Acitretin in Dermatology A.D
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BJD GUIDELINES British Journal of Dermatology British Association of Dermatologists guidelines on the efficacy and use of acitretin in dermatology A.D. Ormerod, E. Campalani* and M.J.D. Goodfield Department of Dermatology, University of Aberdeen, Foresterhill, Aberdeen AB9 2ZB, U.K. *Department of Dermatology, Royal London Hospital, Whitechapel Road, London E1 1BB, U.K. Department of Dermatology, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, U.K. Correspondence Acitretin, a synthetic retinoid, is the pharmacologically active Anthony Ormerod. metabolite of etretinate. It replaced etretinate in the late 1980s E-mail: [email protected] because of its more favourable pharmacokinetic profile, and it is an established systemic second-line therapy for severe psori- Accepted for publication asis resistant to topical therapy. Bioavailability is enhanced by 9 February 2010 food, especially fatty food.1 Acitretin is 50 times less lipophilic Key words than etretinate and has a shorter elimination half-life. How- acitretin, ichthyosis, psoriasis, safety, systematic ever, there is evidence that small amounts of acitretin are review, treatment guidelines re-esterified to etretinate, which has a very long half-life, especially in the presence of alcohol.2,3 Intracellularly, it inter- Conflicts of interest acts with cytosolic proteins and nuclear receptors, which are None declared. part of the steroid-thyroid hormone superfamily. We know that these nuclear receptors act as transcriptional factors for This is a new set of guidelines prepared for the BAD specific DNA sequences; however, their role in the retinoid Clinical Standards Unit, made up of the Therapy & pathway is largely unknown. In psoriasis and other disorders Guidelines Subcommittee (T&G) and the Audit & of keratinization, acitretin normalizes epidermal cell prolifera- Clinical Standards Subcommittee (A&CS). Members tion, differentiation and cornification.4,5 It is thought to exert of the Clinical Standards Unit are: H.K. Bell these effects by interfering with the expression of epidermal (Chairman T&G), L.C. Fuller (Chairman A&CS), N.J. Levell, M.J. Tidman, P.D. Yesudian, J. Lear, growth factor genes. There is also evidence that acitretin has J. Hughes, A.J. McDonagh, S. Punjabi, N. Morar, immunomodulatory properties by inhibiting dermal micro- 6 7,8 S. Wagle (British National Formulary), S.E. vascular endothelial cells and neutrophil migration. Acit- Hulley (British Dermatological Nursing Group), retin is licensed for use in severe extensive psoriasis which K.J. Lyons (BAD Scientific Administrator) and M.F. is resistant to other forms of therapy, including topical, Mohd Mustapa (BAD Clinical Standards Manager). light and systemic; palmoplantar pustular psoriasis; severe Darier disease (keratosis follicularis) and severe congenital Guidelines produced in 2010 by the British ichthyosis. Association of Dermatologists; proposed revision in It is highly teratogenic and must not be used by women 2015. who are pregnant or are planning a pregnancy. Acitretin is Disclaimer highly bound to plasma protein and metabolized in the These guidelines have been prepared on behalf of the liver. It is excreted to an equal extent by renal and hepatic British Association of Dermatologists (BAD) and routes. reflect the best data available at the time the report Although available for 20 years there have not been any was prepared. Caution should be exercised in published guidelines on the use of acitretin. Its clinical use is interpreting the data; the results of future studies almost completely restricted to dermatology and it has impor- may require alteration of the conclusions or tant metabolic, skeletal and teratogenic side-effects. We felt it recommendations in this report. It may be necessary important to produce evidence-based guidelines on its use in or even desirable to depart from the guidelines in the dermatology. interests of specific patients and special circumstances. Just as adherence to guidelines may not constitute defence against a claim of negligence, Materials and methods so deviation from them should not necessarily be deemed negligent. A scoping meeting decided that the guideline would include only evidence pertaining to acitretin and would not make DOI 10.1111/j.1365-2133.2010.09755.x direct inferences from studies of the parent drug etretinate. The target audience for the guideline is dermatologists. Ó 2010 The Authors 952 Journal Compilation Ó 2010 British Association of Dermatologists • British Journal of Dermatology 2010 162, pp952–963 Efficacy and use of acitretin in dermatology, A.D. Ormerod et al. 953 patients acitretin at 10, 25 and 50 mg daily produced a 50% Inclusion criteria improvement in psoriasis in 50%, 40Æ5% and 54%, respec- We included all randomized controlled trials (RCTs) testing tively, compared with 61% with etretinate.14 Anecdotal acitretin but also needed to survey the literature on monitor- reports also suggest a differential response.18 Side-effects, like ing patients taking acitretin and adverse effects which could efficacy, were dose related. include well-designed cohort or case–control analytical studies Pearce et al.19 reanalysed retrospectively the pivotal phase and, for rare but significant side-effects, case reports. three trials and found that common adverse events were two We included in the search papers written in English, to three times more frequent in patients receiving 50 mg daily French, Spanish, Italian and German, and those describing compared with patients receiving 25 mg daily. On 25 mg adverse drug reactions, clinical monitoring and consensus daily changes in liver enzymes and lipids were minimal com- statements from respected authorities based on clinical experi- pared with higher doses. The authors advocated use of a low ence and consensus committees. dose as high doses are limited due to adverse events. Others The following databases were searched: EMBASE, MEDLINE, have advocated gradual dose escalation as optimal.20 CINAHL, PubMed, The Cochrane Library, RCP Guidelines All studies preceded the now standardized proportion Database, DARE; this gave 1325 hits. These abstracts were achieving PASI 75 outcome measure. However, 23% of 112 reviewed and, after sifting, 316 papers were reviewed by the patients achieved 75% improvement in one typical study.14 In authors. The search strategy is available separately online (see one study 90% improvement was achieved by 10% of Data S1). patients.15 A retrospective post hoc analysis of the data from three studies was published using the now more widely Stakeholder involvement and peer review accepted criteria of the proportion of patients achieving at least 50% improvement in PASI (PASI 50) and at least 75% The draft guideline was made available for consultation and improvement (PASI 75).21 This showed 52% achieving PASI review by the BAD membership. The final document was 75 and 85% achieving PASI 50 after 12 weeks in the multi- peer-reviewed by the Clinical Standards Unit of the BAD centre Nordic trial on a median dose of acitretin 40 mg (made up of the Therapy & Guidelines and Audit & Clinical daily.13 This was a per protocol analysis. In the Canadian open Standards Subcommittees) prior to publication. trial17 patients started on acitretin 50 mg daily and were tapered to a mean of 40 mg daily. A total of 46% achieved a Indications and efficacy: review of the PASI 75 response and 76% a PASI 50 response by the end of evidence treatment (intent to treat analysis, average duration 267 days). There is an impression from retrospective anecdotal studies that acitretin is more effective in erythrodermic22 and pustular Psoriasis psoriasis than in chronic plaque psoriasis.23 Etretinate was the We found four RCTs comparing acitretin with placebo9–12 and most effective agent in one study of pustular psoriasis.24 four RCTs comparing acitretin with etretinate,13–16 with one In an open study of 396 patients with nail psoriasis who ) open study.17 The types of disease in these trials and the results received acitretin in doses of 0Æ2–0Æ3mgkg 1 daily for are heterogeneous and include generalized pustular, severe and 6 months, the mean improvement in Nail Psoriasis Severity erythrodermic variants. Acitretin is effective compared with Index was 41% and 25% of patients cleared or almost cleared.25 placebo but many of these studies are poorly reported or dose ranging with small numbers in each dosage group. Higher Combination therapy in psoriasis doses of acitretin (50–75 mg daily) are more effective than low doses in these RCTs,9–11 with lower doses of 10–25 mg daily Acitretin and PUVA not significantly better than placebo,9,11,14 although one trial established efficacy at 25 mg daily.10 Taken together, the ran- Four RCTs compared acitretin and PUVA (rePUVA) with domized period of these studies is short, and longer-term open placebo and PUVA, or additionally etretinate and PUVA extensions with variable doses titrated to the patients’ needs in two.26–28 These show the acitretin-PUVA combination to suggest greater efficacy over time with reduction in area and in- be more effective than PUVA alone, reducing the number creasing percentage of patients cleared between 20 and of PUVA treatments, exposure to ultraviolet (UV) A and the 52 weeks.12,17 Twelve-week studies are likely to underestimate clinical scores, and to be as effective as etretinate-PUVA com- the efficacy of acitretin and optimal response will be seen at bination. A trend was seen towards a higher incidence of 12 weeks or later with 70% showing marked improvement side-effects in the acitretin-treated patients.28 In considering at 1 year in the open study.17 Typically 75% improvement in the preventive action of acitretin against carcinogenesis and Psoriasis Area and Severity Index (PASI) score (PASI 75) was the concerns relating to the carcinogenicity of PUVA therapy seen at 12 weeks.13 However, only 2–10% cleared completely. there are theoretical advantages to this combination which In the comparative studies with etretinate there was a trend help mitigate the more serious side-effects of PUVA.