ORIGINAL ARTICLE See related Commentary on page vi Measuring Atopic Dermatitis Severity in Randomized Controlled Clinical Trials: What Exactly Are We Measuring?

Carolyn Charman, Colette Chambers, and Hywel Williams Center of Evidence-Based Dermatology, Queen’s Medical Center, University Hospital, Nottingham, UK

Well-designed clinical trials are a fundamental aspect of lished scales were used signi¢cantly less frequently evidence-based medicine. Such trials are dependent on over the last 2 y compared to previously (21% vs 74%, the use of valid, reliable, and relevant outcome mea- po0.01). There was lack of consensus on which clinical sures.Wide variation in outcome methodology can have features best re£ect disease severity, with 31 di¡erent de- important detrimental e¡ects on the correct interpreta- scriptions of clinical signs being used across all scoring tion and comparison of results. The objective of this systems. Fifty-six di¡erent ‘‘objective’’ clinical scales study was to describe the variation in outcome metho- were identi¢ed. Patient symptoms were recorded in 80 dology in randomized controlled trials of therapeutic trials (86%) and disease extent in 62 trials (67%). Qual- interventions for atopic dermatitis published between ity of life was measured in only three trials (3%). This January 1994 and December 2001. Of the 93 eligible ran- wide variation in outcome methodology is hindering domized controlled trials identi¢ed using a systematic evidence-based practice, and the widespread use of un- electronic database search strategy, 85 (91%) incorpo- validated outcome measures is a potential source of bias rated an objective measurement of clinical signs. Only and inaccuracy. More emphasis should be placed on 23 (27%) of these trials used a published severity scale, measuring things that are important to patients such as however. The remainder used either modi¢ed versions symptoms and quality of life. Key words: index/outcome of published scales (14%) or unnamed scales with no measures/severity score. J Invest Dermatol 120:932 ^941, 2003 data on validity or reliability (59%), although unpub-

topic dermatitis is a distressing in£ammatory skin little available data on validity or reliability testing (Charman disease a¡ecting between 0.3% and 20% of children and Williams, 2000). worldwide (Williams et al, 1999). In the UK the The aim of this study was to assess the extent of heterogeneity disease accounts for 10%^20% of all referrals to in outcome measures used for recording atopic dermatitis severity dermatologists and about 30% of dermatologic con- in recent RCTs, and to establish which measures were being most Asultations in general practice, with an estimated annual cost of widely used by researchers and clinicians. d47 million for preschool children alone (Emerson et al,2001). Disease prevalence has steadily increased over the last 30 y (Diep- METHODS gen, 2000), signi¢cantly impacting health care resources world- wide, and resulting in a growing ¢eld of atopic dermatitis A systematic electronic search strategy was used to retrieve all RCTs of research. As more and more emphasis is being placed on the therapies for atopic dermatitis published between January 1994 and Decem- results of randomized controlled clinical trials (RCTs) to inform ber 2001. The following electronic databases were searched: Medline, EM- clinical practice, the use of valid and clinically meaningful patient BASE, The Cochrane Controlled Trials Register, and the Cochrane Skin outcome measures is becoming increasingly important. Group Specialized Trials Register. The Cochrane Collaboration highly sen- Given the importance of atopic dermatitis as a health issue, it is sitive electronic search string was used to search Medline (OVID). The surprising that so little e¡ort has been expended by clinicians, re- search string developed by the British Medical Journal Publishing Group searchers, regulatory authorities, and drug companies in trying to for its Clinical Evidence series (Barton, 2001) was used to search EMBASE (OVID). The following disease terms were used; eczema, atopic dermatitis, standardize scoring systems for measuring disease severity in the atopic eczema, infantile eczema, childhood eczema, neurodermatitis, and clinical trial setting. Poor standardization and lack of proven Besnier’s prurigo. Only RCTs of therapeutic agents used in the treatment validity not only hinders the comparison of results and produc- of people with atopic dermatitis (as diagnosed by a physician) of any tion of systematic reviews but also prohibits the meaningful in- age were considered for inclusion. Studies that only reported changes in terpretation of individual studies. The atopic dermatitis literature blood tests or cellular mechanisms were excluded. Studies that included is characterized by a confusing array of severity indices. Even other forms of eczema in the analysis or those that did not specify atopic many of the 13 or so named published scoring systems have dermatitis were also excluded from the analysis. Studies published in non-English languages for which a published English translation was not available were excluded. Manuscript received October 7, 2002; revised December 2, 2002; accepted for publication December 13, 2002 Reprint requests to: Dr. Carolyn Charman, Department of Dermatol- RESULTS ogy, Queen’s Medical Center, Nottingham, NG7 2UH, UK; Email: [email protected] A total of 93 RCTs were identi¢ed (Tab l e I ). Topical and oral Abbreviation: RCT, randomized controlled trial. corticosteroids were the most frequently studied therapeutic

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932 VOL. 120, NO. 6 JUNE 2003 MEASURING ATOPIC DERMATITIS SEVERITY IN RCTS 933

Table I. Treatments for atopic dermatitis studied in RCTs from January 1994 to December 2001 Therapy under investigation Number of RCTs References

Corticosteroids 16 Marchesi et al, 1994; Stalder et al, 1994; Bleehen et al, 1995; Jorizzo et al, 1995; Koopmans et al, 1995; La Rosa et al, 1995; Hiratsuka et al, 1996; Lebwohl, 1996; 1999; Reidhav and Svensson, 1996; Sears et al, 1997; Traulsen, 1997; Maloney et al, 1998; Wolkerstorfer et al,1998; Van Der Meer et al, 1999; Cato et al,2001 Antimicrobials 9 Korting et al, 1994; Broberg and Faergemann, 1995; Harper, 1995; Holland et al,1995; Poyner and Dass, 1996; Ramsay et al,1996;Ewinget al, 1998; Breneman et al, 2000; Lintu et al,2001 Essential fatty acids 7 Biagi et al, 1994; Humphreys et al, 1994; Soyland et al, 1994; Hederos and Berg, 1996; Valsecchi et al, 1996; Gimenez-Arnau et al,1997;Henzet al,1999 Dietary manipulation 7 Isolauri et al,1995;2000;Mabinet al, 1995a; Ventura et al, 1996; Majamaa and Isolauri, 1997; Lever et al, 1998; Niggemann et al,2001 Cyclosporin 6 Munro et al, 1994; Van Joost et al, 1994; Zonneveld et al, 1996; Zurbriggen et al,1999; Czech et al, 2000; Harper et al,2000 Anti-house dust mite measures 6 Galli et al,1994;Tanet al, 1996; Friedmann and Tan, 1998; Ricci et al,2000; Gutgesell et al,2001;Holmet al,2001 Tacrolimus 5 Ruzicka et al, 1997; Boguniewicz et al,1998;Hani¢net al, 2001a (two trials); Paller et al,2001 Ultraviolet light therapy 4 Krutmann et al, 1998; Der-Petrossian et al, 2000; Reynolds et al,2001;Tzanevaet al,2001 Antihistamines 4 Langeland et al,1994;LaRosaet al, 1994; Veien et al, 1995; Patel et al,1997 Doxepin 3 Drake et al, 1994; 1999; Berberian et al,1999 Montelukast 3 Capella et al,2001;Peiet al, 2001a; Yanase and David-Bajar, 2001 Ascomycins 2 Van Leent et al,1998;Lugeret al,2001 Chinese herbal medicine 2 Latchman et al, 1996; Fung et al,1999 Emollients 2 Hani¢n et al, 1998; Andersson et al,1999 Interferon 2 Jang et al, 2000; Noh and Lee, 2001 Massage 2 Schachner et al, 1998; Anderson et al,2000 Sodium cromoglycate 2 Kimata and Hiratsuka, 1994; Moore et al,1998 Acid electrolytic water 1 Sasai-Takedatsu et al,1997 Bioresonance 1 Schoni et al,1997 Detergents 1 Andersen et al,1998 Hamamelis distillate 1 Korting et al,1995 Mycobacterium vaccae 1 Arkwright and David, 2001 Nitrazepam 1 Ebata et al,1998 Platelet activating factor 1 Abeck et al,1997 Psychologic measures 1 Ehlers et al,1995 Pyridoxine 1 Mabin et al,1995b Thymopentin 1 Stiller et al,1994 Wet wrap bandaging 1 Pei et al,2001b agent (16 trials), followed by antibacterial and antifungal prepara- most frequently employed system (11 trials) followed by the tions (nine trials), essential fatty acid supplementation, e.g., eve- Eczema Area and Severity Index (EASI) (three trials) (Hani¢n ning primrose oil, ¢sh oil, and borage oil (seven trials), and et al, 2001b), Costa’s Simple Scoring System (three trials) (Costa dietary manipulation (seven trials). Outcome measures included et al, 1989), the Six Area Six Sign Atopic Dermatitis index (SAS- assessments of physical features of the disease visible to the physi- SAD) (two trials) (Berth-Jones, 1996), the Atopic Dermatitis cian (clinical signs), subjective indicators perceived by the patient Severity Index (ADSI) (one trial) (Van Leent et al, 1998), the Ato- (symptoms), estimations of body surface area involvement, and pic Dermatitis Area and Severity Index (ADASI) (one trial) (Bah- overall impressions of disease severity (global scales). The scores mer and Schubert, 1991), the Total Body Severity Assessment on measurement scales of individual parameters were frequently (TBSA) (one trial) (Van Joost et al, 1992), and the Dry Skin Area combined to form an overall severity index. and Severity Index (DASI) (Serup, 1995) (one trial). The latter index was not designed speci¢cally for measuring atopic Clinical signs Of the 93 trials identi¢ed, 85 (91%) included an dermatitis severity. assessment of clinical signs (Tab l e I I ). Within these 85 RCTs, a total of 31 di¡erent clinical sign descriptions had been used to Modi¢ed published severity indices A further 12 trials (14%) used a measure disease severity. Fifty-six di¡erent objective scoring modi¢ed version of a published index, based on the SCORAD systems were identi¢ed, using 51 di¡erent combinations of index (four trials), SASSAD index (three trials), Costa’s Simple clinical signs. Distinct clinical signs were scored together in Scoring System (two trials), EASI (two trials), or the TBSA (one some trials, e.g., papulation/erosion/scaling or scaling/crusting trial). Modi¢ed scoring systems were sometimes employed for a (Tab l e I I ). The total number of signs used in each index ranged clear reason, e.g., when only half the body was treated (Tzaneva from 1 to 10, and the grading used for measuring individual et al, 2001), or when the head and neck area was not included clinical signs ranged from 02to0100 where speci¢ed. No (Luger et al, 2001). In the majority of trials, however, modi¢ca- sign was common to all studies. Erythema was assessed in 80 of tions were made for no clear reason, and included substituting 85 trials (94%), licheni¢cation in 71 of 85 trials (84%), and clinical signs or using di¡erent gradings from those in the origi- excoriations in 54 of 85 trials (64%), with the remaining signs nal tested scoring system. being recorded in less than 35% of trials. Unpublished severity indices The remaining 50 trials (59%) used a Published severity indices Only 23 of the 85 trials (27%) employed variety of unnamed ‘‘objective’’scoring systems with no published a previously published named scoring system. The SCORAD in- data on validity and reliability testing, using 36 di¡erent combi- dex (European Task Force on Atopic Dermatitis, 1993) was the nations of clinical signs in total. 934 Table II. Clinical signs measured in atopic dermatitis severity indices in RCTs 1994^2001 CHARMAN TAL ET Erythema Erythema/oedema Excoriation or erosion Exudation or weeping or oozing Oozing/crusting Excoriation/ oozing/crusting Crusting Crusting/cracking Papules Pustules Purulence Papulation/erosion/ scaling Vesicles Vesicles/papules Bullae Edema or swelling Edema/ vesiculation Edema or induration/ papulation Infiltration or thickening or induration Induration/ lichenification Dryness or xerosis Dryness/scaling Scaling Scaling/crusting Roughness Cracking or fissuring Lichenification Pigmentation/ depigmentation Squamous lesions Inflammation Surface damage Total number of signs assessed Scale Scale name References n 1 0^3 Mabin et al, 1995a n 1 0^5 Ewing et al, 1998 n 1 0^5 Mabin et al, 1995b n n 2 0^3 Latchman et al,1996 n n 2 0^3 Marchesi et al, 1994 n n 2 0^3 Cato et al,2001 nn n 3 0^3 Ehlers et al, 1995 nn n 3 0^2 Hiratsuka et al,1996 nn n 3 0^2 Kimata and Hiratsuka, 1994 nn n 3 0^2 Sasai-Takedatsu et al,1997 nn n 3 0^3 EASIa Boguniewicz et al, 1998 n nn3 0^3 Humphreys et al,1994 nn n 3 0^3 Munro et al, 1994 nn n 3 0^3 Patel et al, 1997 nn n 3 NS Ventura et al,1996 nn nn4 0^3 EASI Hani¢n et al,2001a nn nn4 0^3 EASIa Luger et al,2001 nn nn4 0^3 EASI Paller et al, þ 2001 nn nn 4 0^4 Abeck et al,1997 n nnn 4 0^4 (DASI) Andersson et al, 1999 n nn n4 0^3 Fung et al, 1999 n n nn 4 0^3 Galli et al, 1994 nn nn 4 0^4 Koopmans et al, 1995 nn n n 4 0^3 La Rosa et al,1995 n nnn

4 0^3 Poyner and Dass, 1996 DERMATOLOGY INVESTIGATIVE OF JOURNAL THE nn nn 4 0^3 Schachner et al, 1998 n nn n 4 0^3 Stiller et al, 1994 n nn n 4 0^10 Soyland et al, 1994 nnn n 4 0^3 ADSI Van Leent et al, 1998 nnn n 4 0^3 Arkwright and David, 2001 n nnn4 0^3 Veien et al, 1995 nnnn n5 0^3 Bleehen et al,1995 nnnn n5 0^3 Lebwohl, 1996 nn n nn5 0^3 Jorizzo et al, 1995 nnn nn 5 0^3 Lebwohl, 1999 nn nn n 5 0^3 Lever et al,1998 nn n nn 5 0^3 Maloney et al, 1998 nnn nn5 0^3 Moore et al, 1998 nn n n n 5 0^3 Ramsay et al,1996 nn n n n 5 0^3 SASSADa Reynolds et al,2001 nn nn n 5 0^3 SCORADa Der-Petrossian et al,2000 nn n nn n 6 0^3 SCORADa Broberg and Faergemann, 1995 O.10 O UE2003 JUNE 6 NO. 120, VOL. nn n nn n 6 0^3 SCORAD Isolauri et al, 1995 nn n nn n 6 0^3 SCORAD Majamaa and Isolauri, 1997 nn n nn n 6 0^3 SCORAD Anderson et al, 1998 nn n nn n 6 0^3 SCORAD Wolkerstorfer et al, 1998 nn n nn n 6 0^3 SCORAD Van Der Meer et al, 1999 nn n nn n 6 0^3 SCORAD Isolauri et al,2000 nn n nn n 6 0^3 SCORAD Ricci et al,2000 nn n nn n 6 0^3 SCORAD Capella et al,2001 nn n nn n 6 0^3 SCORAD Gutgesell et al,2001 nn n nn n 6 0^3 SCORAD Holm et al,2001 nn n nn n 6 0^3 SCORAD Niggemann et al,2001 nn n nn n 6Peiet al,2001a nn n nn n 6Peiet al,2001b nn n nn n 6 0^3 SCORADa Tzaneva et al,2001 nn nn nn6 0^3 SCORADa Lintu et al,2001 nn n nnn 6 0^3 Boguniewicz et al,1998 nn n nnn 6 0^3 Paller et al,2001 nn n nnn 6 0^3 Hani¢n et al,2001a nn n n n n 6 0^3 ADASI Yanase and David-Bajar, 2001 nn nnnn6 0^3 Jang et al,2000 nn n nnn 6 0^9 Hani¢n et al, 1998 nnn nnn 6 0^3 SASSADa Tan et al,1996 nnn nnn 6 0^3 SASSADa Zurbriggen et al, 1999 nn n nnn 6 0^3 SASSAD Harper et al,2000 nn n nnn 6 0^3 SASSAD Breneman et al,2000 nn n nn n 6 0^100 Hederos and Berg, 1996 nn n n nn 6 1^4 La Rosa et al, 1994 nn n n n n 6 0^3 Reidhav and Svensson, 1996 nn n n n n 6 1^4 Valsecchi et al, 1996 nn n n n n 6 0^3 Ruzicka et al, 1997 nnn n nn 6 0^3 Stalder et al,1994 nn n n nn 6 0^3 Zonneveld et al, 1996 RCTS IN SEVERITY DERMATITIS ATOPIC MEASURING nn n n n n n 7 0^3 Sears et al, 1997 nn n n n n n 7 0^4 Traulsen, 1997 nn n nnnn 7 0^3 TBSAa Van Joost et al,1994 nn n nnnn 7 0^3 TBSA Czech et al,2000 nn n n n n nn 8 0^3 Costaa Henz et al,1999 nn n n n n nn 8 0^7 Costa Harper, 1995 nn n n n n nn 8 NS NS Holland et al, 1995 nn n n n n nn 8 0^7 Costa Schoni et al, 1997 nn n n n n nn 8 0^7 Costa Noh and Lee, 2001 nnn n n n n n 8 0^6 Costaa Krutmann et al, 1998 nn nn n n n nn 9 0^3 Biagi et al, 1994 nnn nn n n nn 9 0^3 Korting et al, 1995 nn nnnnnnn n 10 1^5 Korting et al, 1994 ADSI, Atopic Dermatitis Severity Index; ADASI, Atopic Dermatitis Area and Severity Index; Costa, Costa’s Simple Scoring System; DASI, Dry Skin Area and Severity Index; EASI, Eczema Area and Severity Index; SASSAD, Six Area, Six Sign Atopic Dermatitis Severity index; SCORAD, Scoring Atopic Dermatitis Severity index; TBSA,Total Body Severity Assessment; NS, not speci¢ed. amodi¢ed version of index. 935 936 CHARMAN ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Symptoms Of the 93 trials identi¢ed, 80 (86%) included an Changes over time When the 25 RCTs published over the 2 y assessment of patient symptoms (Tab l e I I I ), with up to seven period 2000^1 were compared with trials published in the symptoms being assessed in each trial. The majority of trials preceding 6 y period 1994^9, there was evidence of a signi¢cant assessed only pruritus (36 trials), or pruritus and sleep increase in the use of published severity indices (58% vs 15%, disturbance (34 trials). Other symptoms such as dryness or po0.05), with the SCORAD index (six trials), EASI (three scaling (eight trials) and pain (one trial) were rarely measured. trials), and SASSAD index (two trials) being the most widely The gradings for each of these symptoms ranged from 03to used indices over the last 2 y. There was also a signi¢cant 014 where speci¢ed. In 44 of the 80 trials (55%) patients’ increase in the use of disease extent measurements over the last 2 symptom scores were combined with physicians’ objective y(92%vs 57%, po0.05), but no statistically signi¢cant clinical sign scores to give an overall composite severity score, as di¡erences in the number of RCTs assessing patient symptoms part of the SCORAD index (13 trials), Costa’s Simple Scoring or global changes in disease severity. System (¢ve trials), the EASI (one trial), the ADSI (one trial), Rajka and Langeland’s scoring system (one trial) (Rajka and Langeland, 1989), or in a variety of unnamed scoring systems (23 DISCUSSION trials). Only 17 of these 44 trials also presented the symptom scores separately. The principles of evidence-based medicine are used increasingly in dermatology to guide clinical practice and resource allocation. Disease extent Of the 93 trials identi¢ed, 62 (67%) included an The production of therapy guidelines, compendiums of evidence assessment of disease extent, using one of 20 di¡erent methods of (Charman and Williams, 2001), and systematic reviews (Hoare estimating body surface area involvement (Tab l e I V ). Of these 62 et al, 2000) is dependent on comparison of data from many di¡er- trials, 40 incorporated the disease extent data into a composite ent sources, and is hindered by wide variations in trial methodol- scoring system including other signs and/or symptoms, as part ogy. The current state of outcome measures for atopic dermatitis of the SCORAD index (15 trials), Costa’s score (¢ve trials), can only be described as a mess. There are almost as many scales Rajka’s index (one trial), EASI (¢ve trials), ADASI (one trial), as there are trials, and most are unvalidated and synthesized de DASI (one trial), or as part of an unnamed scoring system (12 novo for each trial. Signs and symptoms are frequently mixed up trials). In only nine of these trials were disease extent data also together, and patient-centered outcome measures seem to be ne- presented separately. glected by an obsession to measure ‘‘objective signs’’,which, when A further 13 trials estimated disease extent indirectly by tested for validity and repeatability, are less objective than one grading clinical signs at several body sites and summing the would like (Charman and Williams, 2000). The huge variation scores for each site. Of these, four trials assessed signs at six in outcome measures for atopic dermatitis described in this paper body sites using the SASSAD index or an earlier version of this refers to just the last 8 y.This time period contains only a fraction index (Van Joost et al,1994;Tanet al,1996;Zurbriggenet al, 1999; of the total number of atopic dermatitis RCTs identi¢ed in a re- Harper et al, 2000). The remaining trials used a variety of cent systematic review covering over 270 trials published be- unnamed scoring systems, assessing clinical signs in either four tween 1966 and 1999 (Hoare et al, 2000), suggesting that the true (Munro et al, 1994; Sasai-Takedatsu et al, 1997), ¢ve (Stalder et al, variation in outcome methodology is likely to be substantially 1994), six (Zonneveld et al,1996),12(Mooreet al,1998),15(Kimata higher. Although analysis of trials over the last 2 y of the review and Hiratsuka, 1994; Hiratsuka et al, 1996), or 20 body sites (La has shown a move towards improved standardization, over 40% Rosa et al,1994;1995;Valsecchiet al,1996). of RCTs are still using either unpublished or modi¢ed scales. Clinical signs A huge profusion of clinical signs have been Global measures of disease severity An overall global severity measured, re£ecting the di⁄culties in de¢ning which objective assessment was performed at the end of the study by the features best re£ect disease severity. Di¡erent gradings have been investigators in 34 trials (37%) and by the patients in 26 trials used to quantify the same clinical features, and no single sign has (28%). Various scales were used although a four-point scale was been used consistently across all studies, making comparison most commonly employed (18 trials). across trials almost impossible. The choice of clinical signs has generally been based on the opinion of panels of experts Other outcome measures Topical steroid requirements were (European Task Force on Atopic Dermatitis, 1993), although an recorded in 15 trials, and antihistamine use in four trials. alternative is to assess which signs best predict changes in Quality of life was measured in only three trials (3%), all patient-assessed morbidity. The latter method has been used published between 2000 and 2001, using either the Children’s recently as part of a wider study1 involving 200 patients with Dermatology Life Quality Index (CDLQI) (Harper et al,2000), atopic eczema, and showed that three clinical signs (erythema, a modi¢ed CDLQI (Pei et al, 2001a), a modi¢ed Dermatology excoriations, edema/papulation) were the best predictors of Life Quality Index (Czech et al, 2000), or the family impact patient-assessed morbidity (in preparation), although others such questionnaire (Harper et al, 2000). The e¡ect of atopic dermatitis as licheni¢cation are likely to be helpful in long-term studies. The on daily living was measured using an unnamed scale in two clinical meaning of percentage changes in continuous objective further trials (Soyland et al,1994;Peiet al, 2001b). A measure of scales will always be di⁄cult to interpret, and need to be atopic dermatitis related distress (Marburg Atopic Dermatitis interpreted in conjunction with other outcome measures, as in questionnaire), global disability ratings and anxiety and practice it is the patient who is treated and not the signs of the depression scales were used in one trial investigating psychologic disease. Furthermore, clinical signs are assessed by physicians at approaches to relapse prevention (Ehlers et al,1995).Aseries one point in time only, and even when assessed every week may of behavioral and anxiety scales were also used in a study fail to capture the £uctuating nature of the disease, especially investigating the e¡ects of massage therapy in children given the short duration of most trials in this study. Another (Schachner et al,1998). serious problem is the risk of bias if investigators choose new combinations of signs in order to amplify the e¡ects of a Duration of assessment The duration of RCTs ranged from 7 speci¢c treatment. In the ¢eld of psychiatry it has already been d to 3 y, with a median trial duration of 6 wk. Only 12 trials demonstrated that trials are more likely to report that a (13%) followed patients for longer than 6 mo (Galli et al,1994; treatment is superior to control when an unpublished index Ehlers et al, 1995; Isolauri et al,1995;2000;Tanet al,1996; is used to make the comparison. In one study of Friedmann and Tan, 1998; Harper et al, 2000; Ricci et al,2000; Gutgesell et al, 2001; Holm et al, 2001; Niggemann et al,2001; 1 Charman CR,Venn AJ,Williams HC. Patient based outcome measures Tzaneva et al,2001). for atopic dermatitis. Br J Dermatol 143 (Suppl 57):34, 2000 (abstr.) VOL. 120, NO. 6 JUNE 2003 MEASURING ATOPIC DERMATITIS SEVERITY IN RCTS 937

Table III. Symptoms of atopic dermatitis assessed in 80 RCTs from 1994 to 2001 Symptom Grading No. of References studies

Pruritus/itch 0^10 32 Drake et al, 1994; 1999; Langeland et al, 1994; Munro et al, 1994; Soyland et al,1994; Broberg and Faergemann, 1995; Ehlers et al, 1995; Isolauri et al,1995;2000;Mabinet al, 1995b; Hederos and Berg, 1996; Majamaa and Isolauri, 1997; Andersen et al, 1998; Boguniewicz et al,1998; Ebata et al,1998;Ewinget al, 1998; Berberian et al, 1999; Zurbriggen et al, 1999; Anderson et al,2000; Czech et al, 2000; Der-Petrossian et al, 2000; Harper et al, 2000; Ricci et al,2000; Capella et al, 2001; Gutgesell et al,2001;Hani¢net al,2001a;Holmet al,2001; Lintu et al, 2001; Niggemann et al, 2001; Reynolds et al,2001;Tzanevaet al,2001 0^9 1 Hani¢n et al,1998 0^7 3 Harper, 1995; Schoni et al, 1997; Noh and Lee, 2001 0^6 3 Soyland et al, 1994; Krutmann et al,1998;Catoet al,2001 0^5 1 Schoni et al,1997 0^4 2 Koopmans et al, 1995; Traulsen, 1997 0^3 or 4-point scale 35 Biagi et al, 1994; Drake et al, 1994; 1999; Galli et al, 1994; Kimata and Hiratsuka, 1994; La Rosa et al, 1994; 1995; Marchesi et al, 1994; Stiller et al, 1994; Van Joost et al,1994; Bleehen et al, 1995; Jorizzo et al, 1995; Korting et al, 1995; Mabin et al, 1995a; Veien et al,1995; Hiratsuka et al, 1996; Lebwohl, 1996; 1999; Poyner and Dass, 1996; Ramsay et al,1996; Reidhav and Svensson, 1996; Valsecchi et al, 1996; Zonneveld et al, 1996; Patel et al,1997; Ruzicka et al, 1997; Sasai-Takedatsu et al, 1997; Andersen et al, 1998; Boguniewicz et al,1998; Maloney et al, 1998; Schachner et al,1998;VanLeentet al,1998;Henzet al,1999;Janget al,2000; Luger et al, 2001; Paller et al,2001 1^3 1 Gimenez-Arnau et al,1997 NS 5 Stalder et al, 1994; Bleehen et al,1995;Hollandet al, 1995; Ventura et al, 1996; Breneman et al,2000 Pruritus relief 0^10 3 Drake et al, 1994; 1999; Berberian et al,1999 0^3 1 Drake et al,1999 5-point scale 1 Drake et al,1994 Sleep disturbance 0^10 19 Majamaa and Isolauri, 1997; Isolauri et al,1995;2000;Mabinet al, 1995b; Hederos and Berg, 1996; Isolauri, 2000; Ewing et al, 1998; Zurbriggen et al, 1999; Anderson et al, 2000; Czech et al, 2000; Der-Petrossian et al,2000; Harper et al, 2000; Ricci et al, 2000; Capella et al, 2001; Gutgesell et al, 2001; Holm et al,2001; Lintu et al, 2001; Niggemann et al, 2001; Reynolds et al,2001 0^7 3 Harper, 1995; Schoni et al, 1997; Noh and Lee, 2001 0^6 1 Krutmann et al,1998 0^5 1 Schoni et al,1997 0^3 10 Kimata and Hiratsuka, 1994; Van Joost et al, 1994; Mabin et al, 1995a; Hiratsuka et al,1996; Zonneveld et al, 1996; Patel et al, 1997; Ruzicka et al, 1997; Sasai-Takedatsu et al,1997; Henz et al,1999;Janget al,2000 1^3 1 Ebata et al,1998 NS 2 Stalder et al, 1994; Bleehen et al,1995 Skin dryness 0^14 1 Andersson et al,1999 0^10 2 Humphreys et al, 1994; Hederos and Berg, 1996 0^7 1 Soyland et al,1994 NS 1 Stalder et al,1994 Dryness/burning 0^10 1 Broberg and Faergemann, 1995 Scaling 0^10 2 Humphreys et al, 1994; Hederos and Berg, 1996 Redness 0^7 1 Soyland et al,1994 0^10 2 Humphreys et al, 1994; Hederos and Berg, 1996 Redness/swelling 0^3 1 La Rosa et al,1995 Crusting 0^10 1 Hederos and Berg, 1996 Smarting pain 0^3 1 Reidhav and Svensson, 1996 Fidgeting 0^10 1 Hederos and Berg, 1996 nonpharmacologic trials, one-third of ‘‘gold standard’’ claims of SCORAD comprises a measurement of six clinical signs at a treatment superiority would not have been made if published representative body site, combined with an assessment of disease scales had been used (Marshall et al,2000). extent and visual analog scales of pruritus and sleep loss to give a maximum possible score of 103. It has been suggested that disease Which named scale to use? Of the named objective clinical severity can be categorized as mild (o15), moderate (15^40), or scales in this review, three scales have been most widely severe (440) according to the objective components of the employed and tested: SCORAD, EASI, and SASSAD. All have index (clinical signs and disease extent), with typical changes in shown evidence of criterion and construct validity against global scores from 4550 to 2530 being demonstrated in recent assessments of disease severity, patient-assessed pruritus, and other clinical trials (Van Der Meer et al, 1999; Capella et al, 2001; Holm variables such as topical steroid use. Some interobserver variation et al, 2001).The index has extensive published data on validity and has been demonstrated with all three indices, and is likely to be a reliability, although licheni¢cation and body surface area problem with all scoring systems involving visual assessment by measurements in particular have shown signi¢cant interobserver physicians. Each has advantages and disadvantages, making it variation in some studies (Charman and Williams, 2000). di⁄cult to recommend one index as superior, although the Although SCORAD is a composite score, the measurements of SCORAD index has been most widely used in trials. disease extent, signs, and symptoms can easily be separated and 938 CHARMAN ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Table IV. Assessment methods used for measuring body surface area involvement in atopic dermatitis in 62 RCTs from 1994 to 2001 Method used to assess disease extent No. of studies References

Scale of 0%^100% using rule of nines 27 Munro et al, 1994; Stiller et al, 1994; Broberg and Faergemann, 1995; Isolauri et al, 1995; 2000; Tan et al, 1996; Zonneveld et al, 1996; Gimenez-Arnau et al, 1997; Majamaa and Isolauri, 1997; Andersen et al,1998; Lever et al, 1998; Schachner et al, 1998; Wolkerstorfer et al,1998; Van Der Meer et al, 1999; Zurbriggen et al, 1999; Der-Petrossian et al,2000; Harper et al, 2000; Jang et al, 2000; Ricci et al, 2000; Capella et al,2001; Gutgesell et al, 2001; Holm et al,2001;Lintuet al,2001; Niggemann et al,2001;Peiet al,2001a;2001b;Tzanevaet al,2001 Scale of 0%^100% using transparent shapes of 100^1000 cm2 1 Ruzicka et al,1997 Scale of 0%^100% using body schema of 1044 squares 1 Ehlers et al,1995 Scale of 0%^100% using series of area scales 1^300 cm2 1 Poyner and Dass, 1996 Scale of 0%^100% (method not speci¢ed ) 3 Hederos and Berg, 1996; Czech et al, 2000; Arkwright and David, 2001 Scale of 0^3 1 Biagi et al,1994 Scale of 1^3 2 Veien et al, 1995; Gimenez-Arnau et al,1997 Scale of 0^6 2 Soyland et al, 1994; Breneman et al,2000 Scale of 0^10 1 Soyland et al,1994 Color-coded drawing using grid of parallel lines 2 cm apart 1 Yanase and David-Bajar, 2001 4 body zones ^ % area assessed in each zone 1 Andersson et al,1999 4 body zones ^ area assessed 0^6 in each zone 5 Boguniewicz et al,1998;Hani¢net al, 2001a; Luger et al,2001; Paller et al,2001 5.5 body zones ^ area assessed 1^3 in each zone 1 Fung et al,1999 6 body zones ^ area de¢ned in thirds in each zone 2 Van Joost et al, 1994; Reynolds et al,2001 10 body zones ^ area assessed 0^3 in each zone 5 Harper, 1995; Schoni et al, 1997; Krutmann et al, 1998; Henz et al, 1999; Noh and Lee, 2001 14 body zones ^ % area assessed in each zone 1 Ewing et al,1998 16 body zones ^ area assessed 0^3 in each zone 1 Lever et al,1998 20 body zones ^ area assessed 1^3 in each zone 1 Latchman et al,1996 20 body zones ^ % area assessed in each zone 1 Humphreys et al,1994 32 body zones ^ % area assessed in each zone 2 Mabin et al, 1995a; 1995b Disease extent classi¢ed as localized, limited, or generalized 2 La Rosa et al,1995;Ramsayet al, 1996 Assessment method not speci¢ed 3 Holland et al, 1995; Ventura et al, 1996; Friedmann and Tan, 1998 presented as individual measurements if required. EASI is a more Symptoms and quality of life ascribed low importance recently developed index, being the second most widely used Although patients’ symptoms are subjective, it is ultimately named scale over the last 2 y. The EASI measures four of the around the control of these symptoms that the treatment of clinical signs used in SCORAD (maximum score 72) and has atopic dermatitis revolves. Although most trials included an shown reasonably good reliability, with induration/papulation assessment of itching or sleep disturbance, patients were rarely assessments showing the most interobserver variability (Hani¢n asked to rate other aspects of their disease such as soreness or et al, 2001b). The assessment of disease extent forms an discomfort,1 and patient global severity ratings were used in less important integral part of the index that is di⁄cult to separate than a third of trials. Furthermore, quality of life was assessed in out from the overall score. The EASI does not attempt to only three of 93 trials. As symptoms are self-rated by patients, include symptoms in the overall score and these should be regular assessments using diary records can be used to capture measured separately. The SASSAD index uses the same six signs £uctuations in disease activity and potentially provide a more as the SCORAD index, with the substitution of cracking for accurate long-term picture of the e¡ects of therapy.The problem edema/papulation (maximum score 108) (Berth-Jones, 1996). of combining severity scores rated by patients with those rated by Clear de¢nitions are included in the index, and validity has physicians has previously been highlighted (Finlay, 1996) but been demonstrated in several trials although reliability data continues to be widely practised in trials using composite are limited to one small study (Charman et al, 2002). Other scoring systems. scales such as Costa’s Simple Scoring System are more time consuming to administer and have been less widely used over An appeal for standardization In the absence of a gold the last 2 y. standard measure of atopic eczema severity, opinion on which aspects of the disease are most important will always vary Surface area of involved skin Disease extent measurements between physicians, and also between physicians and patients. varied widely among RCTs, re£ecting the technical di⁄culties Although it is generally accepted that symptoms, signs, and previously reported for estimating surface area involvement in extent are important, with extent measurements being given skin diseases (Tiling-Grosse and Rees, 1993; Charman et al, 1999). less weighting than signs of disease intensity (Hani¢n, 1989), Atopic dermatitis is characterized by indistinct disease margins, the concept of consensus on an ‘‘ideal’’ objective scale is and the poor reliability of body surface area estimates means unrealistic. It is possible, however, to propose a conceptual that such measurements need to be interpreted with caution. In framework for choosing the domains that should be covered over 50% of the RCTs that measured disease extent, the when measuring atopic dermatitis severity in the clinical trial measurement was then incorporated into a composite score with setting (Tab l e V ). Instead of attempting to design yet further arbitrary and variable weighting given to disease extent, signs, scales let us concentrate on using the most widely validated and symptoms. In such trials, translating how changes in the indices available to allow better comparison between studies, ¢nal score accurately and meaningfully re£ect disease severity resisting modi¢cations to the tested scale unless absolutely becomes extremely di⁄cult. essential. The presentation of parameters in composite indices VOL. 120, NO. 6 JUNE 2003 MEASURING ATOPIC DERMATITIS SEVERITY IN RCTS 939

TableV. Minimum set of outcome measures for future RCTs Biagi PL, Bordoni A, Hrelia S, et al: The e¡ect of g-linolenic acid on clinical status, of treatments for atopic dermatitis red cell fatty acid composition and membrane microviscosity in infants with atopic dermatitis. Drugs Exp Clin Res 20:77^84, 1994 Most extensively validated objective clinical scoring system available Bleehen SS, Chu AC, Hamann I, Holden C, Hunter JA, Marks R: Fluticasone pro- A regular measurement of patient symptoms from baseline to end of study to pionate 0.05% cream in the treatment of atopic eczema: A multicentre study comparing once-daily treatment and once-daily vehicle cream application ver- capture relapses and remissions sus twice-daily treatment. Br J Dermatol 133:592^597, 1995 A single categorical global measure of patient’s perception of improvement at Boguniewicz M, Fiedler VC, Raimer S, Lawrence ID, Leung DY, Hani¢n JM: A end of study randomized, vehicle-controlled trial of tacrolimus ointment for treatment of A single categorical global measure of physician’s perception of improvement atopic dermatitis in children. Pediatric Tacrolimus Study Group. J Allergy Clin at end of study Immunol 102 (4 Part 1):637^644, 1998 A quality of life measure Breneman DL, Hani¢n JM, Berge CA, Keswick BH, Neumann PB: The e¡ect of antibacterial soap with 1.5% triclocarban on Staphylococcus aureus in patients with atopic dermatitis. Cutis 66:296^300, 2000 Broberg A, Faergemann J: Topical antimycotic treatment of atopic dermatitis in the such as SCORAD or EASI separately, in addition to a total score, head/neck area. A double-blind randomised study. Acta DermatoVenereol 75:46^ 49, 1995 allows more meaningful interpretation (Hani¢n et al,2001a; Capella GL, Frigerio E, Altomare G: A randomized trial of leukotriene receptor an- Lintu et al, 2001; Paller et al, 2001). Patient symptom tagonist montelukast in moderate-to-severe atopic dermatitis of adults. Eur J measurements should include an assessment of pruritus, and may Dermatol 11:209^213, 2001 include other symptoms such as sleep disturbance and soreness. Cato A, Swinehart JM, Gri⁄n EI, Sutton L, Kaplan A: Azones enhances clinical Symptoms can be recorded on a regular basis using daily or e¡ectiveness of an optimized formulation of triamcinolone acetonide in atopic weekly diary records in order to capture disease relapses and dermatitis. Int J Dermatol 40:232^236, 2001 Charman C, Williams HC: Outcome measures of disease severity in atopic eczema. remissions (Thomas et al, 2002), and data should be presented Arch Dermatol 136:763^769, 2000 separately from physicians’ clinical measurements. Simple global Charman CR, Williams HC: Atopic eczema. In: Barton S ed. Clinical Evidence. Issue objective scores can provide useful information as they avoid the 5. London: BMJ Publishing Group, June 2001 complexities of composite clinical scoring systems and may Charman CR, Venn AJ, Williams HC: Measurement of body surface area provide a more pragmatic indicator of clinically meaningful involvement in atopic eczema: An impossible task? Br J Dermatol 140:109^111, change to practising physicians and their patients (Luger et al, 1999 Charman CR, Venn AJ, Williams HC: Reliability testing of the Six Area, Six Sign 2001; Paller et al, 2001). Finally, the assessment of the impact of Atopic Dermatitis (SASSAD) severity score. Br J Dermatol 146:1057^1060, 2002 treatment on quality of life is of great importance in a nonlife- Costa C, Rilliet A, Nicolet M, Saurat JH: Scoring atopic dermatitis: The simpler the threatening condition such as atopic dermatitis, and can be easily better? Acta DermVenereol (Stockh) 69:41^45, 1989 measured using a validated scoring system such as the Czech W,Brutigam M,Weidinger G, Sch˛pf E: A body-weight-independent dosing Dermatology Life Quality Index or children’s equivalent (Finlay regimen of cyclosporine microemulsion is e¡ective in severe atopic dermatitis and Khan, 1994; Lewis-Jones and Finlay, 1995). Relative to the and improves the quality of life. JAmAcadDermatol42:653^659, 2000 Der-Petrossian M, Seeber A, H˛nigsmann H, Tanew A: Half-side comparison study large amount of time and resources being poured into the ¢eld on the e⁄cacy of 8-methoxypsoralen bath-PUVA versus narrow-band ultravio- of atopic dermatitis research, too little attention has been paid to let B phototherapy in patients with severe chronic atopic dermatitis. Br J Der- what we are actually measuring and basing our decision-making matol 142:39^43, 2000 on. Although some steps have been taken over recent years, a Diepgen TL: Is the prevalence of atopic dermatitis increasing? In: Williams HC ed. more generalized move towards improved standardization of Atopic Dermatitis: the Epidemiology, Causes and Prevention of Atopic Eczema.Cam- outcome measures in future trials will lead to better utilization bridge: Cambridge University Press, 2000 Drake LA, Fallon JD, Sober A: Relief of pruritus in patients with atopic dermatitis of research ¢ndings and more accurate information on the after treatment with topical doxepin cream. The Doxepin Study Group. JAm e¡ectiveness of therapy for patients with this chronic and Acad Dermatol 31:613^616, 1994 debilitating disease. Drake LA, Cohen L, Gillies R, Flood JG, Riordan AT, Phillips SB, Stiller MJ: Phar- macokinetics of doxepin in subjects with pruritic atopic dermatitis. 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