receiving DSCG first has a higher inflammatory effect on moderate-to-severe and randomisation reduction in eczema scores than did atopic eczema those who received placebo first

Pike & Atherton, No numerical data reported No statistically significant effect between Letter 1988212 the active and placebo treatment

Thirumoorthy & Letter No significant difference between DSCG Eight patients only. Few details given Greaves, 1978199 and placebo

TABLE 18 Difference in itch scores produced by DSCG and beclomethasone and comparison with effects seen in a placebo-controlled trial

Study Stratum No. of treatment No. of control Mean difference 95% CI patients Patients

Hiratsuka et al., 199684 1 21 21 1.65 1.19 to 2.11 (DSCG in itch scores week 0 to week 2) Hiratsuka et al., 199684 2 22 22 1.26 0.60 to 1.91 (beclomethasone week 0 to week 2) Kimata & Igarashi, 1990194 3 25 201 0.47 0.47 to 1.53 (difference in itch scores DSCG minus placebo)

63

Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 8 Dietary interventions

Dietary restriction in established • Marked order effects suggest that the crossover study is not the best method of assessing the atopic eczema benefits of dietary exclusion. In addition to examining the role of dietary exclusion • There is little evidence to support an egg- of possible allergenic foods during pregnancy or and milk-free diet in unselected atopic lactation with a view to preventing the development eczema patients. of atopic eczema, some RCTs have examined the • There is no evidence to support the use of an role of dietary exclusions to improve the severity of elemental- or few-foods diet in atopic eczema. established atopic eczema. No systematic reviews of • There is some evidence that the addition of a dietary manipulation in established atopic eczema probiotic such as Lactobacillus may be beneficial could be identified, although some of the published for atopic eczema in those already on a cows’ studies have been reviewed by Charman.334 The milk whey hydrolysate diet, though in the eight RCTs examining the role of elimination diets absence of a control group on no special diet it in established atopic eczema are summarised in is hard to say if this is a real benefit. Table 19 (Atherton 1980 is the same paper as • There is some evidence to support the use of an Atherton 1978). RCTs of dietary exclusion in the egg-free diet in infants with suspected egg prevention of atopic eczema that have also estimated allergy who have positive specific IgE to eggs in eczema severity in those developing eczema have their blood. already been discussed in Tables 3 and 4. In the three • Methodological concerns such as poor studies looking at dietary exclusion during preg- concealment of randomisation allocation, lack nancy,61,66,67 there was no difference in eczema of blinding and high drop-out rates without an severity between the intervention and control intention-to-treat analysis suggest that the above groups. In the studies looking at dietary exclusion studies should be interpreted with great caution. during breastfeeding, one reported improvement • Future studies should be longer term, more in eczema severity in the intervention versus pragmatic and ensure that randomisation is control group,53 while the other55 did not. concealed. • If participant blinding is not possible, objective outcomes such as photographic records viewed Summary of dietary restriction in by independent blinded observers should be used. established atopic eczema Apart from elimination diets for the treatment of • None of the interventions and study populations established atopic eczema, uncontrolled elimin- were considered sufficiently similar to each other ation diets followed by double-blind placebo- to warrant statistical pooling. controlled food challenges with foods suspected to • Elimination diets are difficult for families and aggravate symptoms have also been tried in atopic patients to follow, even in the highly motivated eczema.365–369 Although such blind challenges have environment of a clinical trial. sometimes been performed in random sequence, • Drop-out rates are particularly high for elimin- they are not the same as RCTs of food elimination. ation diets and those containing hydrolysate Instead they try to answer the question: ‘Does food milk substitutes. X make a particular child’s atopic eczema worse?’ • Those RCTs that employ a parallel design with The precise relationship between such food challenge an unblinded normal control diet risk biasing studies and long-term benefits of exclusion of the motivation and ancillary care in favour of those suspected foods to atopic eczema sufferers the active group. is not clear. Up to 63% of selected children with • Those studies that place all participants on atopic eczema exhibit one or more reactions exclusion diets and introduce the suspected (mainly in the skin) to foods in double-blind offending food versus a control, risk introducing placebo-controlled challenges,370 though such another allergen (e.g. soya) or introducing the reactions are lost after 1–2 years in 26–66% of suspected allergen (e.g. cows’ milk) in an altered patients.371 Blood and skin-prick tests are usually and controlled way that does not mimic real life. only helpful in predicting clinical response if they 65 Dietary interventions

are negative.372,373 It should also be borne in mind the manufacturers concluded that evening that this high negative predictive value has only primrose oil had a modest beneficial effect.375 been shown in relation to provocation of symptoms They included seven small unpublished studies, after double-blind challenge and not clinical and these have not been made available within the response following food elimination, which are public domain for others to evaluate their results not necessarily the same thing. The relationship and quality. They excluded the largest study by between atopic eczema and ‘food sensitivity’, Bamford and colleagues240 in their main analysis as which is subdivided into food hypersensitivity, they implied that the investigators had allowed food intolerance and allergic adverse reactions the active and placebo capsules to become mixed to foods (immunologically mediated), is a complex up on the basis of a subsequent blood analysis one and readers are referred to a clear evidence- conducted within the company. These allegations based work by David374 for further information. have been denied by Bamford (Bamford J, personal written communication, 1996), and it is difficult to see how such a mix up could have occurred given Supplementation with that this was one of the best-quality reported studies essential fatty acids with several measures in place to ensure conceal- ment of allocation. Polyunsaturated fatty acids are essential components of all cell membranes. There are two families of A further meta-analysis of 20 published and such essential fatty acids: n-6 (e.g. linoleic and unpublished RCTs of evening primrose oil has arachadonic acid) and n-3 (e.g. eicosapentanoic been conducted by two of the authors of the acid). Some of these substances are precursors of current report376 in 1997 for the Department of a group of substances called eicosanoids, which Health, but permission to publish the data has may play an important part in the inflammatory not been granted. and immunological processes of atopic eczema. Alterations in linoleic acid metabolism have been There is currently an ongoing, more detailed demonstrated in some patients with atopic eczema, systematic review of oral GLA supplementation suggesting that a defect in the enzymatic conversion being conducted by one of the authors within the of this essential fatty acid by δ-6-desaturase might Cochrane Skin Group, which hopes to publish its be responsible for defects in the lipid barrier of the findings later this year. Pooling has therefore not skin, a decreased postnatal maturation of T-lymph- been attempted in this scoping review. It is ocytes, and the decreased production of anti-inflam- reasonable to consider pooling borage oil with matory metabolites in the skin. These observations evening primrose oil studies on the basis that the are the rationale for dietary supplementation with purported active agent is GLA. essential fatty acids in atopic eczema. Such supple- mentation includes evening primrose oil, containing Borage oils 8–10% gamma-linoleic acid (GLA), and more recently Only one large well-reported RCT has evaluated borage oil (containing at least 23% GLA). Topical borage oil in atopic eczema,249 and that study use of evening primrose oil has also been tried. found no overall benefit or hint of benefit when Fish oils are particularly rich in n-3 fatty acids, and the two main groups were compared. However, a it has been suggested that these may compete with subgroup analysis (proportion unspecified) of the n-6 fatty acids in a way that might reduce the inflam- best complying patients and those with changes in matory components of atopic eczema. blood tests, suggested that there could be a benefit in this subgroup. The authors were rightly cautious We located five RCTs of oral borage oil supple- in interpreting these post hoc findings, and in the mentation,246–250 four RCTs of fish oil supplemen- absence of more detailed analyses, it is difficult to tation,251–254 four RCTs of topical evening primrose say how much of the positive effect was due to oil,232–234,241 two of which repeated the same study,233,234 taking the capsules in the required dose and how and ten published RCTs of oral evening primrose much was due to the blood test changes. It is oil235–240,242–245 (including one study published difficult to generalise from the subgroup data twice242,245) for the treatment of atopic eczema, without knowing more about the poor compliance and these are described in Tables 20–29, respectively. of some patients, as that itself may be a useful outcome measure of the pragmatic usefulness of Comment the intervention. The subgroup analysis does Other and ongoing systematic reviews however call for an RCT of people who are able to A previous meta-analysis of nine placebo-controlled demonstrate an increase in GLA metabolites in the 66 RCTs of evening primrose oil in 1989 conducted by blood as an entry criterion. The four remaining Health Technology Assessment 2000; Vol. 4: No. 37

RCTs were quite small, with two246–248 suggesting an Benefits improvement, and two247–250 suggesting none. Forty-one of the 48 children in this parallel-group RCT study were evaluable at 4 weeks. Median skin Fish oils severity score increased from 92.3 at the beginning The two smaller RCTs of fish oils suggest some of the trial of the pyridoxine group to 109.0 at the possible benefit in atopic eczema, and the magnitude end of the 4-week period. In the placebo group, of relative benefit was very large in the Gimenez- the median skin severity score fell from 125.5 to 77.0 Arnau and colleagues study253 (though baseline at the end of the treatment period. The difference data were not given). The largest and best reported between the median change in skin scores was 29.2 independent study by Soyland and colleagues252 did (95% CIs ranging from a benefit of pyridoxine of not show any hint of difference in benefit between 19.5 to a benefit of placebo of +85.0). There was fish oils and placebo. no statistical difference for skin severity score, daytime itch or nocturnal itch score. With regard Topical evening primrose oil to parental observation, 16% in both groups felt The pilot study of 12 patients by Anstey and that overall the skin was better (p = 0.95). colleagues241 suggested a possible benefit of topical evening primrose oil for patient-assessed changes Harms but not physician-assessed benefit. The success of No serious adverse effects were described in the blinding in that study is suspect as topical evening study, though one child developed a non-specific primrose oil is known to produce an odour on erythematous rash while taking pyridoxine, and contact with the skin,377 and the placebo cream was another taking placebo was reported to be much different from the composition of the vehicle used more itchy than usual. with the active agent. The second study, which compared three increasing doses of GLA with Comment placebo234 did not show any hint of a dose-response This was a well-reported study with method of effect, but the sample size in each group was very randomisation and allocation concealment and small. The two studies of skin barrier function blinding clearly described. No intention-to-treat described by Gehring and colleagues232 do not analysis was performed and no adjustment of the provide any evidence of a useful clinical benefit for different baseline scores was made. Some of the topical evening primrose oil above vehicle control significant improvement of the placebo group at the end of the 4-week treatment period, regard- could partly be due to a regression to the mean less of the formulation. phenomenon. The study did not provide any evidence to support any benefit of pyridoxine in Oral evening primrose oil the treatment of atopic eczema despite the earlier The two largest240,243 and best-reported studies favourable report. did not show any evidence of benefit for evening primrose oil in atopic eczema. The remaining moderate-sized (between 50 and 100 patients) Vitamin E and multivitamins studies show conflicting results,235,237,238,245 ranging from no hint of improvement235 to a definite Three very different RCTs256–258 have evaluated modest 10–20% benefit for some outcome vitamin supplementation in atopic eczema. The measures when compared with placebo. The first was an RCT reported by Czeizel and Dobo three small studies all suggest a benefit to evening in 1994 of the Hungarian optimal family planning primrose oil. programme study looking at the effect of multi- vitamin supplementation around the time of conception and afterwards on postnatal develop- Pyridoxine ment compared with the use of a tablet containing trace elements.256 The other RCT257 was conducted Pyridoxine (vitamin B6) is an essential water- to evaluate the possible benefit of supplementation soluble vitamin and is a core factor in many of with selenium and vitamin E compared with placebo the body’s chemical pathways. Based on an earlier in adults with atopic eczema. The rationale for double-blind placebo-controlled study published this second trial was that reduced concentrations in abstract form only,378 a larger and fully reported of selenium had been observed in whole blood RCT was conducted by Mabin and colleagues255 of patients with atopic dermatitis. The final of pyridoxine versus placebo in the treatment of RCT was a study in Japan of vitamin E in combin- atopic eczema in children with moderate-to- ation with vitamin B2 compared with each severe disease. vitamin separately.258 67 Dietary interventions

Benefits statistical significant increase in atopic eczema In the Czeizel study, data were available on 4122 and in wheezy bronchitis and asthma in those pregnancies that ended in a live birth. Of these, receiving multivitamin supplementation compared 2090 were randomised to the ‘active’ multivitamin with trace element supplementation. The numbers supplementation, compared with 2032 in the trace of patients in these groups are very small and element supplementation group. A whole range of the results therefore may probably be due to postnatal development factors were collected in the chance. Nevertheless, these findings should be study, including a physical examination and study examined in other independent randomised birth of medical records in 90% of the evaluated infants. cohort studies. At the end of the 17-month period, there were no significant differences in the occurrence of chronic The study of selenium and vitamin E,257 while diseases between the two groups, with the exception small, probably excluded moderate-to-large of atopic dermatitis and wheezy bronchitis. Fifteen treatment effects. A method of randomisation was out of 2090 receiving multivitamin supplemen- described (unusual for such an early study), though tation had developed atopic eczema (four had a no intention-to-treat analysis was performed. parent with atopic dermatitis) compared with four out of 2032 receiving trace element supplemen- The short Japanese study258 on the use of tation (none of these children’s parents had atopic combination of vitamin E and B2 is difficult to disease). The authors suggested that these un- interpret in the absence of a placebo-controlled expected findings may be a chance effect. study of either compound. The validity of the study is also threatened by difficulties in blinding In the Fairris and colleagues study,257 60 adults with and post hoc subgroup analysis of dry skin atopic eczema were randomised in a 12-week subtypes at different time intervals. double-blind study to three groups taking either 600 µg of selenium alone, 600 µg of selenium plus 600 IU of vitamin E or a placebo. Using a severity Zinc supplementation assessment based on several skin signs at several body sites, mean severity score fell from 21.0 to 13.7 Oral supplements of zinc salts have become popular in the selenium only group, from 21.8 at baseline to remedies for a range of unrelated medical disorders. 15.3 in the selenium plus vitamin E group, and from They have been specifically recommended for the 20.4 to 14.5 in the placebo group. None of these treatment of atopic eczema possibly because skin differences were statistically significant. There was, lesions are an important feature of zinc deficiency. however, a significant increase in concentration of One RCT conducted by Ewing and colleagues in selenium in whole blood of those taking selenium. 1991259 evaluated the possible benefit of oral zinc sulphate at a dose of 185.4 mg/day versus placebo In the Hakakawa and Ogino study,258 59 participants in 15 children with atopic eczema aged 1–16 years with mild-to-moderate atopic eczema of the dry type for a total of 8 weeks. were randomised to vitamin E (d-α-tocopherol) 100 mg plus vitamin B2 (riboflavin butyrate 20 mg), Benefits or vitamin E 100 mg or vitamin B2 alone for 4 weeks. At the end of the 8-week period, the mean combined Of the 49 evaluable participants, response as disease severity score increased from 36.1 at baseline measured by physician-assessed overall usefulness to 48.7 in the zinc group compared with a change and global rating, was greater in the combination from 34.6 at baseline to 39.3 in the placebo group. vitamin group than in the single vitamin group. Erythema score, surface area score and use of steroids, emollients and antihistamines were also Harms almost identical in both groups and none were The Hungarian study,256 in a sense, has detected statistically significantly different. a possible unwanted harm of an increase of allergic diseases in those given multivitamin Harms supplements in early pregnancy. No adverse effects No adverse effects were reported in this small RCT. were reported in the studies of selenium and vitamin supplementation. Comment Despite the usual reservations on lack of description Comment of the randomisation process and no intention- Although the Hungarian study is not really a thera- to-treat analysis, this small RCT illustrates the peutic trial of an intervention in atopic eczema, importance of an unbiased comparison of possible 68 it is nevertheless a large RCT that has found a treatment benefits when compared with earlier Health Technology Assessment 2000; Vol. 4: No. 37

enthusiastic claims of benefit. Even though Cochrane Skin Group systematic review due to the trial was quite small, the complete lack of report later in 2000. treatment benefit along with small standard errors, argues against missing any moderate-to-large Pyridoxine treatment effects. • One well-supported RCT does not support any benefit of pyridoxine in the management of a child with atopic eczema. Summary of dietary interventions Vitamin E and multivitamins Essential fatty acid supplementation • One large randomised trial of multivitamin • The largest and best-reported study on the use supplementation in early pregnancy has of borage oil supplementation in atopic eczema suggested an unexpected increase in atopic did not suggest any overall benefit compared dermatitis in children born to mothers with placebo. randomised to multivitamins compared • That study did suggest that a further RCT with trace elements. Although this is in those who are able to take high doses probably a chance finding, it needs to be consistently and who have demonstrable looked at specifically in other similar cohort changes in a blood test might be justified. intervention studies. • The largest and best-reported study on fish oil • One small trial of selenium and vitamin E supplementation in atopic eczema did not show supplementation in adults with atopic eczema any benefit above placebo. failed to provide any evidence of a beneficial • There is no good RCT evidence to support the effect on clinical disease activity. use of topical evening primrose in atopic • A Japanese study of short duration found eczema, though it has never been put to the test that vitamin E in combination with vitamin

in a large RCT. B2 was more effective than either vitamin • The nine published RCTs that have evaluated alone in the treatment of dry eczematous the use of oral evening primrose oil have shown skin. The clinical significance of these results conflicting results. is difficult to interpret in the absence of • The two largest and well-reported studies of a placebo. evening primrose oil do not show any benefit over placebo. Zinc supplementation • The RCTs of GLA (evening primrose oil and • One RCT has failed to show any benefit of zinc borage oil) are the subject of an ongoing supplementation in atopic eczema.

69 Dietary interventions continued Marked order effect i.e. effect order Marked at greater improvements end of first vs second the diet period whatever content milk (which itself can Soya be allergenic in atopic ‘control’ eczema) used as food History intolerance of food in patients not confirmed during study Small study of an intervention that is unpalatable, impractical and hospitalisation and requires dietetic input reported,Well though very small study conducted and alongside a before after study diet used as control Soya Method of randomisation and concealment unclear Study described as double- blind, though some unblinding of parents cannot be excluded and high No ITT analysis rate (44%) drop-out Method of randomisation and concealment unclear Unclear if the reported ‘double-blinding’ was of the successful in view composition of different diets. the two with a No ITT analysis rate 24% drop-out Method randomisation described Concealment of allocation unclear Study described as double- blind, though almost half mothers correctly identified substitutes was attempted ITT analysis diet (NS) Of 20 children who Of 20 children completed the trial, 13 an improvement showed during the trial diet period, no change and six showed deterioration one showed diet period, On control showed three improvement, 11 no change and six deteriorated Itch was not statistically the two significant between groups Of 25 evaluable patients, Of 25 evaluable out of 16 improved five on the elemental diet out with four compared of nine on the placebo Itch, sleeplessness, antihistamine use and tests were immunological the between no different groups two Of 17 mothers completing the study, the activity 20% in by decreased scores and babies on soya four one on egg and milk different No statistically the between mean scores groups two in period effect Marked of mothers on that children period normal diet in third to improve continued Eczema area and activity Eczema area using an unpublished composite score, of degree to diet and skin- adherence prick tests Various unpublished extent Various and intensity signs scored –3 and +3, between and before photographs after, patient itch and sleep, and various serum markers of inflammation of ‘major activity’ score A > 100 was defined as the a positive criterion for to treatment response Combined area/intensity (unpublished) with a score max. of 60 score follow-up Crossover design that Crossover 4-week examined three periods; during the first and periods,third patients were placed on an egg and mill elimination diet and allocated to a randomly or preparation soy-based one containing egg and milk cows’ Parallel group RCT of Parallel group hospitalised patients on 3 weeks diets for study crossover 12-week 4-week divided into three periods; during first two periods, mothers excluded milk,cows’ egg and other their diet and from foods randomised in first or were milk second period for substitutes containing cows’ milk and egg or soya period Normal diet in third 36 children aged 2–8 years 36 children attending a dermatology typical clinic with clinically atopic eczema 33 adults with atopic more eczema covering than 10% of the body, 13 of whom had a history of intolerance to one or elements food more 19 mothers and babies with established atopic eczema (co-treatments) and sample size description and results reporting Egg and cows’ milk Egg and cows’ exclusion diet (with soya milk substitution) vs diet with egg and control milk cows’ (hydrocortisone, emollients and antihistamines) Elemental diet (amino acids, essential fatty acids, glucose, trace elements, sorbic acid and vitamins) vs a blended diluted diet consumed by of foodstuffs hospital inpatients (emollients, a topical and antihistamines) steroid Exclusion of egg and cows’ substitute) milk (with soya in mothers of infants with atopic eczema who were vs breastfeeding exclusively inclusion of egg and milk and (topical steroids emollients) Studies of elimination diets in the treatment of those with established atopic eczema Studies of elimination diets in the treatment et al., et al., et al., 230 229 228 Study Interventions Study population design Trial Outcome measures Main reported Quality of Comment Atherton 1978 England Munkvad 1984 Denmark England 70 Cant 1986 TABLE 19 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued High drop-out rate due High drop-out to diet too difficult to adhere was a Unclear if there effect period or carry-over CIs suggested that if anything, patients did on the exclusion vs worse normal diet Good description of and patient flow interventions 35 out of 39 drop-outs in the diet group, were illustrating the difficulty of diet foods adopting the few a motivated in even hospital group to supportNo evidence diet and some benefit from suggesting that evidence diet was better control Highly selected population Highly concerned Study mainly in comparison of growth amino-acid vs hydrolysate formulae Main statistical comparison of change in eczema the two between severity not reported in groups results, in though children had amino acid group higher baseline score Method of randomisation and concealment of allocation unclear ‘double- Study reported as blind’, though test substances might have tasted differently and high No ITT analysis rate (25%) drop-out Method of randomisation described clearly Concealment of allocation unclear Study described as investigator-blind and veryNo ITT analysis rate (46%) high drop-out Method and concealment of randomisation allocation unclear Randomised part of the not blinded study probably No drop-outs Of 40 evaluable patients, Of 40 evaluable was little difference there (area, change in score for use) itch co-treatment the treatment between periods and none were significant statistically Of 46 evaluable patients, Of 46 evaluable 16 (73%) of the 22 controls and 15 (58%) of the diet 24 who received than a greater showed in skin 20% improvement score severity in skin Improvement in controls score severity in itch score and daytime group hydrolysate the whey significantly was statistically in the 12 statistical out- come comparisons made Weight gain and infant Weight less length was statistically hydrolysate in the whey group decreased Eczema severity a SCORAD of 17 to 5 from on whey in 22 children with compared hydrolysate a baseline of 21 to final of 4 at 8 months in score the amino acid group Patient reported itch and sleep loss, use of co- treatments, composite and intensity of area score and skin-prick tests Skin severity score Skin severity incorporating extent and severity, and parental of itch,record sleep loss and global improvement Atopic eczema severity (extent, intensity of signs and symptoms) measured the SCORAD system by was also Infants’ growth measured follow-up Crossover trial with three Crossover periods;6-week during first periods,and third patients placed on an egg and were milk exclusion diet cows’ and randomised to either or a milk containing soya milk egg and cows’ Parallel single-blind RCT until with follow-up 6 weeks Parallel prospective randomised study drawing an initial patients from study to determine cows’ milk allergy followed-up were Children 8 months for 53 unselected atopic eczema outpatients aged 1–23 years 85 children (median age 85 children with atopic 2.3 years) eczema which persisted despite conventional and involving treatment than 12% of body more were children Breast-fed excluded 45 children who were not who were 45 children being breast-fed, who had substitute cows’ been fed at least 6 months milk for a positive and who showed to a masked reaction milk challenge with cows’ Studies of elimination diets in the treatment of those with established atopic eczema Studies of elimination diets in the treatment (co-treatments) and sample size description and results reporting Egg- and cows’ milk-free Egg- and cows’ as diet (using soya substitute) vs normal diet and (topical steroids antihistamines) Children allocated to Children groups:three foods i) few diet (eliminating all but plus to eight foods) five hydrolysate;whey ii) few diet plus casein foods hydrolysate; or iii) remain on usual diet (antihistamines and topical steroids) with atopic Children eczema allocated to whey vs an amino- hydrolysate formula acid derived containing no peptides et al., et al., et al., 226 227 231 Study Interventions Study population design Trial Outcome measures Main reported Quality of Comment Neild England 1986 Mabin 1995 England Finland Isolauri 1995 71 TABLE 19 contd TABLE Dietary interventions Authors report statistical the change significance for baseline to from in score the end of study each for separately intervention, but do not between test the difference treatments the two to the mean Regression accounted for could have improvement the greater group in the probiotic Study suggested that egg- diet in those with a free RAST test to egg positive be useful may Methodological concerns such as lack of randomisation concealment and increased motivation and ancillary in intervention group care in bias resulted could have Method and concealment of randomisation allocation unclear No blinding reported No drop-outs Method of randomisation unclear Randomisation performed same dietician who was by giving the intervention unblinded;Parents assessor reported as blinded No ITT analysis use not Co-treatment reported = 0.04) p = 0.02) p Of 27 evaluable children, Of 27 evaluable the median SCORAD at baseline was 21 and 26 in alone vs whey the whey groups, plus probiotic respectively; these to 19 and 15, decreased respectively, at the end of 1 month Of 55 evaluable children, Of 55 evaluable by involved the area from eczema reduced 19.6% to 10.9% in egg-free with compared group 21.9% to 18.9% in control ( group reduced score Severity 33.9 to 24.0 in the from compared group egg-free with 36.7 to 33.5 in the ( group control statement of a priori Atopic eczema severity SCORAD by measured No minimum clinically minimum significant benefit Eczema severity as assessed Eczema severity extent in % terms and a by in score composite severity 16 body sites follow-up Parallel randomised study prospective 1 month for monitored Parallel randomised study of prospective duration 4 weeks’ 27 infants with clinical history of cows’ suggestive milk allergy who were confirmed as being milk to cows’ sensitive double-blind placebo- by challenge controlled also 19% of the children had gastrointestinal symptoms 62 children all with 62 children IgE blood positive antibodies to egg, only of which had a seven history of suggestive egg allergy Studies of elimination diets in the treatment of those with established atopic eczema Studies of elimination diets in the treatment (co-treatments) and sample size description and results reporting Cows’ milk elimination Cows’ hydrolysed (extensively with and formula) whey without a probiotic (Lactobacillus GG) Egg exclusion diet for as advised children young a dietician vs general by a dietician advice from only (mild-to-moderate topical and emollients) steroids 224 et al., 225 Study Interventions Study population design Trial Outcome measures Main reported Quality of Comment RAST, test Radio-allergosorbent Majamaa & Isolauri, 1997 Finland Scotland 72 Lever 1998 TABLE 19 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 * * oil 19 placebo drop-outs, 17 borage oil and drop-outs and drop-outs Antihistamines, corticosteroids No other treatment permitted Antihistamines, hydrocortisone, emollients Unclear Topical steroids Topical Unlimited emollient Topical diflucortolone-21 Topical valerate Emollients Placebo (oleic acid) Palm oil in similar dose Unclear Olive oilOlive Eight Placebo (liquid paraffin) One placebo, borage two Miglyol lipid as placebo Miglyol daily capsules three -3) ten n docosahexaenoic acid (fish oil) vs linoleic acid oil) (vegetable containing 500 mg t.d.s. capsules daily capsules containing 80 mg GLA + linoleic acid small amounts of palmintic acid, oleic and stearic acids capsules daily capsules Chronic and Chronic severe severe score in borage score and palm oil 1.63 and 1.89, respectively and moderate * moderate 14 weeks Borage oil Corn seed oil Two 12 weeks acid + Eicosapentaenoic 4 months fish oil daily Six capsules Corn oil as placebo 4 months Borage oil, capsules two 12 weeks Max-Epa fish oil ( 14 weeks Borage oil, 500 mg capsule 24 weeks Borage oil, 500 mg three 12 weeks 2 x 1 g borage oil Placebo 2 x 1 g palm oil 18 24.2 15–38 24 3–17 eczema Chronic patients (years) patients (years) Crossover, RCT Parallel, RCT 145 18–64 Moderate to Parallel 48 Mean age Parallel, RCT 12 20–48 Mean ADASI Parallel, RCT 31 16–56 Unclear Parallel, RCT 160 14–65 stable Relatively Parallel, RCT 31 2–11 RCT 50 Mild to 246 Design, patient characteristics and interventions of included studies: oils fish Design, patient characteristics and interventions of included studies: oils borage 253 et al., et al., et al., et al., et al., 1997 247 252 251 249 250 248 No data given No data given Study Design No. of Age Duration Severity Treatment* Comparator Co-treatmentsStudy Withdrawls Design No. of Age* Duration Severity Treatment Comparator Co-treatments Withdrawls ADASI,jAtopic Dermatitis Area Severity Index Area ADASI,jAtopic Dermatitis Borrek Borrek 1997 Soyland Soyland 1994 Gimenez-Arnau et al., Bahmer & Schafer, 1992 Bjornboe 1987 Henz 1999 Valsecchi Valsecchi 1996 Buslau & Thaci, Buslau & 1996 73 TABLE 21 TABLE TABLE 20 TABLE Dietary interventions continued Three drop-outs Three 31 drop-outs: 14 evening oil,primrose 17 placebo Tw o One One and drop-outs and drop-outs Weak topical steroids, Weak emollients Topical steroids, Topical emollients, antihistamines Emollients, topical steroids, oral antihistamines None None mentioned ‘Usual topical treatments outside test areas’ emollient ™ ™ Placebo olive oil = 10 Placebo olive mg vitamin E Placebo (olive oil)Placebo (olive 21 drop-outs 500 mg liquid paraffin and 10 IU of vitamin E Study 1: was 20% miglyol Vehicle Study 2: was liquid Vehicle paraffin without essential fatty acids Atoderm E45 cream 500 mg 107 mg (contains ™ ™ oil 0.5 g/kg/day primrose evening Low-dose + oil 50% mix 0.5 g/kg/day placebo capsules fish oil) (containing GLA) vs Efamol 2–4 capsules evening 2–4 capsules oil b.d. primrose > 15 years evening 6–8 capsules oil b.d. primrose Evening primrose in an primrose Evening amphiphilic oil in water emulsion Study 2: oil in a primrose Evening emulsion water-in-oil GLA vs borage oil (24% hip oil GLA) vs rose (35–40% GLA) in a water oil emulsion * * Active and using Active a topical steroid 10 or over moderate 8 weeks primrose High-dose evening 16 weeks Epogam 3 months < 15 years 4 weeks Study 1: 4 months Emollients containing 10% 14 days oil cream primrose Evening 13–60 16–66 19–42 of score Atopy 12 4–46 mild to Typical 154 2–16 each 20 in study patients (years) patients (years) Parallel, RCT 51 2.2–8.5 Parallel, RCT 133 7–12 Crossover, RCT Parallel, RCT 23 3–15 In remission Two within- Two person right/left forearm parallel studies RCT, within person right/left arm parallel Design, patient characteristics and interventions of included studies: primrose oil – orals evening Design, patient characteristics and interventions of included studies: primrose oil – topicals evening et al., et al., et al., et al., et al., 237 243 240 234 232 241 Biagi 1994 Study Design No. of Age Duration Severity Treatment ComparatorStudy Co-treatments Design Withdrawls No. of Age Duration Severity Treatment Comparator Co-treatments Withdrawls Berth-Jones & Grahan-Brown, 1993 Bamford Bamford 1985 Ferreira Ferreira 1998 Gehring 1999 Anstey Anstey 1990 E45 cream™, Crooke, UK 74 Atoderm™, not available in the UK TABLE 23 TABLE TABLE 22 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 Two from evening from Two oil group primrose Six: placebo and two four active 16 adults, children three One evening primrose oil; primrose One evening not mentioned in placebo group and drop-outs Usual treatment allowed, steroid/antihistamines Topical steroids Topical Mild topical steroids, emollients, oral antihistamines Emollient, oral antihistamines, mild topical steroids Mild topical steroids Weak steroids, Weak emollients Placebo 500 mg + 10 mg sunflower vitamin E Liquid paraffin 300 mg with 10 mg vitamin E Placebo 500 mg liquid paraffin Liquid paraffinPlacebo 500 g liquid paraffin Not mentioned primrose oil,primrose 40 mg gamma- linolenic acid, 10 mg Vitamin E 500 mg + vitamin E 10 12 x daily acid, 45 mg gamma-linolenic acid divided into three adults doses for different doses different and two children) for primrose oil + 45 mg primrose gamma-linolenic acid) b.d., capsules Adults – four b.d. capsules – two Children mg linoleic acid, 50 mg oleic acid, 45 mg gamma-linolenic b.d. capsules acid) four topical steroids severe Moderate to severe Atopic eczema at least 6 for months severe * 16 weeks Epogam, 500 mg evening 16 weeks oil primrose Evening 12 weeks Efamol (360 mg linoleic 3 weeks each 3 weeks 12 weeks Efamol, (500 mg evening oil (360 primrose Evening 4 weeks Efamol, 0.5 g/day oil placebo Olive Not mentioned 15–58 14–32 patients (years) Parallel 60 1–16 Need regular Parallel 58 AdultsCrossover Moderately 99 0.8–11 Crossover 32 1.5–13 Parallel, RCT 25 19–31 Moderate to Parallel, RCT 24 2–4 Design, patient characteristics and interventions of included studies: primrose oil – orals evening et et al., , Searle, UK et al., 236 , Scotin, UK ™ et al., ™ 235 242 238 244 239 1987 Epogam Study Design No. of Age Duration Severity Treatment Comparator Co-treatmentsEfamol Withdrawls Hederos & Berg, Hederos 1996 Lovell Lovell 1981 Wright & Burton, 1982 Schalin-Karrila Schalin-Karrila al., Humphreys Humphreys 1994 Bordoni Bordoni 1987 75 TABLE 23 contd TABLE Dietary interventions RoNAA Ra jka Multiple area Costa Multiple area Costa global global assessment named (if global global assessment named (if severity severity (method modified severity severity (method modified Physician Patient Area Scale Physician Patient Area Scale assesssment assessment used) specify) assesssment assessment used) specify)

Sleep loss Sleep loss

Doctor itch Doctor itch also inflammation

Patient itch 248 Patient itch

Induration Induration

Infiltration Infiltration

Crusts Crusts also disease extension and course of eczema 253 Inflammation Inflammation et al.,

Oedema Oedema also pigmentation;Thaci Buslau &

Oozing/weeping 247 Oozing/weeping et al., Pustules/papules Pustules/papules

Vesiculation Vesiculation

Exudation Exudation

Fissuring Fissuring also effect on daily living;also effect Gimenez-Arnau Cracking Cracking 252

Lichenification Lichenification et al.,

Scaling Scaling

Xerosis Xerosis

Dryness Dryness

Excoriation Excoriation

Purulence Purulence also visibility and severity; Soyland also pigmentation/depigmentation and amount of topical steroid; Borrek 251 Erythema Erythema 249 et al., 253 et al., 246 1998 251 250 248 252 247 249 et al., 1987 1996 1994 Outcome measures signs and symptoms:Outcome measures oil borage 1997 Outcome measures signs and symptoms:Outcome measures oils fish 1999 et al., et al., et al., et al., et al., Study Study Note: Additional outcomes: Henz Bahmer & Schafer, 1992 Borrek Thaci,Buslau & 1996 Henz Valsecchi Note: Additional outcomes: Bjornboe 76 Bjornboe Gimenez-Arnau Soyland TABLE 24 TABLE TABLE 25 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 Costa 243 RoNAA Leicester/ global global assessment named (if severity severity (method modified also surface damage also surface Physician Patient Area Scale assesssment assessment used) specify) 238

Sleep loss et al., Doctor itch t with appearance, appetite and stress; Berth-Jones & Graham-Brown, and irritation after sodium lauryl sulphate provocation Patient itch

Induration also fidget; Humphreys Infiltration 235

Crusts

Inflammation

Oedema

Oozing/weeping

Pustules/papules also pigmentation; & Berg, Hederos

Vesiculation 239

Exudation et al.,

Fissuring

Cracking

Lichenification

Scaling

Xerosis

Dryness Excoriation

Purulence also physician-assessed visibility and severity,also physician-assessed patient-assessed flakiness, visibility, severity, on daily living, effect discomfor 240 No data available Erythema also evidence of infection,also evidence pigmentation and extent; Bordoni et al., 237 study only evaluated objective laboratory of skin barrier loss,study only evaluated measures function including water transepidermal skin hydration 236 232 242 et al., 235 1987 240 239 232* 234 1999 241 1994 244 237 1985 et al., 1987 1999 1998 Outcome measures signs and symptoms:Outcome measures primrose oil evening 1990 et al., 243 1981 et al., 1994 et al., et al., et al., et al., et al., et al., et al., The Gehring Study Berth-Jones & Graham- Note: Additional outcomes: Bamford Topicals Anstey Ferreira Gehring Orals Bamford Brown, 1993 Biagi Bordoni & Berg,Hederos 1996 Humphreys Lovell Schalin-Karrila Wright & Burton, 1982 also pigmentation; Biagi * 77 TABLE 26 TABLE Dietary interventions

TABLE 27 Results: borage oils

Study Main reported results Authors’ conclusions Quality/comment

Bahmer & Using within-patient change in ADASI score, Positive effect of borage oil in atopic Pilot study awaiting full translation. Novel Schafer, 1992246 five out of seven patients treated with borage eczema warrants a larger study use of time-series data to analyse within- oil showed a favourable effect compared patient changes in ADASI score with one out of five treated with palm oil

Borrek et al., After 10–14 weeks of treatment there was There was no improvement of the eczema Small study, which showed no difference 1997247 no improvement of the eczema under under borage oil group compared with between active drug and placebo.Awaiting active compared with placebo. Both groups placebo translation for methodological quality showed improvement while taking placebo. This result could be seen in the objective investigations (Costa score, three times per treatment period) as well as in the daily patients documentation.The patients whose eczema has improved under borage oil (n = 10) had no special characteristics, so that authors could not identify any responder-type

Buslau & Thaci, Of the 32 evaluable patients, 14 out of 18 Borage oil showed good effects on the Awaiting full translation. No ITT analysis 1996248 patients (78%) in the borage oil group course of mild-to-moderate atopic eczema carried out and large drop-outs. Unclear compared with six out of 14 (43%) what a ‘significant improvement’ meant to patients in the palm oil group showed a patients in terms of magnitude of response significant improvement in ADASI score compared with baseline

Henz et al., The reduction in Costa score points was This study shows no overall efficacy of Method and concealment of randomisation 1999249 similar in the placebo- and borage oil- gamma-linolenic acid-containing borage oil not stated, study described as double-blind, treated groups, though improvement of in atopic eczema, with steroid use being success of blinding not recorded. No ITT individual symptoms over placebo was the primary response parameter, though it analysis.Authors state that all previous observed for erythema, vesiculation, suggests that a subgroup of patients may evening primrose oil studies look at 8–10% crusting, excoriation, lichenification, and benefit from this well-tolerated treatment gamma-linolenic acid, whereas borage oil insomnia, but not for pruritus (no data looked at 23% gamma-linolenic acid given). No statistically significant differences concentration. Significant effect shown in were noted between the two treatment subgroup (post hoc) of best compliers and groups regarding the primary efficacy whose blood changed. No overall difference criterion ‘corticosteroid dosage until in main comparison response’ (p = 0.8949). Significant benefit shown in a subgroup of ‘good compliers’

Valsecchi et al., There was no statistically significant Dietary supplements of GLA resulted in a Method and concealment of randomisation 1996250 difference (p = 0.165) between the mean significant improvement in the clinical not stated, blinding not stated, no ITT. reduction from baseline clinical score of conditions of atopic eczema compared with Published as a letter only. No difference the placebo (48.4) and the GLA group baseline; however, a simultaneous between the two groups, but study under- (70.8). Mean baseline score was higher in improvement of the clinical status, powered to detect modest benefits the GLA group at 281.0 compared with compared withy baseline, was observed 251.3 in placebo with placebo, and there was no significant difference between the two treatments

TABLE 28 Results: fish oils

Study Main reported results Authors’ conclusions Quality/comment

Bjornboe et al., The total patient’s symptom score showed Results favoured the experimental group Method and concealment of randomisation 1987251 significantly greater improvement in the with regard to scale itch and overall unclear, study described as double-blind. experimental group compared with control subjective severity compared with the Eight withdrawals and drop-outs, no ITT group; mean change 11.3 and 1.3, respect- controls analysis carried out. Discrepancy of out- ively, baseline scores not given (p < 0.02). comes between patients and physicians. The physician-assessed scores showed no Multiple outcomes statistically significant difference between the groups

Gimenez-Arnau Only 6-week results presented for all Linoleic acid is useful to treat atopic Method and concealment of randomisation et al., 1998253 three groups due to high drop-out rate eczema unclear, study described as double-blind. in vegetable oil and placebo groups.This Very scant methods and results data. No showed a 75% reduction in median Rajka mention of withdrawals or drop-outs scores in the fish oil group compared with 5.3 in the placebo and 8.8 in the vegetable oil groups (p < 0.001). Baseline scores not given

Soyland et al., The mean clinical score for the six param- There was a progressive significant Method and concealment of randomisation 1994252 eters evaluated the physicians showed an improvement of the clinical condition in unclear, study described as double-blind. improvement from 4.4 to 3.1 (30%, both groups, compared with baseline Twenty-four withdrawals/drop-outs, no ITT p < 0.001) in the fish oil group, and from scores. However, there was no significant analysis carried out. Large study with no 4.2 to 3.2 (24%, p < 0.001) in the corn oil difference between the two groups, which hint of any difference of response between group. No significant differences between causes the possibility of a placebo effect the two groups 78 the two groups for any outcome Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 29 Results: evening primrose oil

Study Main reported results Authors’ conclusions Quality/comment

Topicals Anstey et al., Analysis of results revealed a significant Topical evening primrose oil has potential Method and concealment of randomisation 1990241 difference between the two groups in the as treatment for atopic eczema and unclear, study described as double-blind. mean absolute change in patient scores warrants further clinical studies Marked discrepancy between patient and over the 14-day period (p = 0.006) and doctor assessment may suggest unblinding. also in percentage change over 14 days One drop-out, no ITT analysis carried out. (p = 0.021). In both cases the change was A very small sample over a very short time positive, indicating improvement in of only 2 weeks, but acknowledged as a eczema and that evening primrose oil pilot study was the better cream.There were no significant differences for change in doctor’s assessment

Ferreira et al., Clinical assessment of xerosis and pruritus GLA-containing emollients can be a useful Method of concealment of randomisation 1998234 revealed improvement in all four groups, improvement in the management of atopic unclear, no mention of blinding.Two drop- slightly more pronounced in the three eczema patients outs/withdrawals, no ITT analysis carried GLA groups. None of the changes out.To be included, eczema had to be in statistically significant remission, those who had eczema flare became failures. No hint of a dose/benefit between the different concentrations of evening primrose oil

Gehring et al., In study 1, which compared oil-in-water That the choice of vehicle is an important Method and concealment of randomisation 1999232 evening primrose oil emulsion to vehicle, factor in the efficacy of evening primrose oil not described. No ITT analysis. Described barrier function assessed in various ways as double-blind.This study described two improved in both groups equally. In study different studies. In study 1, an evening 2, which compared a water-in-oil evening primrose oil-in-water emulsion was compared primrose oil emulsion to a different vehicle, with vehicle in a right/left forearm comparison the authors claimed that there was evidence in 20 participants, and in study 2, an of a stabilising effect of the active prepar- evening primrose oil water-in-oil emulsion ation above vehicle, yet the graphs for was compared against a different vehicle in graphs for skin hydration and transepi- 20 different participants.The authors then dermal water loss and irritation potential make inferences about one emulsion do not suggest any clinical or statistically compared against the other without any differences at the end of the 4-week study direct data to support this.The authors’ conclusions are not supported by their data.The study shows the general improve- ment of barrier function that occurs with oil applied to the skin, but provides no evidence of efficacy of evening primrose oil above vehicle Orals Bamford et al., No significant effect on erythema, scale, Evening primrose oil had no significant Method and concealment of randomisation 1985240 excoriation, lichenification, or overall effect on the lesions of patients with a unclear, study described as double-blind. severity in 123 patients with atopic eczema diagnosis of atopic eczema and lesions of Thirty-one drop-outs, no ITT analysis of average severity while they took oral average severity carried out. Study very clearly written up, doses of evening primrose oil (2 or 4 g in good information on how many patients children, 6 or 8 g in adults).Actual data were approached and how compliance was shown graphically in four figures checked. Later correspondence by company accused authors of mixing up tablets

Berth-Jones & At 16 weeks, the mean (SEM; no. patients) Our study, which avoided the Method and concealment of randomisation Graham-Brown, improvements in Leicester scores were methodological and analytical problems of unclear. Study described as double-blind. 1993243 8.48 (2.85; 33) for patients on Epogam, previous studies, found no effect of No ITT (21 drop-outs).Well-reported study 2.54 (2.89; 35) for patients on Efamol essential fatty acid supplementation in otherwise. No improvement in evening marine, and 7.15 (2.88; 34) for those on atopic eczema primrose oil or Efamol marine singly or placebo. On neither active regimen was combined, similar in children and adults mean improvement significantly different from placebo at 16 weeks (p = 0.74 for Epogam, 0.26 for Efamol marine)

Biagi et al., There was a trend towards improvement The overall severity of atopic eczema Randomisation and concealment not stated, 1994237 in the low-dose group, which approached improved significantly on a high dose of blinding not elaborated/tested for. No ITT significance (p = 0.077) and a significant evening primrose oil compared with analysis, three drop-outs. Benefit only in improvement in the high-dose group placebo, independent of whether the higher-dose group and for one out of three compared with placebo (p = 0.046) for children had manifestations of IgE- main outcome measures regardless of overall physician-rated severity.There were mediated allergy whether children were atopic or not no significant changes for the symptoms of itch and for the extent of disease in the evening primrose oil group compared with placebo continued

79 Dietary interventions

TABLE 29 contd Results: evening primrose oil

Study Main reported results Authors’ conclusions Quality/comment

Bordoni et al., After 4 weeks, the symptoms of patients Evening primrose oil substantially improved Method and concealment of randomisation 1987239 treated with evening primrose oil signif- the clinical symptoms of atopic eczema in unclear,‘doctor unaware of which patients icantly improved (p < 0.01), in placebo- two-thirds of the treated children after receiving which treatment’ suggests single- treated children the clinical status remained 4 weeks of therapy blind study. Drop-outs not mentioned, largely unchanged. No summary data of presume ITT analysis. Evening primrose oil magnitude of benefit given, but can be suggested benefit, very short-term study. visualised in figure High-dose capsules for children

Hederos & Berg, Both groups of patients were substantially Study demonstrated significant Method and concealment of randomisation 1996235 improved with respect to baseline but no improvements in atopic eczema during the unclear. Study described as double-blind. significant differences between Epogam and 16 weeks’ treatment, but no significant Well described study. No size differences placebo groups were observed.The mean difference was found between active and between two groups. ITT analysis carried % improvement from baseline for patient placebo treatment in a group of children out, two withdrew in evening primrose oil global assessment was 10.0 and 7.1% for who need regular treatment with topical group Epogam and placebo, respectively.The steroids corresponding % improvement for physician-assessed global improvements were 11.0 and 13.8% for evening primrose oil and placebo, respectively

Humphreys et al., Twenty-three out of 27 patients taking Adjunctive treatment with gamolenic acid Method and concealment of randomisation 1994238 active treatment showed an improvement in evening primrose oil should be unclear, blinding unclear. No ITT analysis in their clinical score for erythema by the considered in patients with chronic atopic carried out, (six drop-outs) good end of the treatment period compared eczema description of drop-outs though. Statistics with 11 out of 23 in the placebo group. well described.Well-described study but The results for surface damage were very three groups a little confusing. Baseline similar, 12 out of 23 in the placebo group severity very different in GLA group than showing an improvement in clinical score, placebo but this was adjusted in analysis compared with 23 out of 27 in the GLA group. No benefit for lichenification

Lovell et al., Doctor assessment baseline 6.26 (±0.24) Patients receiving Efamol showed a modest Method and concealment of randomisation 1981244 reduced to 5.27 (±0.38) after evening but significant improvement on both the unclear, study described as double-blind. primrose oil and 5.64 (±0.38) after placebo. doctor’s and their own assessment Clinical significance of a change in score Patient assessment baseline 5.96 (±0.16) from 5.96 to 5.02 not clear. Possibly not reduced to 5.02 (±0.37) after evening done correct statistical test on differences primrose oil and 5.54 (±0.38) after placebo between scores

Schalin-Karrila et In the evening primrose oil group, Thus in every clinical parameter the degree Random method and concealment method al., 1987236 a statistically significant improvement was of improvement was significantly greater in not mentioned, success of blinding not observed in the overall severity and grade the evening primrose oil group than in the recorded, yet possible that placebo group of inflammation (p < 0.001) from baseline placebo group could have bowel problems given they had and a significant reduction in the surface 4 g of liquid paraffin daily. No ITT analysis area involved as well as in dryness and itch (one from evening primrose oil, not compared with baseline (p < 0.01). Patients mentioned in placebo group).The evening in the placebo group showed a significant primrose oil group started off more severe. reduction in inflammation compared with Authors concluded that evening primrose baseline (p < 0.05). Unclear if there was a oil superior for global severity, inflammation, comparison of change in clinical scores dryness, itch between the two groups

Wright & Burton, In the low-dose groups itch was the only Various doses of oral evening primrose oil Random method and concealment method 1982242 symptom that responded better to evening in 99 patients with atopic eczema showed not mentioned, success of blinding not primrose oil than placebo. In the high-dose that the preparation produced a significant recorded. No ITT analysis, 16 adults and groups the patient assessments showed clinical improvement when taken in high three children dropped out. Only itch that the evening primrose oil was signifi- dosage improved in low-dose groups whereas most cantly superior to the placebo with regard improved in high-dose groups. Multiple to itch (p < 0.003), scaling (p < 0.002), and significance tests. Published separately twice general impression of severity (p < 0.01). The doctor assessments also showed a beneficial effect of the active treatment on the overall severity of the condition (p < 0.002).The other symptom scores showed the same trend but failed to reach statistical significance

80 Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 9 Non-pharmacological treatments

House dust mite reduction mite numbers. There was no significant clinical improvement in those who had been allocated There is strong circumstantial evidence that house to natamycin versus placebo. The mean symptom dust mite antigens are an important precipitating score (maximum score 288) in the natamycin and factor for atopic eczema.267 The presence of vacuum group changed from 55.2 at baseline to immune sensitisation and allergic reactivity to 38.6 at 4 months compared with 45.2 to 35.8 in the house dust mite in the majority of atopic eczema group with no natamycin and no daily vacuuming. patients, the fact that cutaneous patch tests with house dust mite extract produces an eczematous A second small, but important RCT was conducted reaction in which allergen-specific helper T-lympho- by Tan and colleagues263 in 1996 with duplicated cytes are found, the improvement of atopic eczema publication in 1998 and again in 1999. Tan and when sufferers are removed to low house dust mite colleagues randomised 60 patients (30 adults and environments, and the exacerbation of existing 30 children) for a total of 6 months to an intensive atopic eczema areas following direct application of dust mite eradication regimen comprising Gore- house dust mite extract,379 all argue for a possible Tex ® (Intervent, UK) bedding covers, benzyl- role of house dust mite allergen in atopic eczema. tannate spray to kill mites and denature their There are many methods for attempting to reduce allergens, and a high filtration vacuum cleaner, house dust mite levels in the home including the or to a control group of plain cotton bedcovers, use of mattress and pillow covers that are impervious placebo spray and a standard upright vacuum to house dust mites, frequent vacuum cleaning (with cleaner with a poor filtration performance. One or without high performance filtration), and use of trained nurse applied the bedcovers and spray each acaricidal sprays. It has been argued that measures week, and participants were encouraged to vacuum such as sprays (e.g. benzyl benzoate or permethrin) bedrooms daily. They showed a dramatic and very which only kill mites380 are not effective as a sole similar reduction in concentration of house dust treatment because the allergenic faeces and dead mite major allergen (Der p1) in bedroom carpets in mites are still present.267 both the active and placebo treatment groups at the end of 6 months. Disease activity, as recorded in In chapter 13 (Treatments with no RCTs), it is pointed terms of surface area involvement and a composite out that no RCTs on house dust reduction as the severity score (maximum score 108) measured at sole therapy for prevention of atopic eczema could one point at the end of the 6 months, reduced by a be identified. A total of five RCTs evaluating the small amount in both groups, but more so in the role of house dust mite reduction in the treatment active group. The mean reduction in scores for the of established atopic eczema were identified.260–263,267 active and placebo groups were 12.6 and 4.2 units, Two further studies of changing housing environ- respectively. Those in the active treatment group ments by Sanda and colleagues381 and Fukaya and were more severe to begin with, and so an analysis colleagues382 were excluded as the intervention of covariance was conducted to allow for baseline groups were not randomised. Another two studies scores and initial house dust mite antigen levels. described as prospective randomised studies383,384 This showed a mean difference of 4.2 in change of were excluded as they did not involve any random- score (95% CI 1.7 to 6.7 units; p = 0.008) between ised therapeutic intervention comparisons. the two treatments. Further analysis also suggested that it was changes in the mattress and carpet dust Benefits in the bedroom that mediated much of the The first small RCT by Colloff and colleagues262 treatment effect. Subgroup analysis suggested that evaluated the daily use of natamycin (a spray used only children had a clinically and statistically to kill house dust mites) versus matched placebo significant benefit, and that there was no spray with and without vacuum cleaning in a parallel correlation between clinical improvement and group study for 4 months in 20 young adults with positive skin prick tests at the study outset. atopic eczema. They demonstrated that it was the vacuum cleaning and not the natamycin spray that Another small study in Japan by Endo and had a significant impact on reducing house dust colleagues261 evaluated the potential benefit 81 Non-pharmacological treatments

of intensive vacuum cleaning in the rooms of of very different vacuum cleaners. It is also unclear 30 children with atopic eczema for a total of which method of reducing house dust mites is the 12 months. Both groups were visited every 3 weeks most efficient as studies have tended to use several by a team of mite specialists who either cleaned measures at once. Data from the Tan and colleagues263 room floors, mattresses and quilts very thoroughly study suggest that just vacuuming with an ordinary and encouraged parents to clean in the same way household cleaner achieves similar and massive in-between visits, versus a less intensive clean reductions of house dust mite antigen levels in (vacuum suction power reduced to 50%) with bedroom carpets to those achieved by the more similar cleaning in-between visits. Parents were expensive high filtration vacuum cleaners that are thus unblinded to the intervention. A statistically advertised in patient support group magazines. significant decrease in mite numbers in favour of The Tan and colleagues study suggests a definite the intensive cleaning group was only noted for benefit for a range of intensive measures to reduce the room floors. Clinical scores, as evaluated by house dust mite levels around the home, but the a physician blind to treatment allocation, were clinical relevance of the small changes in scores significantly improved in the active group compared observed is difficult to determine in the absence with baseline but not in the control group. Clinical of patients’ evaluations or outcome measures that scores were given in graphical form only and the capture the chronicity of disease over the entire appropriate statistical test of mean difference 6-month period. The Endo and colleagues261 study between the two treatments was not reported. suggested some clinical benefit with frequent intensive vacuum cleaning, but this could not be Another unblinded RCT by Nishioka and collea- related to reduction in house dust mite numbers. gues260 evaluated the benefit of encasing quilts and On the basis of the Tan study, the Endo study mattresses in microfine fibres versus simple cleaning could be criticised for comparing two active measures alone in 57 Japanese infants with atopic treatments, and that a comparison of frequent eczema who were not allergic to house dust mite vacuuming versus ‘normal cleaning’ would have as determined by blood tests at the study outset. been better given the fact that any form of active After 1 year, they found that 31% of children in intervention for intensive or high-filtration the encasement group compared with 63% in the vacuuming is difficult to blind. control group had serological evidence of house dust mite sensitivity (p < 0.02). The authors did Both Tan and Endo are to be commended for not report any outcomes on atopic eczema disease conducting such long-term studies. Further such activity in that paper. Correspondence with the studies in other populations, separating the authors suggests that there were no differences different interventions for reducing house dust between the two groups at the end of the study for mite, are needed. It is important that such trials the clinical outcomes, though there was a reduction are as pragmatic as possible to determine which in topical corticosteroid requirement in the inter- groups respond best, which interventions are vention group. the most cost-effective and whether the laborious interventions are sustainable in less- Harms motivated people. None of the studies reported any adverse events of the anti-house dust mite treatments. This does not necessarily imply that none occurred. The imposition House dust mite hyposensitisation of daily vacuuming for a long period has a cost in terms of time for parents and sufferers, as does Hyposensitisation refers to the technique of trying the purchase of a high filtration vacuum cleaner, to induce an immunological and clinical tolerance impermeable mattress covers and mite sprays. to allergens that might be playing a role in allergic disease by repeated and progressive exposure to Comment increasing amounts of allergen, as is performed for It is a pity that so few studies on house dust mite example, in hay fever desensitisation. Three RCTs avoidance have been performed on atopic eczema. that evaluated the role of desensitising atopic Those that have been done tend to be small and eczema patients to potential causative allergens were difficult to generalise in the absence of more prag- located.264–266 Another study385 was excluded as it matic studies. In none of the studies was the method was unclear whether participants were randomised. of randomisation and concealment reported, and no intention-to-treat analyses were performed Benefit (though drop-outs were quite low). The validity of The first small study by Glover and Atherton264 82 blinding in the Tan study in unclear due to the use evaluated the use of a tyrosine-adsorbed extract of Health Technology Assessment 2000; Vol. 4: No. 37

house dust mite in 26 children with atopic eczema recorded deaths due to anaphylaxis. Weekly who were house dust mite positive on skin-prick injections for children are also painful and testing. In the first part of the study, children were require attendance at a healthcare facility. randomly allocated to weekly active or placebo injections for 8 months. Clinical scores improved Comment dramatically in both groups, but there were no It is possible that the lack of statistical significance obvious differences between the groups. In the in the Glover study was due to lack of power or a second part of the study, the 13 children who had large placebo effect due to the injections. Improved been allocated active treatment in the first part of treatment concordance and ancillary care could the study were offered a further 6-month period also explain the impressive improvements in those of monthly injections. The seven who accepted having placebo injections. Similarly, the lack of were then randomly allocated to receive active obvious benefit in the Galli study could be due to treatment or placebo. Redness and skin thickening inadequate numbers, other concurrent treatments scores (but not surface damage) deteriorated more such as reduction in house dust mite measures, or in the control group and these differences were that the oral allergen hyposensitisation therapy was statistically significant. inactive via the gut route. It is difficult to make any further judgement on the Wen paper due to the Another study by Galli and colleagues265 looked at scant methodological details provided. the possible benefit of a mixture of house dust mite allergens given in an oral suspension three times weekly in children with atopic eczema who Avoidance of enzyme-enriched were sensitised to house dust mite. Three groups detergents were compared, one non-randomised group of children with concurrent asthma and or rhinitis Detergent enzymes may cause skin irritation and (n = 26), and two groups with exclusive atopic occasionally hypersensitivity reactions leading some eczema who were randomised to oral hyposensit- physicians to advise atopic eczema patients to avoid isation (n = 16) or no specific treatment other than the use of such detergents in favour of alternative ‘conventional therapy’ and measures to reduce ‘non-biological’ detergents.386 The authors located house dust mite (n = 18). Comparison of change one RCT that tested the hypothesis that enzyme- in clinical scores between the two randomised containing detergents are more likely to aggravate groups did not reveal a statistically significant or atopic eczema than a non-biological detergent.268 clinically relevant improvement in the active group. Benefits A further study by Wen and colleagues266 was After a 1-month washout using their normal conducted in Shanghai with allergenic extracts of detergent, 26 adults with mild-to-moderate atopic house dust mite manufactured at that university. eczema (mean age 25 years) were randomised in In that study, 56 patients with atopic eczema (mean a double-blind crossover study to receive either a age 24.8 years) were randomly allocated to weekly trial detergent containing enzyme concentrations injections of local allergenic extract (18 patients), reflecting the highest quantity in commercial a partially purified extract (20 patients) and enzyme-enriched detergents or a visually identical normal saline placebo (18 patients) for 1 year. detergent without enzymes as control, for a Clinical scores (unspecified) were reduced in all 1-month period followed by a further month with three groups and possibly more so in the two active the opposite detergent. Topical steroids were groups, though no statistical tests were performed. permitted during the study and weighed. In the The data was presented in graphical form only. 25 patients completing the trial, there was no hint of difference between the active detergent and the Harms control in terms of SCORAD score (29 on active, Apart from local discomfort at injection sites 29 on control, with 95% CIs for the mean (similar in each group), no adverse effects were difference extending from –4 to +5 on a scale of reported in either small study. Caution is needed 108), usage of topical steroid (44 g/month in based on the rare but potentially life-threatening active versus 43 g/month on control), patient- hazard of an anaphylactic reaction when desensit- reported itch (1.3 versus 1.3), or patient-reported isation has been done with bee sting or hay fever eczema activity (1.4 versus 1.4). allergy. Wen and colleagues state in their paper that allergenic extracts of house dust mite have Harms been used for 20 years for treating and diagnosing None of the patients had contact dermatitis to mite allergy in China and that there have been no enzymes when patch tested at the end of the study, 83 Non-pharmacological treatments

and there was no evidence of specific blood IgE warp-knits compared with jersey knits, but no against any of the enzymes. different for cotton and polyester of fine fibre construction (assessed by scanning electron Comment microscopy). Garment comfort in all groups was Although this study was small, the virtual absence reduced after sweating. of any differences between the enzyme and non- enzyme detergents and the corresponding narrow In the Seymour study,271 cloth nappies were CIs provide convincing evidence of a lack of harmful compared with cellulose core nappies versus effect. The study was not sponsored by industry. cellulose core nappies containing absorbent gelling material in 85 babies aged less than 20 months of age who had atopic eczema and Benefit from specialised clothing who were recruited by an advertising campaign. Average grade of eczema on the body as well as Intolerance to wool is frequently reported in atopic degree of nappy rash was scored by an independent eczema patients and has been used as a minor dermatologist. At the end of the 26-week period, criterion for diagnosing this condition. We found there was no clinical or statistical difference between three RCTs269–271 evaluating clothing material in the different nappy types for overall grade of atopic atopic eczema, two of which, by Diepgen and eczema. Nappy rash, however, was significantly less colleagues in 1990 and 1995,269,270 evaluated the in the group using cellulose nappies with absorbent irritative capacity of poncho-like shirts made of four gelling material, compared with the others at different materials (cotton versus other synthetics 26 weeks and throughout the trial (p < 0.05). of different fibre structure). The other RCT by Seymour and colleagues271 evaluated the clinical Harms effects of different types of nappies on the skin of No adverse effects are reported in these small normal infants and infants with atopic eczema in studies, though specialised cotton clothing for a 26-week trial. atopic eczema sufferers is more expensive than other synthetic fibres. Benefits In the Diepgen 1990 study,269 55 patients with No specific adverse effects were reported in the atopic eczema were compared with 31 control trial of different nappies, though nappy rash itself patients without atopic eczema and randomised (the main efficacy outcome of this study) could to one of four poncho-like shirts of varying fibre be considered an adverse effect, which is desirable roughness. The intensity of itching or discomfort due to prevent. to repeated wearing of these shirts was evaluated by means of a points system, whereby 10 equals a max- Comment imum comfort and 1 equals maximum discomfort. The studies by Diepgen and colleagues in 1990 At the end of the study, those wearing cotton reported and 1995 tested the hypothesis that cotton clothing a comfort score of 8.4 compared with 7.3, 3.6 and is best for atopic eczema sufferers. The success of 3.3 for the other textile shirts in increasing order blinding in both trials is under question in view of of weight and fibre roughness (estimated from the different roughness of the various shirt fibres. graph). The difference between the cotton and other Magnitude of effects were not stated in the Diepgen fibres was significant only for the latter two groups. 1995 paper, and it is possible that the study could have missed small differences between cotton and The 1995 study by Diepgen and colleagues270 polyester fabrics comfort. The purported need for (published in a German textile journal) evaluated specialised clothing can result in considerable seven different garments on 20 atopic eczema increased economic burden to eczema families and patients with mild-to-moderate disease (average to the State. The two RCTs both suggest that there age 25.3 years) with and without a ‘sweat test’ is nothing special about cotton for atopic eczema designed to lower the itch threshold. The garments sufferers apart from smooth fibres. Other synthetic included cotton, and polyester garments made fibres can be constructed with similar smooth with different fibre roughness, yarn roughness fibres using yarns and fabric construction that is and fabric weaves. The study was a randomised just as comfortable for atopic eczema sufferers. crossover study (Diepgen T, personal oral commun- It would be wise to repeat such studies in the UK ication, January 2000), with each garment worn and elsewhere before implementing policy decisions, under standardised conditions on 4 consecutive and public knowledge of the availability and cost days. Comfort, as assessed on a visual analogue of cotton alternatives would be an advantage to 84 scale, was statistically significantly higher for eczema sufferers. Health Technology Assessment 2000; Vol. 4: No. 37

It was good also to locate an RCT evaluating different Comment nappy types in atopic eczema. It was unclear in this Quality of reporting was good in the Adachi study, study if the group with atopic eczema simply wearing but they compared two types of salt that could have a cloth nappy were randomised in the same way as been equally active. We agree with the author’s the other two groups and whether statistical compar- conclusions that possibly a longer contact with sea isons were made to the control population who water is necessary. The study duration was also very were not part of the same randomised group. short (1 week). The uptake of an intervention that The study, nevertheless, suggests that nappy rash consists of spraying each other with a concentrated is less severe in atopic infants who wear nappies salt solution is also likely to be limited in the UK with gel absorbent material, though there appears and possibly quite costly to patients. It is a pity that to be no benefit for the general eczema control a simple RCT comparing salt baths versus ordinary elsewhere. There was no evidence to support any baths has not been done. Even an RCT comparing benefit of conventional disposable nappies over the effect of regular versus irregular bathing would cloth nappies, though the study may have lacked be informative given the different strongly held power to demonstrate small differences. views of frequency of bathing recommendations in children with atopic eczema. One recent non- randomised study388 from Japan has compared Salt baths the benefit of sea water therapy at a beach with and without dolphins to encourage children with Salt has been used for centuries in the treatments of severe atopic eczema to enjoy the sea water. This skin diseases, particularly psoriasis, popularised by needs to be tested further in an RCT. holidays at the Dead Sea where the combination of high salinity and ultraviolet light may benefit patients. Some physicians recommend regular salt baths as a Nurse education measure for controlling atopic eczema, presumably based on anecdotal reports of patients’ eczema clear- The effective topical treatment of a child with ing after bathing in the sea while on holidays. Salt atopic eczema is dependent upon good manage- could help atopic eczema because of its cleansing ment by the parents. Good parental concordance properties (saline is a weak antiseptic agent) or by can be achieved by regular follow-up visits and drawing fluid out of oedematous acute eczematous good patient–physician relationships, and also skin. Despite its advocates, we could find no RCTs by active training and information given in an comparing the use of salt baths versus ordinary baths. educational session by a nurse or other appropriate One RCT (published in German) of 40 patients with carer. One RCT273 has evaluated the possible psoriasis and atopic eczema evaluating synthetic Dead additional benefit of a single session provided by a Sea salt baths plus phototherapy against 3% salt baths nurse in educating parents of children with atopic was excluded as results for the eight atopic eczema eczema versus conventional dermatological care. patients were not given separately.387 We did locate one Japanese RCT comparing deep-sea salt versus physio- Benefits logical saline, which will be reported further here.272 Fifty consecutive patients aged 4 months to 6 years 2 months, with atopic eczema of varying severity Benefits were randomised to either conventional treatment One-hundred patients with mild-to-severe atopic by a dermatologist or the same treatment plus a eczema aged 15 years and over were randomised single session by a nurse (‘a nurse lesson’), which to either deep-sea water or physiological saline. included general information about atopic eczema Both waters were sterilised and heated to 65 degrees and environmental control, information and centigrade then sprayed onto the body before home demonstration of topical treatment and also a bathing and washed away after 10 minutes. Treat- discussion of realistic expectations. The study ment was daily for 1 week. Doctor’s global evaluation lasted for 3 months and was unblinded. At the end and several other skin signs reduced by only a small of the 3-month evaluation period, mean eczema amount (~15%) in each group after 1 week, and score (maximum score 96) had fallen from 26.4 at there were no clinical or statistical differences in baseline to 7.1 in the group given standard derma- the change in scores between each group. tological care plus education compared with 21.3 at baseline to 10.8 for conventional care alone Harms (p < 0.05). This comparison was not adjusted for No adverse effects were reported in this study. baseline scores, which were different. Each score There were five drop-outs for reasons not related also showed a statistically significant reduction in to the treatment. favour of the education group compared with the 85 Non-pharmacological treatments

standard dermatological care, and hydrocortisone Benefits consumption was significantly greater in the inter- Thirty-six children with atopic dermatitis admitted vention group. as inpatients to a high-altitude specialist treatment centre for atopic eczema in Davo, Switzerland were Harms randomised according to sex, age and severity of No adverse effects were reported in this study. Those disease to receive sham (placebo) or active treat- patients in the intervention group had to attend ment with the bioresonance apparatus. The bio- one additional session with the nurse. resonance was conducted exactly as described in the specific literature and by a qualified BIT therapist Comment for at least 4 weeks. Blinding was obtained by a This RCT suggests a modest benefit from a single specially designed switchbox operated by an engineer nurse education session following standard derma- who kept its randomisation code outside the clinic tological care. The authors are to be applauded in a sealed envelope. Patients were allowed their for randomising the treatment groups, though the normal treatment with creams, emollients and lack of blinding and failure to perform an intention- dietary restrictions as required throughout the study. to-treat analysis limits the study quality. The study For the short-term outcome (at least 4 weeks), total nevertheless suggests a modest benefit to a single disease severity score in the active group had fallen session of nurse education, though the component from 39.8 to 27.3 at the end of the study period of the ‘package’ of the nurse education that compared with a fall from 35.3 to 26.6 at the end conferred the most benefit is unclear. It is possible of the sham treatment (p = 0.23). No difference for instance that most of the benefit could be was observed for the sleep score, though pruritus due to increased and appropriate use of hydro- score was slightly improved in the actively treated cortisone, which tends to be underused in the group (p = 0.12). There were no clinically or community because of inappropriate fear of statistically significant differences between the two adverse effects. Further RCTs in other countries treatment groups in a number of immunological that use a similar educational package and blinded markers in the blood and long-term outcomes outcome measures are needed. measured 8 months after the treatment.

Harms Bioresonance No adverse effects were described in the study, though the therapy can attract a considerable Bioresonance therapy, also called biophysical financial cost outside of health services. information therapy (BIT) has become popular as an alternative medical treatment for a variety Comment of allergic diseases in Europe. Bioenergy is defined This study was very carefully reported and authors as the bioelectric magnetic field which is unique to were meticulous in giving the bioresonance a ‘fair materials, and that bioelectric waves produced by test’ by following the intervention as meticulously people can have diagnostic and therapeutic as possibly. The study was blinded, and random- purposes. The proponents of this theory claim isation and concealment of allocation were well that the main purpose of BIT is to give a strong described, though an intention-to-treat analysis impulse to spontaneous healing energies of the was not performed (4 out of 36 children dropped body for self-regulation. The ultrafine electro- out). The results do not show any evidence to magnetic waves of the patient’s body, as well as support benefit of bioresonance therapy. Although their disturbances and presence of allergens, are the study was relatively small, the study was purported to be transmitted for diagnostic and powered to exclude a 35% benefit of relevant therapy using brass wire electrodes analysed by treatment benefit of bioresonance therapy in the a ‘bioresonance apparatus’. This electronic sensitive COSTA scoring method. Therefore, instrument allegedly distinguishes between although small benefits cannot be excluded by pathological and normal healthy waves from a the study, the study failed to show evidence of patient. Pathological waves can be reversed any moderate or large treatment effects of this electronically (‘corrected to healthy ones’) by mode of treatment. It may be argued that the the separator, and transmitted back to the patient treatment was tried in a situation where marked for a therapeutic effect. The use of such BIT is treatment benefits were already occurring as a frequently accompanied by claims of complete result of inpatient stay at high altitude (with very cure for allergies. One RCT conducted in low house dust mite levels), and ideally a similar Switzerland has evaluated the efficacy of bioreson- RCT could be performed in a more usual 86 ance in children with atopic eczema.274 outpatient setting. Health Technology Assessment 2000; Vol. 4: No. 37

Psychological approaches • application of hydrocortisone cream for the entire 5-week period Psychological approaches to the management of • application of betamethasone valerate atopic eczema may be quite diverse ranging from (a strong topical steroid) for 3 weeks followed specific cognitive approaches to behavioural by hydrocortisone for the remaining 2 weeks approaches such as habit reversal. Psychological • application of hydrocortisone plus habit-reversal and emotional factors have always been considered for the 5-week period important in atopic eczema, though it is unclear to • application of betamethasone plus habit-reversal what extent such factors are a result of the eczema for the first 3 weeks followed by hydrocortisone rather than the other way round. It has been plus habit-reversal for the remaining 2 weeks. postulated that much of the scratching (which can be pleasurable) in atopic eczema becomes a habit, The study was unblinded. Results are reported more and that such habit is detrimental, as scratching fully in the section on topical corticosteroids (see damages the skin and leads to further eczema chapter 4 and appendix 3). The authors reported forming in the so-called scratch–itch–scratch cycle. significant differences between the behaviour Habit-reversal is a modified behavioural technique, therapy groups and those taking steroids alone for which teaches patients to recognise the habit, total skin status. Scratching was reduced by 65% in identify situations that provoke the habit, and the hydrocortisone only group, 74% in the then to progressively train them to develop a betnovate followed by hydrocortisone group, 88% ‘competing response practice’ such as simply in the hydrocortisone plus habit-reversal group, touching, squeezing or tapping the itching area, and 90% in the betnovate and hydrocortisone and or to develop other ways of moving their hands habit-reversal groups (statistics not presented). away from the itching area.389 The technique has been described in two RCTs106,276 conducted by the The study by Ehlers and colleagues in 1995275 same team from Sweden, and compared with topical evaluated the use of an autogenic training as a cortiscosteroids. A further RCT has evaluated the form of relaxation therapy (ATP) versus a potential benefit of three psychological approaches cognitive-behavioural treatment (BT), versus a versus dermatological education in the prevention standard dermatological educational programme of relapse in atopic eczema.275 Another RCT390 of (DE) versus combined DE and BT (DEBT). psychiatry support for patients with eczema was One hundred and thirteen patients attending an excluded as close inspection revealed that the outpatient clinic in Germany were randomised to patients had eczematous dermatoses of diverse types these four groups and were also compared with and only one case of atopic eczema was present in an additional standard medical treatment group that study. who were not part of the random assignment. Investigators were blinded as to the group Benefit allocation. The intervention was for 3 months In the Melin and colleagues study,276 17 patients and patients were followed-up for 1 year in order with atopic eczema aged 19–41 years were random- to evaluate disease relapse. At the end of 1 year, ised into two groups. One group was treated with mean skin severity lesion score dropped from hydrocortisone cream alone and the other group 29.5 to 28.8 in the DE group, 33.7 to 19.8 in the was treated with the cream plus two sessions of ATP group, 31.0 to 20.7 in the BT group, and habit-reversal treatment during the first week of 35.4 to 25.8 in the DEBT group. There were no the treatment period of 28 days. The study was significant differences in mean severity of itching unblinded. At the end of the assessment period, between the four randomised groups. DEBT led there was a 67% mean reduction in global eczema to significantly larger improvement in global score in the habit-reversal plus hydrocortisone skin severity than DE alone and this was also cream group compared with 37% score reduction accompanied by significant reductions in topical in the hydrocortisone only group (p < 0.05). Total steroid use. score of self-assessed annoyance was also markedly reduced in the active versus comparator groups. Harms Mean percentage reduction of scratching episodes In the Ehlers study, the behavioural approaches per day was 79% in the habit-reversal and hydro- required 12 weekly group sessions of 1.5 to 2 hours cortisone group compared with 49% in the hydro- each with a group size of between five and seven cortisone only group (p < 0.01). In the later study patients. No adverse events were reported in any conducted by the same team,106 45 patients (mean of the trials, though some of the drop-outs could age 24.8 years) were randomised in a parallel possibly be related to the fact that extra visits were fashion to four groups for a period of 5 weeks: needed for the behavioural technique. 87 Non-pharmacological treatments

Comment psoralen photochemotherapy. Psoralen is a photo- The Ehlers study275 was clearly reported and active drug taken by mouth or mixed in a bath, included an assessment of patient expectation of which is given with UVA radiation to enhance treatment benefit. No intention-to-treat analysis its effectiveness. PUVA has proven efficacious in was performed, but drop-outs were low (nine out psoriasis and is currently used in the treatment of 113 at 3 months). Over 14 outcome measures of eczema.393 were reported in the study, which introduces the possibility of multiple hypothesis testing. The The mechanisms by which ultraviolet light affects authors also performed statistical tests in comparison atopic eczema are not completely understood. to a non-randomised control group, which may not However UVB is immunosuppressive because it be justified. Nevertheless, the magnitude of improve- blocks the function of antigen-presenting Langer- ment for those receiving behavioural techniques in hans cells and alters the production of cytokines by addition to their standard dermatological care (which keratinocytes. There is also evidence that UVA is included topical corticosteroids) was moderately able to alter both Langerhans cell and eosinophil large, and carried more weight than the Melin and functions in patients with atopic eczema.394 Noren studies because assessments were made by an investigator blinded to the treatment allocation. We located six RCTs278–283 published in six papers The combination of habit-reversal plus judicious evaluating the use of ultraviolet light in atopic use of topical corticosteroids seems an attractive eczema, and these are summarised in Table 30. The one and evidence from two RCTs supports its use. only two RCTs of PUVA that might have included Both RCTs were unblinded, and conducted in the atopic eczema patients had to be excluded as it hands of enthusiasts. The generalisability of these was either not clear if those with ‘chronic hand findings to other populations should be determined eczema’ were atopic393 or because data on the in further RCTs, using objective assessment methods subset of atopic eczema patients were not given that are clinically meaningful, and conducted by separately.395 Statistical pooling of summary investigators blinded to group allocation. The measures was not possible due to the differences in magnitude of the benefits in these unblinded the type of ultraviolet light in each study and the studies were considerable, particularly when these lack of common outcomes at the same endpoints. were above that which could be expected with topical corticosteroids. Comment Generally the studies were quite small and poorly reported. Blinding was likely to have become Ultraviolet light unmasked in placebo-controlled trials due to the obvious tanning on one half of the body, along A proportion of atopic eczema sufferers have fewer with mild burning and marked treatment effects. flare-ups and decreased skin lesions during summer. Although the right/left body comparison design This observation, along with the benefit of ultra- had its limitations in terms of blinding, the lack violet light in psoriasis led to the introduction of of effect on placebo-treated body halves argues different forms of ultraviolet light for the treat- against a systemic effect of ultraviolet light treat- ment of atopic eczema.391 ment. Treatment effects were generally large and of rapid onset (i.e. within 1–2 weeks). Future studies Ultraviolet radiation (UVR) makes up a fraction should consider using a simple parallel group of the electromagnetic spectrum, which can be design and they should be of longer duration in further subdivided into: order to capture duration of remissions.

• UVC – the rays that do not pass through the Harms earth’s atmosphere Treatment with ultraviolet light usually ties patients • UVB – the rays responsible for nearly all to twice- or thrice-weekly visits to hospitals. Mild biological effects following sunlight exposure degrees of skin redness and burning are also including tanning, burning and skin cancer, and common short-term adverse effects. Occasionally • UVA – those rays closest to the visible spectrum more severe burning may occur. There is no direct that pass through glass, and are the least information on the long-term risk of skin cancer in harmful to the skin.392 atopic eczema patients undergoing ultraviolet light treatment. Although data on cohorts of psoriasis Hence, treatment is with either UVA or UVB or patients undergoing PUVA suggest that cancer risk a combination of both. Another form of UVA only increases after around 250 treatment sessions, 88 exists called PUVA (psoralen plus UVA) or extrapolating from these studies to another Health Technology Assessment 2000; Vol. 4: No. 37

inflammatory disease with a generally younger Salt baths patient population raises some concerns. This is • A Japanese RCT of 1-week duration has not particularly so for melanoma skin cancer where found any difference between deep-sea water it is thought that most risk is acquired from ultra- and physiological saline sprays before bathing. violet light in the first 20 years of life. Specific • RCTs comparing salt versus ordinary baths and cohort studies of different modalities of ultra- regular versus infrequent baths in people with violet light treatment of atopic eczema treatment atopic eczema are needed. are recommended. Bioresonance • There is no RCT evidence to support the use of Summary of non-pharmacological bioresonance treatment in atopic eczema. treatments Psychological approaches House dust mites • The results of three RCTs suggest that • Considering that the circumstantial evidence for psychological interventions such as behaviour- implicating house dust mites in atopic eczema is therapy habit-reversal techniques are a so strong, it is surprising that only three RCTs useful adjunct to dermatological treatment have examined the usefulness of house dust in atopic eczema. Generalising from these mite reduction. RCTs to other centres with less enthusiastic • There is some evidence that reduction of house and appropriately trained staff requires dust mite allergen around the home can result further evaluation. in a benefit to atopic eczema sufferers. • The clinical relevance of such benefit and Nurse education whether it is sustainable is unknown. • One small unblinded RCT has suggested a • The most clinically useful and easiest method of modest benefit from supplementing a reducing house dust mite allergen around the dermatological consultation with a single home in atopic eczema is not known. session with a dermatological nurse to provide • There is little evidence to support the use of more background information and to high-filtration vacuum cleaners above demonstrate the use of topical treatments. ordinary ones. • There is no evidence to support the sole use of Ultraviolet light sprays, which only kill house dust mites. • There is some RCT evidence to support the use • More studies on house dust mite eradication of UVB (broad and narrow band) versus placebo are needed, which separate the different in atopic eczema. interventions. • There is some RCT evidence to support the use • Such studies should be larger and more of high dose UVA in preference to UVB/UVA in pragmatic than those already done and should atopic eczema. include a cost-effectiveness analysis. • There is some RCT evidence to support the use • The role of hyposensitisation therapy in atopic of narrow band UVB (TLO1) in preference to dermatitis has not been adequately tested. ordinary UVA in atopic eczema. • There is some RCT evidence to indicate a Enzyme detergents benefit of high-dose UVA in the treatment of • Although parents of children with atopic eczema acute eczema flares, with efficacy slightly in the UK commonly avoid enzyme-containing superior to topical steroids. detergents in the belief that alternative agents • Missing evidence includes a comparison of are ‘kinder’ to the skin, one Danish RCT did not high-dose UVA versus narrow band UVB, find any evidence to support such a notion. PUVA versus placebo, PUVA versus UVB or topical steroids, and any form of ultraviolet Cotton clothing light versus other systemic immuno- • Two RCTs suggest that specially woven smooth modulatory treatments. synthetic garments are just as comfortable as • Future studies should be long term cotton to people with atopic eczema. (i.e. 6 months or more), in order to note the • Another RCT suggests that disposable nappies duration of remissions and the effects of containing an absorbent gelling material result ultraviolet light on disease chronicity. in less nappy rash than conventional disposable • Long-term multicentre surveillance studies are nappies or cloth nappies, though no benefit for needed in large cohorts of patients in order to atopic eczema in general was demonstrated. estimate subsequent skin cancer risk. 89 Non-pharmacological treatments continued Both treatments induced Both treatments large improvements with baseline,compared with some small significant statistically of UVA change in favour Most patients preferred UVA This thesis also presents studies reported the two 1988 in more in Jeckler detail; a further three small left/right comparison also described studies are vs UVB comparing UVA UVB vs and low-dose UVA/B, vs and UVA UVA/B, but it is unclear if RCTs these were Further details of study 1992 in Jeckler found thesis.This study of high- UVB vs low-dose suggested very little the between difference two, of study is but power very limited Unclear if randomisation to side of referred treatment active/placebo or whether to type of minimal erythemal dose Large magnitude of all for effect treatment parameters Large (11/17) drop-outs ‘intercurrent due to disease’ and lack of time treatments for Described as single-blind and randomised but methods unclear tan on UVA Differential to side of the body likely unblinded study have and drop- 12 withdrawals outs, no description given, and no ITT analysis Described as randomised but method unclear No blinding or drop- No withdrawals outs Methods very scanty Randomisation unclear; unblinded probably No ITT analysis Described as randomised but method unclear. due to Blinding unlikely mild burning on UVB- side treated No ITT analysis < 0.001).Thus p = 0.002 for difference in difference = 0.002 for p Improvement from mean from Improvement baseline of 10.3 (range clinical signs 6–18) for decreased (total score) and 6.4 UVA to 5.5 for UVB for separately Pruritus scored with baseline of 2.2 to 1.1 after improving and 1.3 after UVB UVA A decrease from baseline from A decrease of 10.8 to 5.2 for score UVB and 6.1 for UVAB ( treatments) between scores 21/24 patients reported mild burning with UVB, in six which was sever with patients compared episodes of mild three (none burning with UVA/B severe) improvement in 15/25 on improvement high-dose UVB vs 16/25 (NS) with low-dose Improvement from Improvement baseline of 1.5 (mean) to UVB and 1.4 for 0.7 for clinical overall placebo for ( response was the total score the for lower significantly side UVB treated Patients assessed for pruritus, lichenification, scaling, xerosis, vesiculation, excoriations, erythema and an overall of on a score evaluation 0–3 (none to severe) on a Healing evaluated scale of 3 to –1 (3 = healed, –1 = worse) Patients assessed for pruritus, lichenification, scaling, xerosis, vesiculation, excoriations, erythema and an overall of on a score evaluation 0–3 (none to severe) on a healing evaluated scale of 3 to –1 (3 = healed, –1 = worse) Same as for study 1 aboveSame as for Clearing or considerable Patients assessed for pruritus, lichenification, scaling, xerosis, vesiculation, excoriations, erythema assessed on a Variables scale of 0–3, plus a global assessment Prospective, randomised left/right parallel study of duration 8 weeks’ Prospective, randomised left/right parallel study of duration 8 weeks’ Randomised right/left side 8 weeks parallel study for Prospective, RCT left/right parallel study of 8 weeks’ duration follow-up 33 patients with mean age of 23.3 years Mean disease duration of 19.6 years Most with skin type III 30 patients with mean age and mean of 24.8 years disease duration of 20.5 years 25 patients with mean age of 25.9 years, most with skin type III 17 patients over the age 17 patients over of 15 years, most of whom had skin type III (tans easily, seldom burns up to 2 ) vs placebo 2 ) vs UVB (0.85 times per ) three 2 2 mW/cm (emollients and week hydrocortisone) UVA (average 8.1 (average UVA mW/cm (74%) and UVA Mixed UVB (26%) vs three times per week UVB three times per week UVB three at 80% of minimal given to produce dose required (MED) vs UVB at redness 40% of MED (emollients and hydrocortisone) UVB three times per week UVB three (20–153 mJ/cm 63–816 mJ/cm (visible light) three times (visible light) three (emollients and per week hydrocortisone) (co-treatments) and sample size description and RCTs of ultraviolet light in atopic eczema RCTs of ultraviolet 282 280 281 280 Jekler, 1992 Study 2 Jeckler & Larko, Jeckler 1988 & Larko, Jekler 1991 Study Interventions Study population design Trial Outcome measures Main reported results Quality of reporting Comment 90 & Larko, Jekler 1988 Study 1 TABLE 30 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Unclear if patients randomised but confirmed authors by – effects Large treatment of high-dose all in favour UVA/B over UVA1 Published in abstract form at time of report only 47 out of 73 patients Only completed study partlyStudy possibly unblinded due to lack of pigmentary changes on one side and burning in others Very short duration Very Results had to be graphs estimated from a Useful to have comparison with topical steroids Study suggests superiority a over of high-dose UVA topical steroid Described as ‘randomly Described as selected patients’ but method unclear Author contact randomly ‘treatments allocated’ No blinding or No drop-outs withdrawals Study described as randomised (in balanced blocks), controlled, and double-blind No ITT analysis ‘A randomisation sequence random generated by numbers’ No blinding or No withdrawals drop-outs = p < 0.001 p = 0.02) for narrow- = 0.02) for p < 0.0001 against comparator change) data for Comparative but not given UVA-UVB form in graphical shown only; 52 at UVA–UVB baseline changed to 38 graph) (estimated from A decrease from baseline from A decrease to 14 score) of 53 (overall ( after UVA1 0.02 compared with 0.02 compared placebo) sleep loss Changes for statistical failed to reach significance The proportion of patients The proportion in itch reporting reduction was 24 treatments over 90% ( band UVB, UVA 63% for placebo ( and 53% for Improvement over baseline over Improvement total clinical score: for baseline high-dose UVA1 to 26, of 56 reduced fluocortolone baseline to 35 and of 60 reduced baseline of UVA-UVB to 42 (all 60 reduced treatment); after 10 days’ p in total Mean reduction disease activity was 9.7 for patients on 21 evaluable UVB,narrow-band 4.8 on and 0.4 on placebo, UVA the change significant at narrow- for the 5% level band UVB vs placebo only Costa scoring system: erythema, oedema, vesicles, exudation, crusts, excoriations, scales, lichenification, pruritus, loss of sleep on a 7-point scale (0 = no lesion, severe) 6 = extremely Five clinical features at six clinical features Five separate body sites plus itch and sleep loss (VAS), and extent of disease one observer by recorded Costa scoring system: erythema, oedema, vesicles, exudation, crusts, excoriations, scales, lichenification, pruritus, loss of sleep on a 7-point scale (0 = no lesion, severe) 6 = extremely Prospective, randomised, parallel study of 15 days’ duration Prospective, randomised, double-blind parallel study duration of 12 weeks’ Prospective, randomised, parallel study of 10 days’ duration follow-up 25 young adults with 25 young atopic eczema and definite atopy 73 adult patients with atopic moderate-to-severe eczema 53 patients acute severe exacerbation of atopic eczema 2 2 ) or 2 UVA 2 ) vs UVA 2 o.d.) vs UVA–UVB o.d.) 2 RCTs of ultraviolet light in atopic eczema RCTs of ultraviolet therapy (up to 30 mj/cm therapy High-dose UVA1 (0–130 High-dose UVA1 J/cm UVB and 7.5 j/cm daily (emollients) daily (co-treatments) and sample size description and placebo (visible light) all (mild-to- twice weekly moderate topical steroids plus emollients) Narrow-band UVB (up to Narrow-band max of 1.2 J/cm High-dose UVA1 130 J/cm High-dose UVA1 o.d. vs o.d. fluocortolone or ointment 0.5% cream minimal vs UVA–UVB erythema dose- dependent o.d. (up to max of 15 J/cm et al., et al., et al., 283 278 279 Study Interventions Study population design Trial Outcome measures Main reported results Quality of reporting Comment Krutmann 1992 1998 Krutmann Reynolds Reynolds 1999 91 TABLE 30 contd TABLE Non-pharmacological treatments A small study that took that both to ensure care in given were treatments equal doses Big falls in SCORAD both for scores with little treatments the between difference two Study described as randomised, and blinded investigator carried No ITT analysis out; withdrawals, two one due to exacerbation of atopic dermatitis, an another due to a in response differential terms of less erythema to the bath- reactions side PUVA = 0.48) p Baseline scores of 100% Baseline scores bath-PUVA SCORAD for by and UVB reduced bath-PUVA- 65.7% for side and 64.1% treated side UVB-treated for ( Patient-rated itch and 0–10 cm) sleep loss (VAS as part of SCORAD, global doctor-rated severity, doctor-rated global changes of modified eight signs SCORAD for and symptoms Prospective, randomised, single-blind half side comparison of 6 weeks’ duration follow-up 12 patients with atopic severe/chronic dermatitis with a mean ±age of 27 years SD of 11.3 years RCTs of ultraviolet light in atopic eczema RCTs of ultraviolet Narrow-band UVB vs bath Narrow-band 1 mg/l as 8-MOP PUVA times per week three (co-treatments) and sample size description and et 277 2000 Study Interventions Study population design Trial MED, Outcome measures minimal erythema dose Main reported results Quality of reporting Comment al., 92 Der-Petrossian TABLE 30 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 10 Systemic immunomodulatory agents

Allergen–antibody complexes was probably successful. The ‘beneficial’ treatment of house dust mite effects are difficult to interpret given the use of an invalidated exploded scale and absence of a Anti-house dust mite antibodies are very common patient’s perspective. The modest benefit demon- in atopic eczema patients and may play a part in strated in this study needs to be replicated elsewhere the disease process. Previous studies in the field of before the intervention can be recommended as a asthma have suggested that injection of complexes treatment option. of house dust mite allergen (Der p 1) with antibodies may result in clinical improvement. We found one RCT285 that evaluated the role of house dust mite Cyclosporin allergen–antibody complex injections versus placebo in the treatment of atopic eczema. The study was Cyclosporin is a polypeptide of fungal origin. It is covertly duplicated the following year in the Journal a potent inhibitor of T-lymphocyte-dependent of the American Academy of Dermatology, and both immune responses and interleukin 2 production.396 papers were used to generate the summary as each Primarily, cyclosporin was introduced as an immuno- contained additional details. The later publication suppressive agent to prevent graft rejection after documented 24 patients who were randomised tissue transplantation. In dermatology, cyclosporin compared with 23 in the original report. The missing is used for the treatment of immune-mediated patient is documented in the secondary report as skin diseases such as cutaneous graft-versus-host he no longer satisfied the entrance criteria at the reaction, immunoglobulous diseases, psoriasis time of the first injection. Twenty-four adults with and atopic dermatitis.391 severe atopic eczema, all of whom had evidence of sensitisation to house dust mite were entered into Cyclosporin is usually restricted to short-term use a placebo-controlled study of injections of house in severe refractory atopic dermatitis in adults and dust mite allergen–antibody complexes 4 months children.397 It requires careful monitoring due to after an initial washout period of 6 weeks. The study its potential adverse effects, notably kidney toxicity was followed by a more prolonged open period. and hypertension.398 Although cyclosporin has a low degree of penetration through the skin, topical Benefits applications have been suggested for reducing the Of the 23 evaluable patients at 4 months, there was potentially serious adverse effects associated with a statistically significant improvement in disease oral cyclosporin.297 intensity index in those receiving active injections. Disease intensity was measured on a complex scale, Cyclosporin can be administered orally in doses which multiplied extent versus six physical signs. of between 2.5 mg/kg and 5 mg/kg body weight34 This reduced from 1000 to 612 in the active and or topically in an ointment or gel containing cyclo- from 1000 to 859 in the placebo group. Percentage sporin microcrystalline 10%.294 mean reduction in itching was not so large, reducing from 3.3 to 2.2 in the active group and from 3.3 to Statistical methods 2.6 in the placebo group. Rate differences were estimated for categorical variables and differences in means for continuous Harms variables. The Mantel–Haenszel type method of Three patients in the active group developed a Greenland and Robins399 was used to estimate the delayed-type inflammatory action at the injection pooled rate difference for all strata under the site and itching increased within 24 hours after assumption of a fixed-effects model. A CI for the injection in four patients on active and on two pooled risk difference was calculated using the patients receiving placebo therapy. Greenland–Robins variance formula.399 The Q (‘combinability’) statistic is given with its associated Comment probability on k (number of strata) minus one Method of randomisation and concealment of degree of freedom. This has low power as a strict allocation was unclear in this study, though blinding test of homogeneity. There are no comprehensive 93 Systemic immunomodulatory agents

rules on when to use random effects and when to consistent control is achieved with continuous use fixed effects models; debate continues in the therapy when given over a 1-year period. This statistical community.400 However, when this was longer-term study did not demonstrate any clinically significant at the 0.05 level, a random effects significant change in kidney function (serum analysis was applied.401 The pooled mean effect creatinine) and blood pressure in either group. estimate was calculated using weights calculated as the inverse of the variance for each study. Three of the remaining six reports were of the same trial293,295,298 with most of the outcome data In the trials, estimates of error were not reported reported in the Sowden and colleagues report.295 in a consistent manner. When standard errors were None of the studies compared cyclosporin with an reported for both the treatment and control arms, active agent, with all three remaining RCTs being both were used in the calculations. When only the comparisons of cyclosporin with placebo.290,292,295 pooled estimate was given, the variances for the Those studies gave some poolable data because of treatment and control arms were assumed to be the similarities in study design and the use of a consistent same. When quantitative values were reported in visual metric analogue scale for scoring itch (Table graphical form only, these were read electronically 36). However, because of the crossover design used from the scanned images and the responses and their in all three trials, only the first phase of each study associated variances were estimated by linear inter- was used so that our estimates were not confounded polation as described by Poolsup and colleagues.402 by carry-over effects. Table 37 shows the estimated mean difference in itch scores for the cyclosporin Results group compared with the placebo group for each Of the twelve eligible reports of RCTs (Tables 31–36), of the three studies as well as the pooled estimate two dealt with topical cyclosporin294,297 and ten with at the end of the first period. oral cyclosporin.286–293,295,296 Irrespective of whether a fixed- or random-effects Topical application model was used, the pooled estimate showed that The two reports294,297 on the use of topical cyclo- cyclosporin was effective in relieving eczematous sporin gave conflicting results. While in a study of itch compared with placebo as shown in Figures 4 20 patients, De Prost and colleagues297 reported (fixed effects) and 5 (random effects). positive results based on assessments of pruritus, erythema, oozing, crusts, xerosis and lichenification, Generally positive results were reported for sleep De Rie and colleagues294 reported no benefit in a loss, area involvement, reduction in steroid use study of seven patients with atopic eczema. Both and erythema. studies used an intrasubject design with randomised applications to comparable lesions. Neither provided The small study remaining by Miranda and any justification for sample size chosen. On the basis colleagues287 compared oral cyclosporin A with of the available evidence, the efficacy of cyclosporin oral transfer factor for 6 months and found no in atopic eczema has yet to be rigorously evaluated. statistical differences in a range of outcomes between the two. No intention-to-treat analysis was Oral therapy performed. Three patients in the cyclosporin A Of the ten reports of RCTs of oral cyclosporin group reported excess hair growth (hypertrichosis). therapy, those by Zonneveld and colleagues288 and Zurbriggen and colleagues289 were comparisons of Comment dose schedule and formulations, respectively, and There is little doubt that cyclosporin is effective for therefore provided little evidence on the value of the treatment of atopic eczema when compared cyclosporin. One of the trials291 adopted a random- with placebo but that continued use is necessary ised parallel group design with 23 patients receiving for the prevention of relapse, which is rapid once cyclosporin and 23 placebo. The study showed that therapy is discontinued. Clinical scores return both disease severity and area involvement were close to baseline values within 8 weeks.292 Adverse reduced by cyclosporin treatment (5 mg/kg/day) effects of the drug, notably on the liver and kidneys, by week 6. At the end of the 6-week trial, 15 of 19 suggest that long-term treatment is not justifiable. of the patients on cyclosporin compared with six of Even in short-term trials, cases of hypertension and 19 patients on placebo reported at least a moderate elevations of serum bilirubin and creatinine have improvement. The estimated rate difference was been reported.291 Reducing dose schedules or 39% (95% CI 10 to 62). One small study by Harper prolongation of treatment-free intervals have and colleagues286 of continuous versus intermittent yielded unconvincing results with obvious poorer 94 cyclosporin A in children, suggested that more control of the disease and modest decrease in drug Health Technology Assessment 2000; Vol. 4: No. 37 * One to adverse effects One to adverse Four crossed over prematurely (p-c) prematurely over crossed Four Six did not complete second phase (c-p) Four crossed over prematurely (p-c) prematurely over crossed Four Six did not complete second phase (c-p) Three in treatment group, in treatment Three in transfer two factor group Four crossed over prematurely (p-c) prematurely over crossed Four Six did not complete second phase (c-p) Five 48: lack of efficacy, effects, adverse non- compliance excluded after baseline due to Three abnormal assessments out during dropped A further eleven the study 18 due to lack of response from from 18 due to lack of response trial medication One: violation protocol None * * Topical steroids Topical Topical steroids Topical Monitored steroids and steroids Monitored emollients 1% hydrocortisone Topical steroids Topical Topical steroids Topical Antihistamines, emollients, antibiotics, steroids of any steroids Topical potency Hydroxyzine 10 or 25 Hydroxyzine mg, emollients 1% hydrocortisone, emollients ™ 4–4.5 mg/kg Neoral factor in escalating dose (units not specified) Max. of 5 given mg/kg/day as intermittent 3-month course ™ 10% topical gel Placebo 10% topical gel Placebo 5 mg/kg/day Placebo 5 mg/kg/day Placebo 4 mg/kg Oral transfer 5 mg/kg/day Placebo 5 mg/kg/day Placebo 5–3 mg/kg/day 3–5 mg/kg/day Max. of 5 mg/kg/day continuously 5 mg/kg/day Placebo 4–4.5 mg/kg Sandimmun 5 mg/kg/day Placebo * standing * Stable,moderate or severe 8 3–55 3 weeks 20 2–29 2 weeks Stable 33 17–56 16 weeks Severe 33 17–56 16 weeks Severe 33 17–56 16 weeks Severe 24 19–48 8 weeks Chronic 46 17–68 6 weeks 78 18–70 8 weeks Severe, long 43 2–16 12 months Severe 14 20–64 8 weeks Severe 10 22–42 10 days patients (years) dosage drop-outs , Novartis, UK; * Same study of 33 patients Left/right comparison, double- blind, randomised Left/right comparison, double- blind, randomised ™ Crossover, double- blind, randomised Crossover, double- blind, randomised Parallel study 23 3–40 6 months Not stated Crossover, double- blind, randomised Crossover, double- blind, randomised Crossover, double- blind, randomised Parallel, double- blind, randomised Crossover, double- blind, randomised Parallel, open, randomised, dose- finding study Parallel, unblinded, randomised 287 , Neoral Design, patient characteristics and interventions of included studies: cyclosporin ™ et et al., 298* et al., et al., et al., et al., et al., 289 et al., et al., 294 297 et al., 293* 286 292 295* 291 296 288 1999 De Rie 1991 de Prost de Prost 1989 StudyOrals Design No. of Age Duration Severity Oral cyclosporin Comparator Co-treatments and Withdrawals Topicals Sandimmum Allen, 1991 Salek 1993 Cordero Miranda, 1999 (Spanish, translated) Harper 2000 van Joost van Joost 1994 Zurbriggen al., Munro Munro 1994 Wahlgren Wahlgren 1990 Sowden Sowden 1991 1996 Zonneveld Zonneveld 95 TABLE 31 TABLE Systemic immunomodulatory agents

TABLE 32 Outcome measures: oral cyclosporin

Study Outcome measure Scale

Allen, 1991298* Erythema, purulence, excoriation or crusting, dryness or scaling, cracking or fissuring, and 0–3 scale lichenification at six body sites Extent of disease Rule of Nines Patient-assessed sleep and itch 0–100 mm VAS

Salek et al., Disease activity: erythema, purulence, excoriation or crusting, dryness or scaling, cracking or 0–3 scale 1993293* fissuring, and lichenification at six defined body sites Disease extent: Rule of Nines Max. score 108 Patient-assessed itch and sleep loss 1–100 mm VAS Patient-assessed health-related quality of life UKSIP,EDI

Sowden et al., Clinician-assessed disease activity of erythema, purulence, excoriation or crusting, dryness or 0–3 scale 1991295* scaling, cracking or fissuring, and lichenification at six defined body sites Clinician-assessed extent of disease Rule of Nines Patient-assessed itch and sleep loss 0–100 mm Patient and doctor global assessments Five-point scale

Munro et al., Composite scale for erythema, excoriation, lichenification using Rule of Nines 0–3 1994292 Itch and sleep loss 10 cm VAS van Joost et al., Physician-assessed severity in six regions for erythema, infiltration, vesicles and papules, 0–3 scale 1994291 dryness and scaling, cracking and fissuring, excoriation and crusting Lichenification scored separately 0–3 scale Physician-assessed extent of disease Rule of Nines Physician-assessed itching and sleep loss 0–3 scale Patient-assessed global assessment Four-point scale

Wahlgren et al., Patient-assessed itch Symtrack 1990296 Patient-assessed itch 100 mm VAS Physician-assessed severity at 20 areas (no details) 0–3 grading

Zonneveld et al., Area assessment Rule of Nines 1996288 Severity assessment of six body regions for erythema, lichenification, vesicles/papules, 0–3 dryness/scaling, cracking/fissuring, excoriation Patient-assessed itch and sleep loss 0–3 scale Patient and physician global assessment 0–3 scale

Zurbriggen et al., Area assessment Rule of Nines 1999289 Severity assessed at six sites for (no more detail given) 0–10 scale Itch and sleep loss. Note: reference given for details (see Sowden paper)

Cordero Physician-assessed erythema,‘eczema’, lichenification, itch, oedema 0–3 Miranda, 1999287 Global physician’s assessment every 15 days Five categories (cure, excellent, moderate, no change, worse)

Harper et al., Patient-rated itch, irritability, sleep loss and global severity 100 mm VAS 2000286 Doctor-rated global severity Five-point scale SASSAD score Doctor-rated extent using Rule of Nines Renal function and blood pressure

UKSIP, UK Sickness Impact Profile; EDI, Eczema Disability Index; SASSAD, Six Area, Six Sign,Atopic Dermatitis

96 Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 33 Outcome measures: topical cyclosporin

Study Outcome measure Scale

de Prost et al., Observer-assessed pruritus, erythema, vesicles and oozing, crusts, xerosis and lichenification 0–3 1989297 Global evaluation Five grades (cure–deterioration)

De Rie et al., ADSI: pruritus, erythema, exudation, excoriations, lichenification. 0–15 1991294 exposure. As recommended by Zaki and colleagues,397 Comments cyclosporin should be reserved for the short-term The quality of this study was surprisingly good for treatment of refractory disease, and even then its such an early publication with a clear description superiority over oral steroid therapy, a substantially of the blinding process and testing for success of cheaper alternative, is as yet untested. blinding. Despite the lack of intention-to-treat analysis and very small sample size, there is not a hint of any benefit of levamisole in this study or in Levamisole the Alomar study. The placebo benefit in the studies was quite remarkable in that they were greater than Levamisole hydrochloride is a drug widely used in those on active treatment. The authors conclude veterinary medicine for treating helminthic parasites. that the study emphasises the need for randomised The drug was found to have wide immune-enhanc- double-blind comparisons for new drugs such as ing properties particularly on stimulating white blood levamisole in view of the previous claimed excellent cells. Because patients with atopic eczema have results from uncontrolled studies. Although the study some evidence of decreased cell-mediated immune was under-powered to miss small treatment effects, responses and recurrent secondary infections, it it is unlikely that levamisole has any long-term moder- seemed reasonable to consider a possible benefit ate-to-large treatment benefit in atopic eczema. of levamisole in cases of atopic eczema. One small RCT of levamisole in atopic eczema has been published.299 Another double-blind placebo- Platelet-activating factor antagonist controlled study of 15 children in Spain403 was published in the same year, though it was unclear Platelet-activating factor (PAF) is a powerful mediator if randomisation had been used in that study. of certain inflammatory reactions and has been The Alomar study403 showed no evidence of any implicated in inducing itch and contact urticaria. benefit of levamisole. The White and Hanifin study299 Thus, it seemed reasonable to try a PAF antagonist will be described in more detail. in atopic dermatitis, a disease characterised by itching and various inflammatory processes. One Benefits RCT300 compared a solution of PAF antagonist with Thirty-six patients aged 13–64 years with atopic vehicle (placebo) in a study of 44 patients who eczema were randomised to levamisole hydro- applied one solution or the other on opposite sides chloride or placebo according to body weight of symmetrical lesions of atopic eczema for a period with topical triamcinolone as co-treatment. Of of 28 days. Patients were mainly young adults and 26 evaluable patients at the end of the 6-month trial, were recruited from five centres in Europe. there were no clinical or statistically significant differences in patients’ objective improvement, Benefits frequency of infections, physician prediction of Based on an intention-to-treat population analysis, active treatment, clinical scores, or immunological 57% of those on the experimental PAF antagonist markers such as IgE changes. In the active groups, ‘responded’ (response not defined by authors) six of 11 patients noticed improvement compared compared with 61% on placebo at the end of the with six of 15 in the placebo group. Mean percen- treatment period. Based on the evaluable population tage improvement in a composite sign score (not of 36 patients, 18 of the experimental group showed defined) was 44% in the levamisole group and marked improvement or total clearing on the site 16% in the placebo group. treated with the solution compared with 17 of the 36 for the site treated with placebo. Other parameters Harms of atopic dermatitis severity showed similar lack of One patient developed urticaria and another devel- difference apart from a transient statistically signifi- oped nausea and vomiting while taking levamisole. cant benefit for itching at Day 14 but not on Day 28. 97 Systemic immunomodulatory agents ADSI RoNAA RoNAA RoNAA RoNAA RoNAA RoNAA RoNAA global global assessment named (if global global assessment named (if severity severity (method modified severity severity (method modified Physician Patient Area Scale Physician Patient Area Scale assesssment assessment used) specify) assesssment assessment used) specify)

Sleep loss Sleep loss

Itch Itch

Induration Induration

Infiltration Infiltration

Crusts Crusts

Inflammation Inflammation

Oozing Oozing

Pustules/papules Pustules/papules

Vesiculation Vesiculation

Exudation Exudation

Fissuring Fissuring

Cracking Cracking

Lichenification Lichenification

Scaling Scaling

Xerosis Xerosis

Dryness Dryness

Excoriation Excoriation

Purulence Purulence

Erythema Erythema 289 288 296 291 297 295* 294 292 1999 1996 293* 1990 1994 1989 1991 1991 1994 Outcome measures: cyclosporin oral versus placebo – signs and symptoms Outcome measures: topical cyclosporin – signs and symptoms et al., 1993 et al., 298* et al., et al., et al., et al., et al., et al., et al., de Prost de Prost De Rie Study Study Allen, 1991 Salek Sowden Munro van Joost Wahlgren Zonneveld Zurbriggen 98 *Same study of 33 patients TABLE 34 TABLE 35 TABLE Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 36 Itch data reported in or derived from the cyclosporin trials

Study Cyclosporin group Placebo group

No. of Mean difference in No. of Mean difference in patients itch scores (SD) patients itch scores (SD)

Munro et al., 1994292 12 35.9 (22.9) 12 16 (20.1) Sowden et al., 1991295 17 27.7 (17) 16 36 (17) Wahlgren et al., 1990296 10 7 (10.8) 10 –1 (12.7)

TABLE 37 Estimates of mean difference in itch scores for cyclosporin

Study Stratum No. of treatment No. of control Mean Approximate 95% CI patients patients difference

Munro et al., 1994292 1 12 12 19.9 2.66 to 37.14 Sowden et al., 1991295 2 17 16 24.1 12.49 to 35.70 Wahlgren et al., 1990296 3 10 10 8.0 –2.33 to 18.33 Pooled estimate of weighted mean difference (WMD) in itch score = 15.92 Approximate 95% CI = 8.87 to 22.96 Chi-square (for WMD) = 19.62 (df = 1);p < 0.0001 Q (‘combinability’ for WMD) = 4.37 (df = 2); p = 0.1125 DerSimonian–Laird pooled WMD = 16.70 Approximate 95% CI = 5.87 to 27.54 DerSimonian–Laird Chi-square = 9.13 (df = 1); p = 0.0025

Harms treated by gamma-interferon or saline. It was Fourteen out of 15 patients complained of skin dry- unclear if these patients were also participants in ness and burning immediately after application of the larger study reported in 1993,302 and the the treatment. Data were not presented separately lack of methodological detail precluded further for the active versus vehicle treatment. There was discussion of this study. one case of possible contact dermatitis related to the trial medication and another who developed Benefits severe erythema. In a 12-week multicentre study of 83 patients with severe atopic eczema aged between 2 and 65 years, Comment daily subcutaneous injections of recombinant There appears to be no benefit from the PAF interferon-gamma at a dose of 50 µg/m2 was antagonist in this small study, although it lacks compared with placebo injections with topical the power to exclude a potentially useful benefit. corticosteroids continued as co-treatment. All Randomisation, concealment of allocation, and patients were instructed to take oral acitamin- blinding was poorly described, though an inten- ophen (an analgesic) before and after injections tion-to-treat analysis was performed. to protect against headaches and aching limbs associated with interferon therapy. Those random- ised to active treatment were significantly older Interferon-gamma than those on placebo. At the end of the assess- ment period, 45% of 40 patients on active treatment One of the immunological abnormalities charac- compared with 21% of 43 on placebo were reported teristic of atopic eczema is reduction in a chemical as having greater than 50% global improvement messenger called interferon-gamma. Recombinant (p = 0.016) as judged by a physician who was interferon-gamma inhibits IgE synthesis by human blinded to treatment allocation. Corresponding peripheral blood lymphocytes in vitro. Since atopic figures for the proportion of patients with more eczema is characterised by excessive production of than 50% patient/parent-reported global improve- IgE in response to ingested and airborne allergens, ment was 53% and 21% for active versus placebo a potential therapeutic role for a substance such treatment, respectively (p = 0.002). Other physical as interferon-gamma, which helps to switch off IgE signs, such as redness and scratch marks, were synthesis, has been postulated and demonstrated statistically significantly reduced by about 30% in in an open study.404 Two RCTs of interferon-gamma the active group, and a similar magnitude of in atopic eczema were located.302,303 An earlier improvement was seen for induration, itching, abstract405 quoted in Renz and colleagues (1992)301 dryness and lichenification, though these were not referred to an RCT of 14 atopic eczema patients statistically significant. Response was greatest in 99 Systemic immunomodulatory agents

FIGURE 4 Difference in itch scores (fixed effects)

Munro et al., 1994292

Sowden et al., 1991295

Wahlgren et al., 1990296

–10 0.0 10 30 50 Pooled weighted mean difference = 15.92 (95% CI, 8.87 to 22.96)

FIGURE 5 Difference in itch scores (random effects)

Munro et al., 1994292

Sowden et al., 1991295

Wahlgren et al., 1990296

–10 0.0 10 30 50 DL pooled weighted mean difference = 16.70 (95% CI, 5.87 to 27.54)

younger patients. Serum IgE levels did not fall interferon-gamma dose groups, except perhaps significantly. Another more recent study by Jang with a more rapid benefit in the first 6 weeks in the and colleagues303 has compared high- versus low- higher dose group. A host of other immunological dose interferon gamma (1.5 versus 0.5 million markers were assessed. units/m2) versus placebo given subcutaneously three times week to patients with recalcitrant Harms atopic dermatitis aged 18–42 years for 12 weeks. At Despite taking analgesia, 60% of those on active the end of the evaluation period, clinical improve- treatment in the Hanifin and colleagues study ment measured by means of a composite of different experienced headache, 32% muscle ache and physical signs and surface area, was markedly better 39% chills compared with 28%, 12% and 5%, in the two interferon gamma groups compared respectively, for those on placebo. A fall in white 100 with placebo (p < 0.05), but not between the two cell count occurred in five patients on interferon- Health Technology Assessment 2000; Vol. 4: No. 37

gamma which normalised with continued treatment. Thymostimulin is a mixture of heat-stable polypep- Seven patients on active treatment had mild eleva- tides extracted from calf thymus and given by tions of liver transaminase levels that did not affect injection. Thymopentin is a synthetic pentapeptide therapy. Three out of the 41 patients treated with corresponding to some of the amino acid sequences intereferon-gamma in the Jang and colleagues study of human thymopoetin, the hormone responsible discontinued therapy: two due to disease flare and for promoting differentiation and function of one due to abnormal liver function tests. Despite mature lymphocytes. taking acetaminophen as required for flu-like symptoms, 54% of those taking interferon-gamma Benefits experienced adverse effects including fever and Thymomodulin muscle aches. Rates of adverse events in the Two RCTs of thymomodulin in atopic eczema were placebo group were not described. identified from the same research group304,305 but could not be combined as each dealt with quite Comment different patient groups and interventions. Quality of reporting was pleasantly high in the The Fiocchi and colleagues study304 compared Hanifin study with a clear description of thymomodulin syrup at a dose of 3 mg/kg/day generation of randomisation sequence and an with placebo in 12 children with atopic eczema intention-to-treat analysis. Description of placebo followed-up for 6 months. They showed improve- and concealment of allocation was unclear, and ment in several clinical signs in the intervention blinding was likely to have been unmasked due to group (e.g. extent decreased by 12.3 versus 24.0 in the marked therapeutic response and interferon- the thymomodulin and placebo groups, respectively, related adverse effects in those on active treatment. measured on a scale with a maximum of 60 points), Quality of reporting was less satisfactory in the Jang and also in a number of blood immunological and colleagues study. The methods of random- indices. The Cavagni and colleagues study305 isation and concealment were not described. The compared thymomodulin syrup at a dose of fact that the three groups were of very different 120 mg/day versus placebo in a group of 19 sizes (20 and 21 in low- and high-dose interferon children with food allergy who were also placed versus only ten in the placebo group) suggests that on restriction diets. At the end of 90 days, signif- some method other than simple randomisation was icant improvements were noted in only one of used. Blinding was not mentioned in the report, four clinical signs (excoriations). Those on thymo- and an intention-to-treat analysis was not carried out. modulin appeared to react less to re-challenge with foods that were considered allergic. There seems little doubt that interferon-gamma was markedly effective in these two studies of Thymostimulin severely affected individuals, but at a cost in terms Two studies have evaluated thymostimulin in atopic of adverse events. The inconvenience and cost eczema, one in adults306 and one in a mixture of of daily injections is a limiting factor in a chronic adolescents and adults.307 The Staughton and disease that can last many years. colleagues study306 has only been published in abstract form and reports that reduction in disease severity (actual values not given and results not Thymic extracts and their statistically significant) was noted in an unspecified synthetic derivatives number of adults randomly allocated to thymo- stimulin 1.5 mg/kg twice weekly versus placebo Impaired T-lymphocyte cell function and sustained in a crossover study. The Harper and colleagues serum IgE levels have been described consistently study307 randomly allocated 29 young adults to in atopic eczema. This, along with observation that thymopentin 1.5 mg/kg twice weekly for 10 weeks patients with primary T-cell immunodeficiency, versus placebo injections. Co-treatment with such as Wiskott–Aldrich syndrome, have elevated topical steroids, emollients and antihistamines was IgE and lesions identical to atopic eczema, has allowed. Of the 26 evaluable patients, the median prompted researchers to explore the therapeutic percentage score (measured on a multiparameter value of agents that promote the differentiation scale) in the placebo group was 99% of baseline and function of mature lymphocytes. Initial compared with 80% in the thymostimulin group work on calf thymic extracts given as an elixir (p = 0.008), though there was no statistically or injection (thymomodulin and thymostimulin) significant differences for patient-assessed itch and was superseded by synthetic pentapeptides (thymo- sleep loss. Longer-term follow-up for 12 months pentin) given by injection. Thymomodulin is calf showed a loss of the differences between the two thymus acid lysate given orally in syrup form. groups within 4 weeks. 101 Systemic immunomodulatory agents

Thymopentin whereas three out of eight of those later randomised Four RCTs were identified. The patient populations to placebo dropped out because of a flare-up and interventions were not sufficiently similar to of disease. permit pooling of efficacy data. The first study by Kang and colleagues311 in 1983 was a small study Harms of 18 participants (mean age 33 years) who were No information on harms was given in the Fiocchi, randomised to three times weekly injections of Cavagni, Staughton, Kang or Hsieh studies. One thymopentin (50 mg) or placebo for 6 weeks. patient in the Harper trial was withdrawn due to Mean improvement in a compound score (maximum possible thymopentin-induced diffuse alopecia 18) was 2.38 and 0.82 in the active and placebo areata. Drop-outs in the placebo and active arms groups, respectively (p < 0.05), with five out of eight of the Harper trial were very high after 12 months participants in the active group and two out of ten (about 70% in each arm). Fourteen of 48 patients in the placebo group reporting ‘good’ improve- (29%) and ten of 52 patients (19%) in the thymo- ment (p < 0.05). The second much larger study pentin and placebo groups, respectively, reported by Leung and colleagues310 in 1990 randomised adverse effects in the Leung study, with no 100 young adults with moderate-to-severe atopic particular differences between the two groups eczema in parallel fashion to either daily subcuta- apart from three patients in the active group neous thymopentin (50 mg) or placebo injections developing local swelling at injection sites lasting for 6 weeks. They found that improvement in itch up to 30 minutes. Fifteen out of eighteen patients was observed in 66% of thymopentin-treated versus on thymopentin compared with sixteen out of 40% of placebo-treated patients (p = 0.02), and seventeen on placebo experienced adverse events also statistically significant differences for global in the Stiller study, which were not specified any severity scores and eczema extent in favour of further apart from possibly more cutaneous those on active treatment. Baseline scores and co- infections in the placebo group. treatment usage was very similar in the two groups. The third study by Stiller and colleagues308 in 1994 Comment randomised 39 adults with severe atopic eczema The quality of reporting of studies in this category to three times weekly thymopentin (50 mg) or was generally poor, with none (except the placebo for 12 weeks. They reported a statistically Leung study) explicitly describing randomisation significant improvement in total severity score procedure, concealment, success of blinding and (maximum 3) from 2.19 to 1.68 in the active none performing an intention-to-treat analysis. group versus 2.18 to 2.02 in the placebo group Study participants were generally well described. (p = 0.029). Overall patient-assessed improvement The Fiocchi and colleagues study failed to perform (on a scale of 1 to 5 where 1 = excellent, 2 = good, the appropriate statistical test (i.e. they only 3 = fair, 4 = poor and 5 = very poor) was also statis- compared before and after scores for eczema tically significantly greater in the active group severity instead of the difference between (from 3.11 initially to 2.78 at week 12) compared thymomodulin and placebo). The Kang and with the placebo group (from 3.00 initially to colleagues study erroneously used statistical tests 2.92 at week 12). for paired data when the data were unpaired, and they also put great emphasis on enhanced The fourth study by Hsieh and colleagues309 was treatment response in patients under the age of 34 an unusual one, which was mainly interested in years – a post hoc finding. Success of blinding was elucidating disease mechanisms. Instead of also controversial, for example, in the Kang and evaluating the effectiveness of thymopentin, they colleagues study because physicians were able to looked at the effect of withdrawal as surrogate guess the correct treatment in 72% of patients. evidence of efficacy. Thus they treated 16 children Studies were generally very small, introducing the with three times weekly injections of thymopentin risk of discarding a potentially useful treatment (50 mg) for 6 weeks and then randomised them to because the studies were under-powered from the continue with either thymopentin or saline outset. The largest study (Leung et al.) was well injections for a further 6 weeks. The data suggest described and demonstrated a potentially clinically an impressive decline in total severity score useful effect of thymopentin in the 6-week trial (maximum 15, with higher scores signifying worse period. Although the Stiller study also showed a disease) from 6.0 at 6 weeks to 12.8 at 12 weeks statistically significant benefit, the clinical relevance compared with 5.8 to 4.0 in those who continued of the small changes in complex scores is unclear. on active injections (p < 0.001; values estimated It is also apparent that the Stiller study was part of from graph as data not given). All eight patients in a much larger multicentre study whereupon the 102 the thymopentin group finished the 12-week trial, authors freely admit to a policy of conducting a Health Technology Assessment 2000; Vol. 4: No. 37

separate statistical analysis for each centre. However, in atopic dermatitis, transfer factor has been tried the number of other centres is never stated, and in this condition. One small RCT313 was identified we have been unable to locate the published data and translated from Spanish. This study compared from the other studies. There are therefore strong intramuscular injections of transfer factor with grounds to suspect publication bias. placebo injections in 24 adult outpatients with atopic dermatitis using a parallel group design for Despite these quality limitations, some of the studies a total duration of 8 weeks. The main outcomes do suggest some benefit of thymic extracts/synthetic of interest to the authors were immunological derivatives in severe atopic eczema, and it is unclear markers in the blood such as immunolglobulin why this mode of treatment was abandoned around levels and T-lymphocyte subset counts. Global 10 years ago. This could be due to cost or the fact clinical improvement according to a physician is that three times weekly injections are not a practical also recorded. At the end of 8 weeks, six out of 12 treatment of a chronic skin disease such as atopic patients (50%) in the transfer factor group were eczema, particularly in children. reported to have experienced ‘major’ improve- ment compared with four out of 12 (33%) in the placebo group (not statistically significant). The Immunoglobulin 95% CI around the 17% difference between the two treatments ranged from –22% (i.e. a 22% One small RCT published in French was identified difference in favour of placebo), to a +55% in and translated.312 Based on earlier observations that favour of transfer factor. Various statistically systemic immunoglobulin may be helpful for nasal significant differences in immunological para- and eye allergy, this study evaluated intramuscular meters were noted at the end of the study. injections of immunoglobulin (Allerglobulin™, not available in the UK) versus albumin in a course of Harms ten injections over 3 months. In total, 47 adults and No adverse effects were reported in this small children over the age of 2 years were studied (mean study. No drop-outs were reported. Intramuscular age 15.5 years; age range 2–37 years). Eczema extent injections are painful. and a range of intensity items such as erythema, oedema, itching, and lichenification were recorded, Comment as well as a global evaluation. The authors reported This was a small study lacking power to pick up that 72.8% of the 22 patients receiving immuno- even moderate clinical benefits, though it is globulin had a global amelioration of their disease acknowledged that clinical response was not compared with only 36% of the 25 patients in the the primary aim of the paper. The method of control group. Results for all of the intensity randomisation was clearly described, and the items were not fully reported, though it was study was described as double-blind. The method commented that itching, degree of lichenification, of conceal-ment of allocation was unclear. and topography of lesions were all significantly Numbers were exactly the same in each group (statistically) improved. (n = 12), which in the absence of blocking, raises concerns as to whether simple random- Harms isation was implemented. Adverse effects were not discussed in this paper. Comment Summary of systemic Positive results are difficult to assess due to their immunomodulatory agents multiplicity and unclear clinical relevance. Random- isation, concealment of allocation, and blinding Allergen–antibody complexes was poorly described, and it was unclear whether • One small RCT has suggested benefit for an intention-to-treat analysis was performed. Never- allergen–antibody complex of house dust mite theless, the positive results of this small preliminary in the treatment of atopic eczema. study deserve further work. Cyclosporin A • There is no evidence to support the efficacy of Transfer factor topical cyclosporin A in atopic eczema. • Oral cyclosporin A is effective in atopic eczema Transfer factor is an extract from white blood cells but the long-term adverse effects on kidneys and that is thought to play a key role in cellular immunity. blood pressure are a serious concern, particularly As cellular immunity has been claimed to be impaired when treating a young population. 103 Systemic immunomodulatory agents

• The value of a short holiday period of symptom eczema, and it is unclear why this mode of relief in a chronic condition such as atopic treatment has been abandoned. eczema is questionable. • Cost and the need for weekly injections are • The cost-effectiveness of cyclosporin or oral limiting factors for long-term treatment with steroids versus azathioprine needs to be tested. thymopentin, particularly in children.

Levamisole Systemic immunoglobulin • There is little evidence to support any benefit in • One small study of intramuscular immuno- the use of levamisole in atopic eczema. globulin versus albumin suggests marked benefit in children and adults with atopic dermatitis. PAF This study needs to be replicated. • There is no evidence to support a useful treatment benefit of PAF antagonist based on the results of Transfer factor a small right/left comparison study in 36 patients. • One Cuban RCT of intramuscular transfer factor did not find any evidence of any clinical Interferon-gamma benefit, though the study was too small to pick • Daily interferon-gamma injections are an up even moderately large clinical benefits. effective treatment for severe atopic eczema but at the cost of frequent flu-like symptoms despite Systemic immunomodulatory agents taking analgesia. • At present, there appear to be no effective and convenient systemic immunodulatory Thymic extracts treatments with a good long-term safety • There is some evidence of benefit of thymic record available for the treatment of severe extracts/synthetic derivatives in severe atopic atopic eczema.

104 Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 11 Complementary therapies

e define complementary therapies as a group damage (the net effect of papulation, vesiculation, Wof therapeutic and diagnostic disciplines that scaling, excoriation and lichenification) plus exist largely outside the institutions where conven- percentage area affected (maximum score 180) tional healthcare is taught and provided.406 and patient preference. Median percentage changes of the clinical scores from baseline were 51% for Chinese herbs compared with 6.1% for Chinese herbal medicine placebo for erythema, and 63.1% and 6.2% change for surface damage in the herbs versus placebo Chinese herbal medicine forms part of a system groups, respectively. A 1-year follow-up study of the that includes oral and/or topical Chinese herbs, children concludes that Chinese herbal medicine, acupuncture, diet and exercise for both treatment in the medium term, proved helpful for approx- and prophylaxis of disease. Medicinal plants of imately half the children who originally took part various kinds can be taken orally usually in in the RCT.409 combination with others as a decoction by boiling them in water, and drinking the ‘tea’ produced, The adult study by Sheehan and colleagues314 or as external applications directly to the skin. evaluated Chinese herbs (as above) in a decoction Prescriptions are individually determined based upon versus ‘inert plants’ placebo, once daily, in 40 adult an overall assessment of the patient including patients with atopic dermatitis. Skin was assessed pulse, appearance of tongue, and disease features, using a score of 0–3 for erythema, surface damage hence, standardised formulae are not generally (the net effect of papulation, vesiculation, scaling, prepared. Mode of action points towards anti- excoriation and lichenification) plus percentage inflammatory and immunosuppressive properties area affected. Maximum score was 180 and by down-regulating local T cell-mediated reactions.407 patients’ subjective comments included itch, sleep loss and preference. Geometric mean total body Benefits score for erythema at the end of Chinese herbs We located one systematic review408 reporting two treatment was 12.6 and at end of placebo phase randomised trials of atopic eczema,314,315 one on was 113 (baseline scores not given). The geometric adults and one on children, which the authors did mean for surface damage at the end of Chinese not feel were appropriate to pool. Adverse effects herbs treatment was 11.3 compared with 111 at the such as slight abdominal distension and headaches end of placebo phase (baseline values not given). were highlighted in that review. The authors conclude: “At present it is unclear whether Chinese herbal The study by Latchman and colleagues317 evaluated treatments of eczema do more good than harm.” the same combination of Chinese herbs as above (finely ground) versus the same Chinese herbs in a In addition to these two trials we have identified a new palatable form of freeze-dried granules in 18 further two,316,317 which evaluated oral Chinese patients with atopic eczema over an 8-week period. herbal decoction compromising Ledebouriella Skin was assessed using a score of 0–3 for erythema, seseloides, Potentilla chinensis, Clematis armandii, surface damage. There was a significant reduction Rehmannia glutinosa, Paenia lactiflora, Lophatherum in erythema and surface damage compared with gracile, Dictamnus dasycarpus, Tribulus terrestris, baseline (p < 0.001). The groups showed no Glycyrrhiza glabra, Schizonepeta tenuifolia, except difference in clinical outcome between formulations. Sheehan315 who used Anebia clematidis instead of Clematis armandii. All four RCTs are reported below. The study by Fung and colleagues316 evaluated the same combination of Chinese herbs above versus The efficacy study of children by Sheehan and ‘inert plants’ placebo in 40 patients with atopic Atherton315 evaluated Chinese herbs (as above) in eczema over an 8-week period. Scores based on the a decoction versus placebo comprising a mixture severity and extent of erythema, surface damage, of ‘inert’ plant materials, once daily, in 47 children lichenification and scaling were recorded. There with atopic eczema over an 8-week period. Skin was was a general trend of clinical improvement for assessed using a score of 0–3 for erythema, surface both Chinese herbs and placebo. There was no 105 Complementary therapies

statistically significant treatment effect over placebo compared with only scaling in the control group, for all four clinical parameters, except for licheni- though the appropriate statistical comparison of fication at week 4. differences between the two groups was not done.

Harms Harms Unpalatability of the herbs in both active and No adverse effects were reported in this study. The placebo groups was a common adverse effect cost of instruction by a therapist and video for one causing ten drop-outs in Sheehan and Atherton315 session was estimated at $30. study and eight drop-outs in the Sheehan and colleagues314 study. Other adverse effects included Comment abdominal distension, headaches, transient dizziness, This small pilot study showed that parents and their gastrointestinal upsets, one lichenoid eruption and children who were allocated to massage therapy in one facial herpes. There is a concern with Chinese addition to their standard care were less anxious herbs of potential hepatotoxicity; however, all the and more able to cope. Even though much of studies, except Latchman and colleagues carried these effects could have been partly due to the out pre and post-treatment liver function tests with unblinded nature of the study, increased coping no abnormalities detected. with a chronic disease is a desirable goal. It appears that the technique of massage can be taught cheaply Comments and quickly. It is unclear whether the technique All studies were randomised but method and has any specific benefit on overall atopic eczema concealment of allocation were not described. All activity, and more trials in other countries are needed. were described as double-blind, except Latchman and colleagues317 where no blinding was mentioned. No intention-to-treat analysis was carried out. It is Hypnotherapy/biofeedback questionable whether the placebo plants are truly inert in the treatment of eczema. The children Hypnotherapy and biofeedback used to develop study by Sheehan and Atherton315 reports large relaxation techniques with or without mental effects from Chinese herbal medicine highlighting imagery may be beneficial in the management a promising treatment of atopic eczema. This has not of atopic eczema to distract from the symptoms been replicated in the other studies, though they associated with the itch–scratch–itch cycle.320 One are all quite similar. Clearly more RCTs with larger RCT has been located that addresses the use of sample sizes over a longer period of time are needed. these techniques in atopic eczema.320

Benefits Massage therapy Forty-four children with atopic eczema were randomised to either hypnotherapy, biofeedback It is possible that massage therapy might be beneficial or discussion only, for a period of 20 weeks after in atopic eczema as a stress-reducing and enjoyable being stabilised on topical and oral treatment in a interaction between parent and child, by increasing 2-week run-in period. This study attempted to peripheral circulation (which may be defective in measure changes in the objective symptoms of atopic eczema) or by increasing compliance with erythema, surface damage and lichenification, topical treatments. One small RCT of massage which resulted from attempts to reduce children’s therapy in young children has been identified.321 subjective experience of itching (and subsequent scratching) using: Benefits Twenty children with atopic eczema (mean age • relaxation that focused specifically on reducing 3.8 years) were randomised to continue with itching (hypnotherapy) standard therapy with topical corticosteroids, • relaxation that did not involve any direct emollients and antihistamines or standard therapy imagery per se (biofeedback) plus a course of daily 20-minute massage following • an ‘attention placebo’ group who were video demonstration for a period of 1 month. encouraged to discuss the eczema without any Parents in the massage group reported greater mention of symptom control. degrees of improvement in anxiety scores, tactile defensiveness, and a coping index when compared The children in the hypnotherapy and biofeedback with the control group. Certain eczema activity groups showed a significant reduction from signs (e.g. scaling and excoriation) improved baseline in the severity of surface damage and 106 statistically from baseline in the active group lichenification compared with the control group. Health Technology Assessment 2000; Vol. 4: No. 37

There was no difference between the two relax- counselling and massage with essential oils by ation techniques. Erythema was not changed by both the therapist and the mother or the same the interventions. treatment without essential oils. Parent-assessed day-time irritation score, night-time disturbance Harms scores and general improvement scores were No adverse effects were reported in this study. assessed for a period of 8 weeks. The results showed a statistically significant improvement of the eczema Comments in the two groups of children following therapy, but This study shows that relaxation techniques, there was no significant improvement shown between with or without direct imagery, may be of some the experimental and control groups. Corres- benefit in the management of atopic eczema. pondence with the author confirms the study was The girls in the hypnotherapy group showed randomised. The full report will be available shortly. greater improvement than the girls in other groups and showed greater improvement than the boys in the hypnotherapy group. Lack of Summary of complementary blinding threatens the validity of the study. The therapies authors state that all the parents and children in the study were aware that the aim of the study Chinese herbs was to help them with their symptoms further • Two studies of Chinese herbal treatment threatening the validity of the study. In particular conducted in children and adults by the the ‘attention placebo’ was designed to avoid same research team found significant benefits mentioning symptom control. There were 13 compared with placebo. drop-outs but no explanation was given for • Two further RCTs conducted by independent reasons. No intention-to-treat analysis was carried groups failed to demonstrate any clear out, hence, it is not clear what effect the high clinical benefit. number of drop-outs had on the results. • Further larger and long-term RCTs of Chinese herbal treatment seem worthwhile.

Homeopathy and aromatherapy Hypnotherapy/biofeedback • One unblinded study of hypnotherapy and bio- We located one study protocol318 in German with feedback suggests a benefit in terms of surface an English abstract assessing the efficacy of classical damage and lichenification but not erythema. homeopathic treatment in 60 patients with atopic dermatitis. The patients were randomised to Aromatherapy receive a homeopathic treatment or a placebo for • One small study of massage with and without a period of 8 months. The homeopathic doctor essential oils plus counselling has suggested was free to change remedies, dosages or potencies benefits of counselling and tactile contact but if required by the reaction or a new case-picture no benefit from addition of essential oils. of the patient presented according to classical homeopathy principles and guidelines. Massage therapy • One small study of massage therapy in addition We located one abstract319 of a preliminary study to standard care in children has suggested on the effect of aromatherapy on childhood atopic benefit in terms of reduced anxiety and better eczema. Sixteen children were treated with either coping skills.

107

Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 12 Other interventions

Nitrazepan inhibition of histamine activity. Based on the observations that a few atopic patients treated with Nitrazepan is a widely used benzodiazepine drug for ranitidine for gastric ulcer have improved, Veien night-time sedation. As itching at night can be a major and colleagues323 conducted an RCT of ranitidine problem for patients with atopic eczema, the benefit treatment for hand eczema in patients with atopic of nitrazepam in atopic eczema has been evaluated eczema versus placebo. by an RCT conducted by Ebata and colleagues.322 Benefits Benefits Forty-seven adults with a clear description of hand Ten adult outpatients with atopic eczema were eczema and atopic eczema elsewhere (allergic contact entered into a double-blind placebo-controlled cross- eczema excluded) were randomly allocated to oral over trial of three successive nights whereby they ranitidine, 300 mg twice daily or placebo tablets of were given either 5 mg of nitrazepan or a placebo, identical appearance for a total of 4 months. with a washout interval of 4 days. An infrared video A potent topical steroid cream (beta-methasone camera to identify bouts of scratching lasting more valerate) and lubricating ointment to be used on than 5 seconds was used to calculate the percentage the hands only was permitted throughout the trial. of total scratch time in each group as an index of Thirty-eight of the 47 patients completed the 4-month nocturnal scratching. Total scratch time was very trial, and intention-to-treat analysis was conducted. similar between the two groups, occurring in 6.5% The total in a composite position-assessed sign score of the time for those taking nitrazepan compared with was reduced from a mean of 10.17 to 4.91 in the 5.4% of the time with placebo. Frequency of bouts group receiving ranitidine and a topical steroid of scratching was slightly less in the nitrazepan group, compared with a reduction from a mean of 10.58 but the mean duration of scratching bouts was longer to 7.46 in the group receiving placebo in the in the nitrazepan group compared with placebo (both topical steroid (p = 0.07). Most of this reduction comparisons statistically significant at the 5% level). was due to significant reduction in area Degree of itching and the condition of atopic derma- involvement. Seventeen out of the 23 patients titis did not change during the 2 weeks of the study. treated with ranitidine reported clearing or marked alleviation compared with eight out of the Harms 24 patients in the placebo group (p = 0.02). Although no adverse effects were mentioned in the results section, the authors comment that none of Harms the patients experienced any rebound insomnia or No adverse effects from either ranitidine or residual sedative effect following the nitrazepan tablet. placebo were reported in this study.

Comment Comment This very small study lacks power to exclude Although most trials of ‘hand eczema’ had to be moderate-to-small treatment benefits of nitrazepan, excluded from this report because the nature of though there was no indication of any benefit in the eczema was unspecified, this study provides a the patients studied. The most interesting thing clear description to indicate that those included about the study was the novel method use to assess probably had atopic eczema as the sole cause for nocturnal itch, though it remains to be seen their hand dermatitis. Although the method of whether this objective measure is a good predictor randomisation, concealment and degree of success of general eczema improvement as measured by of blinding is unclear, the intention-to-treat analysis validated scales or patient-evaluated measures. was helpful. The proportion of patients cleared or markedly alleviated (a combined physician/ patient score) and other composite scoring Ranitidine methods suggest a modest benefit of ranitidine in this subgroup of adult atopic eczema patients. The histamine type 2 receptor antagonist, raniti- It is important to replicate the results of this dine, modifies the immune system, possibly by its single RCT. 109 Other interventions

Theophylline changes. Reduction in the score for redness was highlighted by the authors as being statistically The β-adrenergenic theory of atopy implies a general significant in favour of the ointment and tablet defect of β-receptors in atopic eczema patients salbutamol when compared with placebo, though leading to low levels of cAMP within cells. In order baseline scores were very different. Baseline redness to test the importance of the β-adrenergenic theory score for patients on salbutamol ointment was 22 in atopic eczema, Ruzicka324 conducted a small at the beginning and this decreased by 9.5 at Day RCT crossover study of the phosphodiesterese 14 (maximum possible score 60). Baseline median inhibitor theophylline (which increases cAMP score for oral salbutamol was 29 with a median levels) versus placebo in adults with atopic eczema. decrease of 10.5 compared with a baseline score of 14 for the placebo and median decrease of 8.5. Benefits Fourteen adults were included in the study, 12 of Harms whom were evaluable at the end of 2 weeks. They There were five withdrawals with three due to took either 300 mg of a theophylline/ethylene- adverse effects. Tremor was reported by five diamine preparation or identical placebo tablets patients taking oral salbutamol and in one patient daily in addition to antihistamines. At the end of using the salbutamol ointment. Some degree of the 2-week period, the mean number of antihista- systemic absorption of salbutamol ointment was mine tablets used by the patients was 1.65 and 1.78 demonstrated in two patients. in the theophylline and placebo periods, respectively. Mean symptom score was 1.82 in the theophylline Comment and 1.68 in the placebo period, and sleep disturbance The method of randomisation, concealment of was 5.0 out of 14 nights in the theophylline group allocation, and investigator blinding in this study compared with 4.4 out of 14 in the placebo groups. was not described. No intention-to-treat analysis No other differences were statistically significant. was performed. Although the statistically significant improvement in redness in those taking salbutamol Harms has been highlighted, this was not declared as a main No adverse effects were mentioned in this study, outcome measure out of the six outcome measures but theophylline is a drug with a narrow thera- beforehand, and could probably be explained by peutic range which can result in cardiac toxicity. regression to the mean given the higher baseline scores for those taking salbutamol. Although no Comment clinically useful benefits of salbutamol ointment Methodological details of this short report are scanty. were demonstrated in this study, it is probably too Although there was no obvious difference between small to exclude even large treatment effects. the two groups, the study was very small and of very short duration. It is difficult to exclude any possible benefit of theophylline on the basis of this study. Papaverine

Papaverine is a naturally occurring compound Salbutamol found in opium but lacking in the narcotic activity. It is a potent inhibitor of the enzyme phospho- Based on previous animal studies, which demon- diesterase and it is this property that provides a β strated that the 2-adrenoceptor agonist salbutamol possible beneficial action for atopic eczema. Atopic can reduce inflammation, Archer and MacDonald325 eczema is characterised by elevated phospho- conducted an RCT of salbutamol ointment (1% base diesterase levels in mononuclear cells. Papaverine in white soft paraffin, twice daily) plus a placebo has been advocated for many years for the treatment oral tablet with oral salbutamol (a slow-release of atopic eczema, and based on a previous open study, spandet 8 mg twice daily plus white soft paraffin Berth-Jones and Graham-Brown326 conducted a cross- placebo ointment twice daily) versus a placebo over RCT of oral papaverine versus placebo in atopic spandet and white soft paraffin only in a 2-week eczema. Another RCT was published a year after by crossover study in 20 adults with atopic eczema. Shupack and colleagues327 of a similar small placebo- controlled crossover trial of oral papaverine hydro- Benefits chloride in the treatment of atopic eczema. Itching, number of affected zones, skin thickening, vesiculation, epidermal change and redness were Benefits recorded as outcomes and none of these showed In the Berth-Jones and Graham-Brown study, 110 any clinically useful or statistically significant 50 patients with a mean age of 25.6 years were Health Technology Assessment 2000; Vol. 4: No. 37

randomised to receive either papaverine hydro- the trial with an enthusiasm for papaverine based chloride 100 mg four times daily or 60 mg four on a previous open study, the study has demons- times daily for children under 12 years, or matching trated the need to use methods such as RCTs to placebo each for 4 weeks. All patients had moderate- reduce the possible bias associated with the to-severe atopic eczema and were allowed to reporting of such open studies. The abnormal liver continue with emollients, a bath oil and a topical function tests in the Schupack study are also a steroid preparation throughout the trial. Outcome cause for concern. measures included itching assessed on a visual analogue scale by patients, clinical scoring of extent and severity and rate of usage of topical steroid Suplatast tosilate preparation. Of the 45 evaluable patients, mean itch score in the last 7 days of each treatment It has been suggested that a rebound phenomenon period was 58.6 in the active phase compared with occurs in people with atopic eczema who have 55.7 in the placebo phase (maximum score 140). been treated for prolonged periods with strong Clinical score (maximum of 720) in the active phase topical corticosteroids. We found one small RCT328 was 178 and 176 in the placebo phase. Baseline that evaluated the role of an anti-allergic medication scores were not presented in the papers. Topical called suplatast tosilate (which down-regulates steroid usage was very similar between the two groups. production of IgE and related cytokines) versus bufexamace ointment to prevent rebound from In the Shupack and colleagues study, 30 patients topical steroids in atopic eczema. aged 18 and above were randomised into a crossover study of papaverine hydrochloride in doses of Benefits 150–300 mg three times daily compared with Thirty-two patients who had been treated with strong placebo as an adjunctive treatment to emollients steroid ointment for several years were randomised and topical steroids. Of the 20 (out of 30) patients to either bufexamace ointment (a non-steroidal anti- who completed both phases of the crossover, no inflammatory ointment) or bufexamace ointment statistically significant advantage over placebo for and oral suplatast tosilate (400 mg/day). In the any of the parameters of itching, physician’s and control group, 15 patients experienced the rebound patient’s global evaluation were reported. Apart phenomenon after 2 weeks compared with only from non-significant p-values, the actual data for two of 17 patients in the active group (rebound these changes were not presented in the paper. was undefined). Several cytokines increased in the control group but not in the active group. Harms No serious adverse effects were reported in the Harms Berth-Jones study and symptoms such as tiredness No adverse effects were reported in this small study. were similar in both groups. In the Shupack study, however, three of the study patients on active treat- Comment ment developed abnormal liver function tests, which The issue of rebound from regular use of topical were not due to infectious hepatitis. Nausea occur- steroids is a serious and important one as it is red in 46% of patients on papaverine compared possible that the regular use of corticosteroids with 27% on placebo, though this difference was increases the chronicity of disease while benefiting not statistically significant. the short-term control of flare-ups. This small study was unblinded (the control group did not have an Comment oral placebo) and the ‘rebound’ was completely The method of randomisation in both of these undefined and therefore highly prone to investi- studies was unclear as was concealment of gator bias. The study should be followed by a allocation of randomisation. Drop-out rates were randomised, controlled double-blind trial over a modest in both studies and no intention-to-treat long period with clinical outcomes and a vehicle- analysis was performed. Although both studies only comparison group. were small, the Berth-Jones study in particular provides additional data to inform the reader on the possibility of missing clinically useful benefits. Summary of other interventions Based on their results, the power of their study to detect the 25% improvement in the itch score was Nitrazepam over 85% and the power of the study to detect a • One small RCT failed to show any benefit of 25% improvement in the clinical score was between nitrazepam at night for night-time scratching as 75% and 80%. Although the authors clearly started detected by infrared camera. 111 Other interventions

Ranitidine Papaverine • One RCT has suggested a modest benefit of • Two small RCTs do not suggest that oral oral ranitidine treatment above placebo for papaverine has a clinically important benefit in hand eczema in patients with atopic eczema. the short-term treatment of atopic eczema. These results need to be replicated elsewhere. Suplatast tosilate Theophylline • One small unblinded study suggests a possible • One RCT of 12 patients has compared oral theo- benefit of suplatast tosilate in preventing phylline versus placebo for 2 weeks in atopic the steroid ‘rebound phenomenon’, but is eczema and not found any treatment benefits. difficult to interpret in the absence of a vehicle- only group. Salbutamol • There is no RCT evidence to support the use of topical or oral salbutamol in atopic eczema.

112 Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 13 Discussion

Treatments with no RCT evidence TABLE 38 Therapeutic interventions currently in practice for which no RCTs could be found As pointed out in chapter 1, a systematic review that is driven only by published RCT data can Pharma- Comple- Miscellaneous cological mentary only answer questions that have been asked by treatments such trials. Many other treatments, combinations of treatments, and management approaches are • Antimetabolites • Acupuncture • Antibacterial clothing such as used for people with atopic eczema throughout the methotrexate • Calendula • Climatotherapy (high-altitude cream low-allergen environments) world. Some, such as climatotherapy are probably • Cytotoxic very rarely used if at all in the UK, whereas others immunosuppres • Spa treatment • Different ways of using sants e.g. conventional treatments e.g. such as wet-wrap bandages and oral azathioprine Mycophenolate short bursts of strong topical 36 mofetil steroids vs longer-term are used by a large number of UK dermatologists. weaker preparations* Questions need to be asked about these therapeutic • Leukotrine • Exercise options in order to identify possible research gaps. receptor antagonists e.g. • Extracorporeal photopheresis Therapies that had not been identified by our Montelukast* • Hospital admission team were canvassed from colleagues and profes- • Oral sional networks as described in chapter 2, and the azathioprine* • Occlusive dressings e.g. Duoderm™/ Granuflex™ results are shown in Table 38. • Oral prednisolone* • Organisation of care, e.g. special eczema clinics, Division between RCTs and • Thalidomide community liaison nurses, no RCTs is arbitrary • Type IV nurse follow-up clinics, joint phospho- primary/secondary care Table 38 probably only identifies some of the diesterase chronic disease clinics questions that can be asked of therapies that are inhibitors • Stress management currently used in atopic eczema. Some treatments • Water softening devices (e.g. type IV phosphodiesterase inhibitors) are • Ways of improving adequate relatively new and experimental, and clinical trials dosage/concordance, e.g. use will hopefully be conducted (or are currently in of the fingertip unit progress) in the near future. It should also be • Impregated bandages, e.g. ™ ™ remembered that just because treatments for Ichthopaste or Quinabands which some RCT evidence was found, mentioned • Wet-wrap bandages in the previous chapters, this does not mean that *Ongoing trials have been identified for these agents DuoDERM™, Granuflex™, ConvaTec, UK; Ichthopaste™, Smith & Nephew the questions regarding each of those inter- Health, UK; Quinabands™, SSL, UK ventions have been answered. Thus in the section on emollients, there are at least ten important unanswered questions remaining. Similarly, just Difficult sites and combinations of because there is one RCT evaluating deep-sea treatments water versus physiological salt water does not In addition to the interventions mentioned in mean that the evidence for salt water baths has Table 38, consideration also has to be made of been ‘sorted’, as no RCTs have been located that treatment of atopic eczema at specific difficult answer the more urgent question of whether salt body sites such as the scalp or backs of hands, as baths have any benefit above ordinary baths. there may be specific issues such as formulation, The division between treatments for which no penetration, cosmetic acceptability and adverse RCTs could be found and those for which some effects related to such sites. It has also been RCTs were found is therefore somewhat arbitrary. pointed out that future studies should consider Table 38 should be viewed as an indication of evaluating entire management approaches that some aspects of therapies that were not discussed mimic real practice. Thus, combinations of treat- in the commentaries in the results chapters, ments such as emollients, topical steroids and rather than as a comprehensive blueprint of education should be evaluated together rather unanswered questions for future primary and than in isolation (Meredith B, personal oral secondary research. communication, 1999). 113 Discussion

Prevention Missed studies It is also important to always consider prevention of It is acknowledged that a predominantly electronic atopic eczema in the widest sense by means of intra- bibliographic database search will miss certain RCTs uterine or early life environmental manipulation.16 that have been misclassified on those databases, Although the links between the environment and articles from journals not listed on those databases atopic eczema are still in the early stages of research,5 and unpublished studies. In terms of a reference energy needs to be directed at prevention as well as standard for published studies, we compared the treatment of established cases with pharmaceutical results of handsearching the entire contents of agents that at best only control symptoms. Clinical and Experimental Dermatology for atopic eczema trials and those with our electronic searching. Diagnostic tests None of the five controlled trials had been missed Although diagnostic tests are not regarded strictly as by our searching methods. Two were included as ‘treatments’, certain tests such as patch tests also RCTs, two excluded as non-RCTs and a further study need to be evaluated as an aspect of the management was excluded as it evaluated experimentally induced of atopic eczema. This is because discovering a super- reactions in atopic eczema patients. Our yield of imposed contact allergy (e.g. to lanolin, a steroid RCTs of antihistamines in atopic eczema (31 reduced or a preservative in a cream) could significantly to 21 after evaluating the hard copies) was very improve the disease, which had all been put down similar to the yield identified by a more intensive to constitutional factors. Ideally the benefit of such independent search by members of the Cochrane testing, which has considerable time and health costs Skin Group (Diepgen P, personal oral commun- if applied to all atopic eczema sufferers, needs to be ication, 2000). We found eight more RCTs for put to the test by means of RCTs. This will reduce antihistamines than a recently published ‘systematic selection bias and will also permit evaluation of review’ of antihistamines in atopic eczema.362 clinical outcomes as opposed to just positive patch test results, the clinical significance of which is not Given the fact that at least 200 specialist dermat- always clear in atopic eczema patients. Likewise, the ology journals have been identified (Delamere F, popular request for ‘allergy tests’ among families of personal oral communication, 2000), many of which children with atopic eczema in the belief that their are not registered with MEDLINE, it is likely that child’s atopic eczema is caused by one specific allergy, some RCTs of atopic eczema have been missed, partic- needs to be put to the test in an RCT with long-term ularly in non-English and less-well-read journals. clinical measures rather than blood or skin tests as outcomes. This applies to the lucrative high-street The authors also suspect that there is a large body industry of performing ‘allergy tests’ on vulnerable of unpublished data held by pharmaceutical comp- atopic eczema sufferers in addition to the more anies for various reasons. Clinicians who have lacked conventional tests performed in hospitals.410 the time or motivation to publish their results also hold such unpublished data. It is likely that Horizon scanning more ‘negative’ studies fall into these categories. It is likely that the next 5 years will witness an Estimating the magnitude of this hidden part of the increase in the number of topical pharmaceutical iceberg of evidence is difficult without additional agents for treatment of atopic eczema. Thus treat- research. In the field of evaluating evening primrose ments such as tacrolimus and ascomycin derivatives oil for instance, two of the authors of the current are already well down the road to development report were commissioned by the Department of and evaluation, and others such as cytokines Health in 1997 to conduct a meta-analysis of all and phosphodiestarase inhibitors are following. trials. Sadly, permission to publish this report has Two recent review articles have considered never been granted, but it did contain the results future developments.26,391 of nine additional small unpublished studies held on file by the company. Despite writing to the company for any unpublished data for this report, Validity and robustness of results no data have been forthcoming to date (Tables 39 and 40). The extent of holding unpublished data Sensitivity analyses in the traditional sense of on file by pharmaceutical companies is difficult to exploring the effects of removing certain studies assess, but it is likely to continue to some degree if with particular characteristics within a meta- the UK drug licensing process (which is privy to all analysis is very limited within this report due to such data) maintains its current code of keeping the little pooling that was possible. Further such data out of the public domain.411 Some large consideration of the validity of the results of this drug companies such as Glaxo Wellcome and 114 report is worth a brief mention in this section. Schering Healthcare have recently signed-up to Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 39 Responses from pharmaceutical companies of requests a policy of making all unpublished RCT data for unpublished or missed RCTs available to Cochrane reviewers. This is a welcome development. There is a case to be made for it to be Company Response? Result compulsory that all clinical data relating to trials on Glaxo Wellcome Yes All in public domain patients within the NHS to be made available as Janssen-Cilag No part of ethical approval of any study. UCB Pharma No Hoescht Marion Yes No RCTs Author bias As stated in chapter 2, blinding of authors/ Schering-Plough Yes No new, all in public domain institution was unrealistic as certain key words Wyeth No would have immediately identified the study to one Stafford-Miller Yes No RCTs of the reviewers who is very familiar with the field. Novartis Yes No new RCTs Although bias in the way certain drugs or inter- ventions are described is bound to happen in any Merck Sharp No subjective narrative report, the authors have striven Pfizer Yes No research in this area to minimise such effects by adopting a standard Sinclair Yes No RCTs approach and by explicitly separating the reported Fisons No data from their own comments. Searle Yes Compiling data External validity Only one127 out of 283 studies contained a clear indication (such as the words general practice, TABLE 40 Responses from pharmaceutical companies of requests community or primary care in the title, abstract or for unpublished or missed RCTs methods) that the study was carried out in a Company Response? Result primary care setting. Given that most cases of atopic Leo Yes Six RCTs eczema are treated in the UK, the generalisability of the results of the studies conducted in a hospital Summary of FU9202DK unpublished trial excluded setting summarised in this report may be limited. because unspecific hand eczema, The magnitude of benefit from say, a topical Ramsay 96 already included, excluded Poyner 1996 unclear corticosteroid, may be reduced substantially in whether had atopic eczema, and milder disease in the community as there is less Hill 1998 hand eczema, one, two included:Wilkinson 1985 and potential to improve from a higher baseline severity Thaci 1999 score. Other issues such as patient preference, and Galderma No different concordance rates in primary care may Bioglan Yes Two RCTs further limit the generalisability of studies conducted in well-motivated patients in hospital. Berberian 1999 and Drake 1994 already included both trials on file It is for these reasons that future pragmatic trials No unpublished papers available should be considered in primary care. Yamanouchi No The need for updating Crookes Yes No RCTs but a very useful file sent containing research on E45 Inevitably, RCTs are continually being performed in emollient published and atopic eczema, and there will be a time when research unpublished data stands still in order to summarise the totality of Seton No evidence. Based on our own search updates, we Scholl No estimate that around one new RCT on atopic eczema Kestrel No is published each month. In addition, we are aware of at least ten ongoing RCTs in atopic eczema Quinoderm No including interventions such as topical cortico- Bristol Myers Yes No unpublished RCTs carried out steroids, Montelukast and tacrolimus through Steifel No informed contacts, the Cochrane Skin Group and Dermal Yes/No No unpublished RCTs the National Research Register. Those making Schering Healthcare Yes None on file treatment guidelines or recommendations based Typharm No on the results of this report are therefore advised to update their conclusions with further searches. Phyto pharmaceuticals Yes Those topic areas that will be taken forward as Cochrane Reviews will be updated automatically as Squibb No part of the Cochrane Collaboration process. 115

Health Technology Assessment 2000; Vol. 4: No. 37

Chapter 14 Summary and conclusions

Research included in the review insufficient evidence to decide between them at present. The lack of informative RCTs for the Coverage and clinical relevance most widely used treatments for atopic eczema To the best of our knowledge, this is the first (i.e. emollients and bath additives) is striking. ever comprehensive glimpse of all RCTs of atopic This is particularly so when a recent detailed eczema conducted to date. The quality and quantity economic study in Nottingham suggested that of 272 included RCTs covering treatments for the emollient and bath oils accounted for 81% atopic eczema is highly variable, and the clinical of total NHS prescribing costs for children with relevance is often difficult to understand because atopic eczema in the community.412 of complex quantitative outcome measures. It is clear that most RCTs have been about issues that In addition to the ‘pull’ of the Pharmaceutical are important to the Pharmaceutical Industry, Industry’s agenda, lack of public investment into often competing for a niche in a ‘me too’ market. researching the treatment of atopic eczema has This is understandable, but as chapter 13 pointed been another factor leading to the unbalanced out, there is a major discrepancy between what coverage of the tree of RCTs in atopic eczema. answers these studies provide and what physicians We did not identify one RCT of atopic eczema and their patients often ask. As Figure 6 suggests, supported by the UK Medical Research Council issues such as prevention of atopic eczema, manip- in our search. Clinical trials are expensive and ulation of trigger factors and organisation of care time consuming to run, and it is a credit to some are mere twigs in the tree of atopic eczema RCTs working in the NHS that they have managed to at present. carry out well-designed large independent RCTs in their own time.243 It is also possible that some FIGURE 6 The tree of RCTs of atopic eczema over the past 40 of the obvious gaps in researching atopic eczema years has been a lopsided one treatment have not been addressed simply because researchers working in relative isolation have not Prevention of Topical steroids asked the right questions, or because the more atopic eczema? practical questions concerning comparison of More topical several commonly used treatments are too difficult Organisation of steroids healthcare ‘Me too’ or are perceived as less interesting to researchers Cyclosporin than testing a ‘new’ drug. Combinations of GLA treatments Interferon Another Despite the authors’ familiarity with the subject Once-daily antihistamine area, some genuine surprises occurred as a result topical steroids of the review, such as the finding of two RCTs that suggest cotton clothing is no better than soft synthetic fibres, identifying a well-conducted RCT on bioresonance that did not show any benefit, Much investment has gone into evaluating different and finding out that there is no good RCT evidence topical corticosteroids, yet we still know little about to support the use of topical antibiotic/cortico- the best way to use them. Little is known about steroid combinations. On the positive side, there other simple cheap alternatives such as topical coal were some RCTs indicating a potentially useful tar, use of bandages and salt water baths. Many benefit of psychological and various non-pharma- newly developed and potentially toxic drugs such cological approaches. It was also interesting to as cyclosporin A have been thoroughly studied locate five RCTs that suggested there was little, (12 RCTs), yet there is a complete absence of RCTs if any, advantage in using topical corticosteroids on some alternatives such as azathioprine and oral twice as opposed to once daily as this might have steroids. Such a discrepancy can give rise to the clear benefits to patients in terms of convenience illusion that one is useful and the other is not in of fewer adverse effects, as well as offering the current climate of evidence-based medicine, potentially very large cost savings to the NHS if whereas the correct conclusion is that there is adopted on a national scale. 117 Summary and conclusions

What about non-RCT data? adoption of the CONSORT statement (designed While it is perfectly appropriate to use non-RCT to improve clinical trial reporting) by journals data to answer questions on natural history and such as the Archives of Dermatology, Journal of the adverse effects, the authors have stuck to their American Academy of Dermatology and the British policy of only considering the RCT as the study Journal of Dermatology is a welcome step forward.416 design that is able to minimise bias the most. Throughout the report there are examples of Study design issues RCTs (levamisole299 in chapter 10 and papaverine327 Five points are worthy of further consideration in in chapter 12) not demonstrating any benefit to an terms of study design for atopic eczema studies intervention despite earlier enthusiastic results and these are discussed below. from non-RCT studies. The RCT design does not guarantee freedom from bias of course, and Studies need to be longer threats to the validity of individual studies have Perhaps the most important point is to encourage been commented upon throughout the report. longer duration of future RCTs of atopic eczema. For most people, atopic eczema is a chronic inter- Quality of reporting mittent disease, and studies that evaluate numbers Quality of reporting was generally very poor in of relapses and duration of symptom-free periods most of the studies. Our primary quality criteria of are required in addition to studies that measure a clear description of generation of the random- short-term reduction in clinical signs. isation sequence, concealment of allocation of randomisation, adequate description of blinding Awareness of a large placebo/vehicle effect and an intention-to-treat analysis were hardly ever As some studies have demonstrated,299 the placebo fulfilled. These features have been shown to lead or vehicle effect in atopic eczema can itself account to biased estimates of treatment effects.46 Some for around 30% improvement. This needs to be studies just reported p-values and no data. Others taken into account when conducting sample size have performed multiple significance tests on six estimates for RCTs. or more different physical signs at different time intervals and highlighted those that are positive Profusion of outcome measures of uncertain without declaring any a priori main outcome clinical significance measures. This is akin to throwing a dart and Given such a range of outcome measures and drawing a dartboard around it.413 Other common complex scales with different symptom and sign problems were lack of CIs, failure to take different weightings in atopic eczema, there is plenty of baseline scores into account, and testing changes scope for introduction of bias when assessing a new between baseline for two drugs separately as drug by selecting a scale that is likely to enhance opposed to comparing the change in scores the specific feature which the drug is designed between treatments.414 to improve (e.g. erythema or itch). Many of the ‘named’ scales have not been tested adequately.417 Many studies, particularly earlier ones, were In many studies, the word ‘validated’ when referring clearly under-powered. This is not necessarily a to a scale simply meant that it had been used problem providing they have been interpreted before. There are almost as many un-named scales correctly with CIs to present a range of plausible as there are trials, and these may introduce a major treatment effect, but this was seldom the case.415 bias towards enhancement of treatment response.418 More worryingly was the fact that several authors There has been a tendency to concentrate on the misinterpreted lack of evidence of treatment physical signs of atopic eczema in such scales to benefit in small studies as being equivalent to the exclusion of patient data on the basis that the evidence of no effect. Duplicate publication was also former is ‘objective’ and the latter is ‘subjective’. rife, as indicated by the list shown in appendix 4. Yet the variability of the ‘objective’ measures is often more than patient’s symptoms, and their The situation has probably improved over the past repeatability between physicians is often poor.31 10 years, particularly with the major dermatology The clinical significance of a difference in a journals. Thus, studies such as that conducted by quantitative score of 13.4 between two treatments Boguniewicz and colleagues159 are a pleasure to is also difficult for physicians to relate to patients.337 read as there is a clear description and flow chart Greater consideration should therefore be given to of what has happened to all those who were including patient-derived outcome measures originally entered into the study. These changes alongside the physician-based scales, and use of probably reflect a change in standards of clinical scales should be restricted to a few well-tested ones 118 trial reporting in larger journals. The recent unless there are good reasons to do otherwise. Health Technology Assessment 2000; Vol. 4: No. 37

Future studies need to make it very clear whether highlighted. This type of research is important the arm of treatment is to control symptoms, improve when extrapolating from cost-effectiveness studies quality of life for patient and family, or to clear the of motivated patients in secondary care to a entire rash (which may be unrealistic at present). primary care setting. It may be the case that an inexpensive single treatment delivered with a Crossover designs simple package of care may be more effective than Although the efficiency in terms of reduced numbers an expensive therapy without any such support. for a crossover design is attractive for trials of agents in atopic eczema, the fluctuating nature of Clearly it is impossible to commission all of these the disease makes it less suitable for this type of proposals, and the authors prioritisation of the approach. Data from the second half of a crossover six most urgent research themes are shown in study may have to be discarded in the presence of Table 42. Studies on disease prevention also need a period or carry-over effect, though this has rarely to be considered. been tested for in the trials. Left/right body or limb comparisons are also popular but introduce Secondary research problems with blinding and systemic absorption. Perhaps one of the most useful aspects of this Simple parallel group RCTs that are pragmatic in scoping review is that it will serve as a generator of nature are most justifiable. other more detailed specific systematic reviews. Already therefore, titles for reviews on the reduction Separate atopic eczema patients from others of house dust mite, antihistamines, Chinese herbs As can be seen from appendix 2, there is a large and dietary approaches have been registered with wastage of RCT evidence for many interventions the Cochrane Skin Group, and it is hoped that that have included people with atopic eczema, as others will use the data contained within this review they have been lumped in with other inflammatory as a backbone for additional systematic reviews. dermatoses such as psoriasis or lichen simplex, and their results not separated. Discarding such evidence Methodological might appear a little harsh. Although some might There is a clear need for a programme of method- feel comfortable in generalising from studies ological research to accompany the primary evaluating all forms of eczema to atopic eczema, research if patients and their carers are to make the RCT evidence discussed in the section on sense of the study findings. Further research, such topical corticosteroids suggests that different as the current research by this team to identify a inflammatory diseases respond differently to the simple list of patient-derived outcome measures same treatment. Atopic eczema patients therefore for atopic eczema, is needed. A recent review32 of need to be separated from patients with other ‘named’ outcome scales used in atopic eczema inflammatory dermatoses, or at least their results identified 13 different instruments, none of which should be presented separately. had undergone full testing for validity, repeatability and responsiveness. In addition to completing the validity testing of such ‘named’ scales, further Future research priorities research involving consumers and carers is required to determine a minimum list of similar Primary research outcome measures, for example a quality-of-life With such glaring gaps in our current knowledge measure, patient-rated global disease improvement about the effectiveness of treatments for atopic and the ‘best’ of the current named objective eczema, it is difficult to know where to start in doctor-rated scales for use in future atopic eczema recommending research priorities. In order to trials. This will vastly aid the comparability of avoid bias on behalf of the authors choosing just studies providing such a list has been derived using what they think is important in future primary the best quality external evidence with ownership research, results of the survey of 25 researchers from a wide range of stakeholders. Drug regulatory and clinicians with an interest in atopic eczema authorities could occupy a key role in recom- and six consumers with atopic eczema are shown in mending the use of such measures. Table 41. There was remarkable similarity between the different groups in calling for research on The RCTs highlighted in this study also provide an similar themes. Research themes fall mainly into opportunity to explore more generic issues such as assessing the things that we already have rather the relationship between magnitude of benefit and than assessing the role of newer agents. Research study quality or design issues. Future RCTs in that evaluates the delivery of whole packages dermatology can also consider using a Bayesian of care such as involvement of nurses was also approach, particularly where there is pre-existing 119 Summary and conclusions

TABLE 41 Primary research questions identified by 25 clinicians and six consumers

Intervention Question

Disease prevention What is the role of vaccination in triggering atopic eczema expression? Role of maternal dietary manipulation and house dust mite avoidance

Emollients Does regular use of emollients reduce disease relapse? Topical corticosteroids What is the most optimal use of topical steroids? Do topical steroids suppress growth? Are the ‘newer’ once-daily topical steroids more effective than older preparations? Do topical corticosteroids cause long-term skin damage when used appropriately? Tacrolimus and How do the newer topical agents such as tacrolimus and ascomycin compare with topical corticosteroids? ascomycin Should tacrolimus or ascomycin be used after inducing a remission with topical steroids? Diets Role of exclusion diets Factors affecting Do different patterns of atopic eczema (discoid, reverse pattern, flexural) require different treatments? treatment response How important is the presence of S. aureus in managing disease? Are there any genetic markers for predicting treatment response? Trigger factors What are the most important modifiable trigger factors? Treatments for How does ultraviolet treatment compare with oral immunomodulatory treatment in severe disease? severe disease Should potentially toxic treatments be used on a rotational basis? Efficacy of agents such as azathioprine, methotrexate, anti-leukotrienes, naltrexone Disease dimensions What are the most effective interventions at reducing the itch of atopic eczema? Does any treatment alter the natural history of disease if used properly and for long enough? Which is the best treatment approach for mild-to-moderate disease? The role of tests What is the usefulness of allergy tests in disease management What is the role of allergic contact dermatitis in topic eczema? Environmental Are water softeners effective? manipulation Does removal of pets influence disease activity? How important is control of humidity and excessive heat in the home? Psychological Which are the most psychological/psychotherapeutic approaches and how well do patients respond to such approaches outside approaches the hands of enthusiasts? Bandages How effective are wet-wraps, with and without emollients or topical steroids? Organisation of How effective are educational approaches in improving the correct use of first-line treatments? care/education What is the role of specialist nurses in helping people with atopic eczema? How effective is a multiprofessional team approach compared with a dermatologist alone? How important is patient concordance in predicting disease control? Bathing Are salt baths helpful? Is there an optimal frequency of bathing? Issues of safety Long-term adverse effects of cyclosporin in children Long-term adverse effects of ultraviolet light in children

TABLE 42 The six most urgent primary research priorities

Question Justification

How effective are wet-wrap bandages with topical steroids or emollients Widespread use with no RCT backing. Potentially large and useful vs the same treatment and no wet-wraps? treatment effect but also greater potential for local and systemic adverse effects of topical steroids How useful are blood allergy tests at predicting benefits from allergen Large demand for such tests matched by lack of evidence that they mean avoidance? anything useful in terms of eczema outcomes Does the installation of a water-softening device improve atopic eczema? Sold widely to eczema sufferers. Some epidemiological evidence that hard water might be important. Modifiable environmental factor What is the role of specialist nurses in managing patients with atopic Some observational evidence of benefit in some centres. May be a cost- eczema? effective complement to current doctor-dominated approach Head-to-head cost-effectiveness comparison of topical corticosteroids Newer agents likely to be taken up eagerly in view of corticosteroid against topical tacrolimus or ascomycin ‘phobia’, but true benefit and cost–benefit unclear Trials aimed at prevention of atopic eczema Large potential health gains in high-risk populations

120 Health Technology Assessment 2000; Vol. 4: No. 37

epidemiological evidence (e.g. as in the case of house through usage. On the other hand, some RCTs dust mite and water hardness) to inform the prior have failed to show any benefit for some probabilities. In other areas where there is a multi- interventions and these could perhaps be looked at plicity of new interventions being introduced carefully in terms of the rationale for their constantly, consideration should be given to more continued widespread use. This is easier said than flexible and pragmatic approaches such as the use done as advice such as avoidance of synthetic fibres of tracker studies. and enzyme-containing washing powders, and frequent bathing have all become deeply engrained in the rituals of atopic eczema advice. Implications for healthcare Similarly, use of twice-daily topical corticosteroids or dilutions of topical corticosteroids have also The strength of evidence supporting the various become deeply embedded in clinical practice. interventions have already been summarised in the Crucial factors such as patient choice, adverse key points of the results chapters. The strength of effects and cost also have to be taken into account evidence in relation to those interventions which when making recommendations. are commonly used in the UK are summarised qualitatively in Table 43. Given the virtual absence Trying to split Table 43 into further first-line, of long-term studies, the data can only refer to second-line and third-line treatment guidelines is short-term control of disease. beyond the scope of this systematic review and is an approach that is hazardous without a much Some ‘health’ warnings wider consultation and more detailed synthesis of Table 43 gives the authors’ opinion on the value of adverse effect data, patient preference data and the evidence base for the interventions considered. cost data, which by definition is always contextual It is not intended as a substitute for the dose exam- and limited in time. Decision analysis approaches ination of the original studies in the context of local should also be used to determine which inter- guideline and policy development. Any attempt at ventions are amenable to change in the future. summarising the RCT evidence (or lack of such evidence) for such a wide range of interventions is fraught with hazard, perhaps the most important Summary of which is that absence of RCT evidence for an intervention is not the same as providing evidence • RCTs of interventions for atopic eczema have to reject that intervention. Therefore it might be often not answered the questions of most entirely reasonable to continue to use a range of importance to patients and their carers. emollients in atopic eczema based on lower hierar- • This mismatch is possibly due to the lack of chies of evidence until appropriate RCTs are done, independent investment into primary atopic given the fact that they have become ‘consecrated’ eczema research.

TABLE 43 Results of systematic review of treatments and prevention of atopic eczema

Interventions with reasonably Interventions with insufficient Interventions for which RCT Interventions with no RCT established efficacy (based on evidence to make recommen- evidence does not support a evidence whatsoever at least one high-quality RCT and dations (only one small RCT or clinically useful benefit (at least a clinically useful effect) conflicting RCTs where the largest one RCT that fails to show a and best-quality RCTs do not convincing benefit on overall suggest a clear and clinically disease activity) useful benefit)

• Oral cyclosporin • Maternal antigen avoidance for • Avoidance of enzyme washing • Short bursts of potent vs longer- • Topical corticosteroids disease prevention during and powders term weaker topical steroids • Psychological approaches after pregnancy • Cotton clothing as opposed to • Dilution of topical • Ultraviolet light • Antihistamines soft-weave synthetics corticosteroids • Chinese herbs • Biofeedback • Oral prednisolone • Dietary restriction in established • Twice-daily as opposed to once- • Azathioprine atopic eczema daily topical corticosteroids • Salt baths • House dust mite reduction • Topical antibiotic/steroid • Impregnated bandages • Homeopathy combinations vs topical steroids • Wet-wrap bandages • Massage therapy alone • Water-softening devices • Hypnotherapy • Antiseptic bath additives • High filtration as opposed to • Evening primrose oil ordinary vacuuming • Emollients • Routine patch testing • Topical coal tar • Combinations of different • Topical doxepin treatments • Different approaches to organisation of care 121 Summary and conclusions

• There are some glaring gaps in our current • A profusion of outcome measures knowledge regarding the use of some should be avoided in favour of a few interventions that are commonly used such as clinically understandable and patient- emollients and wet-wrap bandages. orientated ones. • This review has identified some lesser known • There is much scope for improving the RCTs, which suggest that some interventions standard of clinical trial reporting in atopic such as bioresonance and avoidance of synthetic eczema by journals adopting CONSORT clothing are ineffective. and by registering ongoing trials with the • The review has also failed to find any evidence Cochrane Skin Group. to support the use of twice-daily as opposed to • This review has identified several primary once-daily topical steroids or topical antibiotic/ research gaps, which need to be addressed steroid combinations as opposed to topical mainly by RCTs. steroids alone in infected atopic eczema. • The review is likely to be a useful generator of • The review has helped to place non- future more detailed systematic reviews. pharmacological treatments in their context • The RCT database contained within this report alongside conventional drug approaches. provides a good opportunity to conduct some • Future RCTs should consider using a parallel general research into the relationship between group design and be of longer duration. study quality and treatment benefit.

122 Health Technology Assessment 2000; Vol. 4: No. 37

Acknowledgements

Role of authors Ms Helena Varonen (Helsinki) for helping to Colette Hoare performed all of the searches, exclude a Finnish study. checked for eligible studies, obtained hard copies of studies, conducted the focus group, abstracted Identifying additional treatments not on our list data from included studies, wrote the section on of RCTs complementary therapies, managed the references Dr D Atherton, (Hospital for Sick Children, and finalised the appendices and report layout. Great Ormond Street); Professor Peter Friedmann, (Southampton); Dr J Berth-Jones, (Coventry); Hywel Williams wrote the study proposal, super- Dr S Lewis-Jones (Dundee); Dr J Vesty (Sunder- vised the day-to-day running of the project, hand- land); Dr D Paige (Royal London Hospital); searched conference proceedings, checked on Professor A Taieb (Bordeaux); Dr C T Kennedy excluded studies, abstracted and summarised data (Bristol); Dr M R Judge (Bolton); Dr R Chalmers from most of the included studies, and wrote the (Manchester); Dr J D Wilkinson (Amersham); final report with help from Colette Hoare. Dr M Glover (Newham Health Care NHS Trust London); Dr E A Bingham (Belfast); Dr A Anstey Alain Li Wan Po provided advice on the methods, (Newport). part-wrote the sections on cyclosporin, cromo- glycate and once- versus twice-daily topical cortico- Authors providing additional data on published trials steroids and approved the final report. Professor Thomas Diepgen (Heidelberg); Professor John Harper (London); Dr David Atherton The authors wish to thank the following people for (London); Dr Tom Poyner (Stockton-on-Tees); their helpful contribution to this report: Dr Mary Glover (London); Professor Mark Lebwohol (New York); colleagues of the late Searching Professor Hjorth; Professor Toshi Aoki (Osaka); Dr Finola Delamere, Trials Search Co-ordinator, Professor Frederik Bahmer (Germany); Dr Kenji Cochrane Skin Group, Nottingham; Dr Carole Nishioka (Japan). We also wish to thank all the Lefebvre, UK Cochrane Centre, Oxford; pharmaceutical companies mentioned in Tables 41 Mrs Christine Clarke (Manchester) and staff of the and 42 who kindly responded to our request for Greenfield Medical Library, University of Nottingham, any missed or unpublished studies. colleagues in the Cochrane Complementary Medi- cines Field; and the BMJ Publishing Group for use Proofreaders and commentators of their search strategy for clinical trials on EMBASE. Mrs Kim Thomas (Nottingham); Dr Phil Alderson (UK Cochrane Centre, Oxford); Mrs Margaret Translators Cartman (Nottingham); Dr Carolyn Charman Dr Urba Gonzalez (Spain) and Mrs Maxine Whitton (Nottingham); and Miss Mara Ozolins (Nottingham). (UK) for translation of Spanish and Portugese articles. We also thank the four HTA reviewers for their Dr Yukihiro Ohya (Tokyo) and Professor Toshi Aoki helpful and thoughtful comments. (Osaka) for translation of Japanese articles. Professor Thomas Diepgen (Heidelberg), Consumers working with the Cochrane Skin Group Dr Berthold Rzany (Mannheim), Dr Jan von der Werth who helped to identify unanswered questions on (UK) and Ms Christine Scholtyssek (Germany) for the treatment of atopic eczema translation of German articles. Mr David Potter, Mr Jack Stein, Mr John Fulton, Professor Vladimir Vlassov (Moscow) for translation Mrs Margaret Newton, Ms Barbara Meredith, of Russian articles. Dr Elisabeth Curling and Mr Paul Mellows. Professor Alain Taieb for translation of French articles. Individuals who helped to identify the main Dr Åke Svensson for helping to exclude a unanswered questions for future atopic eczema Danish study. clinical trial research Ms Kirsten Lone Jensen (Copenhagen) for help Professor Andrew Finlay (Cardiff); Dr J Berth-Jones in identifying Nordic RCTs. (Coventry); Dr Alex Anstey (Newport); Dr Tom Fahey 123 Acknowledgements

(Bristol); Professor Rona MacKie (Glasgow); Dr Ian Netherlands); Professor Gimpiero Girolomoni Coulson (Burnley); Dr John Adams (Cheadle); Dr Colin (IRCCS, Rome); Dr Tony Avery (University of Munro (Glasgow); Dr Tom Poyner (Stockton-on-Tees); Nottingham); Dr. Dilys Harlow (Bristol); Professor Professor Kevin Cooper (Cleveland, USA); Professor Peter Friedman (University of Southampton); Jon Hanifin (Oregon, USA); Professor Tim David Dr Mary Judge (Bolton); Dr Robin Graham-Brown (Manchester); Dr Åke Svensson (Malmoe, Sweden); (Leicester); Dr Ann Bingham (Belfast); Dr Pamela Dr Jan Bouwes Bavinck (Leiden, The Netherlands); McHenry (Glasgow). Professor Luigi Naldi (Bergamo, Italy); Dr Ann Braae Olesen (Åarhus, Denmark); Professor Donald Leung Help with photocopying (USA); Dr Pieter-van Coenraads (Groningen, The Mr Steven Chambers and Mr Peter Berry.

124 Health Technology Assessment 2000; Vol. 4: No. 37

References

1. Archer CB. The pathophysiology and clinical 15. Schultz-Larsen F, Holm NV, Henningsen K. Atopic features of atopic dermatitis. Williams HC, editor. dermatitis. A genetic-epidemiological study in a Atopic dermatitis. Cambridge: Cambridge population-based twin sample. J Am Acad Dermatol University Press; 2000. 1986;15:487–94. 2. Williams HC, Wüthrich B. The natural history of atopic 16. Williams HC. Atopic eczema – why we should look dermatitis. Williams HC, editor. Atopic dermatitis. to the environment. BMJ 1995;311:1241–2. Cambridge: Cambridge University Press; 2000. 17. Williams HC, Strachan DP, Hay RJ. Childhood eczema: 3. Williams HC. What is atopic dermatitis and how disease of the advantaged? BMJ 1994;308:1132–5. should it be defined in epidemiological studies? 18. McNally N, Phillips D. Social factors and atopic Williams HC, editor. Cambridge: Cambridge dermatitis. In: Williams HC, editor. Atopic University Press; 2000. dermatitis. Cambridge: Cambridge University Press; 4. Hanifin JM, Rajka G. Diagnostic features of atopic 2000. p. 139–47. eczema. Acta Derm Venereol (Stockh) 1980;92:44–7. 19. Strachan DP. Hayfever, hygiene, and household 5. Williams HC. The future research agenda. size. BMJ 1989;299:1259–60. Williams HC, editor. Atopic dermatitis. Cambridge: 20. Shaheen S. Discovering the causes of atopy. Cambridge University Press; 2000. BMJ 1997;314:987–8. 6. Williams HC, Forsdyke H, Boodoo G, Hay RJ, 21. Burrell-Morris C, Williams HC. Atopic dermatitis Burney PGF. A protocol for recording the sign in migrant populations. In: Williams HC, editor. of visible flexural dermatitis. Br J Dermatol Atopic dermatitis. Cambridge: Cambridge 1995;133:941–9. University Press; 2000. p. 169–82. 7. Herd RM. The morbidity and cost of atopic derma- 22. Olesen AB, Ellingsen AR, Olesen H, Juul S, titis. Williams HC, editor. Atopic dermatitis. Vol. 85–95. Thestrup-Pedersen K. Atopic dermatitis and birth Cambridge: Cambridge University Press; 2000. factors: historical follow up by record linkage. 8. Williams HC, Robertson CF, Stewart AW, on behalf BMJ 1997;314:1003–8. of the ISAAC Steering Committee. Worldwide 23. Hanifin JM. Atopic eczema. In: Marks RM, editor. variations in the prevalence of atopic eczema Eczema. London: Martin Dunitz; 1992. p. 77–101. symptoms. J Allergy Clin Immunol 1999;103:125–38. 24. Bos JD, Wierenga EA, Smitt JHS, van der Heijden FL, 9. Williams HC. Is the prevalence of atopic dermatitis Kapsenberg ML. Immune dysregulation in atopic increasing? Clin Exp Dermatol 1992;17:385–91. eczema. Arch Dermatol 1992;128:1509–12. 10. Herd RM, Tidman MJ, Prescott RJ, Hunter JAA. 25. McHenry P, Williams HC, Bingham EA. Treatment Prevalence of atopic eczema in the community: of atopic eczema. BMJ 1995;310:843–7. the Lothian atopic dermatitis study. Br J Dermatol 1996;135:18–9. 26. Hanifin JM, Chan S. Biochemical and immunologic mechanisms in atopic dermatitis: new targets for 11. Emerson RM, Williams HC, Allen BR. Severity emerging therapies. J Am Acad Dermatol distribution of atopic dermatitis in the community 1999;41:72–7. and its relationship to secondary referral. Br J Dermatol 1998;139:73–6. 27. Shum KW, Lawton S, Williams HC, Dochety G, Jones J. The British Association of Dermatologists 12. Dotterud LK, Kvammen B, Lund E, Falk ES. audit of atopic eczema management in secondary Prevalence and some clinical aspects of atopic care. Phase 1: audit of service structure. dermatitis in the community of Sør-Varanger. Br J Dermatol 1999;141:430–7. Acta Derm Venereol 1995;75:50–3. 28. Shum KW, Lawton S, Williams HC, Dochety G, 13. Herd RM, Tidman MJ, Prescott RJ, Hunter JAA. Jones J. The British Association of Dermatologists audit The cost of atopic eczema. Br J Dermatol of atopic eczema management in secondary care. Phase 1996;135:20–3. 2: audit of service process. Br J Dermatol 2000;142:274–8. 14. Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic 29. Charman CR, Morris A, Williams HC. Topical eczema: its impact on the family and financial cost. steroid ‘phobia’ in patients with atopic eczema. Arch Dis Child 1997;76:159–62. Br J Dermatol 2000;142:931–6. 125 References

30. Finlay AY. Measurement of disease activity and 48. Lilja G, Dannaeus A, Foucard T, Graff-Lonnevig V, outcome in atopic dermatitis. Br J Dermatol Johansson SGO, Oman H. Effects of maternal diet 1996;135:509–15. during late pregnancy and lactation on the develop- ment of atopic diseases in infants up to 18 months 31. Charman CR, Venn AJ, Williams HC. Measurement of age – in vivo results. Clin Exp Allergy 1989;19:473–9. of body surface involvement in atopic eczema: an impossible task? Br J Dermatol 1999;140:109–11. 49. Zeiger RS, Heller S. The development and prediction of atopy in high-risk children: follow-up 32. Charman C, Williams HC. Outcome measures of at age seven years in a prospective randomized disease severity in atopic eczema. Arch Dermatol study of combined maternal and infant food 2000;136:763–9. allergen avoidance. J Allergy Clin Immunol 33. Chren MM, Lasek RT, Flocke SA, Zyzanski SJ. 1995;95(6):1179–90. Improved discriminative and evaluative capability 50. Hide DW, Matthews S, Matthews L, Stevens M, of a refined version of SKINDEX, a quality-of-life Ridout S, Twiselton R, et al. Effect of allergen instrument for patients with skin diseases. avoidance in infancy on allergic manifestations 133 Arch Dermatol 1997; :1433–40. at age two years. J Allergy Clin Immunol 34. Anonymous. British National Formulary. No. 38. 1994;93(5):842–6. London: BMJ Books; 1999. 51. Zeiger RS, Heller S. Development of nasal 35. Williams HC. Too soon to market: problem is acute basophilic cells and nasal eosinophils from age in dermatology. BMJ 1998;316:229. 4 months through 4 years in children of atopic parents. J Allergy Clin Immunol 1993;91(3):723–34. 36. Lear JT, English JSC, Jones PW, Smith AG. Retrospective review of the use of azathiprine in 52. Falth-Magnusson K, Kjellman NI. Allergy prevention severe atopic dermatitis. J Am Acad Dermatol by maternal elimination diet during late pregnancy 1996;35:642–3. – 5-year follow-up of a randomized study. J Allergy Clin Immunol 1992;89(3):709–13. 37. Anonymous. Undertaking systematic reviews of research on effectiveness: CRD guidelines for those 53. Chandra RK, Puri S, Suraiya C, Cheema PS. carrying out or commissioning reviews. CRD report Influence of maternal food antigen avoidance No. 4. York, UK: NHS Centre for Reviews and during pregnancy and lactation on incidence of Dissemination, The University of York; 1996. atopic eczema in infants. Clin Allergy 1986;16(6):563–9. 38. Anonymous. Preparation of reviews for the HTA 54. Miskelly FG, Burr ML, Vaughan-Williams E, Fehily AM, Programme. UK: University of Southampton; 1999. Butland BK, Merrett TG. Infant feeding and allergy. Arch Dis Child 1988;63(4):388–93. 39. Mulrow CD, Oxman A. How to conduct a Cochrane Systematic Review. Version 3.0.2. San Antonio: 55. Hide DW, Matthews S, Tariq S, Arshad SH. Allergen Cochrane Collaboration; 1997. avoidance in infancy and allergy at 4 years of age. Allergy 1996;51(2):89–93. 40. MEDLINE Electronic Database (1966–2000) URL: http://www.bids.ac.uk/medline/ 56. Kjellman NI, Johansson SG. Soy versus cow’s milk in infants with a biparental history of atopic disease: 41. EMBASE Electronic Database (1980–2000) URL: development of atopic disease and immuno- http://www.bids.ac.uk/embase/ globulins from birth to 4 years of age. Clin Allergy 42. The Cochrane Library. The Cochrane Controlled 1979;9(4):347–58. Trials Register. 1999 Issue 4. Update-Software. 57. Porch MC, Shahane AD, Leiva LE, Elston RC, 43. The Cochrane Library. The Skin Register. 1999 Sorensen RU. Influence of breast milk, soy or Issue 4. Update-Software. two hydrolyzed formulas on the development of allergic manifestations in infants at risk. Nutr Res 44. Donald A, Barton S, Muthu V. Clinical evidence. 1998;18(8):1413–24. Issue 2. London: BMJ Publishing Group; 1999. 58. Oldaeus G, Anjou K, Bjorksten B, Moran JR, 45. Procite® Software [Windows 95/NT Version 4]. Kjellman N-IM. Extensively and partially hydrolysed USA: Research Information Systems. infant formulas for allergy prophylaxis. Arch Dis Child 1997;77(1):4–10. 46. Moher D, Jadad AR, Nichol G, Penman M, Tugwell T, Walsh S. Assessing the quality of randomised 59. Mallet E, Henocq A. Long-term prevention of controlled trials: an annotated bibliography of allergic diseases by using protein hydrolysate scales and check lists. Controlled Clin Trials formula in at-risk infants. J Pediatr 1992;121 1995;16:62–73. (5 Pt 2):S95–100. 47. Moher D, Cook DJ, Jadad AR, et al. Assessing the 60. Lucas A, Brooke OG, Morley R, Cole TJ, Bamford MF. quality of reports of randomised trials: implications Early diet of preterm infants and development of for the conduct of meta-analyses. Health Technol allergic or atopic disease: randomised prospective 126 Assess 1999;3(12). study. BMJ 1990;300(6728):837–40. Health Technology Assessment 2000; Vol. 4: No. 37

61. Chandra RK, Puri S, Hamed A. Influence of 73. Traulsen J. Hydrocortisone buteprate versus beta- maternal diet during lactation and use of formula methasone valerate for once-daily treatment of feeds on development of atopic eczema in high risk atopic dermatitis. J Dermatol Treat 1997;8(2):109–14. infants [published erratum appears in BMJ 74. Wolf-Jurgensen-P. Efficacy of bufexamac cream versus 1989;299(6704):896]. BMJ 1989;299(6693):228–30. betamethasone valerate cream in contact dermatitis: 62. Perdomo-Ponce D, Benarroch L, Gonzalez-Cerrutti R, a double-blind trial. Curr Med Res Opin 1979;5:779–84. Barroso R, Carneiro F, Meijomil P. [Family education, 75. Haneke E. The treatment of atopic dermatitis with a model for allergy prevention]. Invest Clin methylprednisolone aceponate (mpa), a new topical 1996;37(4):221–45. corticosteroid. J Dermatol Treat 1992;3 Suppl 2:13–15. 63. Moore WJ, Midwinter RE, Morris AF, Colley JR, 76. Lebwohl M. Efficacy and safety of fluticasone Soothill JF. Infant feeding and subsequent risk of propionate ointment, 0.005%, in the treatment of atopic eczema. Arch Dis Child 1985;60(8):722–6. eczema. Cutis 1996;57(2 Suppl):62–8. 64. Odelram H, Vanto T, Jacobsen L, Kjellman NI. 77. Thaci D KJaKR. Fusidic acid/betamethasone Whey hydrolysate compared with cow’s milk-based 17-valerate in potentially infected atopic dermatitis. formula for weaning at about 6 months of age in J Eur Acad Dermatol Venereol 1999;12 Suppl 2:S163. high allergy-risk infants: effects on atopic disease and sensitization. Allergy 1996;51(3):192–5. 78. Amerio PL, Biggio P, Bossi G, Cainelli P, Cappugi P, Cerimele D, et al. Mometasone furoate 0.1% once a 65. Marini A, Agosti M, Motta G, Mosca F. Effects of a day in allergic contact dermatitis and in atopic dietary and environmental prevention programme dermatitis: controlled study versus betamethasone on the incidence of allergic symptoms in high valerate. Dermatol Clin 1998;18(4):255–60. atopic risk infants: three years’ follow-up. Acta Paediatrica 1996;Suppl 414:1–21. 79. Bagatell FK, Barkoff JR, Cohen HJ, Lasser AE, McCormick GE, Rex IH, et al. A multi-center 66. Vandenplas Y, Hauser B, Van den Borre C, comparison of alclometasone dipropionate cream Clybouw C, Mahler T, Hachimi-Idrissi S, et al. 0.05% and hydrocortisone cream 1.0% in the The long-term effect of a partial whey hydrolysate treatment of atopic dermatitis. Curr Ther Res Clin formula on the prophylaxis of atopic disease. Exp 1983;33(1):46–52. Eur J Pediatr 1995;154(6):488–94. 80. Gelmetti C, Grimalt R, Del Campo G, Caputo R. 67. Chandra RK, Singh G, Shridhara B. Effect of Tolerability and efficacy of topical budesonide in feeding whey hydrolysate, soy and conventional the treatment of atopic dermatitis in pediatric age. cow milk formulas on incidence of atopic disease G Ital Dermatol Venereol 1994;129(3):XIII–XVII. in high risk infants. Ann Allergy 1989;63(2):102–6. 81. Sears HW, Bailer JW, Yeadon A. Efficacy and safety 68. Camacho F, Garcia Bravo B, Diaz Perez JL, Aguirre of hydrocortisone buteprate 0.1% cream in patients A, Arnau C, Garcia Barbal J, et al. A comparative with atopic dermatitis. Clin Ther 1997;19(4):710–19. intraindividual double-blind assay between prednicarbate and fluocortolone in the management 82. Wolkerstorfer A, Strobos MA, Glazenburg EJ, of atopic dermatitis. Actas Dermo Sifiliograficas Mulder PGH, Oranje AP. Fluticasone propionate 1996;87(1-2):59–63. 0.05% cream once daily versus clobetasone butyrate 0.05% cream twice daily in children 69. Koopmans B, Lasthein Andersen B, Mork NJ, with atopic dermatitis. J Am Acad Dermatol Austad J, Suhonen RE. Multicentre randomized 1998;39(2 I):226–31. double-blind study of locoid lipocream fatty cream twice daily versus locoid lipocream once daily and loco- 83. Munkvad M. A comparative trial of clinitar versus base once daily. J Dermatol Treat 1995;6(2):103–6. hydrocortisone cream in the treatment of atopic eczema. Br J Dermatol 1989;121(6):763–6. 70. Bleeker J. Double-blind comparison between two new topical corticosteroids, halcinonide 0.1% and 84. Hiratsuka S, Yoshida A, Ishioka C, Kimata H. clobetasol propionate cream 0.05%. Curr Med Res Enhancement of in vitro spontaneous IgE prod- Opin 1975;3(4):225–8. uction by topical steroids in patients with atopic dermatitis. J Allergy Clin Immunol 1996;98(1):107–13. 71. Gehring W, Gloor M. Treatment of the atopic dermatitis with a water-in-oil emulsion with or 85. Majerus JP, Reiffers-Mettelock J. Sicorten: without the addition of hydrocortisone – a synthetic corticosteroid for topical treatment results of a controlled double-blind randomized of common dermatoses. J Int Med Res study using clinical evaluation and bioengineering 1986;14(1):46–9. methods. H+G Zeitschrift Fur Hautkrankheiten 1996;71:554–60. 86. Korting HC, Schafer-Korting M, Klovekorn W, Klovekorn G, Martin C, Laux P. Comparative 72. Reidhav I, Svensson A. Betamethasone valerate efficacy of hamamelis distillate and hydrocortisone versus mometasone furoate cream once daily in cream in atopic eczema. Eur J Clin Pharmacol atopic dermatitis. J Dermatol Treat 1996;7:87–8. 1995;48(6):461–5. 127 References

87. Bleehen SS, Chu AC, Hamann I, Holden C, 101. Vernon HJ, Lane AT, Weston W. Comparison Hunter JA, Marks R. Fluticasone propionate of mometasone furoate 0.1% cream and hydro- 0.05% cream in the treatment of atopic eczema: a cortisone 1.0% cream in the treatment of multicentre study comparing once-daily treatment childhood atopic dermatitis. J Am Acad Dermatol and once-daily vehicle cream application versus 1991;24(4):603–7. twice-daily treatment. Br J Dermatol 102. Binder R, McCleary J. Comparison of fluocinonide 1995;133(4):592–7. in a double-blind study with betamethasone 88. Jorizzo J, Levy M, Lucky A Shavin J, Goldberg G, valerate. Curr Ther Res Clin Exp 1972;14(1):35–8. Dunlap F, et al. Multicenter trial for long-term safety 103. Korting HC, Zienicke H, Schafer-Korting M, Braun- and efficacy comparison of 0.05% desonide and 1% Falco O. Liposome encapsulation improves efficacy hydrocortisone ointments in the treatment of of betamethasone dipropionate in atopic eczema atopic dermatitis in pediatric patients. J Am Acad but not in psoriasis vulgaris. Eur J Clin Pharmacol Dermatol 1995;33(1):74–7. 1990;39(4):349–51. 89. Kaplan RJ, Daman L, Rosenberg EW, Feigenbaum S. 104. Van Der Meer JB, Glazenburg EJ, Mulder PGH, Topical use of caffeine with hydrocortisone in the Eggink HF, Coenraads PJ. The management of treatment of atopic dermatitis. Arch Dermatol moderate to severe atopic dermatitis in adults 1978;114(1):60–2. with topical fluticasone propionate. Br J Dermatol 90. Wachs GN, Maibach HI. Co-operative double-blind 1999;140:1114–21. trial of an antibiotic/corticoid combination in 105. Vanderploeg DE. Betamethasone dipropionate impetiginized atopic dermatitis. Br J Dermatol ointment in the treatment of psoriasis and atopic 1976;95(3):323–8. dermatitis: a double-blind study. South Med J 91. Stalder JF, Fleury M, Sourisse M, Rostin M, 1976;69:862–3. Pheline F, Litoux P. Local steroid therapy and 106. Noren P, Melin L. The effect of combined topical bacterial skin flora in atopic dermatitis. Br J steroids and habit-reversal treatment in patients 131 Dermatol 1994; (4):536–40. with atopic dermatitis. Br J Dermatol 92. Almeyda J, Burt BW. Double blind controlled study 1989;121(3):359–66. of treatment of atopic eczema with a preparation of 107. Meenan FO. A double-blind comparative study to hydrocortisone in a new drug delivery system versus compare the efficacy of locoid c with tri-adcortyl in betamethasone 17-valerate. Br J Dermatol children with infected eczema. Br J Clin Pract 1974;91(5):579–83. 1988;42(5):200–2. 93. Leibsohn E, Bagatell FK. Halcinonide in the 108. Duke EE, Maddin S, Aggerwal A. Alclometasone treatment of corticosteroid responsive dermatoses. dipropionate in atopic dermatitis: a clinical study. Br J Dermatol 1974;90(4):435–40. Curr Ther Res Clin Exp 1983;33(5):769–74. 94. Lupton ES, Abbrecht MM, Brandon ML. Short- 109. Kuokkanen K, Sillantaka I. Alclometasone term topical corticosteroid therapy (halcinonide dipropionate 0.05% vs hydrocortisone 1.0%: ointment) in the management of atopic dermatitis. potential to induce cutaneous atrophy in children. Cutis 1982;30(5):671–5. Clin Ther 1987;9(2):223–31. 95. Sudilovsky A, Muir JG, Bocobo FC. A comparison 110. Rajka G, Verjans HL. Hydrocortisone 17-butyrate of single and multiple applications of halcinonide (locoid) 0.1% fatty cream versus desonide (apolar) cream. Int J Dermatol 1981;20(9):609–13. 0.1% ointment in the treatment of patients 96. Fisher M, Kelly AP. Multicenter trial of fluocinonide suffering from atopic dermatitis. J Int Med Res in an emollient cream base. Int J Dermatol 1986;14(2):85–90. 1979;18(8):660–4. 111. Hjorth N, Schmidt H, Thomsen K. Fusidic acid plus 97. Roth HL, Brown EP. Hydrocortisone valerate. betamethasone in infected or potentially infected Double-blind comparison with two other topical eczema. Pharmatherapeutica 1985;4(2):126–31. steroids. Cutis 1978;21(5):695–8. 112. Heddle RJ, Soothill JF, Bulpitt CJ, Atherton DJ. 98. Dickey RF. Parenteral short-term corticosteroid therapy Combined oral and nasal beclomethasone in moderate to severe dermatoses. A comparative diproprionate in children with atopic eczema: a multiclinic study. Cutis 1976;17(1):179–83. randomised controlled trial. BMJ Clin Res Ed 1984;289(6446):651–4. 99. Yasuda T. Clinical experiences with hydrocortisone 113. Veien NK, Hattel T, Justesen O, Norholm A, 17-butyrate. Dermatologica 1976;152 Suppl 1:221–9. Verjans HL. Hydrocortisone 17-butyrate (Locoid) 100. Wahlgren CF, Hagermark O, Bergstrom R, Hedin B. 0.1% cream versus hydrocortisone (Uniderm) Evaluation of a new method of assessing pruritus 1% cream in the treatment of children suffering and antipruritic drugs. Skin Pharmacol from atopic dermatitis. J Int Med Res 128 1988;1(1):3–13. 1984;12(5):310–13. Health Technology Assessment 2000; Vol. 4: No. 37

114. Sefton J, Loder JS, Kyriakopoulos AA. Clinical 128. Ramsay CA, Savoie JM, Gilbert M, Gidon M, evaluation of hydrocortisone valerate 0.2% Kidson P. The treatment of atopic dermatitis ointment. Clin Ther 1984;6(3):282–93. with topical fusidic acid and hydrocortisone acetate. J Eur Acad Dermatol Venereol 1996;7 Suppl 115. Lassus A. Clinical comparison of alclometasone I:S15–S22. dipropionate cream 0.05% with hydrocortisone butyrate cream 0.1% in the treatment of atopic 129. Rafanelli A, Rafanelli S, Stanganelli I, Marchesi E. dermatitis in children. J Int Med Res Mometasone furoate in the treatment of atopic 1983;11(5):315–19. dermatitis in children. J Eur Acad Dermatol Venereol 1993;2(3):225–30. 116. Lebwohl M, Lane A, Savin R, Drake L, Berman B, Lucky A, et al. A comparison of once-daily 130. Malzfeldt E, Lehmann P, Goerz G, Lippold BC. application of mometasone furoate 0.1% cream Influence of drug solubility in the vehicle on compared with twice-daily hydrocortisone valerate clinical efficacy of ointments. Arch Dermatol Res 0.2% cream in pediatric atopic dermatitis patients 1989;281(3):193–7. who failed to respond to hydrocortisone. Int J Dermatol 1999;38(8):604–6. 131. Marchesi E, Rozzoni M, Pini P, Cainelli T. Comparative study of mometasone furoate and 117. Wilkinson RD, Leigh DA. Comparative efficacy of betamethasone dipropionate in the treatment of betamethasone and either fusidic acid or neomycin atopic dermatitis. G Ital Dermatol Venereol in infected or potentially infected eczema. Curr 1994;129(1-2):IX–XII. Ther Res 1985;38:177–82. 132. Maloney JM, Morman MR, Stewart DM, Tharp MD, 118. el Hefnawi H, el Shiemy S, Paris R, Tadros SS. Brown JJ, Rajagopalan R. Clobetasol propionate Double- blind paired comparison clinical trial emollient 0.05% in the treatment of atopic of halcinonide and hydrocortisone. Cutis dermatitis. Int J Dermatol 1998;37(2):142–4. 1978;22(1):97–9. 133. Lucky AW, Grote GD, Williams JL Tuley MR, 119. Bluefarb SM, Howard FM, Leibsohn E, Schlagel CA, Czernielewski JM, Dolak TM, et al. Effect of Wexler L. Diflorasone diacetate: vasoconstrictor desonide ointment, 0.05%, on the hypothalamic- activity and clinical efficacy of a new topical pituitary-adrenal axis of children with atopic corticosteroid. J Int Med Res 1976;4(6):454–61. dermatitis. Cutis 1997;59(3):151–3. 120. Morley N, Fry L, Walker S. Clinical evaluation of 134. Korting HC, Zienicke H, Braun-Falco O, et al. clobetasone butyrate in the treatment of children Modern topical glucocorticoids and anti-infectives with atopic eczema, and its effect on plasma for superinfected atopic eczema: do prednicarbate corticosteroid levels. Curr Med Res Opin and didecyldimethylammoniumchloride form a 1976;4(3):223–8. rational combination? [Published erratum appears in Infection 1995;23(1):67]. Infection 121. Bjornberg A, Hellgren L. [Comparison between 1994;22(6):390–4. 2 steroid dosage forms in psoriasis and eczema]. [German]. Zeitschrift Fur Hautkrankheiten 1975; 135. Lassus A. Alclometasone dipropionate cream Suppl 2:13–15. 0.05% versus clobetasone butyrate cream 0.05%. A controlled clinical comparison in the treatment 122. Almeyda J, Fry L. Controlled trial of the treatment of atopic dermatitis in children. Int J Dermatol of atopic eczema with a urea-hydrocortisone 1984;23(8):565–6. preparation versus betamethasone 17-valerat. Br J Dermatol 1973;88(5):493–5. 136. Sefton J, Kyriakopoulos AA. Comparative efficacy of hydrocortisone valerate 0.2 percent ointment 123. Rampini E. Methylprenisolone aceponate (mpa) – in the treatment of atopic dermatitis. Cutis use and clinical experience in children. J Dermatol 1983;32(1):89–91. Treat 1992;3 Suppl 2:27–9. 137. Mali JW. An evaluation of betamethasone 124. Hoybye S, Balk Moller S, De Cunha Bang F, dipropionate (diprosone) versus locacorten Ottevanger V, Veien NK. Continuous and 0.02% cream. Dermatologica 1976;153(3):177–8. intermittent treatment of atopic dermatitis in adults with momethasone furoate vs. hydrocortisone 17- 138. Nolting S. [Treatment with topical corticosteroids butyrate. Curr Ther Res Clin Exp 1991;50:67–72. in severe or resistant dermatoses]. [German]. Dermatosen in Beruf Und Umwelt 1985;33(4):140–4. 125. Chapman RS. Treatment of atopic dermatitis. Practitioner 1979;223(1337):713–16. 139. Van DelRey ML, Geller M, Azulay RD. Estudo duplo-cego sobre a eficacia e a seguranca do 126. Brock W, Cullen SI. Triamcinolone acetonide in creme de alcometasoma no tratamento de flexible collodion for dermatologic therapy. Arch dermatite atopica. / [Double-blind study on the Dermatol 1967;96(2):193–4. efficacy and safety of alclomethasone cream in 127. Anonymous. Treatment of eczemas and infected the treatment of atopic dermatitis.] An Bras eczemas. Br J Clin Pract 1967;21(10):505–7. Dermatol 1983;58:177–80. 129 References

140. La Rosa M, Musarra I, Ranno C, Maiello N, Negri L, 152. Larregue M, Devaux J, Audebert C, Gelmetti DR. Miraglia Del Giudice J, et al. A randomized, double- A double-blind controlled study on the efficacy and blind, placebo-controlled crossover trial of systemic tolerability of 6% ammonium lactate cream in flunisolide in the treatment of children with severe children with atopic dermatitis. Nouv Dermatol atopic dermatitis. Curr Ther Res Clin Exp 1996;15(10):720–1. 1995;56(7):720–6. 153. Pigatto PD, Bigardi AS, Cannistraci C, Picardo M. 10% 141. Ulrich R, Andresen I. Double-blind comparative urea cream (Laceran) for atopic dermatitis: a clinical trial involving 0.5% halomethasone (Sicorten™) and laboratory evaluation. J Dermatol Treat 1996;7:171–5. cream versus 0.25% prednicarbate cream in 154. Kantor I, Milbauer J, Posner M, Weinstock IM, patients with acute episodes of atopic dermatiti. Simon A, Thormahlen S. Efficacy and safety of Fortschr Med 1991;109(36):49–50 and 53–4. emollients as adjunctive agents in topical cortico- 142. Hoybye S, Balk Moller S, De Cunha Bang F, steroid therapy for atopic dermatitis. Today Ther Ottevanger V, Veien NK. Continuous and Trends 1993;11:157–66. intermittent treatment of atopic dermatitis in 155. Andersson AC, Lindberg M, Loden M. The effect of adults with mometasone furoate versus hydro- two urea-containing creams on dry, eczematous skin cortisone 17-butyrate. Curr Ther Res Clin Exp in atopic patients. I. Expert, patient and instrumental 1991;50(1):67–72. evaluation. J Dermatol Treat 1999;10(3):165–9. 143. Olholm Larsen P, Brandrup F, Roders GA. Report 156. Hanifin JM, Hebert AA, Mays SR, Paller AS, on a double-blind, left-right study comparing the Sherertz EF, Wagner AM, et al. Effects of a low- clinical efficacy of mildison (hydrocortisone 1%) ™ ™ potency corticosteroid lotion plus a moisturizing Lipocream with Uniderm (hydrocortisone 1%) regimen in the treatment of atopic dermatitis. cream in the treatment of children with atopic Curr Ther Res Clin Exp 1998;59(4):227–33. dermatitis. Curr Ther Res Clin Exp 1988;44(3):421–5. 157. Wilhelm KP, Scholermann A. Efficacy and tolerability 144. Andersen BL, Andersen KE, Nielsen R, Stahl D, of a topical preparation containing 10% urea in Niordson A, Roders GA. Treatment of dry atopic patients with atopic dermatitis. Aktuel Dermatol dermatitis in children. A double-blind comparison 1998;24(1-2):26–30. between mildison Lipocream™ (1% hydrocortisone) and Uniderm™ (1% hydrocortisone) ointment. 158. Anstey A, Wilkinson JD. Lithium succinate ointment Clin Trials J 1988;25(4):278–84. in the treatment of atopic eczema [1]. J Dermatol Treat 1991;2(1):37–8. 145. Richelli C, Piacentini GL, Sette L, Bonizzato MC, Andreoli A, Boner AL. Clinical efficacy and 159. Boguniewicz M, Fiedler VC, Raimer S, Lawrence ID, tolerability of clobetasone 17-butyrate 0.5% lotion Leung DY, Hanifin JM. A randomized, vehicle- in children with atopic dermatitis. Curr Ther Res controlled trial of tacrolimus ointment for treat- Clin Exp 1990;47(3):413–17. ment of atopic dermatitis in children. Pediatric Tacrolimus Study Group. J Allergy Clin Immunol 146. Zienicke H. Topical glucocorticoids and anti- 1998;102(4 Pt 1):637–44. infectives: a rational combination? Curr Probl Dermatol 1993;21:186–91. 160. Reitamo S, Rissanen J, Remitz A, Granlund H, Erkko P, Elg P, et al. Tacrolimus ointment does not 147. Konzelmann M, Harms M. [Diflorasone diacetate affect collagen synthesis: results of a single-center cream compared to betamethasone dipropionate randomized trial. J Invest Dermatol 1998;111(3):396–8. cream in the treatment of eczemas]. [German]. Schweiz Rundsch Med Prax 1983;72(20):709–11. 161. Ruzicka T, Bieber T, Schopf E, Rubins A, Dobozy A, Bos JD, et al. A short-term trial of tacrolimus oint- 148. Sanabria-Silva E, Laterza AM, Tamayo L, Ruiz- ment for atopic dermatitis. European tacrolimus Maldonado R. Evaluation of rebound phenomenon multicenter atopic dermatitis study group. N Engl J in children with atopic dermatitis treated with Med 1997;337(12):816–21. topical corticosteroids. Dermatologia Revista Mexicana 1991;35(2):84–9. 162. Van Leent EJ, Graber M, Thurston M, Wagenaar A, Spuls PI, Bos JD. Effectiveness of the ascomycin 149. Harder F, Rufli T. [Therapy of eczema. Once macrolactam SDZ ASM 981 in the topical treatment daily use of diflorasone diacetate in comparison of atopic dermatitis. Arch Dermatol 1998;134(7):805–9. to thrice daily use of betamethasone-17-valerate]. [German]. Schweiz Rundsch Med Prax 163. Ewing CI, Ashcroft C, Gibbs AC, Jones GA, Connor PJ, 1983;72(39):1240–2. David TJ. Flucloxacillin in the treatment of atopic dermatitis. Br J Dermatol 1998;138(6):1022–9. 150. Savin RC. Betamethasone dipropionate in psoriasis and atopic dermatitis. Conn Med 1976;40(1):5–7. 164. Stalder JF, Fleury M, Sourisse M, Allavoine Th, Chalamet C, Brosset P, et al. Comparative effects of 151. Niordson AM, Stahl D. Treatment of psoriasis with two topical antiseptics (chlorhexidine vs kmn04) clinitar cream. A controlled clinical trial. Br J Clin on bacterial skin flora in atopic dermatitis. Acta 130 Pract 1985;39(2):67–8. Dermato Venereol (Stockh) 1992;Suppl issue 176:132–4. Health Technology Assessment 2000; Vol. 4: No. 37

165. Holland KT, Bojar RA, Cunliffe WJ. A comparison 176. Monroe EW. Relative efficacy and safety of of the effect of treatment of atopic eczema with and loratadine, hydroxyzine, and placebo in chronic without antimicrobial compounds. In: Lever R, idiopathic urticaria and atopic dermatitis. Clin Ther Levy J, editors. The bacteriology of eczema. UK: 1992;14(1):17–21. The Royal Society of Medicine Press Limited; 1995. 177. Wahlgren CF, Hagermark O, Bergstrom R. 166. Harper J. Double-blind comparison of an antiseptic The antipruritic effect of a sedative and a non- oil-based bath additive (Oilatum Plus) with regular sedative antihistamine in atopic dermatitis. Br J Oilatum (Oilatum Emollient) for the treatment of Dermatol 1990;122(4):545–51. atopic eczema. In: Lever R, Levy J, editors. The 178. Berth-Jones J, Graham-Brown RA. Failure of bacteriology of eczema. UK: The Royal Society of terfenadine in relieving the pruritus of atopic Medicine Press Limited; 1995. dermatitis. Br J Dermatol 1989;121(5):635–7. 167. Lever R, Hadley K, Downey D, Mackie R. 179. Doherty V, Sylvester DG, Kennedy CT, Harvey SG, Staphylococcal colonization in atopic dermatitis Calthrop JG, Gibson JR. Treatment of itching in and the effect of topical mupirocin therapy. atopic eczema with antihistamines with a low Br J Dermatol 1988;119(2):189–98. sedative profile. BMJ 1989;298(6666):96. 168. Broberg A, Faergemann J. Topical antimycotic 180. Patel P, Gratton D, Eckstein G, Aberer W, treatment of atopic dermatitis in the head/neck Pryzbilla B, Chelly M, et al. A double-blind study area. A double-blind randomised study. Acta of loratadine and cetirizine in atopic dermatitis. Dermato Venereol 1995;75(1):46–9. J Dermatol Treat 1997;8(4):249–53.

169. Salo OP, Gordin A, Brandt H, Antikainen R. 181. Savin JA, Dow R, Harlow BJ, Massey H, Yee KF. The Efficacy and tolerability of erythromycin acistrate effect of a new non-sedative h1-receptor antagonist and erythromycin stearate in acute skin infections (ln2974) on the itching and scratching of patients of patients with atopic eczema. J Antimicrob with atopic eczema. Clin Exp Dermatol 1986;11(6):600–2. Chemother 1988;21 Suppl D:101–6. 182. Frosch PJ, Schwanitz HJ, Macher E. A double blind 170. Weinberg E, Fourie B, Allmann B, Toerien A. The trial of h1 and h2 receptor antagonists in the use of cefadroxil in superinfected atopic dermatitis. treatment of atopic dermatitis. Arch Dermatol Res Curr Ther Res Clin Exp 1992;52(5):671–6. 1984;276(1):36–40. 183. Simons R, Estelle F, Simons KJ, Becker AB, 171. Sasai-Takedatsu M, Kojima T, Yamamoto A, Haydey RP. Pharmacokinetics and antipruritic Hattori K, Yoshijima S, Taniuchi S, et al. Reduction effects of hydroxyzine in children with atopic of Staphylococcus aureus in atopic skin lesions with dermatitis. J Pediatr 1984;104(1):123–7. acid electrolytic water – a new therapeutic strategy for atopic dermatitis. Allergy 1997;52(10):1012–6. 184. Foulds IS, MacKie RM. A double-blind trial of the h2 receptor antagonist cimetidine, and the h1 172. Hizawa T, Sano H, Endo K, Fukuzumi T, Kataoka Y, receptor antagonist promethazine hydrochloride Aoki T. Is povidone-iodine effective to the lesions of in the treatment of atopic dermatitis. Clin Allergy atopic dermatitis? Skin Res 1998;40 Suppl 20:134–9. 1981;11(4):319–23. 173. Zuluaga de Cadena A, Ochoa de VA, Donado JH, 185. Savin JA, Paterson WD, Adam K, Oswald I. Effects Mejia JI, Chamah HM, Montoya de Restrepo F. of trimeprazine and trimipramine on nocturnal Estudio comparativo del efecto de la hidroxicina scratching in patients with atopic eczema. Arch la terfenadina y el astemizol en ninos con Dermatol 1979;115(3):313–15. dermatitis atopica: Hospital General de Medellin-Centro de Especialistas C.E.S. 1986–1988 186. Hjorth N. Terfenadine in the treatment of chronic [Comparative study of the effect of the hidroxicina idiopathic urticaria and atopic dermatitis. Cutis the terfenadina and the astemizol in children with 1988;42(4A):29–30. atopic demratitis: Hospital General de Medellin- 187. Henz BM, Metzenauer P, O’Keefe E, Zuberbier T. Centro de Especialistas C.E.S. 1986-1988.] Differential effects of new-generation h1-receptor CES Med 1989;3:7–13. antagonists in pruritic dermatoses. Allergy 53 174. Ishibashi Y, Tamaki K, Yoshida H, Niimura M, 1998; (2):180–3. Harada S, Ueda H, et al. Clinical evaluation of E- 188. Langeland T, Fagertun HE, Larsen S. Therapeutic 0659 on atopic dermatitis. Multicenter double-blind effect of loratadine on pruritus in patients with study in comparison with ketotifen. Rinsho Hyoka atopic dermatitis. A multi-crossover-designed study. 1989;17(1):77–115. Allergy 1994;49(1):22–6. 175. Estelle F, Simons R. Prospective long term safety 189. La Rosa M, Ranno C, Musarra I, Guglielmo F, evaluation of the H1-receptor antagonist cetirizine Corrias A, Bellanti JA. Double-blind study of in very young children with atopic deramtitis. cetirizine in atopic eczema in children. J Allergy Clin Immunol 1999;104:433–40. Ann Allergy 1994;73(2):117–22. 131 References

190. Hannuksela M, Kalimo K, Lammintausta K, 203. Atherton DJ, Soothill JF, Elvidge J. A controlled trial Mattila T, Turjanmaa K, Varjonen E, et al. Dose of oral sodium cromoglycate in atopic eczema. Br J ranging study: cetirizine in the treatment of atopic Dermatol 1982;106(6):681–5. dermatitis in adults. Ann Allergy 1993;70(2):127–33. 204. Kavli G, Larsen PO. Double-blind crossover trial 191. Klein GL, Galant SP. A comparison of the antipruritic comparing systemic chromosome-carboxylic acid efficacy of hydroxyzine and cyproheptadine in with placebo in patients with atopic dermatitis. children with atopic dermatitis. Ann Allergy Allergy 1981;36(8):597–600. 1980;44(3):142–5. 205. Businco L, Benincori N, Nini G, Businco E, Cantani A, 192. Hamada T, Ishii M, Nakagawa K, Kobayashi H, De Angelis M. Double-blind crossover trial with Kitajima J, Chanoki M, et al. Evaluation of the oral sodium cromoglycate in children with atopic clinical effect of terfenadine in patients with atopic dermatitis due to food allergy. Ann Allergy dermatitis. A comparison of strong cortico-steroid 1986;57:433–8. therapy to mild topical corticosteroid combined 206. Larsen PO, Larsen FS. Clinical trial of a new with terfenadine administration therapy. Skin Res chromone compound for systemic treatment of 1996;38(1):97–103. atopic dermatitis. Acta Derm Venereol 1979;59(3):270–1. 193. Ishibashi Y, Ueda H, Niimura M, Harada S, 207. Burks AW, Sampson HA. Double-blind placebo- Tamaki K, Imamura S, et al. Clinical evaluation of controlled trial of oral cromolyn in children E-0659 in atopic dermatitis in infants and children. with atopic dermatitis and documented food Dose-finding multicenter study by the double-blind hyper-sensitivity. J Allergy Clin Immunol method. Skin Res 1989;31(3):458–71. 1988;81(2):417–23. 194. Kimata H, Igarashi M. Topical cromolyn (disodium 208. Birkeland SA, Larsen PO, Larsen FS. Sub- cromoglycate) solution in the treatment of young populations of lymphocytes and lymphocyte children with atopic dermatitis. Clin Exp Allergy transformation tests in atopic dermatitis: evaluation 1990;20(3):281–3. of a systemic treatment with a new chromone compound and comparison with a normal group. 195. Larsen FS, Jacobsen KU. Atopic dermatitis and J Invest Dermatol 1981;76(5):367–70. systemic treatment with a new chromone compound (FPL 57787): a double blind clinical trial. Acta Derm 209. Kjellman NI, Gustafsson IM. Topical sodium cromo- Venereol Suppl (Stockh) 1980;(Suppl 92):128–9. glycate in atopic dermatitis. A disappointing but informative trial. Allergy 1986;41(6):423–8. 196. Haider-SA. Treatment of atopic eczema in children: clinical trial of 10% sodium cromoglycate ointment. 210. Lindskov R, Knudsen L. Oral disodium cromo- BMJ 1977;1:1570–2. glycate treatment of atopic dermatitis. Allergy 1983;38(3):161–5. 197. Graham P, Hall-Smith SP, Harris JM, Price ML. A study of hypoallergenic diets and oral sodium 211. Ventura A, De Seta L, Martelossi S, Florean P, cromoglycate in the management of atopic eczema. Maggiore G, Salvatore CM, et al. Soy allergy and Br J Dermatol 1984;110(4):457–67. DSCG in atopic eczema: ‘much ado about nothing’? Pediatr Med Chir 1996;18(3):283–8. 198. Moore C, Ehlayel MS, Junprasert J, Sorensen RU. Topical sodium cromoglycate in the treatment of 212. Pike MG, Atherton DJ. Failure of a new topical moderate-to-severe atopic dermatitis. Ann Allergy sodium cromoglycate formulation to improve Asthma Immunol 1998;81(5 Pt 1):452–8. atopic dermatitis [letter]. Eur J Pediatr 1988;148(2):170. 199. Thirumoorthy T, Greaves MW. Disodium cromoglycate ointment in atopic eczema [letter]. 213. Kemmett D, Barneston RST. Topical nedocromil BMJ 1978;2(6135):500–1. sodium: a double blind placebo controlled study in atopic dermatitis. Br J Dermatol 1987;123 Suppl 37:60. 200. Croner S, Fagerlund E, Kjellmann NIM, Leijon I. Sodium cromoglycate ointment in atopic 214. Van Bever HP, Stevens WJ. Nedocromil sodium eczema during childhood. Opuscula Medica cream in the treatment of atopic dermatitis [letter]. 1081;26(2):49–50. Eur J Pediatr 1989;149(1):74. 215. Benton EC, McFarlane HA, Barnetson RS. Trial of 201. Kimata H, Hiratsuka S. Effect of topical cromo- nedocromil sodium in atopic eczema. Br J Dermatol glycate solution on atopic dermatitis: combined 1990;122(6):817–20. treatment of sodium cromoglycate solution with the oral anti-allergic medication, oxatomide. 216. Falk ES. Ketotifen in the treatment of atopic Eur J Pediatr 1994;153(2):66–71. dermatitis. Results of a double blind study. Rev Eur Sci Med Farmacol 1993;15(2):63–6. 202. Ariyanayagam M, Barlow TJ, Graham P, Hall-Smith SP, Harris JM. Topical sodium cromoglycate in the 217. White MP, MacDonald TH, Garg RA. Ketotifen management of atopic eczema – a controlled trial. in the young asthmatic – a double-blind placebo- 132 Br J Dermatol 1985;112(3):343–8. controlled trial. J Int Med Res 1988;16(2):107–13. Health Technology Assessment 2000; Vol. 4: No. 37

218. Drake LA, Fallon JD, Sober A. Relief of pruritus 231. Isolauri EMD, Sutas YMD, Makinen-Kiljunen SMSc, in patients with atopic dermatitis after treatment Oja Simo S MD, Isosomppi RMSc, Turjanmaa KMD. with topical doxepin cream. The doxepin study Efficacy and safety of hydrolyzed cow milk and group. J Am Acad Dermatol 1994;31(4):613–16. amino acid-derived formulas in infants with cow milk allergy. J Pediatr 1995;127(4):550–7. 219. Breneman DL, Dunlap FE, Monroe EW, Schupbach CW, Shmunes E, Phillips SB. Doxepin 232. Gehring W, Bopp R, Rippke F, Gloor M. Effect cream relieves eczema-associated pruritus within of topically applied evening primrose oil on 15 minutes and is not accompanied by a risk of epidermal barrier function in atopic dermatitis rebound upon discontinuation. J Dermatol Treat as a function of vehicle. Arzneimittelforschung 1997;8(3):161–8. 1999;49(7):635–42.

220. Berberian BJ, Breneman DL, Drake LA, Gratton D, 233. Ferreira MJ, Fiadeiro T, Silva M, Soares AP. Topical Raimir SS, Phillips S, et al. The addition of topical gamma-linolenic acid therapy in atopic dermatitis. doxepin to corticosteroid therapy: an improved A clinical and biometric evaluation. Allergo J treatment regimen for atopic dermatitis. Int J 1998;7(4):213–16. Dermatol 1999;38(2):145–8. 234. Ferreira MJ, Fiadeiro T, Silva M, Soares AP. 221. Drake LA, Cohen L, Gillies R, Flood JG, Riordan Electrical conductance: a controversial parameter AT, Phillips SB, et al. Pharmacokinetics of doxepin in the evaluation of emollients in atopic dermatitis. in subjects with pruritic atopic dermatitis. J Am Acad Skin Res Technol 1998;4(3):138–41. Dermatol 1999;41(2 I):209–14. 235. Hederos CA, Berg A. Epogam evening primrose oil treatment in atopic dermatitis and asthma. Arch Dis 222. Czarnetzki BM, Brechtel B, Braun-Falco O, Child 1996;75(6):494–7. Christophers E, Schopf E, Reckers-Czaschka R, et al. Topical tiacrilast, a potent mast cell degranulation 236. Schalin-Karrila M, Mattila L, Jansen CT, Uotila P. inhibitor, does not improve adult atopic eczema. Evening primrose oil in the treatment of atopic Dermatology 1993;187(2):112–4. eczema: effect on clinical status, plasma phospho- lipid fatty acids and circulating blood prosta- 223. Atherton DJ. Dietary antigen avoidance in the glandins. Br J Dermatol 1987;117(1):11–19. treatment of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1980;99–102. 237. Biagi PL, Bordoni A, Hrelia S, Celadon M, Ricci GP, Cannella V, et al. The effect of gamma-linolenic acid 224. Majamaa H, Isolauri E. Probiotics: a novel approach on clinical status, red cell fatty acid composition in the management of food allergy. J Allergy Clin and membrane micro-viscosity in infants with atopic Immunol 1997;99(2):179–85. dermatitis. Drugs Exp Clin Res 1994;20(2):77–84. 225. Lever R, MacDonald C, Waugh P, Aitchison T. 238. Humphreys F, Symons JA, Brown HK, Duff GW, Randomised controlled trial of advice on an egg Hunter JAA. The effects of gamolenic acid on adult exclusion diet in young children with atopic atopic eczema and premenstrual exacerbation of eczema and sensitivity to eggs. Pediatr Allergy eczema. Eur J Dermatol 1994;4(8):598–603. Immunol 1998;9(1):13–19. 239. Bordoni A, Biagi PL, Masi M, Ricci G, Fanelli C, 226. Neild VS, Marsden RA, Bailes JA, Bland JM. Egg Patrizi A, et al. Evening primrose oil (efamol) in the and milk exclusion diets in atopic eczema. Br J treatment of children with atopic eczema. Drugs Exp Dermatol 1986;114(1):117–23. Clin Res 1987;14(4):291–7.

227. Mabin DC, Sykes AE, David TJ. Controlled trial of a 240. Bamford JT, Gibson RW, Renier CM. Atopic eczema few foods diet in severe atopic dermatitis. Arch Dis unresponsive to evening primrose oil (linoleic and Child 1995;73(3):202–7. gamma-linolenic acids). J Am Acad Dermatol 1985;13(6):959–65. 228. Cant AJ, Bailes JA, Marsden RA, Hewitt D. Effect of maternal dietary exclusion on breast fed infants 241. Anstey A, Quigley M, Wilkinson JD. Topical evening with eczema: two controlled studies. BMJ Clin Res primrose oil as treatment for atopic eczema. Ed 1986;293(6541):231–3. J Dermatol Treat 1990;1(4):199–201. 242. Wright S, Burton JL. Oral evening-primrose- 229. Munkvad M, Danielsen L, Hoj L, Povlsen CO, seed oil improves atopic eczema. Lancet Secher L, Svejgaard E, et al. Antigen-free diet in 1982;2(8308):1120–2. adult patients with atopic dermatitis. A double-blind controlled study. Acta Derm Venereol 1984;64(6): 243. Berth-Jones J, Graham-Brown RC. Placebo-controlled 524–8. trial of essential fatty acid supplementation in atopic dermatitis. Lancet 1993;341(8860):1557–60. 230. Atherton DJ, Sewell M, Soothill JF, Wells RS, Chilvers CE. A double-blind controlled crossover 244. Lovell CR, Burton JL, Horrobin DF. Treatment of trial of an antigen-avoidance diet in atopic eczema. atopic eczema with evening primrose oil [letter]. Lancet 1978;1(8061):401–3. Lancet 1981;1(8214):278. 133 References

245. Wright S. Atopic dermatitis and essential fatty acids: 260. Nishioka K, Yasueda H, Saito H. Preventive effect of a biochemical basis for atopy? Acta Derm Venereol bedding encasement with microfine fibers on mite (Stockh) 1985;Suppl 114:143–5. sensitization. J Allergy Clin Immunol 1998;101(1 Pt 1):28–32. 246. Bahmer FA, Schafer J. [Treatment of atopic dermatitis with borage seed oil (glandol) – a time 261. Endo K, Fukuzumi T, Adachi J, Kojima M, Aoki T, series analytic study]. [German]. Kinderarztl Prax Yoshida M, et al. [Effect of vacuum cleaning of 1992;60(7):199–202. room floors and bed clothes of patients on house 247. Borrek S, Hildebrandt A, Forster J. Gammalinolenic- dust mites counts and clinical scores of atopic acid-rich borage seed oil capsules in children with dermatitis. A double blind control trial]. atopic dermatitis. A placebo-controlled double- [Japanese]. Arerugi 1997;46(10):1013–24. blind study. Klin Padiatr 1997;209(3)100–4. 262. Colloff MJ, Lever RS, McSharry C. A controlled trial 248 Buslau M, Thaci D. Atopic dermatitis: Borage oil for of house dust mite eradication using natamycin in systemic therapy. Z Dermatol 1996;182(3):131–2 and homes of patients with atopic dermatitis: effect on 134–6. clinical status and mite populations. Br J Dermatol 1989;121(2):199–208. 249. Henz BM, Jablonska S, van de Kerkhof PCM, Stingl G, Blaszczyk M, Vandervalk PGM, et al. Double- 263. Tan BB, Weald Dawn, Strickland Ian, Friedmann blind, multicentre analysis of the efficacy of borage PS. Double-blind controlled trial of effect of oil in patients with atopic eczema. Br J Dermatol housedust-mite allergen avoidance on atopic 1999;140:685–8. dermatitis. Lancet 1996;347(8993):15–18. 250. Valsecchi R, Di Landro A, Pansera B, Reseghetti A. 264. Glover MT, Atherton DJ. A double-blind controlled Gammalinolenic acid in the treatment of atopic trial of hyposensitization to dermatophagoides dermatitis [1]. J Eur Acad Dermatol Venereol 1996;7(1):77–9. pteronyssinus in children with atopic eczema. Clin Exp Allergy 1992;22(4):440–6. 251. Bjorneboe A, Soyland E, Bjorneboe G-EA, Rajka G, Drevon CA. Effect of dietary supplementation with 265. Galli E, Chini L, Nardi S, Benincori N, Panei P, eicosapentaenoic acid in the treatment of atopic Fraioli G, et al. Use of a specific oral hypo- dermatitis. Br J Dermatol 1987;117(4):463–9. sensitization therapy to dermatophagoides 252. Soyland E, Funk J, Rajka G, Sandberg M, Thune P, pteronyssinus in children with atopic dermatitis. Rustad L, et al. Dietary supple-mentation with very Allergol Immunopath (Madr) 1994;22(1):18–22. long-chain n-3 fatty acids in patients with atopic 266. Wen T, Wang E, Shen S, Jiang C, Tian R, Kang K, dermatitis. A double-blind, multicentre study. Br J et al. Allergenic potency of smu-df extract in Dermatol 1994;130(6):757–64. comparison with vus-df extract; and diagnosis and 253. Gimenez-Arnau A, Barranco C, Alberola M, Wale C, immunotherapy for atopic dermatitis and rhinitis Serrano S, Buchanan MR, et al. Effects of linoleic with smu-df extract in china. Arb Paul Ehrlich acid supplements on atopic dermatitis. Adv Exp Med Inst Bundesamt Sera Impfstoffe Frankf A M Biol 1997;433:285–9. 1992;85:217–27. 254. Bjorneboe A, Soyland E, Bjorneboe GE, Rajka G, 267. Friedmann PS, Tan BB. Mite elimination – clinical Drevon CA. Effect of n-3 fatty acid supplement to effect on eczema. Allergy 1998;53 Suppl 48:97–100. patients with atopic dermatitis. J Intern Med Suppl 1989;225(731):233–6. 268. Andersen PH, Bindslev-Jensen C, Mosbech H, Zachariae H, Andersen KE. Skin symptoms in 255. Mabin DC, Hollis S, Lockwood J, David TJ. Pyridoxine patients with atopic dermatitis using enzyme- in atopic dermatitis. Br J Dermatol 1995;133(5):764–7. containing detergents. A placebo-controlled study. Acta Derm Venereol 1998;78(1):60–2. 256. Czeizel AE, Dobo M. Postnatal somatic and mental development after periconceptional multivitamin 269. Diepgen TL, Stabler A, Hornstein OP. Irritation supplementation. Arch Dis Child 1994;70(3):229–33. from textiles in atopic eczema and controls. 257. Fairris GM, Perkins PJ, Lloyd B, Hinks L, Clayton BE. Textile intolerance in atopic eczema: a controlled The effect on atopic dermatitis of supplementation clinical study. Z Hautkrankheiten 1990;65(10): with selenium and vitamin E. Acta Derm Venereol 907–10. 1989;69(4):359–62. 270. Diepgen TL, Salzer B, Tepe A, Hornstein OP. 258. Hakakawa R, Ogino Y. Effects of combination A study of skin irritations by textiles under therapy with vitamins E and B2 on skin diseases. standardized sweating conditions in patients with Doudle blind controlled clinical trial. Skin Res atopic eczema. Melliand English 1995;12:268. 1989;31(6):856–81. 271. Seymour JL, Keswick BH, Hanifin JM, Jordan WP, 259. Ewing CI, Gibbs AC, Ashcroft C, David TJ. Failure Milligan MC. Clinical effects of diaper types on the of oral zinc supplementation in atopic eczema. skin of normal infants and infants with atopic 134 Eur J Clin Nutr 1991;45(10):507–10. dermatitis. J Am Acad Dermatol 1987;17(6):988–97. Health Technology Assessment 2000; Vol. 4: No. 37

272. Adachi J, Sumitsuzi H, Endo K, Fukuzumi T, Aoki T. 286. Harper JI, Ahmed I, Barclay G, Lacour M, [Evaluation of the effect of short-term application Hoeger P, Cork MJ, et al. Cyclosporin for of deep sea water on atopic dermatitis]. [Japanese]. severe childhood atopic dermatitis: Short Arerugi 1998;47(1):57–60. course versus continuous therapy. Br J Dermatol 2000;142(1):52–8. 273. Broberg A, Kalimo K, Lindblad B, Swanbeck G. Parental education in the treatment of childhood 287. Cordero Miranda MA, Flores Sandoval G, atopic eczema. Acta Derm Venereol 1990;70(6):495–9. Orea Solano M, Estrada Parra S, Serrano Miranda E. [Safety and efficacy of treatment 274. Schoni MH, Nikolaizik WH, Schoni-Affolter F. for severe atopic dermatitis with cyclosporin A Efficacy trial of bioresonance in children with and transfer factor]. [Spanish]. Revista Alergia atopic dermatitis. Int Arch Allergy Immunol Mexico 1999;46(2):49–57. 1997;112(3):238–46. 288. Zonneveld IM, De Rie MA, Beljaards RC, Van-Der- 275. Ehlers A, Stangier U, Gieler U. Treatment of atopic Rhee-HJ, Wuite-J, Zeegelaar-J, et al. The long-term dermatitis: a comparison of psychological and safety and efficacy of cyclosporin in severe dermatological approaches to relapse prevention. refractory atopic dermatitis: a comparison of two J Consult Clin Psychol 1995;63(4):624–35. dosage regimens. Br J Dermatol 1996;135(Suppl 276. Melin L, Frederiksen T, Noren P, Swebilius BG. 48):15–20. Behavioural treatment of scratching in patients with 289. Zurbriggen B, Wuthrich B, Cachelin AB, Wili PB, atopic dermatitis. Br J Dermatol 1986;115(4):467–74. Kagi MK. Comparison of two formulations of 277. Der-Petrossian M, Seeber A, Honigsmann H, Tanew A. cyclosporin A in the treatment of severe atopic Half-side comparison study on the efficacy of dermatitis. A double-blind, single-centre, 8-methoxypsoralen bath- PUVA versus narrow-band cross-over pilot study. Dermatology ultraviolet B phototherapy in patients with severe 1999;198(1):56–60. chronic atopic dermatitis. Br J Dermatol 290. Wahlgren CF. Itch and atopic dermatitis: clinical 2000;142(1):39–43. and experimental studies. Acta Derm Venereol 278. Krutmann J, Diepgen TL, Luger TA, Grabbe S, 1991;Suppl Issue 165:4–53. Meffert H, Sonnichsen N, et al. High-dose UVA1 291. van Joost T, Heule F, Korstanje M, van den Broek therapy for atopic dermatitis: results MJ, Stenveld HJ, van Vloten WA. Cyclosporin in of a multicenter trial. J Am Acad Dermatol atopic dermatitis: a multicentre placebo-controlled 1998;38(4):589–93. study. Br J Dermatol 1994;130(5):634–40. 279. Reynolds NJ, Franklin V, Gray JC, Diffey BL, Farr PM. 292. Munro CS, Levell NJ, Shuster S, Friedmann PS. Effectiveness of narrow-band UVB (TL01) compared Maintenance treatment with cyclosporin in atopic to UVA in adult atopic eczema: a randomised eczema. Br J Dermatol 1994;130(3):376–80. controlled trial. Br J Dermatol 1999;141(Suppl 55):20. 293. Salek MS, Finlay AY, Luscombe DK, Allen BR, 280. Jekler J, Larko O. UVb phototherapy of atopic Berth-Jones J, Camp RD, et al. Cyclo-sporin greatly dermatitis. Br J Dermatol 1988;119(6):697–705. improves the quality of life of adults with severe 281. Jekler J, Larko O. UVa solarium versus UVb photo- atopic dermatitis. A randomized, double-blind, therapy of atopic dermatitis: a paired-comparison placebo-controlled trial. Br J Dermatol study. Br J Dermatol 1991;125(6):569–72. 1993;129(4):422–30. 282. Jekler J. Phototherapy of atopic dermatitis with 294. De Rie MA, Meinardi MM, Bos JD. Lack of efficacy ultraviolet radiation. Acta Derm Venereol Suppl of topical cyclosporin a in atopic dermatitis and 1992;171:1–37. allergic contact dermatitis. Acta Derm Venereol 1991;71(5):452–4. 283. Krutmann J, Czech W, Diepgen T, Niedner R, Kapp A, Schopf E. High-dose uva1 therapy in the 295. Sowden JM, Berth-Jones J, Ross JS, Motley RJ, treatment of patients with atopic dermatitis. Marks R, Finlay AY, et al. Double-blind, controlled, J Am Acad Dermatol 1992;26(2 Pt 1):225–30. crossover study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet 284. Leroy BP, Boden G, Lachapelle JM, Jacquemin MG, 1991;338(8760):137–40. Saint-Remy JM. A novel therapy for atopic dermatitis with allergen-antibody complexes: a double-blind, 296. Wahlgren CF, Scheynius A, Hagermark O. placebo-controlled study. J Am Acad Dermatol Antipruritic effect of oral cyclosporin a in 1993;28(2 Pt 1):232–9. atopic dermatitis. Acta Derm Venereol 1990;70(4):323–9. 285. Leroy BP, Boden G, Jacquemin MG, Lachapelle JM, Saint-Remy JMR. Allergen-antibody complexes in 297. de Prost Y, Bodemer C, Teillac D. Double-blind the treatment of atopic dermatitis: preliminary randomized placebo-controlled trial of local results of a double-blind placebo-controlled study. cyclosporine in atopic dermatitis [letter]. Acta Derm Venereol 1992;Suppl Issue 176:129–31. Arch Dermatol 1989;125(4):570. 135 References

298. Allen BR. A multicentre double-blind placebo 309. Hsieh KH, Shaio MF, Liao TN. Thymopentin treat- controlled crossover to assess the efficacy and ment in severe atopic dermatitis – clinical and immuno- safety of cyclosporin A in adult patients with logical evaluations. Arch Dis Child 1992;67(9):1095–102. severe refractory atopic dermatitis. In: Wolff K, 310. Leung DY, Hirsch RL, Schneider L, Moody C, editor. Cyclosporin A and the skin: Proceedings Takaoka R, Li SH, et al. Thymopentin therapy reduces of a satellite symposium to the 2nd congress the clinical severity of atopic dermatitis. J Allergy of the European Academy of Dermatology Clin Immunol 1990;85(5):927–33. and Venereology, 12 Oct. 1991. Athens, Greece. London: Royal Society of Medicine Services Ltd; 311. Kang K, Cooper KD, Hanifin JM. Thymopoietin 1991. p. 29–37. pentapeptide (tp-5) improves clinical parameters and lymphocyte subpopulations in atopic 299 White CR, Hanifin JM. Levamisole therapy in atopic dermatitis. J Am Acad Dermatol 1983;8(3):372–7. dermatitis: randomized double-blind evaluation. Arch Dermatol 1978;114(9):1314–15. 312. Pons-Guiraud-A. [Value of Allerglobulin in the treatment of atopic dermatitis in children and 300. Abeck D, Andersson T, Grosshans E, Jablonska S, young adults. A double-blind randomized study]. Kragballe K, Vahlquist A, et al. Topical application Rev Med Intern 1986;7(5):537–42. of a platelet-activating factor (paf) antagonist in atopic dermatitis. Acta Derm Venereol 313. Valdes Sanchez AF, Fernandez Ortega C, 1997;77(6):449–51. Gomez Echeverria AH, Gillama Niebla E, Lastra Alfonso G, Lopez Saura P. [Atopic dermatitis. 301. Renz H, Jujo K, Bradley KL, Domenico J, Gelfand EW, Treatment with transfer factor. A controlled clinical Leung DY. Enhanced il-4 production and il-4 trial]. [Spanish]. Revista Alergia 1991;38(6):158–62. receptor expression in atopic dermatitis and their modulation by interferon-gamma. J Invest Dermatol 314. Sheehan MP, Rustin MH, Atherton DJ, Buckley C, 1992;99(4):403–8. Harris DW, Brostoff J, et al. Efficacy of traditional chinese herbal therapy in adult atopic dermatitis 302. Hanifin JM, Schneider LC, Leung DY, Ellis CN, [published erratum appears in Lancet Jaffe HS, Izu AE, et al. Recombinant interferon 1992;340(8812):188] Lancet 1992;340(8810):13–17. gamma therapy for atopic dermatitis. J Am Acad Dermatol 1993;28(2 Pt 1):189–97. 315. Sheehan MP, Atherton DJ. A controlled trial of traditional chinese medicinal plants in widespread 303. Jang I, Yang J, Lee H, Yi J, Kim H, Kim C, et al. non-exudative atopic eczema. Br J Dermatol Clinical improvement and immunohistochemical 1992;126(2):179–84. findings in severe atopic dermatitis treated with interferon gamma. J Am Acad Dermatol 316. Fung AY, Look PC, Chong LY, But PP, Wong E. 2000;42(6):1033–40. A controlled trial of traditional Chinese herbal medicine in Chinese patients with recalcitrant 304. Fiocchi A, Grasso U, Rottoli A, Travaglini P, atopic dermatitis. Int J Dermatol 1999;38(5):387–92. Mazzanti P, Cazzola P, et al. A double-blind clinical trial on the effectiveness of a thymic derivative 317. Latchman Y, Banerjee P, Poulter LW, Rustin M, (thymomodulin) in the treatment of children with Brostoff J. Association of immunological changes with atopic dermatitis. Int J Immunother 1987;3(4):279–84. clinical efficacy in atopic eczema patients treated with traditional chinese herbal therapy (zemaphyte). 305. Cavagni G, Piscopo E, Rigoli E, Iuliano P, Bertolini P, Int Arch Allergy Immunol 1996;109(3):243–9. Cazzola P. Food allergy in children: an attempt to improve the effects of the elimination diet with an 318. Remy W, Rakoski J, Siebenwirth J, Ulm K, immunomodulating agent (thymomodulin). Wiesenauer M. Classical homeopathic treatment A double-blind clinical trial. Immunopharmacol in atopic dermatitis. Study protocol. Allergologie Immunotoxicol 1989;11(1):131–42. 1995;18(6):246–52. 306. Staughton RCD, Byrom NA, Nagvekar NM, 319. Anderson C, Lis Balchin M. The effect of aroma- Harper JI, Mobayen M, Perry DE, et al. A double- therapy on childhood atopic eczema (presented at blind cross-over trial of thymostimulin in atopic the 5th Annual Symposium on Complementary eczema. Br J Dermatol 1983;109(Suppl 24):39–49. Healthcare, 10–12 December 1998, Exeter). FACT: Focus on Alternative & Complementary Therapies 307. Harper JI, Mason UA, White TR, Staughton RC, 1998;3:189. Hobbs JR. A double-blind placebo-controlled study of thymostimulin (tp-1) for the treatment of atopic 320. Sokel B, Kent CA, Lansdown R, Atherton D, Glover M, eczema. Br J Dermatol 1991;125(4):368–72. Knibbs J. A comparison of hypnotherapy and biofeedback in the treatment of childhood atopic 308. Stiller MJ, Shupack JL, Kenny C, Jondreau L, eczema. Contemp Hypnosis 1993;10(3). Cohen DE, Soter NA. A double-blind, placebo- controlled clinical trial to evaluate the safety and 321. Schachner L, Field T, Hernandez-Reif M, Duarte AM, efficacy of thymopentin as an adjunctive treatment Krasnegor J. Atopic dermatitis symptoms decreased in atopic dermatitis. J Am Acad Dermatol in children following massage therapy. Pediatr 136 1994;30(4):597–602. Dermatol 1998;15(5):390–5. Health Technology Assessment 2000; Vol. 4: No. 37

322. Ebata T, Izumi H, Aizawa H, Kamide R, Niimura M. 336. Lagos BR, Maibach HI. Frequency of application of Effects of nitrazepam on nocturnal scratching in topical corticosteroids: an overview. Br J Dermatol adults with atopic dermatitis: a double-blind 1998;139:763–6. placebo-controlled crossover study. Br J Dermatol 1998;138(4):631–4. 337. Williams HC. Do topical steroids reduce relapses in adults with atopic dermatitis? Evidence Based 323. Veien NK, Kaaber K, Larsen PO, Nielsen AO, Dermatology Section of Archives of Dermatology Thestrup-Pedersen K. Ranitidine treatment of hand 1999;135:1530–1. eczema in patients with atopic dermatitis: a double- blind, placebo-controlled trial. J Am Acad Dermatol 338. Gibson JR, Kirsch JM, Darley CR, Harvey SG, 1995;32(6):1056–7. Burke CA, Hanson ME. An assessment of the relation- ship between vasoconstrictor assay findings, clinical 324. Ruzicka T. Effect of theophylline in atopic dermatitis: efficacy and skin thinning effects of a variety of a double-blind cross-over study. Arch Dermatol Res undiluted and diluted corticosteroid preparations. 1980;269(1):109–10. Br J Dermatol 1984;111 Suppl 27:204–12. 325. Archer CB, MacDonald DM. Treatment of atopic 339. Clement M, du Vivier A. Concern about the current dermatitis with salbutamol. Clin Exp Dermatol clinical practice of diluting topical glucocorticoid 1987;12(5):323–5. preparations. Clin Exp Derm 1984;9:286–9. 326. Berth-Jones J, Graham-Brown RA. Failure of 340. Clement M, DuVivier A. Concern about the current papaverine to reduce pruritus in atopic dermatitis: clinical practice of diluting topical glucocorticoid a double-blind, placebo-controlled cross-over study. preparations. Clin Exp Dermatol 1984;9:286–9. Br J Dermatol 1990;122(4):553–7. 341. Deeks T. Compounding and dilution of topical 327. Shupack J, Stiller M, Meola T Jr, Orbuch P. steroids. Br J Pharmaceut Pract 1985;134–40. Papaverine hydrochloride in the treatment of atopic dermatitis: a double-blind, placebo- 342. Hornstein O. In: Ruzicka T, Ring J, Przybilla B, controlled crossover clinical trial to reassess safety editors. Guidelines for topical treatment of atopic and efficacy. Dermatologica 1991;183(1):21–4. eczema. Handbook of atopic eczema. Berlin: Springer-Verlag; 1991. p. 350. 328. Kimata H. Selective enhancement of production of IgE, IgG4, and Th2-cell cytokine during the rebound 343. Marks R. How to measure the effects of emollients. phenomenon in atopic dermatitis and prevention J Dermatol Treat 1997;8:15–18. by suplatast tosilate. Ann Allergy 1999;82(3):293–5. 344. Cork MJ. Complete emollient therapy. The National 329. Anonymous. Allergic factors associated with the develop- Association of Fundholding Practices Official Year- ment of asthma and the influence of cetirizine in a book. Dunstable: BPC Waterlow; 1998. p. 159–68. double-blind, randomised, placebo-controlled trial: 345. Newbold PC. Comparison of four emollients in the first results of ETAC. Early Treatment of the Atopic treatment of various skin conditions. Practitioner Child. Pediatr Allergy Immunol 1998;9:116–24. 1980;224(1340):205–6. 330. Kramer MS. Does breast feeding help protect 346. Williams HC. In: Stevens ARJ, editor. Dermatology. against atopic disease? Biology, methodology, Health care needs assessment. Oxford: Radcliffe and a golden jubilee of controversy. J Pediatr Medical Press; 1997. p. 261–348. 1988;112:181–90. 347. Boardman L. The use of emollients in dry skin 331. Kramer MS. Maternal antigen avoidance during conditions. MeReC Bulletin 1998;9:45–8. lactation for preventing atopic disease in infants of women at high risk (Cochrane Review). The 348. Chalmers TC. When should randomisation begin? Cochrane Library. Oxford: Update Software; 1999. Lancet 1968;i:858. 332. Lovegrove JA, Hampton SM, Morgan JB. 349. Ruzicka T, Asmann T, Homey B. Tacrolimus – the The immunological and long-term atopic outcome drug for the turn of the millenium? Arch Dermatol of infants born to women following a milk-free diet 1999;135:574–80. during late pregnancy and lactation: a pilot study. 350. Nakagawa H, Etoh T, Ishibashi Y, Higaki Y, Br J Nutr 1994;71:223–38. Kawashima M, Torii H, et al. Tacrolimus ointment 333. Hepburn DJ, Aeling JL, Weston WL. A reappraisal for atopic eczema. Lancet 1994;344:883. of topical steroid potency. Pediatr Dermatol 351. Bos JD, Bartin P, de Vries HJC, Ebelin ME, Graeber M, 1996;31:239–45. van Leent EJM. SDZ ASM981: Clinical efficacy in 334. Charman C. Atopic eczema. In: Godlee F, editor. adults. Proceedings of SDZ ASM981 Symposium, Clinical evidence. London: BMJ Publishing Group; 8th EADV, Amsterdam. 1999. 1999. 352. Ortonne JP. SDZ ASM 981 does not induce skin 335. Anonymous. Once-a-day topical corticosteroids. atrophy: a randomised, double-blind controlled Drug Ther Bull 1995;33:21–2. study. J Eur Acad Dermatol Venereol 1999;12(1.2):S140. 137 References

353. Leyden JE, Marples RR, Kligman AM. Staphylo- 370. Sampson HA. The immunopathogenic role of food coccal aureus in the lesions of atopic dermatitis. hypersensitivity in atopic dermatitis. Acta Derm Br J Dermatol 1974;90:525–30. Venereol Suppl 1992;176:34–7. 354. Anonymous. Antiseptic/emollient combinations. 371. Sampson HA, Broadbent KR, Bernhisel-Broadbent J. Drug Ther Bull 1998;11:84–6. Spontaneous release of histamine from basophils and histamine-releasing factor in patients with 355. Noble WC. Microbiology and pathogenic cocci in atopic dermatitis and food hypersensitivity. atopic dermatitis. In: Lever RLJ, editor. The N Engl J Med 1989;321(4):228–32. Bacteriology of atopic eczema. London: Royal Society of Medicine Press Ltd; 1995. p. 1–5. 372. Sampson HA. Comparative study of commercial food antigen extracts for the diagnosis of food hyper- 356. Hauser C. The role of staphylococcus aureus on sensitivity. J Allergy Clin Immunol 1988;82(5 Pt 1):718–26. atopic eczema. Int J Dermatol 1986;25:573–4. 373. Sampson HA, Ho DG. Relationship between food- 357. McFadden JP, Noble WC, Camp RDR. Super- specific IgE concentrations and the risk of positive antigenic exotoxin-secreting potential of stapjylo- food challenges in children and adolescents. cocci isolated from atopic eczematous skin. J Allergy Clin Immunol 1997;100(4):444–51. Br J Dermatol 1993;128(6):631–2. 374. David TJ. Food and food additive intolerance 358. Baraf CS. Treatment of pruritis in allergic dermatoses: in childhood. Oxford: Blackwell Scientific an evaluation of the relative efficacy of cyproheptadine Publications; 1993. and hydroxyzine. Curr Ther Res 1976;19(1):32–8. 375. Morse PF, Horrobin DF, Manku MS, Stewart JCM, 359. Corbett MF. Cross-over designs for clinical trials. Allen R, Littlewood S, et al. Meta-analysis of Br J Dermatol 1991;124:208. placebo-controlled studies on the efficacy of 360. Eysenbach G, Williams H, Diepgen TL. Antihista- epogam in the treatment of atopic eczema. Br J mines for atopic eczema (Protocol for a Cochrane Dermatol 1989;121:75–90. Review). Issue 4. Update-Software, Oxford, 1999. 376. Li Wan Po A, Williams HC. A systematic review of 361. Anonymous. Severity scoring of atopic dermatitis: Epogam in the treatment of atopic eczema. the SCORAD index. Consensus Report of the London: Department of Health; 1997. European Task Force on Atopic Dermatitis. 377. MacDonald KJS, Green C, Raffle EJ. Topical evening Dermatology 1993;186(1):23–31. primrose seed oil and atopic eczema. Scott Med J 362. Klein PA, Clark RAF. An evidence-based review of 1985;30:267. the efficacy of antihistamines in relieving pruritis in 378. Koller DY, Pirker C, Jarisch R. Pyridoxine HCI atopic dermatitis. Arch Dermatol 1999;315:1522–5. improves atopic eczema dermatitis: changes of IL-1 363. Sabroe RA, Kennedy CTC, Archer CB. The effects beta, IL-2, ACTH and cortisol in plasma. Clin Exp of topical doxepin on responses to histamine, Allergy 1992;22:126 substance P and prostaglandin E2 in human skin. 379. Norris PG, Schofield O, Camp RDR. A study of the Br J Dermatol 1997;137(3):386–90. role of house dust mite in atopic dermatitis. Br J 364. Bernstein JE. Relief of eczema-associated pruritus by Dermatol 1988;118:435–40. doxepin hydrochloride. J Invest Dermatol 1986;86:463. 380. Cameron MM. Can house dust mite-triggered 365. Sloper KS, Wadsworth J, Brostoff J. Children atopic dermatitis be alleviated using acaridides? with atopic eczema I: clinical response to food Br J Dermatol 1997;137:1–8. elimination and subsequent double-blind food 381. Sanda T, Yasue T, Oohashi M, Yasue A. Effective- challenge. Q J Med 1991;80(292):677–93. ness of house dust-mite allergen avoidance 366. Devlin J, David TJ. Tartrazine in atopic eczema. through clean room therapy in patients with atopic Arch Dis Child 1992;67(6):709–11. dermatitis. J Allergy Clin Immunol 1989;3:653–7. 367. James JM, Bernhisel-Broadbent J, Sampson HA. 382. Fukaya M. Change of housing environment and Respiratory reactions provoked by double-blind withdrawal of corticosteroid as treatments of atopic food challenges in children. Am J Respir Crit Care dermatitis. Arerugi 1999;48(5):520–5. Med 1994;149(1):59–64. 383. Darsow U, Vieluf D, Ring J. Evaluating the relevance 368. Fuglsang G, Madsen G, Halken S, Jorgensen S, of aeroallergen sensitization in atopic eczema with Ostergaard PA, Osterballe O. Adverse reactions to the atopy patch test: a randomized, double-blind food additives in children with atopic symptoms. multicenter study. Atopy patch test study group. J Allergy 1994;49(1):31–7. Am Acad Dermatol 1999;40((2 Pt 1)):187–93. 369. Kanny G, Hatahet R, Moneret-Vautrin DA, Kohler C, 384. Varela P, Selores M, Gomes E, Silva E, Matos E, Bellut A. Allergy and intolerance to flavouring dos Santos L, et al. Immediate and delayed hyper- agents in atopic dermatitis in young children. sensitivity to mite anitgens in atopic dermatitis. 138 Allergie Immunol 1994;26(6):204–6. Pediatr Dermatol 1999;16(1):1–15. Health Technology Assessment 2000; Vol. 4: No. 37

385. Pacor ML, Biasi D, Maleknia T. The efficacy of long- 401. DerSimonian R, Laird N. Meta-analysis in Clinical term specific immunotherapy for Dermato- Trials. Controlled Clin Trials 1986;7:177–88. phagoides pteronyssinus in patients with atopic 402. Poolsup N, de Oliveira, Li Wan Po A. Estimating dermatitis. Recenti Progressi in Medicina clinical trial data from graphical reports. J Clin 1994;85:273–7. Pharm Ther 2000. 386. Rothe MJ, Grant-Kels JM. Diagnostic criteria for 403. Alomar A, Gimemez-Camarasa JM, de Moragas JM. atopic dermatitis. Lancet 1996;348:1391–2. The use of levamisole in atopic dermatitis: a 387. Zimmermann J, Utermann S. Photo-brine therapy prospective study. Arch Dermatol 1978;114(9):1316–19. in patients with psoriasis and nueroderm. Hautarzt 404. Boguniewicz M, Jaffe HS, Izu A, Sullivan MJ, York 1994;45:849–53. D, Geha RS, et al. Recombinant gamma interferon 388. Iikura Y, Sakamoto Y, Imai T, Akai T, Matsuoka T, in treatment of patients with atopic dermatitis and Sugihara K, et al. Dolphin-assisted sea water therapy elevated IgE levels. Am J Med 1990;88(4):365–70. for severe atopic dermatitis: a psychological and 405. Schneider LC, Hanifin J, Cooper K, Boguniewicz M, immunological study. 23rd Collegium Internationale Milgrom H, Jaffe HS, et al. Recombinant interferon Allergologicum symposium. Hakone, Japan. 18–23 gamma therapy reduces the clinical severity of atopic May 2000. dermatitis [abstract]. J Allergy Clin Immunol 1991;87:383A. 389. Noren P. Habit reversal: a turning point in the 406. Zollman C, Vickers A. ABC of complementary medicine: treatment of atopic dermatitis. Clin Exp Derm what is complementary medicine? BMJ 1999;319:693–6. 1995;20:2–5. 407. Xu X-J, Banerjee P, Rustin MHA, Poulter LW. 390. Brown DG, Bettley FR. Psychiatric treatment of Modulation by Chinese herbal therapy of immune eczema: A controlled trial. BMJ 1971;2:729–34. mechanisms in the skin of patients with atopic 391. Brehler R, Hilderbrand A, Luger T. Recent eczema. Br J Dermatol 1997;136:54–9. development in the treatment of atopic eczema. 408. Armstrong NC, Ernst E. The treatment of eczema Am Acad Dermatol 1997;36:983–4. with Chinese herbs: a systematic review of random- 392. Diffey BL. Human exposure to ultraviolet light. ised clinical trials. Br J Clin Pharm 1999;48:262–4. Semin Dermatol 1990;9(1):2–10. 409. Sheehan MP, Atherton DJ. One year follow-up of 393. Sheehan-Dare RA, Goodfield MJ, Rowell NR. children treated with Chinese medicinal herbs for Topical psoralen photochemotherapy (PUVA) and atopic eczema. Br J Dermatol 1994;130:488–93. superficial radiotherapy in the treatment of chronic 410. David TJ. Conventional allergy tests. Arch Dis Child hand eczema. Br J Dermatol 1989;121:65–9. 1991;66:281–2. 394. Krutmann J, Elmets C, editors. Photoimmunology. 411. Dent THS, Hawke S. Too soon to market. Br Med J Oxford: Blackwell; 1995. 1997;313:1157–8. 395. Grundmann-Kollmann M, Behrens S, Peter RU, 412. Emerson RM, Williams HC, Allen BR. What are the Kerscher M. Treatment of severe recalcitrant prescribing costs for atopic dermatitis in young dermatoses of the palms and soles with PUVA-bath children? Br J Dermatol 1998;139 Suppl 51:21–2. versus PUVA-cream therapy. Photodermatol Photoimmunol Photomed 1999;15:87–9. 413. Williams HC. Hywel Williams’ top 10 deadly sins of clinical trial reporting. Ned Tijd Derm Venereol 396. Thomas MD, Cook LJ. Drug points: fever associated 1999;9:372–3. with cyclosporin for treating atopic dermatitis. BMJ 1998;317(7168):1291. 414. Sharpe GR, Farr PM. Evening primrose oil and eczema. Lancet 1990;335:1283. 397. Zaki I, Emerson R, Allen BR. Treatment of severe atopic dermatitis in childhood with cyclosporin. 415. Williams HC, Seed P. Inadequate size of ‘negative’ Br J Dermatol 1996;135 Suppl 48:21–4. clinical trials in dermatology. Br J Dermatol 1993;128:317–26. 398. Holden CA, Parish WE. Atopic Dermatitis. In: Rook AJ WDEF, editors. Textbook of dermatology. 416. Cox N, Williams HC. Can you COPE with 6th edition. Oxford: Blackwell Scientific CONSORT? Br J Dermatol 2000;142:1–7. Publications; 1998. 417. Charman C, Williams H. Outcome measures of 399. Greenland S, Robins JM. Estimation of common disease severity in atopic eczema. Arch Dermatol effect parameter from sparse follow-up data. 2000;136:763–9. Biometrics 1985;41:55–68. 418. Marshall M, Lockwood A, Bradley C, Adams C, 400. Fleiss J, Gross AJ. Meta-analysis in epidemiology, with Joy C, Fenton M. Unpublished rating scales – a special reference to studies of the association between major source of bias in randomised controlled exposure to environmental tobacco smoke and lung trials of treatments of schizophrenia. cancer: a critique. J Clin Epidemiol 1991;44:127–39. Br J Psychiatry 2000;176:249–52. 139 References

419. Lundell ER, Koch E. Über ein im Doppelblind- 420. Ramelet AA, Mauracher E. Treatment of resistant Versuch geprüftes neues Corticosteroid. Zeitschrift steroid-responsive dermatoses: a comparison of fur Allgemeinmedizin 1974;50:463–6. Diprolene™ and Neriforte™. Clin Trials J 1982;19:298–307.

140 Health Technology Assessment 2000; Vol. 4: No. 37

Appendix 1 Search strategies

The Cochrane Collaboration highly General skin search (EMBASE and sensitive electronic search string for MEDLINE) MEDLINE (OVID) #1 drug #1 RANDOMIZED CONTROLLED TRIAL.pt. #2 dermatological agent/ #2 CONTROLLED CLINICAL TRIAL.pt. #3 skin/ #3 RANDOMIZED CONTROLLED TRIALS.sh. #4 dermatology/ #4 RANDOM ALLOCATION.sh. #5 dermatolog$.mp. #5 DOUBLE BLIND METHOD.sh. #6 skin disease$.mp. #6 SINGLE BLIND METHOD.sh. #7 or/2-6 #7 or/1-6 #8 1 and 7 #8 (ANIMAL not HUMAN).sh. Date of last search using this strategy for this #9 7 not 8 report was end of November 1999 #10 CLINICAL TRIAL.pt. #11 exp CLINICAL TRTIALS/ #12 (clin$ adj25 trial$).ti,ab. Search string for EMBASE #13 ((singl$ or doubl$ or trebl$ or tripl$) (OVID) developed by the adj25 (blind$ or mask$)).ti,ab. BMJ Publishing Group for its Clinical #14 PLACEBOS.sh. Evidence series #15 placebo$.ti,ab. #1 exp clinical trial/ or clinical #16 random$.ti,ab. trial.ti,ab,hw,tn,mf. #17 RESEARCH DESIGN.sh. #2 exp controlled study/ #18 or/10-17 #3 (clinical trial$ or controlled clinical #19 18 not 8 trial$).ti,ab,hw,tn,mf. #20 19 not 9 #4 (random$ or placebo$).ti,ab,hw,tn,mf. #21 COMPARATIVE STUDY.sh. #5 double blind.ti,ab,hw,tn,mf. #22 exp evaluation studies/ #6 exp Randomized Controlled Trial/ #23 follow up studies.sh. #7 or/1-6 #24 prospective studies.sh. #8 limit 7 to human #25 (control$ or prospectiv$ or volunteer$).ti,ab. #9 explode dermatitis, atopic/ #26 or/21-25 #10 dermatitis, atopic #27 26 not 8 #11 eczema, atopic #28 26 not (9 or 20) #12 eczema #29 9 or 20 or 28 #13 atopic eczema #14 atopic dermatitis #30 explode dermatitis, atopic/ #15 infantile eczema #31 dermatitis, atopic.ti,ab,rw,sh. #16 childhood eczema #32 eczema, atopic.ti,ab,rw,sh. #17 neurodermatitis #33 eczema.ti,ab,rw,sh. #18 besniers prurigo #34 atopic eczema.ti,ab,rw,sh. #35 atopic dermatitis.ti,ab,rw,sh. #19 8 and 18 #36 infantile eczema.ti,ab,rw,sh. Date of last search using this strategy for this #37 childhood eczema.ti,ab,rw,sh. report was end of June 2000 #38 neurodermatitis.ti,ab,rw,sh. #39 besniers prurigo.ti,ab,rw,sh. #40 or/30-39 #42 29 and 40 Date of last search using this strategy for this report was end of June 2000 141

Health Technology Assessment 2000; Vol. 4: No. 37

Appendix 2 Excluded studies

TABLE 44 Table of excluded studies for trials of topical steroids

Author Date Interventions Reason for exclusion Topical steroid vs ‘placebo’ vehicle Cullen 1973 Betamethasone benzoate gel Atopic dermatitis not separated from other 0.025% vs placebo gel dermatoses in results Rosenthal 1980 Clocortolone pivalate 0.1% cream Atopic dermatitis not separated from other vs placebo cream base dermatoses in results Gartner 1984 Diproderm cream 0.05% vs placebo vehicle Atopic dermatitis not separated from other dermatoses in results Guzzo 1991 Halobetasol propionate 0.05% ointment Atopic dermatitis not separated from other vs vehicle dermatoses in results Lebwohl 1996 Fluticasone propionate 0.005% ointment Unclear if ‘eczema’ is atopic dermatitis in this study, vs vehicle especially as most of the subjects were adult – author has been contacted for clarification Schachner 1996 Hydrocortisone 17-butyrate ointment vs vehicle No randomisation mentioned Heuck 1997 Topical bedesonide vs base The atopic dermatitis patients (study one) were part of an open case series.The two remaining RCTs in this study were all on asthma patients Topical steroid vs another topical steroid Zimmerman 1967 Betamethasone 17-valerate 0.05% ointment First study was a case series, and it is unclear vs fluocinolone acetonide 0.025% if randomisation occurred in second study Grater 1967 Flumethasone vs 0.1% triamcinolone Atopic dermatitis not separated from other vs 1% hydrocortisone dermatoses in results Rosenberg 1971` 0.05% fluocinonide Atopic dermatitis not separated from other vs 0.1% betamethasone valerate dermatoses in results Bluefarb 1972 Desonide cream 0.05% Atopic dermatitis not separated from other vs betamethasone valerate cream 0.1% dermatoses in results Meenan 1972 Flucinonide 0.05% vs betamethasone 17 Atopic dermatitis not separated from other valerate cream 0.1% dermatoses in results Borelli 1973 Clocortolone (C168) vs fluocinolone ‘Eczema’ group not specified sufficiently McCuiston 1973 Fluocinonide 0.01% and 0.05% Not clear if randomised, outcome measures vs betamethasone valerate not described at all Polano 1973 Hydrocortisone butyrate 0.1% vs triamcinolone Atopic dermatitis not separated from other acetonide 0.1% vs hydrocortisone acetate 1% dermatoses in results Stewart 1973 Desonide vs triamcinolone acetonide Atopic dermatitis not separated from other vs betamethasone 17-valerate dermatoses in results Nordwell 1974 Betamethasone 17, 21-dipropionate 0.05% cream Atopic dermatitis not separated from other vs fluocortolone caproate 0.25% plus dermatoses in results fluocortolone pivalate 0.25% cream Sparkes 1974 Clobetasol propionate 0.05% vs betamethasone Atopic dermatitis not separated from other 17-valerate ointment and cream vs fluclorolone dermatoses in results acetonide ointment and cream and fluocinonide Laurberg 1975 1% hydrocortisone in a stabilized 10% urea cream Atopic dermatitis results mixed up with patients vs betamethasone 17-valerate 0.1% cream with ‘atopic winter feet’ Lundell 1975 Desoximetasone 0.25% vs fluocinolone acetonide Nature of ‘endogenous eczema’ unclear. 0.025% cream Inadequate description to classify as atopic dermatitis Ludvigsen 1975 Calmuril-hydrocortisone 1% cream Unclear if randomised. No study results given! vs triamcinolone acetonide 0.1% cream Meyer-Rohn 1975 Desoximetason 0.25% Atopic dermatitis not separated from other vs betamethasone-valerate 0.1% dermatoses in results Sudilovsky 1975 Halcinonide cream 0.1% vs fluocinonide Disease definition, i.e.‘eczematous dermatoses 0.05% cream which would normally be treated with topical steroids’ not acceptable as a term synonymous with atopic eczema continued 143 Appendix 2

TABLE 44 contd Table of excluded studies for trials of topical steroids

Author Date Interventions Reason for exclusion Parish 1976 Betamethasone benzoate 0.025% gel Cannot be sure that study subjects with vs betamethasone valerate 0.1% cream ‘eczematous dermatoses’ had atopic eczema Thormann 1976 Hydrocortisone 17-butyrate vs betamethazone Results of five different skin disorders mixed up 17-valerate and only one patient with atopic eczema Roessel 1977 Triamcinolone acetonide benzoyl-β-amino- Atopic dermatitis not separated from other isobutyrate vs betamethasone dipropionate dermatoses in results Khan 1978 1% hydrocortisone plus 10% urea Dry eczematous dermatoses in adults vs 0.05% fluocinonide mixed up with atopic dermatitis Lassus 1979 Clobetasone butyrate 0.05% cream Atopic dermatitis not separated from other vs hydrocortisone butyrate 0.1% cream dermatoses in results Helander 1982 Hydrocortisone 17-butyrate 0.1% cream Atopic dermatitis not separated from other vs betamethasone 17-valerate 0.1% cream dermatoses in results Hersle 1982 Diflorasone diacetate 0.05% Atopic dermatitis not separated from other vs betamethasone valerate dermatoses in results Turnbull 1982 Locoid vs Betnovate lotion Study of seborrhoeic and atopic dermatitis of the scalp with results not separated Gip 1983 Hydrocortisone 17-butyrate 0.1% cream Atopic dermatitis not separated from other vs betamethasone 17-valerate 0.1% cream dermatoses in results Schmidt 1984 D-homosteroids domoprednate 0.1% ointment Atopic dermatitis not separated from other vs 0.1% betamethasone valerate ointment dermatoses in results Gip 1987 Hydrocortisone 17-butyrate 0.1% cream Atopic dermatitis not separated from other vs betamethasone 17-valerate 0.1% cream dermatoses in results Schmidt 1987 Domoprednate 0.1% ointment Atopic dermatitis not separated from other vs hydrocortisone butyrate ointment dermatoses in results Handa 1988 Alcometasone dipropionate 0.05% ointment Atopic dermatitis not separated from other vs 1% hydrocortisone ointment dermatoses in results Panja 1988 Alclometasone dipropionate 0.05% cream Atopic dermatitis not separated from other vs 1% hydrocortisone cream dermatoses in results Celleno 1990 Alclometasone dipropionate 0.1% Atopic dermatitis not separated from other vs 0.1% hydrocortisone 17-butyrate dermatoses in results Viglioglia 1990 Mometasone furoate 0.1% cream once daily Atopic dermatitis not separated from other vs betamethasone valerate 0.1% cream twice daily dermatoses in results Brunner 1991 Halobetasol propionate 0.05% ointment Atopic dermatosis results mixed up with vs 0.1% diflucortolone valerate ointment patients with lichen simplex Datz 1991 Halobetasol propionate ointment 0.05% Atopic dermatitis results mixed up with vs clobetasol 17-propionate ointment 0.05% lichen simplex Rajka 1993 Mometasone furoate 0.1% fatty cream Atopic dermatitis not separated from other vs betamethasone valerate 0.1% cream dermatoses in results Schäfer-Korting 1993 Prednicarbate 0.025% -0.25% vs hydrocortisone Conducted in healthy volunteers not aceponate vs hydrocortisone buteprate 0.1% atopic eczema subjects vs betamethasone 17-valerate 0.1% vs hydrocortisone 1% vs 2 drug-free vehicles Blum 1994 Betamethasone dipropionate 0.05% in propylene Atopic dermatitis not separated from other glycol vs clobetasol propionate 0.05% ointment dermatoses in results Delescluse 1996 Fluticasone propionate ointment 0.005% Atopic dermatitis not separated from other vs betamethasone 17, 21-dipropionate dermatoses in results ointment 0.05% Juhlin 1996 Fluticasone propionate 0.05% cream Atopic dermatitis results not separated from vs hydrocortisone 17-butyrate 0.1% cream patients with other eczemas of a known cause Meffert 1999 Topical methylprednisolone aceponate Whole range of ‘acute eczemas’ not separated in results vs amcinonide, betamethasone valerate, hydrocortisone butyrate and vehicle Topical steroid vs another topical Bjornberg 1967 Crotamiton vs Crotamiton/hydrocortisone combo Atopic eczema not specified/separated Christiansen 1977 Bufexamac vs 0.1% triamcinolone acetonide, Atopic dermatitis results not separated from 1% hydrocortisone cream and placebo other dermatoses continued

144 Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 44 contd Table of excluded studies for trials of topical steroids

Author Date Interventions Reason for exclusion Topical steroid plus additional active agents Bjornberg 1966 Topical flumethasone plus vioform Besnie’s prurigo included, results not separated vs hydrocortisone with 5, 7-Dichlor-8-hydroxy-2- methylquinolin 3% Sasagawa 1970 Betamethasone valerate plus gentamicin sulphate Atopic dermatitis not separated from other vs betamethasone dermatoses in results Weitgasser 1972 Topical dexamethasone vs topical nandrolone Rag bag of dermatoses (atopic dermatitis not among plus chlorhexadine them) and results not separated Aertgeerts 1973 Topical dexamethasone vs topical nandrolone Various dermatoses lumped together plus chlorhexdine Carpenter 1973 Vioform-hydrocortisone cream vs components Atopic dermatitis not separated from other alone and base cream vehicle dermatoses in results Aertgeerts 1976 Dexamethasone plus chlorhexidine Atopic dermatitis not separated from other vs flumethasone – pivalate 0.02% plus dermatoses in results iodochlorohydroxy-quinolone Cunliffe 1976 Fluclorolone acetonite 0.025% in FAPG Atopic dermatitis not separated from other vs betamethasone 17-valerate plus 0.5% neomycin dermatoses in results Strategos 1986 Fusidic acid/betamethasone combination Only five patients with atopic eczema all present vs gentamicin – betamethasone combination in only one treatment arm Weitgasser 1993 Halometasone/triclosan cream vs betamethasone Atopic dermatitis not separated from other dipropionate/getamicin sulphate cream dermatoses in results Poyner 1996 Fusidic acid/hydrocortisone cream Unclear if patients with ‘clinically infected eczema’ vs miconazole/hydrocortisone cream had atopic eczema.Author contacted for clarification Comparison of different formulations of the same topical steroids Pilgaard 1980 Hydroderm™ vs hydrokortison DAK™ Atopic dermatitis not separated from other dermatoses in results Once-daily vs more frequent application of topical steroids Tharp 1996 Fluticasone propionate 0.05% once vs twice daily Eczema unspecified Fredricksson 1980 Halcinonide cream 0.1% once daily Psoriasis and atopic dermatitis results mixed up vs same cream three times daily Schmid 1981 Topical fluocinoloneacetonid 0.025% once daily, Not clearly atopic dermatitis patients twice daily or interval therapy English 1989 Betamethasone dipropionate once vs twice daily Atopic dermatitis not separated from other dermatoses in results Topical steroids in the prevention of relapse Vickers 1976 Maintenance on low-potency topical steroids Not an RCT, though a clear intention to conduct one. switching to high-potency for short periods Subsequent RCT never published vs use of high-potency steroid throughout treatment vs high-potency steroid regularly once daily using a low-potency steroid for the second application Moller 1983 Clobetasol proprionate vs flupredniden acetate Atopic dermatitis not separated from other dermatoses in results FAPG, fatty acid propylene glycol Diproderm™, not available in the UK; Hydroderm™, Schering Corp., Denmark; Betnovate™, Glaxo-Wellcome, UK

145 Appendix 2

TABLE 45 RCTs of ‘eczema’ excluded for other reasons

Author Date Interventions Reason for exclusion Smith 1961 Trimeprazine vs methdilazine Atopic eczema data not separated in results Brown 1971 Psychiatric treatment Only one case of atopic eczema Chan-Yeung 1971 DSCG Asthma study Anonymous 1973 Carbamide in hyperkeratosis Atopic eczema results not separated D’Souza 1973 House dust mites People had asthma or hay fever Baraf 1976 Antihistamines: cyproheptadine vs hydroxyzine Atopic eczema results not separated from other dermatoses Baertschi 1976 Antibiotic prophylaxis ‘Eczema’ only mentioned as adverse effect Friedman 1978 Monoamione oxidase inhibitors Unclear if any of the neurodermatits patients had atopic eczema Buch-Rasmussen 1979 Hydrocortisone alcoholic solutions Study of external otitis Newbold 1980 Emollients Atopic eczema results not given separately Anonymous 1981 5% butyl flufenamate vs bufexamac Atopic dermatitis not separated from other dermatoses in results Bazex 1982 Terfenadine vs clemastine Atopic eczema results not separated from other dermatoses in results Cooper 1983 Thymopoietin pentapeptide No clinical outcomes measured or reported Archer 1984 Adrenoreceptor agonists Not a therapeutic trial Fairris 1984 Superficial X-Ray therapy (of the feet) Unclear if patients had atopic eczema Fairris 1985 Superficial X-Ray therapy (of the hands) Unclear if patients had atopic eczema Meyrick-Thomas 1985 Ranitidine Healthy atopic volunteers Svensson 1985 Diagnostic tool based on clinical criteria Diagnostic study ‘subjects randomly collected’ Bernstein 1986 Doxepin hydrochloride Abstract only Niimura 1988 Oral acyclovir Study of eczema herpeticum Roberts 1988 PAF antagonist vs placebo Not atopic eczema patients Warren 1988 The importance of bradykinin and histamine in Not atopic eczema patients, not a therapeutic trial the skin response to antigen Burr 1989 Risk factors for atopic eczema Not an RCT of an intervention for atopic eczema, instead, an observational study of risk factors for atopic eczema within another breastfeeding RCT Ebden 1989 Evening primrose oil Asthma not atopic eczema Monroe 1989 Nalmefene opiate antagonist vs placebo Atopic eczema results not presented separately Sheehan-Dare 1989 PUVA vs superficial radiotherapy Not clear atopic dermatitis Brandrup 1990 Occlusive dressing ‘Eczema’ only mentioned as adverse effect Markey 1990 PAF Atopic subjects without evidence of atopic eczema Michel 1990 Cetirizine Pollen sensitive patients unspecified Heyer 1991 Substance P and topical mustard oil Not a therapeutic trial Peter 1991 Ketaconazole Study of seborrhoeic dermatitis Schafer 1991 (a) Evening primrose oil No clinical outcomes

Schafer 1991 (b) Phospholipid fatty acid composition and LTB4 No clinical outcomes release of neutrophils Kerscher 1992 Topical steroids Healthy volunteers Korting 1992 Prednicarbate cream Healthy volunteers Nierop 1992 Auranofin Study of asthma only Olsen 1992 Systemic steroids with 2% minoxidil Study of alopecia areata with eczema mentioned as adverse effect Couser 1993 Surfactant Unspecified eczema as outcome measure Lutsky 1993 Loratadine syrup vs terfenadine suspension Atopic eczema results not given separately Rombo 1993 Malaria prophylaxis ‘Eczema’ mentioned as adverse effect continued 146 Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 45 contd RCTs of ‘eczema’ excluded for other reasons

Author Date Interventions Reason for exclusion

Zepelin 1993 Omega-3 fatty acid Psoriasis patients Lee 1994 Surfactant mixturesHealthy volunteers Lovegrove 1994 Milk-free diet vs normal diet No separate data on atopic eczema Nakagawa 1994 Tacrolimus ointment 0.03, 0.1 and 0.3% Randomisation not described, three actives compared in hand and neck area, unblinded Soyland 1994 n-3 omega fatty acid supplementation Atopic eczema severity outcome data not given Syed 1994 Podophyllotoxin cream Study of molluscum Tegner 1994 Skin blanching by hydrogen peroxide Adverse effect study of skin blanching of hydrogen peroxide Zimmermann 1994 Balneophototherapy with daily 15% synthetic Atopic dermatitis not separated from other Dead Sea Salt bath and selective ultraviolet dermatoses in results phototherapy vs balneophototherapy with daily 3% NaCl salt bath and selective ultraviolet phototherapy Roquet 1995 Loratidine Atopic subjects not necessarily having eczema Simon 1995 Ioxaglate vs Iopamidol Not a study of atopic eczema outcomes.A study to see if allergic reactions are commoner in one type of contrast medium in patients with atopic disease Simon 1995 Gamma-interferon No clinical outcomes Snyman 1995 Betahistine Simply ‘atopic volunteers’ not necessarily atopic eczema Verwimp 1995 Whey-protein hydrolysate based formulas Unclear if atopic eczema patients Wahlgren 1995 Interleukin-2 Laboratory experiment with no clinical outcomes, not a therapeutic trial Anonymous 1997 Cetirizine vs placebo No atopic eczema outcomes Kalpakliogu 1997 Heparin Asthma study Heyer 1997 Opiate and H1 antagonist effects Healthy volunteers Kekki 1997 Skin-prick and patch-test reactivity Diagnostics Lippert 1997 Antigen-induced cytokine release Not a clinical trial of a therapeutic agent. Only cytokines measured Pigatto 1997 Colloidal grain suspensions Not a therapeutic trial Rukwied 1997 Cetirizine vs placebo Experimentally-induced flare responses Sabroe 1997 Doxepin vs terfenadine No atopic eczema outcomes Frossard 1998 Cetirizine Healthy volunteers Hill 1998 Betamethasone plus clioquinol cream Hand eczema vs betamethasone plus fusidic acid cream Lippert 1998 Certirizine Laboratory experiment with no clinical outcomes Sorensen 1998 Intravenous immunoglobulin Study of multiple sclerosis with eczema mentioned as side effect Syed 1998 Imiquimod 1% Study of molluscum Warnecke 1998 Ichthyol oil Healthy volunteers Weisshaar 1998 Topical capsaicin vs placebo Effect of capsaicin on experimentally induced whealing from histamine icthyosis Darsow 1999 Aeroallergen sensitization Diagnostics Goh 1999 Mometasone furoate cream Unspecified chromic limb eczema vs clobetasol propionate cream Grundmann- 1999 PUVA bath vs PUVA cream Atopic eczema results not separated Kollmann Ortonne 1999 SDZ ASM 981 vs topical steroids and vehicle Healthy volunteers Rudofsky 1999 Intravenous prostaglandin Study of venous ulcers with eczema mentioned as adverse effect

147 Appendix 2

TABLE 46 RCTs excluded at an early stage because eczema was unspecified

Author Date Interventions Reason for exclusion Topical steroids Leo Pharma- – Fucicort® vs Betnovate Unspecified hand eczema ceuticals unpublished data on file Stahle 1965 Fluocinolone vs tumenol prednisolone Description of ‘patches of eczema’ unclear Stahle 1965 Full vs half strength betamethasone 17-valerate Description of ‘patches of eczema’ unclear Munro 1967 Betamethasone 17-valerate ‘Eczema’ unspecified vs fluocortolone caproate ointment Anonymous 1969 Flurandrenolone with clioquinol in Unclear if ‘eczema’ included atopic eczema 2 different strengths Lloyd 1969 Fluocinolone acetonide 0.025% Nature of inflammatory dermatitis unclear vs flucinolone containing neomycin Portnoy 1969 1% hydrocortisone vs 0.2% fluocortolone ‘Eczema’ unspecified Ashurst 1970 Beclomethasone dipropionate ‘Conditions responsive to topical applications vs betamethasone 17-valerate of steroids’ – unclear if this included atopic eczema Ashurst 1972 Hydrocortisone 17-butyrate vs fluocinolone Inadequate description of ‘eczema’ acetonide vs hydrocortisone butyrate with chlorquinaldol Hall-Smith 1972 Betamethasone valerate vs betamethasone benzoate Description of ‘steroid-responsive dermatoses’ insufficient Harman 1972 Fluclorolone acetonide vs betamethasone 17-valerate Various types of ‘dermatitis’ unclear Neering 1972 Betamethasone 17-valerate vs triamcinolone ‘Eczema’ unspecified acetanide under occlusive dressing Sarkany 1972 Fluocinonide vs betamethasone valerate Type of ‘eczema’ unclear Alexander 1973 Hydrocortisone 17-butyrate vs betamethasone Nature of ‘eczema’ unclear valerate 0.1% Craps 1973 Clocortolone pivalate vs controls in Non-specific ‘eczema’ 17 double-blind trials Cullen 1973 Betamethasone benzoate vs placebo gel ‘Eczematous dermatoses’ not separated Marks 1973 Betamethasone 17-valerate 0.1% ‘Eczema of the hands’ unclear vs formocortal 0.025% Wilson 1973 Betamethasone 17-valerate ointment lanolin-free Type of eczema unclear vs original formulation vs fluclorolone acetonide ointment Garretts 1975 Fluprednylidene acetate cream vs base Inflammatory skin disease unspecified Ronn 1976 Betamethasone vs fluocinonide ‘Eczema’ unspecified Munro 1977 Betamethasone valerate ointment ‘Eczema’ unspecified vs fluocinonide FAPG Palmerio 1977 Halopredone acetate vs betamethasone valerate Nature of ‘eczema’ unclear Dotti 1978 Dexamethasone 17-valerate vs 0.1% betamethasone Nature of ‘eczematous lesions’ unclear vs 1% hydrocortisone acetate Afzelius 1979 Betamethasone diapropionate 0.05% Unclear if atopic eczema included vs fluocinolone acetonide 0.025% Doherty 1979 Diflucortolone valerate 0.3% oily cream ‘Chronic severe eczema’ too non-specific vs clobetasone propionate 0.05% cream Rosenberg 1979 Amcinonide vs betamethasone valerate ‘Eczematous dermatitis’ unclear Vollum 1979 Betamethasone valerate vs halcinonide Nature of eczema lesions unclear Allenby 1981 Clobetasone butyrate 0.05% vs hydrocortisone Unclear if atopic eczema butyrate 0.1% Anonymous 1981 Hydrocortisone 17-butyrate vs betamethasone Unspecified uninfected eczema 17-valerate creams Guenther 1981 Amcinonide cream 0.1% vs halcinonide cream 0.1% Nature of ‘eczematous dermatitis’ unclear Bickers 1984 Amcinonide vs halcinonide Nature of ‘subacute eczematous dermatitis’ unclear Johansson 1984 Diflorasone diacetate vs betamethasone valerate Nature of ‘eczematous dermatitis’ unclear continued 148 Health Technology Assessment 2000; Vol. 4: No. 37

TABLE 46 contd RCTs excluded at an early stage because eczema was unspecified

Author Date Interventions Reason for exclusion August 1985 Diflucortolone vs betamethasone cream Unspecified symmetrical eczema Jegasothy 1985 Clobetasol propionate vs fluocinonide cream Nature of ‘chronic eczema’ unclear Jaffé 1986 Hydrocortisone plus potassium hydroxyquinoline Nature of ‘infected eczema’ unclear vs 1% hydrocortisone plus 2% miconazole cream Barry 1987 Desonide 0.05% and 0.1% cream ‘Non-infected hand eczemas’ unclear Williamson 1987 Hydrocortisone/urea cream vs betamethasone Nature of ‘dry eczema’ unclear valerate cream Lutsky 1993 Loratadine syrup vs Terfenadine suspension Atopic dermatitis not separated from other dermatoses in results Gip 1994 Betamethasone 17-valerate 0.1% lipocream Nature of ‘dry chronic dermatitis’ unclear vs betamethasone 17-valerate 0.1% cream Kejda 1994 1% hydrocortisone cream vs Locoid 0.1% Nature of ‘chronic eczema’ unclear Nakagawa 1994 Tacrolimus ointment 0.03, 0.1 and 0.3% Randomisation not described, unblinded open study Tharp 1996 Fluticasone once daily vs twice daily Unspecified eczema Jorizzo 1997 Clobetasol propionate 0.05% vs emollient vehicle ‘Eczema’ unspecified Radiation King 1984 Superficial radiotherapy vs simulated therapy Nature of ‘palmar’ eczema unclear Cartwright 1987 Grenz vs placebo Nature of ‘bilateral hand ezcema’ unclear if atopic eczema Cromoglycate Dannaeus 1977 SCG vs placebo Unspecified eczema Pacor 1992 DSCG vs oxatomide Nature of eczema unspecified Antihistamines Hellier 1963 Trimeprazine vs amylobarbitone Unspecified eczema Laugier 1978 Mequitazine vs placebo Unspecified ‘dermatological conditions’ Miscellaneous de Gregorio 1970 Topical bendazac vs placebo Nature of ‘eczematous eruptions’ unclear vs 3% hydrocortisone acetate Fredrikksson 1975 Urea creams Nature of eczematous dermatitis of hands unclear Zimmermann 1981 Intravenous demetindenmaleat vs clemastine Nature of ‘allergic dermatoses’ unclear Fairris 1984 Superficial X-ray therapy Nature of unspecified constitutional eczema of the hands unclear Veien 1985 Oral challenge with balsam of Peru vs placebo Various types of ‘dermatitis’ unclear Lauharanta 1991 Emuslion cleansing vs washing with soap Nature of ‘hand eczema’ unclear Drake 1995 5% doxepin cream vs vehicle cream Description of study subjects suggests that ‘eczematous dermatitis’ did not include atopic dermatitis Fucicort®, Leo Pharmaceuticals, UK

149

Health Technology Assessment 2000; Vol. 4: No. 37

Appendix 3 Studies of steroid therapy

151 Appendix 3 continued Large treatment effect Large treatment The study demonstrates the large placebo vehicle/ in atopic response eczema trial Difficult to estimate magnitude of benefit Scant details Patient preference little study gives indication of magnitude of effect Method and concealment of randomisation unclear, study described as ‘code’, double blind drop-outs,three no ITT 69 patients enrolled, 12 did not meet all study critieria yet used in final 63 were assessment Method and concealment of randomisation unclear, study described as double-blind and drop- Withdrawals outs not mentioned Method and concealment of random- isation unclear, study described as double- blind, no withdrawals or drop-outs < 0.001) < 0.0001 p p Improvement over Improvement mean total baseline for was 11.4 symptom score and 11.2 dipropionate for placebo decreasing for dipropionate to 1.6 for placebo at and 8.4 for 3; week Both groups improved Both groups all for substantially parameters greater toward Trend in hydro- improvement but cortisone groups significant not statistically No actual data given for No actual data given valerate hydrocortisone vs placebo. 75% of the patients showed excellent improvement better with the or were valerate hydrocortisone with compared cream 20% with the placebo ratings at the Overall end of the therapy hydrocortisone showed valerate to be more significantly than the effective placebo ( eczema patients one site better active found neither and one found site better Amount of scale, erythema, pruritus, thicknes of lesions and crusting on a 0–4 scale (0 = none, 4 = very severe) <25% Global evaluation to 100% = = worse excellent Doctor-assessed erythema, patient- and assessed roughness itching Other biological measures Pruritus, erythema, scaling, excoriation, lichenification condition and Overall of disease severity Lesion improvement atopic Out of two Prospective, randomised, double- blind study of 3 weeks’ duration Prospective, randomised, left/right, parallel study of 4 duration weeks’ Prospective, randomised, double- blind parallel-group 2 weeks study for Prospective, randomised, double- blind parallel study follow-up 36 patients with moderate-to-severe atopic dermatitis 20 atopic eczema patients 69 patients with atopic dermatitis 40 patients in total two atopic eczema patients and sample size description and 0.05% betamethasone ointment dipropionate b.d. placebo vs vehicle Hydrocortisone 0.2% vs valerate cream placebo t.d.s. Water-in-oil emulsion Water-in-oil b.d. vs 2 weeks for emulsion water-in-oil plus1% hydrocortisone by followed 1 week for in the only the emulsion second week 0.5% triamcinolone acetonide o.d. in flexible ‘flexible collodion vs collodion’ placebo o.d. 71 RCTs of topical corticosteroid vs placebo 105 87 126 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment Vanderploeg, 1976 Gehring & Glooer, 1996 Roth & Brown, 1978 USA Germany Translated 152 & Cullen, Brock 1967 USA TABLE 47 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Very short duration Very using a novel (4 days) to measure approach itch Six trials described in RCTs) (three this paper one of which had only not been published elsewhere Big treatment effect Big treatment duration 4 weeks’ Only Patients with a previous history of poor to topical response were corticosteroids excluded Method and concealment of randomisation unclear, study described as double-blind, drop- four outs, no ITT Method and concealment of randomisation unclear, study described as double-blind (identical coded tubes), three drop-outs, no ITT Method and concealment of randomisation unclear, study described as double-blind 19 lost to follow-up, no ITT Method and conceal- ment of randomisation unclear, study described as double-blind, four drop-outs Withdrawals, no ITT < 0.01) p = 0.0062) p < 0.001) p ‘No pruritus’ on Days 3–4 was 35.8% during betamethasone and 21.5% during placebo ( therapy Mean global evaluation on scores severity 0–100 VAS: valerate hydrocortisone of 34.6 baseline score to 10.3 and decreasing placebo baseline score to of 34.1 decreasing 28.9 after 14 days ( treatment In Halcinonide group 64% excellent, 21% good, 10% fair and 5% poor response 23% In placebo group excellent, 21% good, 36% fair and 20% poor response Of 54 evaluable patients Of 54 evaluable 3,at week 13 (24%) markedly were halcino- for improved clinical nide comparative vs 1 (2%) for response placebo patients ( Intensity of pruritus and using Pain-Track distribution and activity of eczema determined and excoriations counted Pruritus, erythema, scaling, papulation, lichenification and vesiculation using Global evaluation an VAS 0–100, 100 most severe Therapeutic response Therapeutic of lesions on each side as excellent, evaluated good, fair, poor Lesion resolution lesion for evaluated size, erythema, oedema, transudation and lichenification response Therapeutic scale four-point (4 = excellent, 1 = poor) Comparative and Comparative absolute therapeutic responses: erythema, oedema, changes in size of thickness lesions global Physician response Prospective, randomised, double- study of blind crossover duration 4 days’ Prospective, randomized, double- comparison blind paired study of 2 weeks’ duration Prospective, randomised, double- blind left/right parallel study of 2 weeks’ duration Prospective, randomised, right/ left, parallel study of 3 duration weeks’ follow-up 30 adult patients with persistent atopic dermatitis and chronic pruritis 233 patients with mild, moderate and severe atopic dermatitis 64 patients with mild- to-moderate atopic dermatitis 58 atopic eczema patients and sample size description and RCTs of topical corticosteroid vs placebo Betamethasone 0.05% dipropionate b.d.cream vs base placebo b.d. cream Halcinonide ointment 0.1% vs t.d.s. ointment base placebo t.d.s. Hydrocortisone valerate 0.2% ointment b.d. placebo vs vehicle 0.1% halcinonide cream o.d. base plus cream placebo b.d. vs cream base placebo t.d.s. et al., et al., et al., et al., 100 114 94 95 Wahlgren Wahlgren 1988 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment Lupton 1982 Sefton 1984 1981 Sudilovsky Sudilovsky 153 TABLE 47 contd TABLE Appendix 3 continued Unclear why two Unclear why identical large trials multicentre conducted and concurrently repeated Unclear why two Unclear why identical large trials multicentre conducted and concurrently repeated Paper suggests that use Paper alone of topical steroids has a big impact on bacterial colonisation = 80); no ITT = 101); no ITT n n Method and concealment of randomisation unclear, study described as double-blind of Large number and drop- withdrawals outs ( analysis Method and concealment of randomisation unclear, study described as double-blind of Large number and drop- withdrawals outs ( analysis Method and concealment of randomisation unclear, study described as double-blind No mention of and drop- withdrawals outs = 74) = 63) n n = 28) found density n = 26) found n < 0.001) < 0.05) p p Patient’s self assessment Patient’s 29,at day 84% ( fluticasone found vs excellent or good 48% ( excellent or vehicle good adverse Drug-related rare were effects found fluticasone found excellent or good vs 37% ( excellent or vehicle good adverse Drug-related rare were effects Patient’s self assessment Patient’s 29,at Day 81% ( 66.7% desonide group or improvement showed compared resolution with 15.8% in the placebo group ( S. aureus log 2.2 by decreased with log 0.6 compared in the placebo group ( Patient’s self assessment Patient’s efficacy of treatment gross Physician’s assessment, severity signs and of five scores one symptom Patient’s self assessment Patient’s efficacy of treatment gross Physician’s assessment, severity signs and of five scores one symptom Global physician score Global physician based on extent and of lesion severity Local lesion score based on target area bacteriological Various assessments Prospective, randomised, parallel study of 29 days’ duration Prospective, randomised, parallel study of 29 days’ duration Prospective, randomised, double- blind parallel study of 7 duration days’ follow-up 169 patients with atopic eczema 203 patients with atopic eczema 40 children with atopic 40 children dermatitis and sample size description and RCTs of topical corticosteroid vs placebo Fluticasone propionate ointment 0.005% vs placebo vehicle Fluticasone propionate ointment 0.005% vs placebo vehicle Desonide o.d. vs excipient o.d. et al., et al., et al., 116 76 91 Lebwohl Lebwohl 1996 USA (Study 2) Lebwohl Lebwohl 1996 USA (Study 1) Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 154 Stalder 1994 TABLE 47 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 Large study with big effects treatment Baseline scores not Baseline scores given Method and concealment of randomisation unclear, study described as double-blind 26 drop-outs; no ITT Method and concealment of randomisation unclear, study described as double-blind 20 drop-outs; no ITT Seven sign lesion scores Seven over improvement baseline of 9.13 for reduced hydrocortisone 14,to 2.67 at Day and placebo baseline of 9.95 to 6.69 at Day reduced 14 Gross assessment at Gross 78% of 43 showed Day clobetasol-treated good, patients were excellent or cleared with 33% of compared patients placebo-treated Seven disease signs Seven (infiltration, scaling, erythema, lichen- ification, vesicles, papules, and excor- evaluated iation) were scale (0 on a four-point = absent, 3 = severe) Pruritus evaluated on same separately scale four-point improvement Overall scale on a seven-point (1 = cleared, 7 = worse) and global treatment efficacy on a four-point and scale (1 = good 4 = poor) Physician gross Physician assessment based on of % improvement target lesion plus baseline changes from scores in mean severity erythema,for pruritus, induration/papulation, lichenification, erosion/ oozing/crusting, and scaling/dryness and for total signs and symptoms Prospective, randomised, double- blind parallel study of duration 14 days’ Randomised, double- blind parallel study of duration 43 days’ follow-up 194 patients with atopic dermatitis 81 patients with moderate-to-severe atopic dermatitis and sample size description and RCTs of topical corticosteroid vs placebo Hydrocortisone buteprate 0.1% cream base placebo vs cream o.d. Clobetasol propionate 0.05% b.d. vs cream placebo b.d. vehicle et al., et al., 81 132 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment o.d., once daily Sears 1997 Maloney Maloney 1998 155 TABLE 47 contd TABLE Appendix 3 Four However, 65 included in efficacy study None Unspecified 14: or loss to follow-up violations protocol 11 atopic eczema patients None 39 (seven drop-outs,39 (seven 32 evaluated’) ‘not yet drop-outs None Unspecified Unspecified Antihistamines (for allergic Antihistamines (for rhinitis); insulin, antibiotics and tranquilisers Unspecified Unspecified Unspecified ‘No local or systemic permitted medications were affect that could conceivably the dermatoses’ None specified oid) ) 1% cream ™ Clobetasone butyrate ointment 0.05% b.d. Hydrocortisone butyrate Hydrocortisone 0.1% b.d. cream Betamethasone valerate 0.1% t.d.s. cream cream Hydrocortisone 1.0% t.d.s. Betamethasone valerate 0.1% ointment Fluocinolone acetonide 0.025% ointment acetonide Triamcinolone 0.1% ointment Betamethasone valerate t.d.s. 0.1% cream Clobetasone butyrate 0.05% b.d. cream Triamcinolone acetonide Triamcinolone 0.1% ointment acetate Hydrocortisone 1% ointment Hydrocortisone (Uniderm dipropionate ointment dipropionate 0.05% b.d. Alclometasone dipro- 0.05% b.d. pionate cream cream 0.2% t.d.s. cream valerate Hydrocortisone 0.2% t.d.s. cream valerate Hydrocortisone ointment 0.2% emollient cream t.d.s. emollient cream Alclometasone dipro- 0.05% b.d. pionate cream butyrate 0.1% Locoid ointment butyrate (Locoid) cream 0.1% worsening worsening > 1 week moderate worsening > 1 worsening week 2–73 3 weeks Not specified Fluocininide 0.05% subjects (years) 68 > 14 3 weeks Not specified Alclometasone 40 5–11 2 weeks Stable or 19 No data 4 weeks145 Not specified No data valerate Hydrocortisone 2 weeks Mild to (240) 107 atopic eczema 43 No data 2 weeks Stable or 144 No data 7 days Not specified 17- Hydrocortisone 40 < 10 4 weeks Not specified 17- Hydrocortisone Parallel, RCT Parallel, RCT Not translated (Spanish) Parallel, L/R, RCT Parallel, L/R, RCT Parallel, left/right, RCT Parallel, RCT Parallel, L/R, RCT Parallel, L/R, RCT 99 115 135 et Patient characteristics and interventionsPatient of included versus studies (potentially poolable topical steroid another topical ster , not available in the UK 139 ™ et al., et al., 108 136 96 97 113 1983 Study Design No. of Age Duration Severity Treatment Comparator Co-treatments and Withdrawals Uniderm Duke Duke 1983 Lassus, 1984 Fisher & Kelly, 1979 Sefton & Kyriakopoulos, 1983 VanDelRey al., Lassus, 1983 Roth & Brown, 1978 Yasuda, 1976 Veien Veien 156 1984 TABLE 48 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 rovement scale (5 = clear, 1 = worse) igitalised into 0–100, 100 most severe scale, respectively 0–3 scale (0 = absent, 3 = severe) 0–3 scale (0 = absent, 3 = severe) Eight-point scale: (8) (1) to cleared worse severely scale:Four-point 1 = clear, 2 = slight, 3 = moderate, 4 = severe scale (0 = none,Five-point 1 = slight, 2 = moderate, 3 = severe, 4 = very severe) of at least 1,reductions 2 and 3 points on the rating Scale Physician global evaluation of improvement: global evaluation Physician cleared, improvement, marked moderate disease condition in overall improvement evaluated globally Investigator scored Severity Clear = 100%, <50% = slight improvement of improvement degrees different assessed using three results Therapeutic Moderate, good, excellent associated with score Clinical signs and disease sign score: erythema, induration, pruritus global assessment:Physician’s cleared, improvement, marked moderate improvement, slight improvement,no change, exacerbation to status of lesion (moderate improvement, relative Clinical response slight improvement, no significant change, worse) recorded effects Adverse Five-point the other excluding cosmetic preferences efficacy of one agent over regarding preference Patient and physician Erythema, Clear = 100%, induration, <50% = slight imp pruritus improvement, slight improvement, no change, exacerbation Erythema, induration, pruritus reactions adverse Patients examined for condition evaluation Overall symptoms:Five 0–3 scale (0 = absent, pruritus, 3 = severe) erythema, scaling, excoriation, lichenification of severity the end of scale labelled none or clear indicated degree from an investigator made by of the particular sign or symptom) of all lesions Global severity in erythema, decrease Investigator-assessed scaling, oedema, symptoms, subjective such as pruritus and burning sensation response, therapeutic of onset any Rapidity of lesions and maintenance response of improvement degree maximum of the treatment evaluations the overall also rated as criteria for period were of the treatment during the remainder scale (0–9) 0 = clear Ten-point 139 97 136 96 1983 113 108 99 115 135 1984 1983 et al., Outcome measures et al., et al., Study Duke Outcome measure VanDelRey Veien Yasuda, 1976 Fisher & Kelly, 1979 Lassus, 1983 Lassus, 1984 Roth & Brown, 1978 Sefton & Kyriakopoulos, 1983 pruritus, Investigator-assessed erythema, scaling, papulation, lichenification, (the distance of the mark vesiculation d VAS 157 TABLE 49 TABLE Appendix 3 global global assessment named (if severity severity (method modified Physician Patient Area Scale assesssment assessment used) specify)

Sleep loss

Itch

Induration

Infiltration

Crusts

Inflammation

Oedema

Oozing/weeping

Pustules/papules

Vesiculation

Exudation

Fissuring

Cracking

Lichenification

Scaling

Xerosis

Dryness

Excoriation

Purulence

Erythema also burning sensation 99 139 97 96 1983 113 108 99 115 135 1984 1983 Outcome measures signs and symptoms Outcome measures et al., et al., et al., 136 Study 158 Duke Fisher & Kelly, 1979 Lassus, 1983 Lassus, 1984 Roth & Brown, 1978 Sefton & Kyriakopoulos, 1983 VanDelRey Veien Yasuda, 1976 Note: Additional outcomes:Yasuda TABLE 50 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 Method and concealment of randomisation unclear, study described as double-blind or withdrawals No drop-outs Method and concealment of randomisation unclear, study described as double-blind not mentioned and drop-outs Withdrawals “Randomisation correlated with sequential “Randomisation correlated numbers”; study described as double-blind No ITT Table of numbers assured randomisation assured of numbers Table Study described as double-blind No ITT study described as double-blind or withdrawals No drop-outs “The allocation treatments in each study was “The allocation treatments randomisation process a restricted accomplished by to of the treatments equal frequencies to ensure each side in small sequences of consecutively patients”.“Thenumbered were test preparations in coded identical tubes” supplied to investigators out No ITT carried ‘randomised double- assignment followed Treatment blind code’ or drop-outs No withdrawals Method and concealment of randomisation unclear, technique’ suggests single-blind ‘blind evaluator study No ITT = 0.021) p Both creams were effective treatments for atopic for treatments effective were Both creams dermatitis, however, alclometasone dipropionate efficacious more was judged slightly to was found valerate 0.2% cream Hydrocortisone as betamethasone valerate cream be as effective 0.1% cream Hydrocortisone 17-butyrate 0.1% ointment proved Hydrocortisone acetate 1% than hydrocortisone effective more ointment and triamcinolone acetonide 0.1% ointment Both treatments were effective were Both treatments Method and concealment of randomisation unclear, Clinical responses favoured fluocinonide for the fluocinonide for favoured Clinical responses ( atopic dermatitis group Hydrocortisone valerate 0.2% ointment is a safe Hydrocortisone use in mild-to- perparation for and effective moderate atopic dermatitis superior to Uniderm is significantly Locoid cream of atopic dermatitis in in the treatment cream children Clinical sign scores improved continuously during continuously improved Clinical sign scores the study period and, at the end of therapy, over alclometasone conclusively favoured clobetasone > 0.10) p Improvement over baseline as reported by investigator: baseline as reported by over Improvement 11 patients found 17-butyrate superior to triamcinolone,hydrocortisone drugs 17 found comparable 17-butyrate superior to hydrocortisone hydrocortisone 17 patients found acetate, clinical effects) them comparable (for nine found 85% improvement for alclometasone dipropionate group and 86% group alclometasone dipropionate for 85% improvement of signs and symptoms clobetasone butyrate group for improvement (erythema, induration and pruritus) Mean clinical response 4.5 for fluocinonide and 4.38 for betamethasone on fluocinonide and 4.38 for 4.5 for Mean clinical response a scale of 1–5, 5 = excellent or clear where out and seven group Eight out of 20 patients in alclometasone dipropionate 76–100% (marked showed butyrate group of 20 patients in hydrocortisone in signs and symptoms (erythema, improvement or cleared) induration, pruritus) both for clear or excellent improvement 14 out of 19 patients showed and betamethasone valerate 0.1% valerate 0.2% cream hydrocortisone (t.d.s.) cream Needs translating Hydrocortisone valerate 0.2% scored 12.6 compared with 10.7 for 12.6 compared valerate 0.2% scored Hydrocortisone (mean) VAS betamethasone valerate 0.1% with 14.5 for 15.6 compared valerate 0.2% scored Hydrocortisone (mean) VAS triamcinolone acetonide 0.1% with 4.6 for 4.7 compared valerate 0.2% scored Hydrocortisone (mean) VAS fluocinolone acetonide 0.1% in 60% Locoid 0.1% Complete clearance of skin symptoms was found patients patients and in 30% of Uniderm 1% treated treated 75% improvement in alclometasone dipropionate vs 68% improvement vs 68% improvement in alclometasone dipropionate 75% improvement erythema, mean clinical scores in clobetasone butyrate for induration, pruritus ( 99 115 135 et Results 139 et al., et al., 97 96 136 113 108 1983 Lassus, 1984 Lassus, 1983 VanDelRey VanDelRey al., Yasuda, 1976 Roth & Brown, 1978 Fisher & Kelly, 1979 Study Main reported results Authors’ conclusions Quality Sefton & Kyriakopoulos, 1983 Veien Veien 1984 Duke Duke 1983 159 TABLE 51 TABLE Appendix 3 continued Study which claimed equivalence of a very mild corticosteroid against a preparation potent one. Study under- grossly to establish empowered equivalence Study of 88 patients dermatoses, with mixed some responding to the differently treatment Another study which assumes that no of a statistical evidence is the same difference as therapeutic equivalence Difficult to interpret effect treatment without placebo control Difficult to interpret magnitude of effect. Method and concealment of randomisation unclear. Study described as double-blind. No or drop- withdrawals outs Method and conceal- ment of randomisation unclear. Study described as double-blind. or No withdrawals drop-outs “Randomised according study to patient’s Study number” described as double- blind. One lost to follow-up, no ITT Method and concealment of randomisation unclear, study described as double-blind withdrawals/ Three drop-outs, no ITT Table of randomised Table used.numbers Study described as double- blind or No withdrawals drop-outs Mean response of good Mean response or excellent outcome 76% urea and 78% hydrocortisone betamethasone 17- valerate An excellent or good was recorded response in 63% halcinonide patients and 38% betamethasone patients of evaluation overall for response therapeutic 97% ‘excellent’ or ‘good’ hydro- for improvement cortisone 1% and 94% ‘good’ ‘excellent’ or for improvement betamethasone Good effect for both for Good effect preparations; fluprednylidenacetate better than significantly fluocortolone after 2nd week; therapeutic index 0.96 vs 0.86 after 4 weeks Fluocinolone was superior to betamethasone in 70% of patients Lesion response: excellent, good, none, deterioration Decrease of lesion size,Decrease in erythema,reduction oedema, transudation, lichenification and scaling, of pruritus relief and pain Clinical condition assessed as excellent if and cleared completely if partiallygood cleared, and no improvement deterioration Erythema, scaling, weeping, itching (composite score index) therapeutic Lesion improvement Prospective, randomised, left, right, parallel study of duration 3 weeks’ Prospective, randomised. Left right parallel study of duration 3 weeks’ Prospective, randomised, left, right, parallel study of duration 4 weeks’ Prospective, randomised, left/right, parallel study of duration 4 weeks’ Prospective, random- ised, left right parallel study of 2 weeks’ duration follow-up 50 atopic eczema patients Nine patients with atopic dermatitis 36 adults and children with mild, moderate atopic and severe eczema 42 patients with severe atopic dermatitis Ten atopic eczema Ten patients and sample size description and 10% urea and 1% 10% urea hydrocortisone 0.1% vs cream betamethasone 17-valerate cream Halcinonide cream 0.1% Halcinonide cream t.d.s. betamethasone 17- 0.1% valerate cream t.d.s. Hydrocortisone 1% Hydrocortisone vs UHc powder-cream 0.1% betamethasone 17-valerate 0.1% in fluprednylidenaceate vs 0.25% fluocortolone Fluocinonide cream 0.05% q.d.s. vs betamethasone valerate 0.10% q.d.s. cream 93 419 Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid 122 92 102 Almeyda & Fry, Almeyda 1973 Leibsohn & Bagatell, 1974 (German) Lundell, 1974 Almeyda & Burt,Almeyda 1974 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 160 Binder & McCleary, 1972 TABLE 52 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Clear categorical data Clear categorical and seperation of atopic eczema and psoriasis Very short duration Very No placebo arm No data to indicate magnitude of treatment effect Method and concealment of randomisation unclear, study described as double-blind drop-outs;Five no ITT Randomisation unclear Table of random Table assignment Study described as double-blind or No drop-outs withdrawals Method and concealment of randomisation unclear, implies double blinding (neither clinician nor of patient aware identification) or No withdrawals drop-outs 50% betamethasone ‘good’ ‘excellent’ or with compared response 22% hydrocortisone For atopic dermatitis For patients: Desoximetason side was rated treated superior 11 times; betamethasone treated side rated superior eight times three No difference times 92% ‘excellent’ or ‘good’ clinical response overall both halcinonide and for clobetasol No data on clinician rated healing of lesions given data Patient preference reported,only which indicated a non- significant statistically of in favour preference clobetasone butyrate Clinical effectiveness: excellent(>75%), (50–75%),good fair (25–50%), poor (<25%) 0–5 scale assessment of skin morphology Scoring of superior (a>b,treatment or b>a or a=b) Lesions assessed for in erythema,decrease oedema, transudation, lichenification, scaling, pruritus and pain Clinician-assessed lesions as healed, improved, static or plus worse clinician/patient right/left for preference side Prospective, randomised, parallel study of 3 weeks’ duration Prospective, randomised, double- side-to- blind controlled 1-2 side comparison for weeks Prospective, randomised, left/right, parallel study of 2 duration weeks’ Prospective, randomised, left/right, parallel study of 1 week duration follow-up 27 patients with atopic dermatitis 26 moderate, one very severe 22 patients with atopic dermatitis and 24 patients with psoriasis 27 moderate-to-severe atopic eczema patients 71 atopic eczema only patients children and sample size description and Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid Betamethasone ointment dipropionate 0.05% vs hydrocortisone ointment 1% b.d. 0.25% Desoximetasone b.d.cream vs 0.1% betametasone valerate b.d. cream Halcinonide 0.1% cream b.d. vs clobetasol 0.05% propionate b.d. cream 0.05% clobetasone or butyrate cream ointment b.d. vs 0.0125% cream flurandrenolone or ointment b.d. 70 150 et al., 121 120 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment Savin, 1976 Bleeker, 1975 Morley Morley 1976 Bjornberg & Hellgren, 1975 Germany (translated) 161 TABLE 52 contd TABLE Appendix 3 continued Well reported with Well useful data on placebo and psoriasis groups data Useful to have diseases separated by 16 atopic but only eczema patients Some reservation on whether atopic/ is the neurodermatitis same as atopic eczema Underpowered study Underpowered Table of numbers Table randomisation assured Study described as double-blind drop-outs;Seven 32 not hence no evaluated yet ITT Method and concealment of randomisation unclear, study described as double-blind 16 withdrawals, unclear which group from Method and concealment of randomisation unclear, study described as double-blind Nine+ withdrawals, no ITT Method and conceal- ment of randomisation unclear, study described as double-blind and drop- Withdrawals outs not mentioned > 0.10) p Hydrocortisone 17-B Hydrocortisone superior to triam- cinolone 10%, comparable 16%, 3% inferior 17-B Hydrocortisone superior to hydro- cortisone acetate 16%, comparable 9% and 3% inferior 19% betamethasone better much group with 13% compared Locacorten group ( Improvement over Improvement baseline >50% improvement: 71% for both diflorasone and fluocinonide 74% showed clear or 74% showed excellent improvement both hydrocortisone for valerate and beta- methasone valerate Decrease in erythema,Decrease scaling, oedema, symptoms subjective such as pruritus and burning sensation and of lesions improvement Much better, slightly better, no change, worse,slightly much worse Degree of therapeutic Degree 1–25%, response 26–50%, 51–75%, 76–100% clinical resolution, no change or deterio- in severity ration of lesions Symptoms pruritus, erythema, scaling, excoriation, lichenification condition Overall and severity Prospective, randomised, left/right, parallel study of 7 days’ duration Prospective, randomised, parallel study of 3 weeks’ duration Prospective, randomised, parallel study of 3 weeks’ duration Prospective, random- ised, left/right parallel study of 4 weeks’ duration follow-up 144 atopic dermatitis patients 16 atopic dermatitis a total of patients from 66 steroid-responsive dermatoses 210 atopic/ neurodermatitis patients 19 atopic eczema patients and sample size description and Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid Hydrocortisone 17- Hydrocortisone butyrate 0.1% locoid ointment vs triamcinolone acetonide 0.1% ointment or acetate hydrocortisone 1% ointment Betamethasone vs cream dipropionate locacorten 0.02% b.d. Diflorasone diacetate vs 0.05% cream flucinonide 0.05% cream b.d. Hydrocortisone 0.2% vs valerate cream betamethasone valerate 0.1% t.d.s. cream 99 137 et al., 119 97 Mali, 1976 Bluefarb 1976 Yasuda, 1976 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment Roth & Brown, 1978 162 Study 1 TABLE 52 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Difficult to evaluate data without any atopic few Very eczemna patients mixed up with other inflammatory skin diseases Very small number of small number Very very shortpatients over period of time Suspect randomisation method Method and concealment of randomisation unclear, study described as double-blind and drop- Withdrawals outs not mentioned random- Pre-designed isation chart Study described as double-blind and drop- Withdrawals outs not mentioned Method and concealment of randomisation unclear, study described as double-blind or No drop-outs withdrawals Randomisation with correlated sequential numbers Study described as double-blind drop- 11 withdrawals/ outs; no ITT < 0.05) p No actual data given for No actual data given this study judgement of Overall to the two the response medications (defined as cleared, excellent, good, no effect, or worse) hydrocortisone showed valerate to be statist- superior to hydro- ically cortisone ( or 100% improved both for cleared halcinonide and hydro- cortisone (cleared: 80% and 60%, respectively) For overall therapeutic overall For efficacy 83% had cleared improvement or marked in both betamethasone and diflucortolone groups Mean clinical response fluocinonide and 4.5 for betamethasone 4.38 for on a scale of 1–5, where 5 = excellent or clear Symptoms pruritus, erythema, scaling, excoriation, lichenification condition Overall and severity and objective Subjective of evaluations responses Global evaluation Physician-assessed erythema, induration, scaling, crusting, pruritus, excoriation, and pain global Physician assessment of thera- % peutic response improved Clinical response to status of relative lesion Prospective, random- ised, left/right parallel study of 4 weeks’ duration Prospective, random- ised, left/right parallel study of 3 weeks’ duration Prospective, random- ised, parallel study of 14 duration days’ Prospective, random- ised, left/right parallel study of 3 weeks’ duration follow-up 29 atopic eczema patients atopic dermatitis Five patients 12 adults with resistant atopic dermatitis 107 atopic eczema patients and sample size description and Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid Hydrocortisone 0.2% vs valerate cream cream hydrocortisone 1% t.d.s. Halcinonide-neomycin- amphotericin ointment 0.1% vs hydrocortisone 1% ointment Betamethasone 0.05% vs dipropionate diflucortolone valerate 0.3% b.d. Fluocinonide 0.05% t.d.s.emollient cream vs betamethasone valerate t.d.s. 0.1% cream 420 et al., 97 118 96 El-Hefnawi El-Hefnawi 1978 Roth & Brown, 1978 Study 2 Fisher & Kelly, 1979 (Switzerland) Ramelet, 1982 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 163 TABLE 52 contd TABLE Appendix 3 continued Magnitude of efficacy 0.2% hydrocortisone valerate similar to that of a potent preparation Three studies described Three in same paper Three studies described Three in same paper Although written up as a study supporting superiority of the alclometasone, newer is not much there when % who difference improved markedly are or clear is evaluated Useful to have outcome Useful to have as data presented categories Allocation by a Allocation by random- restricted in coded isation process identical tubes lost to 14 initially follow-up, plus three this part of study from out No ITT carried Allocation by a Allocation by random- restricted in coded isation process identical tubes lost to 14 initially follow-up, plus one from this part of study out No ITT carried Allocation by a Allocation by random- restricted in coded isation process identical tubes lost to 14 initially follow-up, plus one from this part of study out No ITT carried Method and concealment of randomisation unclear, study described as double-blind drop- 20 withdrawals/ outs; out no ITT carried Method and concealment of randomisation unclear, study described as double-blind or No withdrawals drop-outs Improvement over Improvement baseline for 44.1 hydrocortisone to 12.6 reduced betamethasone 43.4 to 10.7 reduced Improvement over Improvement baseline for 27.1 hydrocortisone to 4.7, reduced fluocinolone 26.9 to 4.6 reduced Improvement over Improvement baseline for 46.4 hydrocortisone to 15.6 reduced triamcinolone 47.9 to 14.5 reduced 71% alclometasone cleared patients showed improvement or marked to 69% for compared patients hydrocortisone 76–100% improvement or ‘marked-cleared’ was seen in 40% of alclo- metasone patients and 35% of hydrocortisone patients Investigator-assessed pruritus, erythema, scaling, papulation, lichenification, VAS on an vesiculation of 1–100 (100 being most severe) Investigator-assessed pruritus, erythema, scaling, papulation, lichenification, VAS on vesiculation of 1–100 (100 being most severe) Investigator-assessed pruritus, erythema, scaling, papulation, lichenification, vesicul- of 1–100 VAS ation on (100 being most severe) Erythema, induration, pruritus global Investigator evaluation Erythema, induration, pruritus global Physician of evaluation improvement Prospective, randomised, left/right parallel study of weeks duration Prospective, randomised, left/right parallel study of weeks duration Prospective, randomised, left/right parallel study of weeks duration Prospective, randomised, parallel study of 2 weeks’ duration Prospective, randomised parallel study of 3 duration weeks’ follow-up 68 mild-to-moderate atopic eczema patients 26 mild-to-moderate atopic eczema patients 37 mild-to-moderate atopic eczema patients 249 atopic eczema patients 40 children with atopic 40 children eczema and sample size description and Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid Hydrocortisone valerate ointment 0.2% vs betamethasone valerate 0.1% ointment t.d.s. Hydrocortisone valerate ointment 0.2% vs flucinolone 0.025% ointment t.d.s. Hydrocortisone valerate ointment 0.2% vs triamcinolone acetonide 0.1% ointment t.d.s. Alclometasone cream dipropionate 0.05% vs cream hydrocortisone 1.0% t.d.s. Alclometasone cream dipropionate 0.05% b.d. vs hydro- cortisone butyrate 0.1% b.d. cream 115 et al., 136 136 136 79 Sefton & Kyriakopoulos, 1983 Study 1 Lassus, 1983 Sefton & Kyriakopoulos, 1983 Study 3 Sefton & Kyriakopoulos, 1983 Study 2 Bagatell 1983 164 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment TABLE 52 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Difficult to establish equivalence in such a small study Little difference in Little difference effect treatment Similar to above study Similar to above One of the first studies o.d. to evaluate vs more application of application frequent treatment a standard A small equivalence study benefit of Treatment hydrocortisone as butyrate increased study progressed Described as double- blind and randomised but method not clear One patient excluded hydrocortisone from as he had group dermatitis seborrheic Method and concealment of randomisation unclear, study described as double-blind or No withdrawals drop-outs 18 drop-outs, which not assessed were 26 drop-outs (detailed 26 drop-outs description given), no ITT analysis Method and conceal- ment of randomisation unclear, blind evaluator technique suggests single-blind study No ITT Method and concealment of randomisation unclear, study described as double-blind or No withdrawals drop-outs Both treatments gave Both treatments of efficacy similar results from fell sign score Total 7.20 to 1.00 in the alclo- and metasone group 7.14 to 0.93 in the from group hydrocortisone 85% improvement for 85% improvement alclometasone group with 86% compared for improvement for clobetasone group signs three 85% of all patients grade 4 showed improvement (75–100%), no significant difference groups between (Only summary(Only data reported) achieved Both groups results good No significant difference groups between in 75% improvement alclometasone group with 68% compared in improvement for clobetasone group mean clinical score Complete clearance of skin symptoms was in 60% found 17- hydrocortisone patients butyrate-treated with 30% compared 1%- hydrocortisone patients treated Doctor-assessed erythema, of hardening the skin and scaling After treatment evaluated improvement on a scale 1–6, where 1 = 100% improvement Erythema, induration, pruritus and physician of global evaluation improvement Improvement assessed Improvement doctor on five-point by scale 0–100% improvement Improvement as Improvement assessed by: erythema, oedema, lichenification, induration, scaling, excor- iation, itching, exulcer- ation; each assessed with scale four-point erythema,Clinical score induration, pruritus, and global physician assessment of all Global severity lesions Parallel double-blind randomised prospective trial lasting 3 weeks Prospective, randomised parallel study of duration 2 weeks’ Prospective, randomised, open study for parallel-group 3 weeks Prospective, randomised, left/right parallel study of 4 duration weeks’ Prospective, randomised, single-blind study for parallel-group 3 weeks Prospective, randomised parallel study of 3 duration weeks’ follow-up 30 patients over 12 30 patients over old,years than 1 more disease duration year to and resistant treatment 43 atopic eczema patients 98 patients with eczema’ (probably atopic eczema but this is not specified in the paper) 120 patients with acute or subacute eczema 68 atopic eczema patients 40 atopic eczema patients and sample size description and Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid Alclometasone cream 0.05% vs hydrocortisone butyrate Alclometasone cream dipropionate 0.05% b.d. vs clobetasone butyrate 0.05% b.d. cream Alclometasone ointment dipropionate 0.05% b.d. vs clobetasone butyrate ointment 0.05% b.d. 17- Hydrocortisone butyrate (Locoid) 0.1% vs cream hydrocortisone (Uniderm) 1% cream Diflorasonediacetate 0.05% ointment o.d. vs betamethasone 17 valerate 0.1% ointment t.d.s. Diflorasone diacetate o.d.0.05% cream vs betamethasone 0.1% dipropionate cream 147 et 135 139 et al., et al., 149 108 113 1983 Van DelRey DelRey Van al., Spain (translated) Veien Veien 1984 Duke Duke 1983 Harder & Rufli, Harder 1983 Konzelmann & Konzelmann Harms, 1983 Lassus, 1984 Switzerland (Basel) (translated) Switzerland (Zurich) (translated) Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 165 TABLE 52 contd TABLE Appendix 3 continued One of authors was an of the employee that produces company Halomethasone cream Results of all three studies impossible to disentangle RCT mixed inflammatory dermatoses Scaling scores not given Scaling scores on nine out of 30 patients because they did not experience the scaling throughout trial Numbers of atopic eczema patients too any small to make specific comments Randomisation criteria unclear Authors tried to create of severely subgroup patients, affected retrospectively probably then claim They significant advantage for Halomethasone in affected severely patients Method and concealment of randomisation unclear Study described as double-blind, no ITT Method and concealment of randomisation unclear, study described as double-blind 33 drop-outs/ withdrawals; no ITT Method and concealment of randomisation unclear, study described as double-blind No drop-outs Method and concealment of randomisation unclear, study described as double-blind No ITT < 0.05) > 0.05) p p 1. clinical effectiveness: no significant difference groups between 2. onset: no difference 1 or 4 between at Day groups 3. effects: adverse none reported 4 cosmetic acceptability: 51% vs 46% rated it ‘excellent’ (NS) o.d. No actual data for vs methylprednisolone b.d. betamethasone given Mean global severity baseline of over score to 1.3 for 2.8 reduced and 1.7 hydrocortisone desonide ( for Healing was reported in 70% of patients with halometasone cream, 60% with halometasone with ointment compared 90% on betamethasone cream, and 80% on betamethasone ointment clearance in the betamethasone vs groups, desoximetasone ( respectively 1. clinical effectiveness (doctor-assessed, five- point scale) 2. onset of clinical effectiveness (doctor-assessed) 3. effects adverse 4.cosmetic acceptability (patient-assessed five- point scale) Patient and doctor global assessments Doctor assessed 11 signs and symptoms Investigator-assessed and global severity grades of severity erythema, induration and scaling Inflammation, crusting, scaling, lichenification, excoriation, induration, exudate, pruritus, pain (healing, improvement, failure) Physician global ratingPhysician 41% and 53% had Prospective, randomised, double- blind parallel group 2 weeks study for Prospective, randomised, left/right, parallel study of 4 duration weeks’ Prospective, randomised, left/right, parallel study of 4 duration weeks’ Prospective, randomised, parallel study of 3 weeks’ duration Prospective, randomised, parallel RCT of 2 weeks’ duration follow-up 165 patients with active episode of atopic dermatitis suitable for topical exclusively treatment 94 adults with atopic dermatitis 30 moderate-to-severe atopic dermatitis patients 75 atopic dermatitis patients 33 atopic eczema patients with resistant disease in a or severe trial, which also included psoriasis patients and sample size description and Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid 0.05% Halomethasone b.d.cream vs 0.25% cream Prednicarbate b.d. (both topical steroids) 0.1% methylprednisolone aceponate ointment o.d vs 0.1% betamethasone valerate b.d. Hydrocortisone 17- Hydrocortisone butyrate (Locoid) 0.1% vs desonide fatty cream (Apolar) 0.1% ointment b.d. Halometasone 0.05% or ointment vs cream betamethasone valerate or 0.1% cream ointment b.d. Betamethasone 0.05% vs dipropionate 0.25% desoximetasone ointment 75 138 110 85 41 Rajka & Verjans, Rajka & 1986 Haneke, 1992 Germany (translated) Germany Study 1 Ulrich & Andresen, 1991 Majerus & Reiffers- Mettelock, 1986 Nolting, 1985 Germany (translated) 166 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment TABLE 52 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued No final analysis similar effects, Very over small numbers very short term Three studies of three Three comparisons in different age groups different Results of all three studies impossible to disentangle Published in abstract only form Three studies of three Three comparisons in different age groups different Method and concealment of randomisation unclear; blinding unclear; no ITT Method and concealment of randomisation unclear, study described as double-blind 12 drop-outs/ withdrawals; no ITT Method and concealment of randomisation unclear Study described as double-blind, no ITT Method and concealment of randomisation unclear, study described as blind investigator withdrawals Drop-outs/ no data given Method and concealment of randomisation unclear, study described as double-blind drop-outs/ Two withdrawals; no ITT = 0.0025) p 83% good or excellent 83% good budesonide vs 94% for or excellent for good alclometasone statistical (No formal comparison done) 96.3% methyl- patients prenisolone complete achieved healing or distinct compared improvement with 98.1% patients prednicarbate No actual data for b.d. No actual data for vs methylprednisolone b.d. betamethasone given patients significantly vs improvement greater 71% hydrocortisone ( group 97.3% methyl- patients prenisolone complete achieved healing or distinct compared improvement with 100% prednicarbate patients Patient and doctor global assessments Doctor assessed 11 signs and symptoms % of patients who were or excellent good Composite scale of signs and symptoms tolerability Objective and subjective Objective symptoms of erythema, exudation, scaling, itching, hyperkeratosis burning Global therapeutic response No information givenNo information 85% momethasone Objective and subjective Objective symptoms of erythema, exudation, scaling, hyperkeratosis, itching, burning Global therapeutic response Prospective, randomised, parallel study of 2 weeks’ duration Prospective, randomised, parallel study of 3 weeks’ duration Prospective, randomised, left/right, parallel study of duration 4 weeks’ Prospective, randomised, parallel study of 6 weeks’ duration Prospective, randomised, parallel study of 3 weeks’ duration follow-up 40 children with atopic 40 children dermatitis 120 children with 120 children atopic dermatitis 94 adults with atopic dermatitis 96 atopic dermatitis patients 80 children with atopic 80 children dermatitis and sample size description and Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid 0.025% budesonide vs 0.1% cream alclometasone b.d. dipropionate Methylprenisolone aceponate 0.1% o.d. ointment vs 0.25% prednicarbate b.d. cream 0.1% methylpred- nisolone aceponate ointment b.d. vs 0.1% betamethasone valerate b.d. Momethasone furoate o.d. vs hydrocortisone 17-butyrate b.d. Methylprenisolone aceponate 0.1% cream b.d. vs prednicarbate b.d. 0.25% cream 123 123 75 124 et al., 1991 80 Rampini, 1992 Italy (translated) Study 2 Gelmetti 1994 Haneke, 1992 Germany Study 2 Hoybye Hoybye et al., Study 1 Rampini, 1992 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 167 TABLE 52 contd TABLE Appendix 3 Study followed-up by a by Study followed-up longer 6-month follow- up study, which did not signs of skin any show thinning in either group Sponsored study of Sponsored very short duration not were Drop-outs included in analysis, which is worrying given rate the high drop-out (29%) and the fact that dropped at least two out because they worsened Unclear if the o.d. vs b.d. was blinded cream not) (probably but End-points given are unclear what they Method and concealment of randomisation unclear, study described as blind investigator drop-outs/ Two withdrawals; no ITT Randomisation method and concealment not described Stated to be double- blind (14/49 No ITT analysis drop-outs) Method and concealment of randomisation not clear, study described as evaluator-blind = 0.30) at the end of = 0.10) p p 68% desonide patients and 40% hydrocortisone had clearing or marked at 5 weeks improvement Mean improvement in Mean improvement (no score severity at day baselines given) 21 (% of patients with 100% clearance), 87.4% mometasone and for hydrocorti- 79.7% for 21 sone valerate at Day Physicians rated the Physicians side prednicarbate better in 12 patients, the flucortolone side better patients and no in seven in 16 patients difference ( 3 weeks 80% of patients to good recorded excellent improvement on the prednicarbate with 63% side compared the flucortolonefor side ( No statistical difference signs and between noted symptoms were Stinging similar in both groups Physician global Physician improvement, erythema, lichenification excoriations, oozing and crusting, induration and papules Pruritus assessed subjectively Investigator assessed Investigator signs and seven symptoms on a 0–3 scale (0 = none, 3 = and global severe) assessment % improved Itch, erythema, eczema, vesicles/papules lichenification, on a scale of 0–3 and Also physician patient global evaluation of whether one side better than the other Prospective, randomised, parallel study of 5 weeks’ duration Prospective, randomised, parallel study of 21 days’ duration Prospective, randomised, double- blind parallel right/left comparison of 3 weeks’ duration follow-up 113 children with 113 children atopic dermatitis 219 children with 219 children moderate-to-severe atopic dermatitis 49 out-patients with atopic dermatitis aged 19–65 years and sample size description and Non-pooled topical steroid versusNon-pooled topical steroid another topical steroid Desonide 0.05% ointment vs 1% hydrocortisone ointment b.d. 0.1% mometasone o.d. cream furoate vs 0.2% hydrocortisone b.d. valerate cream 0.25% prenicarbate vs 0.2% cream flucortolone b.d. cream monhydrate et al., et al., et al., 88 68 116 Jorizzo Jorizzo 1995 Camacho 1996 USA Lebwohl Lebwohl 1999 Spain (translated) 168 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment TABLE 52 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Study mainly concerned Study mainly with cellular and changes immunological Useful study with a placebo arm, which no evidence provided to support efficacy of hamamelis Difficult to blind due smell of coal tar Difficult to evaluate significance of change due to small in scores sample size and lack of data No placebo arm Method and concealment of randomisation unclear, study described as double-blind of No information or withdrawals drop-outs Method and concealment of randomisation unclear, study described as double-blind withdrawals/ Seven drop-outs; no ITT Method and concealment of randomisation unclear No mention of blinding No withdrawals/drop- outs < 0.01) p Itch and sleep disturbance estimated graph from 2.3 SCG baseline score to 0.7 and 2.4 reduced itch and and 0.5 for sleep disturbance, respectively, at 2 weeks and beclomethasone baseline 2.2 and 2.3 to 0.9 and 0.6 reduced itch and sleep loss, for respectively, at 2 weeks There was no clinical or There statistical difference hamamelis and between of reduction for vehicle itching at 2 weeks changed Mean itch score 2.1 to 0.8 for from and hydrocortisone 2.1 to 1.2 for from hamamelis ( Patient recorded efficacy Patient recorded was also significantly in hydro- improved when cortisone group with hamamelis compared no were There between differences hamamelis and vehicle All five parameters All five significantly reduced period the 4-week over but no significant the between differences treatments two Severity of Severity inflammation, lichenification and 15 body cracking over areas Patient diary for cards itch and sleep loss Laboratory tests Physician and patient Physician global assessments 0–5 scale, 0 = healed where and 5 = worse Itch, erythema, scaling, oedema, papules, pustules, exudation, lichenification, excoriations, fissuring Infiltration, erythema, lichenification, excoriations, dryness, doctor and patient global assessments Prospective, randomised, parallel study of 2 weeks’ duration Prospective, randomised, left/right, parallel study of 2 duration weeks’ Prospective, randomised, left/right, parallel study of 4 duration weeks’ follow-up 43 children with 43 children moderate-to-severe atopic dermatitis 72 patients with moderate-to-severe atopic dermatitis 30 patients with mild- to-moderate atopic eczema and sample size description and Beclomethasone t.d.s.dipropionate vs topical SCG t.d.s. Hamamelis distallate 5.35 g plus 0.64 mg g vs vehicle ketone/100 or 0.5% hydrocortisone Clinitar coal tar vs 1% hydrocortisone 83 RCTs of topical steroids versusRCTs of topical steroids another topical et al., et al., 84 86 Hiratsuka 1996 Japan Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment Korting Korting 1995 Germany Denmark Munkvad, 1989 169 TABLE 53 TABLE Appendix 3 continued Impossible to interpret in such a differences small subsample of atopic eczema patients Treatment responses Treatment very larger slightly were antibiotic steroid/ for combination but none significant statistically similar Bacterial growth groups in all three Author contacted for data but has sadly more deceased no Study provides of improved evidence efficacy of betamethasone/ fusidic acid combination above betamethasone alone in atopic eczema infected Method and concealment of randomisation unclear, study described as double-blind drop- One withdrawal/ out; no ITT Method and concealment of randomisation unclear, study described as double-blind drop-outs;Four no ITT Method and concealment of randomisation unclear, study described as double-blind or No drop-outs withdrawals Change in global score was very the similar for patients allocated three to placebo, betamethasone and bufexamac Improvement over base- over Improvement line on a scale of 0–10 Betamethasone/ gemtamicin group of 6.1 baseline score to 1.0, reduced betamethasone group to 1.8 and 6.1 reduced 6.6 gentamicin group to 4.2 baseline reduced Data for mean atopic Data for dermatitis not given, is investi- result only gator preference: 29 no preference, 22 preferred betamethasone plus fusidic acid and nine betametha- preferred sone alone Patient and investigator global assessment of Severity inflammation, induration, lichenification, crusts, scaling, pruritus Global assessment and severity,overall degree of inflammation, degree of infection, erythema, pruritus, pustules, crusting, exudation, vesiculation, lichenification Bacteriological swabs Clinical symptoms: vesicles, oedema, erythema, excoriation, crusting, lichenification, itching Prospective, randomised, parallel study of 2 weeks’ duration Prospective, randomised parallel study of 22 days Prospective, randomised, left/right, parallel study of 7 days’ duration follow-up follow-up 10 atopic eczema patients within a study of 72 patients with of various forms dermatoses 83 infected moderate- 83 infected atopic to-severe dermatitis patients 60 atopic dermatitis patients with potentially atopic eczema infected and sample size description and and sample size description and RCTs of topical steroids versusRCTs of topical steroids another topical 5% bufexamac b.d.5% bufexamac vs or 0.1% hydrocortisone placebo b.d. Betamethasone valerate vs cream gentamicin/betamethaso ne valerate vs t.d.s. gentamicin cream Betamethasone 17- valerate 0.1% vs betamethasone 17- valerate plus 2% fusidic acid 90 Topical steroid plus additional active agents steroid Topical et al., 74 111 Wolf-Jürgensen, 1979 Norway Wachs & Wachs Maibach, 1976 USA Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment StudyAddition of antimicrobials Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 170 Hjorth 1985 TABLE 54 TABLE TABLE 53 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued Both agents contain an antiseptic, antimicrobial/ and no steroid-only comparator Duplicate publication of 1994 Korting No clinical or statistical between difference groups Difficult to interpret in Difficult to interpret the absence of a betamethasone only arm Method and concealment of randomisation unclear, study described as double-blind on No data given or drop- withdrawals outs Method and concealment of randomisation unclear, study described as double-blind drop- 44 withdrawals/ outs; out no ITT carried Method and conceal- ment of randomisation unclear, study described as double-blind and Nine withdrawals but unclear drop-outs which type of eczema these patients had types of (seven dermatoses reported) < 0.001) p at day 34 at day < 0.001) p Both treatments a highly produced significant ( in the linear reduction all for scores parameters, no significant difference treatments between significant Highly in infection reduction both treatments for ( Clinical score over Clinical score both baseline of 25 for to 13.5 drugs reduced and 13 prednicarbate for plus prednicarbate for didecyl dimethyl- ammoniumchloride 30% patietns still had S. aureus with 100% compared at start 95% patients (91% lesions doctors) felt after beta- improved methasone plus fusidic vs acid after 2 weeks 100% patients (100% beta- doctors) felt methasone plus neomycin No separate data for bacteriological efficacy atopic dermatitis for Pruritus, erythema, lichenification, oozing/crusting, scaling infection for Skin swabs Patient and physician global score Redness, swelling, papulovesicles, vesicles, pustules, bullae, papules, status madidans, crusting and scaling on of 1–5 a score Severity of lesions Severity patient and assessed by doctor as either very severe, severe, moderate, mild, minimal, or absent for Swabs taken infection Prospective, randomised parallel study of 14 duration days’ Prospective, randomised, parallel study of 34 days’ duration Prospective, randomised, parallel study of 2 weeks’ duration follow-up 40 children with 40 children 3 months to eczema for with 14 years secondary infection 180 superinfected atopic eczema patients 43 infected or 43 infected infected potentially atopic eczema patients and sample size description and Topical steroid plus additional active agents steroid Topical Hydrocortisone 17- Hydrocortisone butyrate 0.1% plus 3% vs 0.1% chlorquinaldol triamcinolone acetonide plus 0.25% neomycin plus 0.025% gramicidin nystatin Prednicarbate 0.25% Prednicarbate vs prednicarbate cream plus 0.25% cream didecyldimethyl- ammoniumchloride 0.25% 0.1% betamethasone plus 2% fusidic acid vs 0.1% cream betamethasone plus cream 0.5% neomycin b.d. or t.d.s. 107 117 146 Meenan, 1988 Zienicke, 1993 Wilkinson & Leigh 1985 UK Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 171 TABLE 54 contd TABLE Appendix 3 continued Some evidence of Some evidence benefit of fucidin/hydrocortisone fucidin alone over No evidence to supportNo evidence a clear benefit of plain combination over hydrocortisone Abstract only reported results Only in text given Method and concealment of randomisation unclear, study described as double-blind drop-outs/ Three withdrawals; no ITT Method and concealment of randomisation unclear, study described as double-blind 32 drop-outs/ withdrawals; no ITT Method and concealment of randomisation unclear, study described as double-blind or No withdrawals mentioned drop-outs = 0.04) = 0.21) p p = 0.11) p 36.4% fusidic acid plus failed hydrocortisone and 65.6% treatment fusidic acid failed ( treatment 63.7% fusidic acid plus did not hydrocortisone compared fail treatment with 50.6% in the hydro- cortisone group ( Mean change in clinical not statistically scores significant ( Overall clinical response Overall invrestigator assessed by as ‘clearance’ or ‘marked in 92% improvement’ fusidic acid/betametha- patients,sone cream in 84% fusidic acid/ beta- methasone ointment patients, and 25% oint- patients ment vehicle No statistically significant difference the two between formulations Erythema, scaling, oedema, itching, serous discharge, crusting, extent of lesions and clinical response overall Swabs taken Primary: percentage patients not failing (included treatment signs, and withdrawal various bacteriological criteria) Secondary: erythema, scaling, oedema, itching, discharge, serous crusting, extent of lesions and overall clinical response Bacteriological tests, signs and symptoms on scale, a four-point investigator-assessed clinical response overall Prospective, randomised, parallel study of 2 weeks’ duration Prospective, randomised, parallel study of 2 weeks’ duration Prospective, randomised, parallel study of 10 days’ duration follow-up 68 mild to moderately atopic dermatitis severe 186 mild-to-moderately atopic dermatitis severe 59 patients with infected potentially atopic dermatitis and sample size description and Topical steroid plus additional active agents steroid Topical Fusidic acid and 1% vs 2% hydrocortisone fusidic acid Fusidic acid and 1% vs 1% hydrocortisone hydrocortisone Fusidic acid 2% plus 0.1% betamethasone vs fusidic acid 2% cream plus 0.1% betamethasone ointment vs b.d. vehicle 77 et al., et al., 128 128 Study 2 Ramsay Ramsay 1996 Ramsay Ramsay 1996 Study 1 Germany Thaci, 1999 172 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment TABLE 54 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 Difficult to make any Difficult to make conclusion in such a small subset Useful RCT which combinations evaluates treatment of different which approaches suggests an additional benefit of habit reversal Some evidence to Some evidence of suggest the addition a might have caffeine benefit small additional No evidence to supportNo evidence efficacy of the combination treatment Method and conceal- ment of randomisation unclear, study described as double-blind withdrawals: Drop-outs/ no ITT no data given Length of study not given Method and concealment of randomisation unclear, no blinding drop-outs/ Two withdrawals; no ITT Method and concealment of randomisation unclear, study described as double-blind drop-outs/ Seven withdrawals; no ITT Method and concealment of randomisation unclear, study described as double-blind withdrawals; Drop-outs/ no data given > 0.05) p > 0.05) p Cured or marked Cured 17% for improvement triamcinolone acetonide sulphate and neomycin with 100% for compared triamcinolone acetonide 0.1% and neomycin sulphate plus undecylenic acid At end of 5-week eval- At end of 5-week uation period total skin (not defined status scores in all four fell in paper) so in but more groups that included habit groups pres- (data only reversal form) ented in graphical Similar changes for other skin signs pres- form ented in graphical Mean improvement Mean improvement baseline global over on a impression scale 0–5: hydro- 2.6 to 1.6 for cortisone, 2.1 to 0.8 for and hydro- caffeine cortisone, 2.7 to 0.6 for betamethasone Mean clinical dry skin improvement 73% hydrocortisone alcohol vs 80% 17- hydrocortisone butyrate ( wet skin 67% wet alcohol hydrocortisone vs 68% hydrocortisone 17-butyrate ( No change, some improvement, marked improvement, cured Primary: in reduction scratching, secondary: dryness, scaling, erythema, infiltration, of scratching frequency Pruritus, erythema, scaling, lichenification, oozing, excoriation, global overall impression Erythema, scaling, oedema Prospective, randomised, parallel study Prospective, randomised, parallel study of 5 weeks’ duration Prospective, randomised, parallel study of 3 weeks’ duration Prospective, randomised, left/right parallel study of duration 3 weeks’ follow-up Ten infantile eczema Ten patients within a study of 100 patients with various skin disorders 45 moderate-to-severe atopic dermatitis patients 90 atopic dermatitis patients 40 atopic eczema patients split into two studies applied One group to drycreams skin, the the other after wetting skin first and sample size description and Triamcinolone acetonide 0.1% and sulphate neomycin 0.35% vs triamcinolone acetonide 0.1% and sulphate neomycin 0.35% plus undecylenic acid 2.5% Hydrocortisone vs Hydrocortisone betamethasone valerate vs plus hydrocortisone plus hydrocortisone vs habit reversal betamethasone valerate plus hydrocortisone plus habit reversal Hydrocortisone 0.5% Hydrocortisone vs plus 30% caffeine 0.5% vs hydrocortisone betamethasone valerate 0.1% 0.1% hydrocortisone butyrate ointment vs 1% alcohol hydrocortisone b.d. with 10% urea Topical steroid plus additional active agents steroid Topical 127 et al., 106 89 125 Anon, 1967 Norén & Melin, 1989 Kaplan Kaplan 1978 Chapman, 1979 StudyAddition of antifungal Interventions Study population design, Trial alone Outcome measures plus something else vs topical steroids steroids Topical Main reported results Quality of reporting Comment 173 TABLE 54 contd TABLE Appendix 3 study, 144 et al., Little efficacy difference treatments,between yet the patients preferred Mildison preparation Small study where ten Small study where parameters measured for given and data only some to support enhanced benefit for test substance Very similar to Very Andersen but this time no patient with regards preference to cosmetic acceptibility Study suggests that can markedly vehicle efficacy affect Method and conceal- ment of randomisation unclear, study described as double-blind or No withdrawals drop-outs Method and concealment of randomisation unclear, study described as double-blind drop- withdrawals/ Two outs; no ITT Method and concealment of randomisation unclear, study described as double-blind and drop-outs Five withdrawals; no ITT Method and concealment of randomisation unclear, study described as double-blind or drop- Withdrawals outs not mentioned 0.01) ≤ p Mean reduction in Mean reduction over score severity baseline of 1.7 for Mildison and Uniderm to 0.7 and 0.8, reduced respectively Although data not reported in text, the estimates from that 80% showed figure patients noted evaluable healed or major in improvement liposome group with 60% compared patients in reference 14 at Day group Physician global Physician those assessment for aged <10 years: the of those proportion with moderate, severe, or very severe dermatitis was 94% at baseline and 14% at Mildison for 4 weeks with 94% at compared baseline and 16% at Uniderm for 4 weeks 89% >10 years For baseline to 12% at Mildison for 4 weeks and Uniderm In low solution capacity In low mean global score group 11.9 at baseline from fell 7 compared to 3.8 at Day with 11.9 to 8.2 at baseline 7,and Day respectively, high solution capacity for ( Global severity of Global severity symptoms, global of skin improvement lesions, and investigator patient preference Investigator assessed Investigator ten signs and symptoms of eczema and of patients proportion with major or healed improvement on a and global effect 0–5 scale. 0 = where healed and 5 = worse Lesions: global severity of atopic dermatitis, and patient investigator of preference efficacy therapeutic Investigator assessed Investigator signs on a 0–3 scale five (max. 15) score Prospective, randomised, left/right parallel study of duration 4 weeks’ Prospective, randomised, left/right, parallel study of 2 duration weeks’ Prospective, randomised, left/right parallel study of duration 4 weeks’ Prospective, randomised, left/right parallel study of 5–7 duration days’ follow-up 96 children with atopic 96 children dermatitis 12 patients with atopic dermatitis 60 atopic dermatitis patients 16 patients with atopic eczema and sample size description and 1% ® hydrocortisone vs hydrocortisone Uniderm 1% hydrocortisone Mildison 0.039% liposomal beta- methasone dipropionate vs 0.054% commercial gel glycol propylene Mildison 1% vs hydrocortisone Uniderm 1% hydrocortisone Betamethasone 17- valerate 0.0056% in liquid paraffin vs betamethasone 17- benzoate 0.00056% in neutral oil RCTs comparing different formulations of the same topical steroid formulations RCTs comparing different et al., et al., ,Yamanouchi, UK et al., et al., ® 144 103 143 130 Andersen Denmark 1988 Korting Korting 1090 Germany Olholm 1988 Denmark Malzfeldt Malzfeldt 1989 Germany 174 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment Mildison TABLE 55 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 Table of random Table used numbers Implies double blinding use of placebo by Method and concealment of randomisation unclear Study described as double-blind one No ITT but only drop-out Method and concealment of randomisation unclear investigator Probably blinded but unclear out ITT carried Results of all three studies impossible to disentangle Method and concealment of randomisation unclear Blinding not described Unclear of ITT Method and concealment of randomisation unclear, study described as double-blind 33 drop-outs/ withdrawals; no ITT Method and concealment of randomisation unclear Study described as double-blind one No ITT but only drop-out Method and concealment of randomisation unclear investigator Probably blinded but unclear out ITT carried Method and concealment of randomisation unclear Study described as double-blind No ITT Method and concealment of randomisation unclear Blinding not described Unclear of ITT = 0.35) p = 0.006) noticed p Based on 116 evaluable 3 patients at week 86.2% noticed good or excellent clearance in t.d.s. vs 85.3% in o.d. group No statistical differences 78% o.d. vs 93% b.d. ( considerable or improvement clearance according to patient Patient diary cards in improvement revealed rash, itch and sleep loss both treatment for within first week. groups 80% in o.d. and 85% in b.d. defined as groups clinical success on ITT ( analysis No actual data for o.d. No actual data for vs b.d. methylprednisolone aceponate given Data on severity scores Data on severity in presented only form graphical No obvious differences groups three between No supporting statistics given Comparative and Comparative absolute therapeutic responses: erythema, oedema, changes in size of thickness lesions global Physician response Patient and doctor severity assessed overall Clinical features assessed were erythema, induration, pruritus and excoriation Patient diary for cards itch, rash and sleep disturbance assessed six Physician signs and global assessment Patient and doctor global assessments Doctor assessed 11 signs and symptoms Itching, burning, pain, erythema, oedema, exudation, blisters, bullae, scabs, scaling, lichenification, pooled into a mean score Serum cortisol and tests ACTH Prospective, randomised, right/left, parallel study of duration 3 weeks’ Prospective, randomised, parallel study of 4 weeks’ duration Prospective, randomised, parallel study of 4 weeks’ duration Propsective, random- ised, left/right, parallel study of 4 weeks’ duration Prospective, randomised, right/left, parallel study of duration 3 weeks’ follow-up 149 atopic eczema patients 150 adults and children the age of 12 over from suffering years atopic dermatitis 270 moderate-to- atopic dermatitis severe patients 88 adults with atopic dermatitis 30 children with atopic 30 children eczema and sample size description and 0.1% halcinonide cream o.d. vs 0.1% t.d.s. halcinonide cream 0.1% hydrocortisone b.d. 17-butyrate cream vs o.d. o.d. plus vehicle Fluticasone propionate o.d.0.05% cream vs b.d. Methylprednisolone aceponate ointment o.d. vs b.d. Clobetasone 17- butyrate lotion b.d. (8 am and 3 pm) vs b.d. (3 pm and 8 pm) or o.d. (9 pm) 75 et al., et al., RCTs of once-daily versus more frequent application of steroids (trials the same active compound) RCTs of once-daily versus application of steroids involving frequent more et al., et al., 95 69 87 145 1981 Sudilovsky Sudilovsky USA Bleehen 1995 Finland Koopmans Koopmans 1995 UK Haneke, 1992 Germany Italy Richelli 1990 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment ACTH, adrenocorticotrophic hormone 175 TABLE 56 TABLE Appendix 3 continued Uncertain what type of clobetasone was tested This is important as the is super propionate potent whereas butyrate is moderately so Efficacy advantage of mometasone (classified as potent in UK) not surprising when against a very compared mild product Pity there was no Pity there comparison between o.d. betamethasone Difficult to blind a o.d. with a b.d. treatment treatment of treatments Posology not given Method of random- isation unclear, study described as third party blind or No withdrawals drop-outs Method of randomisation unclear, study described as single blind with an ‘unblinded investigator’ carried were evaluations ‘blinded’ a out by investigator 36 patients experienced clearing of eczema prior to end of study so were withdrawn; no ITT out carried Method of random- isation unclear, study described as third-party blind evaluator or No withdrawals drop-outs Method and conceal- ment of randomisation unclear, study described as single-blind drop-outs/ Ten withdrawals, no ITT < p = 0.30) = 0.01) p p = 0.01) p Total sign/symptom Total over improvement score baseline, 7.8 to 1.1 ( 0.01) for mometa-sone 0.01) for vs 7.2 to 2.4 for clobetasone (NS) For the 12 evaluable For patients mean percentage in total improvement sign/ symptom score mometa- was 95% for hydro- sone vs 75% for cortisone ( The group with more The group than 25% body surface involvement area a wider showed of in favour difference mometasone (92% vs 62%; 100% of mometasone and betamethasone or patients had cleared experienced good 3 week by improvement No baseline values given A comparison of the made by evaluations after VAS patients on a no showed 6 weeks in efficacy difference the two between ( treatments Parent-assessed efficacy Parent-assessed on a four- of treatment point scale (excellent to poor) Investigator-assessed erythema, induration and pruritus, global percentage improvement Doctor-assessed erythema, lichenification, skin surface disruption (crusting, scaling), excoriation, and pruritus on a 0–3 scale, % body surface area and global evaluation Investigator assessed Investigator erythema, induration and pruritus on a 0–3 scale, global evaluation % improvement Patient VAS Patient VAS for severity of eczema, 0–3 score doctor-assessed for erythema, infiltration and pruritus, global of 1–6 scores evaluation Prospective, random- ised, parallel study of duration 6 weeks’ Prospective, randomised, parallel study of 3 weeks’ duration Prospective, randomised, parallel study of 3 weeks’ duration Prospective, randomised, parallel study of 6 weeks’ duration follow-up 48 children with 48 children moderate-to-severe atopic dermatitis with atopic 60 children dermatitis 60 adult patients with atopic eczema of at least moderate severity 96 adult atopic eczema patients and sample size description and Mometasone furoate vs hydro- 0.1% cream cortisone 1.0% cream o.d. Mometasone furoate o.d.0.1% cream vs clobetasone 0.05% b.d. cream Mometasone furoate ointment 0.1% o.d. vs betamethasone ointment dipropionate 0.05% b.d. Mometasone furoate o.d.cream vs 17- hydrocortisone b.d. butyrate cream Once- versus twice-daily application of different topical corticosteroids (trials involving different active compounds) topical corticosteroidsOnce- versus (trials different twice-daily application of different involving et al., et al., et al., et al., 101 129 131 142 USA Italy Vernon Vernon 1991 Rafanelli 1993 Marchesi Marchesi 1994 Italy Hoybye Hoybye 1991 Denmark 176 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment TABLE 57 TABLE Health Technology Assessment 2000; Vol. 4: No. 37 continued No actual efficacy data reported, patient only data given preference No differences between No differences but effect treatments sizes similar to studies of b.d. usage A study reported in Italian; all information the abstracted from English abstract only was no o.d. Pity there betamethasone Method and concealment of randomisation unclear, study described as double-blind drop-outs/ Ten withdrawals; no ITT out carried Method and concealment of randomisation unclear, study described as double-blind withdrawals/ Three drop-outs; no ITT out carried Method and concealment of randomisation unclear, study described as double-blind drop- withdrawals/ Four outs; out no ITT carried Method and conceal- ment of randomisation abstract, unclear from study described as double-blind abstract if Unclear from or withdrawals any drop-outs No significant found were differences of the symptoms any for 4 following scored with treatment weeks’ betamethasone valerate or mometasone furoate The sum of scores of The sum of scores a 8 symptoms showed from mean reduction 13.1 to 2.3 after treatment 2 weeks’ no were There significant differences the two between treatments The mean sum of scores symptoms (eryth-of five ema, scaling, vesicles, papules, pruritus) baseline from decreased 8.3 to 1.6 after 2 weeks hydrocortisone for buteprate vs 8.3 to 1.4 betamethasone for valerate significant A statistically in was found difference of betamethasone favour 83.1% mometasone patients and furoate 89.2% betamethasone valerate patients experienced a reduction in signs and symptoms (NS) Patient assessed pruritus and smarting pain on 0–3 scale, assessed evaluator erythema, scaling, lichenification, excoriation, papules, and on a 0–3 scale vesicles (max. 18) score Erythema, infiltration, lichenification, scaling, vesiculation, papules, excoriations and pruritus on a 0–4 scale Patient-assessed efficacy global and investigator assessment Erythema, infiltration, lichenification, scaling, vesiculation, papules, excoriations and pruritus on a 0–4 scale Patient-assessed efficacy global and investigator assessment Erythema, oedema, essudate, scaling, excoriation, lichenification (objective symptoms) and pruritus and burning (subjective symptoms) Prospective, randomised, left/right, parallel study of duration 4 weeks’ Prospective, randomised, left/right parallel study of duration 2 weeks’ Prospective, randomised, left/right parallel study of duration 2 weeks’ Prospective, randomised, parallel study of 15 days’ duration follow-up 30 patients with atopic dermatitis aged 15–66 years 86 atopic dermatitis patients 12+ years 82 atopic dermatitis patients 12+ years 97 atopic dermatitis patients and sample size description and Betamethasone valerate o.d.0.1% cream vs mometasone furoate o.d. 0.1% cream Hydrocortisone 0.1% buteprate cream o.d. vs betamethasone valerate 0.1% cream o.d. Hydrocortisone buteprate ointment 0.1% o.d. vs betamethasone valerate 0.1% ointment o.d. Mometasone furoate 0.1% o.d. vs betamethasone valerate b.d. Once- versus twice-daily application of different topical corticosteroids (trials involving different active compounds) topical corticosteroidsOnce- versus (trials different twice-daily application of different involving 72 73 73 et al., 78 Reidhav & Reidhav Svensson, 1996 Sweden Traulsen, 1997 Amerio 1998 Traulsen, 1997 Denmark Study 1 Denmark Study 2 Italy Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 177 TABLE 57 contd TABLE Appendix 3 Small sample over a Small sample over short period of time Good to see a longer- term study evaluating as short- as well relapse term efficacy how Difficult to say of the benefit in much was realpse preventing old due to treating healed sites as opposed of new to treatment sites Method and concealment of randomisation unclear, study described as double-blind one drop-out;Only no out carried ITT analysis Method and concealment of randomisation unclear, study described as double-blind drop- 17 withdrawals/ outs; no ITT data up to first Only analysed relapse At week 4,At week three fluticasone patients and one clobetasone patient healed clinically were (SCORAD <9) 68% of patients in the and 39% placebo group in the fluticasone group because of withdrew and relapse recurrence was 2.6 Risk of relapse in active times greater (95% CI,group 1.2 to 5.7) No significant changes detected in either were in group treatment or serum cortisol levels in skin thickness measurements SCORAD composite scale of extent and intensity of eight signs and time Risk of relapse to relapse Clinical assessment SCORAD: erythema, oedema/ papulation, oozing/ crusts, excoriations, lichenification, dryness, pruritus and sleep loss Skin thickness on biopsy specimens Prospective, random- ised, parallel study of duration 4 weeks’ Prospective, random- ised, parallel study of duration 16 weeks’ follow-up follow-up 22 children with atopic 22 children dermatitis 54 patients with moderate-to-severe atopic dermatitis patients identified from a larger set of 112 on the basis of enhanced responses steroid and sample size description and and sample size description and Fluticasone propionate o.d.0.05% cream vs clobetasone butyrate b.d. 0.05% cream Fluticasone propionate 0.005%(g/g) vs placebo Once- versus twice-daily application of different topical corticosteroids (trials involving different active compounds) topical corticosteroidsOnce- versus (trials different twice-daily application of different involving RCTs of topical steroids in the prevention of relapse in the prevention RCTs of topical steroids 82 1998 104 Wolkerstorfer et al., The Netherlands VanDerMeer, 1999 The Netherlands Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 178 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment TABLE 58 TABLE TABLE 57 contd TABLE Health Technology Assessment 2000; Vol. 4: No. 37 No evidence of skin No evidence thinning, though study duration very short Although rebound is Although rebound to,often referred there of was no evidence such a phenomenon in this study No evidence of HPA No evidence in either suppression group Short-term study Method and concealment of randomisation unclear, study described as double blind withdrawals/ Three drop-outs; no ITT Method and concealment of randomisation unclear, open study, no blinding No mention of and drop- withdrawals outs Method and concealment of randomisation unclear, study described as open label drop-outs;Five no ITT < 0.055) p Signs of cutaneous not were atrophy test site observed at any either at beginning or evaluation 3-week period Efficacy similar in both with 88% groups signs and improvement symptoms in alclometasone-treated sites vs 86% hydro- cortisone-treated sites Sudden suspension of Sudden was topical steroids in relapse by followed case but in no every rebound case was there was no statistical There the between difference of relapse frequency groups in the three ( –1.6 and –1.3% change over in cortisol levels for baseline at 28 days desonide and hydro- cortisone groups, respectively Cutaneous atrophy: skin thinning, shininess, striae and fine blood vessels (telangiectasia) as assessed under magnification ‘Rebound phenomenon’ of lesions reactivation intensity with greater than their pre-treatment (<10) days state a few after suspending the with topical treatment steroids, which had them controlled of The extensiveness to lesions according signs three taken Photographs and after before treatment Hypothalamic pituitary–adrenal (HPA) axis (cortisol levels) Prospective, randomised, left/right, parallel study of duration 3 weeks’ Prospective, random- ised, open study of 4 duration with weeks’ suspended 10 days treatment randomised, parallel study of 4 weeks’ duration follow-up 37 children with 37 children eczema 45 children with atopic 45 children dermatitis 20 children Prospective, and sample size description and Alclometasone 0.05% dipropionate vs hydrocortisone 1.0% b.d. Hydrocortisone 1% Hydrocortisone vs betamethasone 0.05% dipropionate placebo vs cold cream Desonide 0.05% ointment vs 2.5% hydrocortisone ointment b.d. Trials that specifically set out to examine adverse of topical corticosteroids that specifically effects Trials 148 et al., 1991 109 133 Kuokkanen & Kuokkanen Sillantaka, 1987 Finland Sanabria-Silva et al., Spain (translated) Lucky 1997 USA Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment 179 TABLE 59 TABLE Appendix 3 Although a placebo been might have group difficult, ethically on patient-based views response treatment been useful have would Big treatment effects Big treatment Crossover study with Crossover significant treatment interactions order effects Large treatment Method and concealment of randomisation unclear, study described as double-blind and drop- Withdrawals outs not mentioned Method and concealment of randomisation unclear, study described as double-blind Withdrawals/drop-outs not mentioned Method and concealment of randomisation unclear, study described as double-blind One withdrawal; no ITT Overall evaluation on a evaluation Overall rating scale: four-point beta- baseline 3.44 for to methasone reduced dexa- 2.89 and 3.62 for methasone reduced to 2.69 Improvement over Improvement total clinical baseline for score:severity A group to 34 and 75 reduced to 29 B 74 reduced group Parental scores for itch for scores Parental and antihistamine use lower significantly were on beclomethasone than placebo, but use of and topical steroids sleep loss did not show significant change any Other significant changes especially surface damage Inflammation, vesiculation, pruritus, exudation, excoriations, evaluation overall Pruritus, erythema/oedema, excoriation, papulation/erosion/ scaling, lichenification Patient assessed itch and sleep loss (VAS) Doctor assessed redness, vesiculation, crusting, excoriation, lichenification follow-up Prospective, random- ised, parallel study of 24 hours’ duration Prospective, randomised, crossover study of 4 weeks’ duration Prospective, randomised, crossover study of 2 weeks’ duration 22 patients with moderate-to-severe atopic dermatitis and sample size description and 27 children with 27 children moderate-to-severe atopic eczema with severe 20 children atopic dermatitis Betamethasone sodium phosphate 4.0 mg/ml injection vs dexa- methasone sodium phosphate 4.0 mg/ml injection o.d. Oral plus nasal beclomethasone q.d.s. dipropionate vs placebo Systemic flunisolide 640–1200 µg b.d. vs placebo 98 Trials that evaluated oral steroids oral that evaluated Trials et al., et al., 112 140 Dickey, 1976 USA Heddle Heddle 1984 UK Italy La Rosa 1995 180 Study Interventions Study population design, Trial Outcome measures Main reported results Quality of reporting Comment TABLE 60 TABLE Health Technology Assessment 2000; Vol. 4: No. 37

Appendix 4 Duplicate and triplicate publications

TABLE 61

Interventions Duplicate or triplicate publications

Fish oils Bjorneboe 1989254 = Bjorneboe 1987251 Evening primrose oil Wright 1985245 = Wright 1982242 Evening primrose oil Ferreira 1998a233 = Ferreira 1998b234 Cyclosporin A Sowden 1991295 = Salek 1993293 = Allen 1991298 Corticosteroids Sefton 1984114 = Sefton 1983136 Corticosteroids Korting 199586 = Zienicke 1993146 House dust mites Friedmann 1998267 = Tan 1996263 Allergen–antibody complexes Leroy 1993284 = Leroy 1992285 Topical corticosteroids Ottevanger 1992 = Hoybye 1991124

181

Health Technology Assessment 2000; Vol. 4: No. 37

Health Technology Assessment Programme

Prioritisation Strategy Group

Members Chair Professor Shah Ebrahim Dr John Reynolds Dr Ron Zimmern Professor Kent Woods Professor of Epidemiology Clinical Director Director, Public Health Director, of Ageing Acute General Medicine SDU Genetics Unit NHS HTA Programme, & University of Bristol Oxford Radcliffe Hospital Strangeways Research Professor of Therapeutics Laboratories University of Leicester Cambridge Professor Sir John Grimley Evans Professor Tom Walley Professor Bruce Campbell Professor of Director Consultant General Surgeon Clinical Geratology Prescribing Research Group Royal Devon & Exeter Hospital University of Oxford University of Liverpool

HTA Commissioning Board

Members Programme Director Ms Christine Clark Professor Jenny Hewison Dr Sarah Stewart-Brown Professor Kent Woods Freelance Medical Writer Senior Lecturer Director, Health Services Director, NHS HTA Bury, Lancs School of Psychology Research Unit Programme, & University of Leeds University of Oxford Professor of Therapeutics Professor Martin Eccles University of Leicester Professor of Professor Alison Kitson Professor Ala Szczepura Clinical Effectiveness Director, Royal College of Director, Centre for Health Chair University of Newcastle- Nursing Institute, London Services Studies upon-Tyne University of Warwick Professor Shah Ebrahim Dr Donna Lamping Professor of Epidemiology Dr Andrew Farmer Head, Health Services Dr Gillian Vivian of Ageing Research Unit Consultant in Nuclear University of Bristol General Practitioner & NHS R&D London School of Hygiene Medicine & Radiology Clinical Scientist & Tropical Medicine Royal Cornwall Hospitals Trust Deputy Chair Truro Professor Jon Nicholl Institute of Health Sciences Professor David Neal Director, Medical Care University of Oxford Professor of Surgery Professor Graham Watt Research Unit Department of Professor Adrian Grant University of Newcastle- University of Sheffield upon-Tyne General Practice Director, Health Services University of Glasgow Research Unit Professor Gillian Parker University of Aberdeen Nuffield Professor of Dr Jeremy Wyatt Senior Fellow Professor Douglas Altman Community Care Dr Alastair Gray University of Leicester Health Knowledge Director, ICRF Medical Director, Health Economics Management Centre Statistics Group Research Centre Dr Tim Peters University College London University of Oxford Institute of Health Sciences Reader in Medical Statistics University of Oxford University of Bristol Professor John Bond Director, Centre for Health Professor Mark Haggard Professor Martin Severs Services Research Director, MRC Institute Professor in Elderly University of Newcastle- of Hearing Research Health Care upon-Tyne University of Nottingham University of Portsmouth

Current and past membership details of all HTA ‘committees’ are available from the HTA website (see inside front cover for details) 189

continued Health Technology Assessment Programme

continued Diagnostic Technologies & Screening Panel Members Chair Dr Paul O Collinson Mr Steve Ebdon-Jackson Dr Peter Howlett Professor Sir John Consultant Chemical Head, Diagnostic Imaging & Executive Director – Grimley Evans Pathologist & Senior Lecturer Radiation Protection Team Development Professor of Clinical St George’s Hospital, London Department of Health, London Portsmouth Hospitals Geratology NHS Trust University of Oxford Dr Tom Fahey Dr Barry Cookson Senior Lecturer in Professor Alistair McGuire Vice Chair Director, Laboratory of General Practice Professor of Health Economics Dr Ron Zimmern Hospital Infection University of Bristol City University, London Director, Public Health Public Health Laboratory Service, London Genetics Unit Dr Andrew Farmer Mrs Kathlyn Slack Strangeways Research General Practitioner & Professional Support Laboratories NHS Clinical Scientist Professor Howard Cuckle Diagnostic Imaging & Cambridge Institute of Health Sciences Professor of Reproductive Radiation Protection Team University of Oxford Epidemiology Department of Health University of Leeds London Mrs Gillian Fletcher Dr Philip J Ayres Antenatal Teacher & Tutor Mr Tony Tester Consultant in Epidemiology National Childbirth Trust Dr Carol Dezateux Chief Officer, South & Public Health Reigate Senior Lecturer in Bedfordshire Community The Leeds Teaching Hospitals Paediatric Epidemiology Health Council NHS Trust Professor Jane Franklyn Institute of Child Health Luton London Professor of Medicine Mrs Stella Burnside University of Birmingham Chief Executive, Altnagelvin Hospitals Health & Social Professor Adrian K Dixon Dr JA Muir Gray Services Trust Professor of Radiology Joint Director, National Londonderry Addenbrooke’s Hospital Screening Committee Northern Ireland Cambridge NHS Executive, Oxford

Pharmaceuticals Panel Members Chair Dr Alastair Gray Mrs Marianne Rigge Dr Ross Taylor Professor Tom Walley Director, Health Economics Director, College of Health Senior Lecturer Director, Prescribing Research Centre London Department of General Research Group Institute of Health Sciences Practice & Primary Care University of Liverpool University of Oxford University of Aberdeen Dr Frances Rotblat Manager, Biotechnology Group Mrs Jeannette Howe Vice Chair Medicines Control Agency Senior Principal Pharmacist Dr Richard Tiner Dr John Reynolds London Department of Health, London Medical Director Clinical Director – Association of the British Acute General Medicine SDU Pharmaceutical Industry Oxford Radcliffe Hospital Dr Andrew Mortimore Mr Bill Sang Consultant in Public Chief Executive London Health Medicine Salford Royal Hospitals Southampton & South West NHS Trust Professor Jenifer Hants Health Authority Wilson-Barnett Dr Felicity J Gabbay Dr Eamonn Sheridan Head, Florence Nightingale Mr Nigel Offen Managing Director, Consultant in Clinical Genetics Division of Nursing Head of Clinical Quality Transcrip Ltd St James’s University Hospital & Midwifery NHS Executive – Eastern Milford-on-Sea, Hants Leeds King’s College, London Milton Keynes

Mr Peter Golightly Professor Robert Peveler Mrs Katrina Simister Mr David J Wright Director, Trent Drug Professor of Liaison Psychiatry New Products Manager Chief Executive Information Services Royal South Hants Hospital National Prescribing Centre International Glaucoma Leicester Royal Infirmary Southampton Liverpool Association, London

190

Current and past membership details of all HTA ‘committees’ are available from the HTA website (see inside front cover for details) Health Technology Assessment 2000; Vol. 4: No. 37

Therapeutic Procedures Panel Members Chair Professor Collette Clifford Mr Richard Johanson Dr John C Pounsford Professor Bruce Campbell Professor of Nursing Consultant & Senior Lecturer Consultant Physician Consultant General Surgeon University of Birmingham North Staffordshire Infirmary Frenchay Healthcare Trust Royal Devon & Exeter Hospital NHS Trust, Stoke-on-Trent Bristol Dr Katherine Darton Information Unit Dr Duncan Keeley Dr Mark Sculpher MIND – The Mental Health General Practitioner Senior Research Fellow in Professor John Bond Charity, London Thame, Oxon Health Economics Professor of University of York Health Services Research Mr John Dunning Dr Phillip Leech University of Newcastle- Consultant Cardiothoracic Principal Medical Officer Dr Ken Stein upon-Tyne Surgeon Department of Health, London Consultant in Public Papworth Hospital NHS Trust Health Medicine Cambridge Professor James Lindesay Ms Judith Brodie North & East Devon Professor of Psychiatry for Health Authority, Exeter Head of Cancer Mr Jonothan Earnshaw the Elderly Support Service Consultant Vascular Surgeon University of Leicester Cancer BACUP, London Gloucestershire Royal Hospital Professor Rajan Madhok Ms Tracy Bury Professor David Field Director of Health Policy Head of Research Professor of Neonatal Medicine & Public Health & Development The Leicester Royal Infirmary East Riding & Hull Chartered Society of NHS Trust Health Authority Physiotherapy, London Professor FD Richard Hobbs Dr Mike McGovern Mr Michael Clancy Professor of Primary Care Branch Head Consultant in A&E Medicine & General Practice Department of Health Southampton General Hospital University of Birmingham London

Expert Advisory Network Members

Professor John Brazier Dr Neville Goodman Dr Sue Moss Dr Sarah Stewart-Brown Director of Health Economics Consultant Anaesthetist Associate Director, Cancer Director, Health Services University of Sheffield Southmead Hospital, Bristol Screening Evaluation Unit Research Unit Institute of Cancer Research University of Oxford Mr Shaun Brogan Professor Robert E Hawkins Sutton, Surrey Chief Executive, Ridgeway CRC Professor & Director of Dr Gillian Vivian Primary Care Group Medical Oncology Mrs Julietta Patnick Consultant in Nuclear Aylesbury, Bucks Christie Hospital NHS Trust National Coordinator Medicine & Radiology Manchester NHS Cancer Screening Royal Cornwall Hospitals Trust Mr John A Cairns Programmes, Sheffield Truro Director, Health Economics Professor Allen Hutchinson Research Unit Director of Public Health & Professor Jennie Popay Mrs Joan Webster University of Aberdeen Deputy Dean, ScHARR Professor of Sociology & Former Chair University of Sheffield Community Health Southern Derbyshire Dr Nicky Cullum University of Salford Community Health Council Professor David Mant Reader in Health Studies Nottingham Professor of General Practice University of York Institute of Health Sciences Professor Chris Price University of Oxford Professor of Professor Pam Enderby Clinical Biochemistry Chair of Community Professor Alexander Markham St Bartholomew’s & The Rehabilitation Director Royal London School of University of Sheffield Molecular Medicine Unit Medicine & Dentistry St James’s University Hospital Mr Leonard R Fenwick Leeds Mr Simon Robbins Chief Executive Chief Executive Freeman Hospital Dr Chris McCall Camden & Islington Newcastle-upon-Tyne General Practitioner Health Authority, London Corfe Mullen, Dorset Ms Grace Gibbs Dr William Rosenberg Deputy Chief Executive Dr Peter Moore Senior Lecturer & West Middlesex Freelance Science Writer Consultant in Medicine University Hospital Ashtead, Surrey University of Southampton

Current and past membership details of all HTA ‘committees’ are available from the HTA website (see inside front cover for details) 191

Health TechnologyAssessment 00 o.4 o 7Treatments for atopic eczema 37 No. 4: Vol. 2000;

Feedback The HTA programme and the authors would like to know your views about this report. The Correspondence Page on the HTA website (http://www.ncchta.org) is a convenient way to publish your comments. If you prefer, you can send your comments to the address below, telling us whether you would like us to transfer them to the website. We look forward to hearing from you.

Copies of this report can be obtained from:

The National Coordinating Centre for Health Technology Assessment, Mailpoint 728, Boldrewood, University of Southampton, Southampton, SO16 7PX, UK. Fax: +44 (0) 23 8059 5639 Email: [email protected] http://www.ncchta.org ISSN 1366-5278