British Association of Dermatologists guidelines on the efficacy and use of acitretin in dermatology

Acitretin, a synthetic retinoid, is the pharmacologically active metabolite of etretinate. It replaced etretinate in the late 1980s because of its more favourable pharmacokinetic profile, and it is an established systemic second-line therapy for severe psoriasis resistant to topical therapy. Bioavailability is enhanced by food, especially fatty food.1 Acitretin is 50 times less lipophilic than etretinate and has a shorter elimination half-life. However, there is evidence that small amounts of acitretin are re-esterified to etretinate, which has a very long half-life, especially in the presence of alcohol.2, 3 Intracellularly, it interacts with cytosolic proteins and nuclear receptors, which are part of the steroid-thyroid hormone superfamily. We know that these nuclear receptors act as transcriptional factors for specific DNA sequences; however, their role in the retinoid pathway is largely unknown. In psoriasis and other disorders of keratinization, acitretin normalizes epidermal cell proliferation, differentiation and cornification.4, 5 It is thought to exert these effects by interfering with the expression of epidermal growth factor genes. There is also evidence that acitretin has immunomodulatory properties by inhibiting dermal microvascular endothelial cells6 and neutrophil migration.7, 8 Acitretin is licensed for use in severe extensive psoriasis which is resistant to other forms of therapy, including topical, light and systemic; palmoplantar pustular psoriasis; severe Darier disease (keratosis follicularis) and severe congenital ichthyosis. It is highly teratogenic and must not be used by women who are pregnant or are planning a pregnancy. Acitretin is highly bound to plasma protein and metabolized in the liver. It is excreted to an equal extent by renal and hepatic routes. Although available for 20 years there have not been any published guidelines on the use of acitretin. Its clinical use is almost completely restricted to dermatology and it has important metabolic, skeletal and teratogenic side-effects. We felt it important to produce evidence-based guidelines on its use in dermatology. A scoping meeting decided that the guideline would include only evidence pertaining to acitretin and would not make direct inferences from studies of the parent drug etretinate. The target audience for the guideline is dermatologists. We included all randomized controlled trials (RCTs) testing acitretin but also needed to survey the literature on monitoring patients taking acitretin and adverse effects which could include well-designed cohort or case–control analytical studies and, for rare but significant side-effects, case reports. We included in the search papers written in English, French, Spanish, Italian and German, and those describing adverse drug reactions, clinical monitoring and consensus statements from respected authorities based on clinical experience and consensus committees. The following databases were searched: EMBASE, MEDLINE, CINAHL, PubMed, The Cochrane Library, RCP Guidelines Database, DARE; this gave 1325 hits. These abstracts were reviewed and, after sifting, 316 papers were reviewed by the authors. The search strategy is available separately online (see Data S1). The draft guideline was made available for consultation and review by the BAD membership. The final document was peer-reviewed by the Clinical Standards Unit of the BAD (made up of the Therapy & Guidelines and Audit & Clinical Standards Subcommittees) prior to publication. We found four RCTs comparing acitretin with placebo9-12 and four RCTs comparing acitretin with etretinate,13-16 with one open study.17 The types of disease in these trials and the results are heterogeneous and include generalized pustular, severe and erythrodermic variants. Acitretin is effective compared with placebo but many of these studies are poorly reported or dose ranging with small numbers in each dosage group. Higher 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 not significantly better than placebo,9, 11, 14 although one trial established efficacy at 25 mg daily.10 Taken together, the randomized period of these studies is short, and longer-term open extensions with variable doses titrated to the patients' needs suggest greater efficacy over time with reduction in area and increasing percentage of patients cleared between 20 and 52 weeks.12, 17 Twelve-week studies are likely to underestimate the efficacy of acitretin and optimal response will be seen at 12 weeks or later with 70% showing marked improvement at 1 year in the open study.17 Typically 75% improvement in Psoriasis Area and Severity Index (PASI) score (PASI 75) was seen at 12 weeks.13 However, only 2–10% cleared completely. In the comparative studies with etretinate there was a trend for acitretin to be slightly less effective and to present a higher incidence of similar side-effects. In an 8-week trial in 175 patients acitretin at 10, 25 and 50 mg daily produced a 50% improvement in psoriasis in 50%, 40·5% and 54%, respectively, compared with 61% with etretinate.14 Anecdotal reports also suggest a differential response.18 Side-effects, like efficacy, were dose related. Pearce et al.19 reanalysed retrospectively the pivotal phase three trials and found that common adverse events were two to three times more frequent in patients receiving 50 mg daily compared with patients receiving 25 mg daily. On 25 mg daily changes in liver enzymes and lipids were minimal compared with higher doses. The authors advocated use of a low dose as high doses are limited due to adverse events. Others have advocated gradual dose escalation as optimal.20 All studies preceded the now standardized proportion achieving PASI 75 outcome measure. However, 23% of 112 patients achieved 75% improvement in one typical study.14 In one study 90% improvement was achieved by 10% of patients.15 A retrospective post hoc analysis of the data from three studies was published using the now more widely accepted criteria of the proportion of patients achieving at least 50% improvement in PASI (PASI 50) and at least 75% improvement (PASI 75).21 This showed 52% achieving PASI 75 and 85% achieving PASI 50 after 12 weeks in the multicentre Nordic trial on a median dose of acitretin 40 mg daily.13 This was a per protocol analysis. In the Canadian open trial17 patients started on acitretin 50 mg daily and were tapered to a mean of 40 mg daily. A total of 46% achieved a PASI 75 response and 76% a PASI 50 response by the end of 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 than in chronic plaque psoriasis.23 Etretinate was the most effective agent in one study of pustular psoriasis.24 In an open study of 396 patients with nail psoriasis who received acitretin in doses of 0·2–0·3 mg kg−1 daily for 6 months, the mean improvement in Nail Psoriasis Severity Index was 41% and 25% of patients cleared or almost cleared.25 Four RCTs compared acitretin and PUVA (rePUVA) with placebo and PUVA, or additionally etretinate and PUVA in two.26-28 These show the acitretin-PUVA combination to be more effective than PUVA alone, reducing the number of PUVA treatments, exposure to ultraviolet (UV) A and the clinical scores, and to be as effective as etretinate-PUVA combination. A trend was seen towards a higher incidence of side-effects in the acitretin-treated patients.28 In considering the preventive action of acitretin against carcinogenesis and the concerns relating to the carcinogenicity of PUVA therapy there are theoretical advantages to this combination which help mitigate the more serious side-effects of PUVA. This is supported for etretinate in the American PUVA cohort29 where the incidence of squamous cell carcinomas was reduced by retinoids. The same could be said for narrowband UVB where the carcinogenic risk is probably less. One RCT, two open studies and one retrospective study compared acitretin in combination with UVB24, 30-33 with UVB alone. Better outcomes and sparing of UVB were consistently seen with acitretin-UVB in combination than with UVB alone. In a recent RCT acitretin and UVB (TL-01) cleared 55·6% of patients compared with 63·3% treated with acitretin and PUVA.34 Two large RCTs combining acitretin with calcipotriol ointment showed additive benefits of the combination although each relied on subjective outcome measures.35 In one study the number of patients clear or almost clear was increased from 41% to 67% by the addition of calcipotriol36 and the number of patients with complete clearance increased in the other from 15% to 40% after 12 weeks.37 Acitretin with hydroxycarbamide and with etanercept have anecdotally been effective for some patients with plaque psoriasis.38 The combination of methotrexate and acitretin has been used in patients with severe psoriasis, where all other treatments have failed.39, 40 This has been based on anecdotal evidence extrapolated from etretinate.41 Although this combination can be very effective, sporadic severe hepatotoxic responses have been reported.42-44 The efficacy of concomitant use of acitretin with ciclosporin is not convincing45 and, in addition, this combination carries the risk of accumulation of ciclosporin as both drugs are inactivated by the same cytochrome P-450 system.46 A recent RCT showed similar efficacy from the combination regimen of acitretin 0·4 mg kg−1 daily and etanercept 25 mg once weekly to that observed with etanercept 25 mg twice weekly. Although a small study, this suggests that the addition of acitretin has an etanercept-sparing effect.47 Two RCTs compared acitretin with placebo in palmoplantar pustulosis.48, 49 Acitretin was significantly more effective than placebo, acting within 4 weeks to produce a fivefold reduction in pustules. After 12 weeks the second study49 comparing acitretin and etretinate showed a tenfold reduction in pustules which was similar for both retinoids. There have been numerous reports of retinoids used as prophylaxis against skin cancer in organ transplant recipients. Three RCTs were systematically reviewed in 2005 by Chen et al.50 These included two parallel studies of 44 and 26 patients followed for 6 and 12 months, and a crossover study of 23 patients. Only the short study had a fixed dose of 30 mg daily. Longer-term studies had differing dose regimens. In the study by George et al.51 acitretin was titrated from 25 mg daily up to 50 mg daily or down to 25 mg on alternate days. In the crossover study there was a 42% decrease in squamous cell carcinoma in the acitretin period compared with drug-free period. A similar trend was seen with basal cell carcinoma although numbers were small. For patients treated for 6 months and off treatment for 6 months, two of 19 patients (11%) in the acitretin group reported a total of two new squamous cell carcinomas during the treatment period, compared with nine of 19 patients (47%) in the placebo group who developed a total of 18 new carcinomas. The two trials counting premalignant lesions showed a significant reduction in these. Keratotic lesions increased by 28% in the placebo group and decreased by 13·4% in the acitretin group.52 The third study which compared different doses of acitretin did not show a difference in tumour rate between doses of 0·4 mg kg−1 daily and 0·4 mg kg−1 daily reducing to 0·2 mg kg−1 for 9 months, nor a significant reduction compared with that observed in the preceding year without acitretin.53 However, thickness of lesions was reduced and numbers of actinic keratoses were reduced. Side-effects were a limiting factor in these studies, leading to significant drop-outs, although lower doses were tolerated. Overall these were small studies with a modest reduction in cancer over a short period of observation, and further studies are required. Other retinoids have anecdotally prevented malignancy in congenital skin cancer syndromes such as xeroderma pigmentosum (isotretinoin)54 and basal cell naevus syndrome (etretinate)55, 56 and it may be implied that acitretin has a place here. Acitretin has been used in severe forms of the heterogeneous group of the ichthyoses where marked hyperkeratosis is the main pathological component. The evidence for its efficacy is based on anecdotal reports. We found five open series, one of which was prospective, describing its use in the ichthyoses.57-60 In one, 29 children had conditions including lamellar ichthyosis (9), nonbullous ichthyosiform erythroderma (5), one of whom responded poorly, bullous ichthyosiform erythroderma (4) and Sjögren-Larsson syndrome (3).57 A patient with Netherton syndrome experienced marked worsening. In another study, 33 patients (21 adults and 12 children) with ichthyoses, palmoplantar hyperkeratosis or Darier disease were treated for a period of 4 months. Most patients showed marked improvement or remission. The results in congenital ichthyosiform erythroderma, lamellar ichthyosis and Papillon-Lefèvre syndrome were judged by the authors empirically as better than those usually reported with etretinate.59 Milder ichthyoses such as ichthyosis vulgaris and X-linked recessive ichthyosis should not require acitretin therapy.61 However, six patients with severe X-linked recessive ichthyosis were successfully treated.62 Among the keratodermas, Vohwinkel syndrome (keratoderma mutilans with hearing loss), keratitis-ichthyosis-deafness (KID) syndrome,63 hereditary punctate palmoplantar keratoderma,64 type I hereditary punctate keratoderma,65 epidermolytic hyperkeratosis (a rare form of ichthyosis sometimes associated with palmoplantar keratoderma)66 and Papillon-Lefèvre syndrome67, 68 have all been recently reported as successfully treated with acitretin in small series. Treatment of epidermolytic palmoplantar keratoderma may result in large erosions.61 In one RCT, Christopherson et al.69 compared acitretin with etretinate in 26 patients and found similar rates of marked improvement or remission in both groups, with 10 of 13 patients responding. An open study of five patients70 showed marked improvement to complete clearance in four. This group found that 10–25 mg daily was sufficient, and lower doses were required in Darier disease than other diseases. This is reflected in the licence. In an open study of 13 patients,71 three patients cleared and seven improved markedly on 30 mg daily, followed by dose reduction. A single retrospective study of 14 patients, of whom nine were treated with either etretinate or acitretin 0·5 mg kg−1 daily for an average period of 18·8 months, achieved partial or complete clearing in seven without major side-effects. Five patients responded to methotrexate 15–25 mg daily but other treatments, including steroids and PUVA, were inconsistent.72 Although anecdotal, the authors considered retinoids to be the first-line treatment for pityriasis rubra pilaris. In one RCT in severe lichen planus (LP), Laurberg et al.73 showed marked improvement in 64% of patients on acitretin 30 mg daily vs. 13% on placebo. In an open 8-week extension, 83% of the placebo patients responded. A total of 17 of 23 patients with associated mucocutaneous disease improved significantly on acitretin. In a meta-analysis, Cribier et al.74 included five open studies with 58 patients with oral LP treated with etretinate (mostly poor-quality studies), and one crossover RCT with 28 patients which showed significant improvement with etretinate over placebo. Etretinate was the favoured retinoid therapy. The authors recommend acitretin as first-line therapy in cutaneous LP and give further anecdotal evidence. Acitretin may also be preferred in the hyperkeratotic variant of LP for its modulating effect on keratinization. In an RCT of 58 patients75 comparing acitretin 50 mg daily for 8 weeks with hydroxychloroquine 400 mg daily, improvement was found in 46% and 50%, respectively, but four patients had to stop acitretin because of side-effects which were more frequent in this group. In one open trial of 20 subjects,76 the result was unsatisfactory in five. In 15 patients, total clearing or marked reduction of all lesions was seen. Acitretin was superior to previous therapy with antimalarials and/or systemic corticosteroids in seven, and five of six patients with subacute cutaneous lupus erythematosus showed complete clearing of their lesions within 2–4 weeks. As in LP, a verrucous variant is seen where the modulation of hyperkeratosis may be an advantage favouring acitretin. One RCT randomized 78 patients but only measured efficacy per protocol in 46 subjects. A total of 14 of 22 patients on acitretin responded compared with six of 24 in the placebo group.77 However, due to the high drop-out rate the study has a high risk of bias (1−; see Appendix 1) and could not be used to make a recommendation. A 51% reduction in hyperkeratotic hand eczema was seen in one RCT of 29 patients.78 In one study of mycosis fungoides, PUVA in combination with interferon alfa-2a was superior to acitretin with interferon.79 The evidence for the use of acitretin for the treatment of warts is sparse and insufficient to base a recommendation. An open study of etretinate in children with severe warts showed clearance in 16 of 20 patients and in four there was improvement then relapse on stopping therapy.80 However, in this age group warts often clear spontaneously. There are a few case reports of warts clearing with acitretin,81, 82 but in one of these the warts only improved in bulk and recurred on stopping therapy.82 Acitretin has been used anecdotally as an adjunct to therapy in giant condyloma acuminatum83 but in this case response was arguably related to excision and imiquimod used in combination. In epidermodysplasia verruciformis acitretin has been suggested as an adjunct in combination with interferon alfa-2a84 but as monotherapy was ineffective.85 Side-effects are seen in most patients receiving acitretin. However, they usually disappear when the dosage is reduced or the medicine is withdrawn. An initial worsening of psoriasis symptoms is sometimes seen at the beginning of the treatment period. Acitretin is teratogenic regardless of the duration of treatment or dosage used. Although since the marketing of acitretin only one report of human teratogenicity associated with acitretin has been published, acitretin is converted to etretinate, which has a much longer half-life and has been associated with several cases of retinoid-induced embryopathy.86-88 Potential teratogenic effects associated with retinoids are characteristic of those associated with hypervitaminosis A.89, 90 Retinoid embryopathy can result in craniofacial dysmorphias such as high palate and anophthalmia, abnormalities of appendages including syndactyly and absence of terminal phalanges, malformations of the hip, meningoencephalocele, and multiple synostosis.89-92 The teratogenic risk is particularly high for women exposed to treatment during the first trimester of pregnancy. Available data do not appear to indicate any reproductive safety risks due to paternal treatment with acitretin.93 The most frequent side-effect is dryness of the lips, which can be alleviated by application of a fatty ointment such as Vaseline® (Unilever, Walton-on-Thames, U.K.). Mucous membranes and transitional epithelia become dried out or exhibit inflammatory lesions. This can occasionally lead to nose bleeds and rhinitis, and to ocular disturbances including photophobia, xerophthalmia and conjunctivitis sometimes resulting in intolerance of contact lenses. Cheilitis, dry mouth and thirst may also occur. Occasionally stomatitis, gingivitis and taste disturbances have been reported. Thinning, redness and of the skin may all over the particularly on the and For many patients the increased and of the skin make and nail and are sometimes can in up to 75% of patients, but is observed in 10% of treated patients. may after acitretin therapy. Occasionally bullous and have been reported. patients may experience side-effect is the initial of psoriasis, which is sometimes seen during the first 4 weeks of A which may psoriasis, can also in up to 25% of patients receiving oral The of mucocutaneous side-effects was found to be dose related in some studies, with a higher incidence at doses of mg However, this was not found to be the case in other 14 severe mucocutaneous during effective therapy with dose reduction should be the usually of liver enzymes may in up to 15% of patients receiving 90 hepatotoxic resulting from retinoid use are and reports include a severe in a patient with a and a severe hepatotoxic with to liver However, data from patients receiving acitretin therapy showed in only A total of patients followed by liver for years showed significant with acitretin other than and are at increased risk for and require more frequent liver is to the dose of acitretin and usually within weeks after The is seen in which in of patients, and is associated with the very low seen in of patients treated with to in both the and/or low and a parallel decrease in the high In addition, have been found to be decreased in 40% of patients taking The has been to the risk of and lipids should be in all patients receiving treatment with acitretin. of to associated with are not although one case of has been These changes in the are dose related and may be controlled by of and/or by reduction of dosage of acitretin. A high was found effective in reducing and increasing in patients treated with etretinate and is also effective, is likely to in patients with factors such as increased or a of these The effects of acitretin on the skeletal are not however, available data suggest to treatment with etretinate was associated with evidence of and However, of the incidence the most common and skeletal by and of the has been reported as a side-effect of systemic retinoids. Two retrospective studies to abnormalities but with dose or duration of treatment has been This study in patients showed evidence of a between and retinoid therapy. A study of patients treated with acitretin over years in only two patients the and that would not have been using A further retrospective study of acitretin cases of have been suggested in the literature but the evidence not this which to consensus is that are not required for acitretin therapy. for may be the use of acitretin in children has from reports of including skeletal and in children on treatment with It should be that very high dose exposure in one case to and in the that and in the other case was a on Five children treated with etretinate had in the or that either developed or on therapy. with and the children had decreased thickness of the second However, of children treated over years did not any abnormalities that would significantly or on growth have not been seen in a further 18 children treated with retinoids at in the of the the is severe to be or and such therapy is because the benefits the then the should be for any abnormalities of growth and An daily dose in children 12 years of age is 0·5 mg occasionally this can be increased up to 1 mg Other that may during therapy with acitretin include and a few cases of and and the most frequent in up to 25% of Two previous small studies a increased risk of in receiving etretinate and this is a of the hypervitaminosis A however, a further study has this and in a study of 30 patients treated for years with was not on has in very rare cases with use of systemic retinoids including one following acitretin In some cases with this effect has been associated with or with severe and should acitretin and be for or decreased has been reported has been reported incidence of due to has been during treatment with are associated with greater and could in patients on These patients should be to their more than in the of Acitretin not significantly There is some evidence that was by retinoids in and that epidermal was reduced by acitretin in However, in a study of 44 in transplant there were significant effects on or There is to stop acitretin for such as and symptoms of with acitretin would probably be similar to A and include and would be to on acitretin without for Appendix 1 for of of evidence and of recommendation. Acitretin monotherapy is in the treatment psoriasis, or psoriasis with severe effects on of systemic therapy, which is resistant to topical therapy, or is for these treatments Acitretin is as a combination with PUVA therapy or narrowband Acitretin is with hydroxycarbamide Acitretin is in combination with calcipotriol ointment The following are not Acitretin with evidence of additive efficacy Acitretin with for severe hepatic in pustular psoriasis hand eczema Darier disease (keratosis follicularis) congenital ichthyosis There is evidence that the following conditions from

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