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Acitretin Revisited

Charles W. Lynde, MD, FRCPC1,2, John N. Kraft, MD1, Carrie B. Lynde, MD1
1 Division of Dermatology, University of Toronto, Toronto, ON, Canada
2 University Health Network (Western Division) Toronto, ON, Canada

ABSTRACT

Acitretin over the last 20 years has proven useful in a number of dermatologic diseases. Evidence of efficacy, side-effect profile, and approach to its use will be reviewed.

Key Words: acitretin, congenital ichthyosis, Darier disease, keratodermas, lichen planus, lichen sclerosus, lupus erythematosus, malignancy, pityriasis rubra pilaris, psoriasis

Acitretin is a synthetic oral retinoid that has been used by dermatologists over the last two decades for a number of cutaneous diseases. It replaced etretinate (the prodrug) in the late 1980’s (1998 in the United States), because acitretin presents a more favorable pharmacokinetic profile. The British Association of Dermatologists has recently produced comprehensive guidelines on the efficacy and use of acitretin in dermatology.1 With this recent development, a further examination of acitretin and its therapeutic application in a wide array of cutaneous diseases is warranted.

Chemistry and Mechanism of Action

Retinoids deliver their biological effects through two members of the steroid/thyroid super family of nuclear hormone receptors: first, the retinoic acid receptors (RAR á, â, ã) and second, the retinoid X receptor (RXR á, â, ã).2-4 Acitretin is a second generation retinoid that activates all three RAR subtypes. Etretinate is an ethyl ester prodrug that is converted into the active metabolite acitretin. Acitretin's effects are thought to be induced by binding to nuclear receptors of genes, controlling cellular differentiation and proliferation, reducing inflammation and keratinization, and inhibiting neutrophil chemotaxis.5

Pharmokinetics and Metabolism

Actitretin is the main active metabolite of etretinate.5 Etretinate is a lipophilic drug with a half-life of approximately 120 days as compared with acitretin, which has a half-life of approximately 50 hours.6 Etretinate can be detected in the serum for up to 2 years post cessation of treatment. Acitretin, with concurrent ethanol consumption, can result in transesterification of acitretin to etretinate.6,7 Acitretin is a US FDA Pregnancy Category X medication and should not be administered to women of child bearing age who may wish to become pregnant during treatment and within 3 years of discontinuation of the drug.5 Patients are advised to take acitretin with food as this can enhance absorption and bioavailability two- to five-fold.6,8

Efficacy in Psoriasis

There are four randomized controlled trials (RCT) comparing acitretin and etretinate, four RCTs comparing acitretin with placebo and one open study.9-16 These studies contain a heterogeneous grouping of generalized pustular, severe, and erythrodermic variants in conjunction with plaque type psoriasis. In addition, these studies preceded the new standardized PASI 75 outcome measure (i.e., 75% improvement from baseline in Psoriasis Area Severity Index score). Nevertheless, a retrospective post hoc analysis of the data would suggest 52% of the patients achieving PASI 75 and 85% achieving PASI 50 after 12 weeks (per protocol analysis) of treatment.17

In the open trial (Canadian), a total of 46% of patients achieved PASI 75 response and 76% PASI 50 response by the end of treatment (intent to treat average duration of 267 days).18 Higher doses (50-75mg daily) were found to be more effective, however, these produced more side-effects. Furthermore, acitretin has demonstrated greater efficacy in pustular and erythrodermic psoriasis than in chronic plaque psoriasis.19

Combination Therapy in Psoriasis

Acitretin and Psoralen + Ultraviolet A (PUVA)

Four RCTs compared acitretin and PUVA.4 These studies showed the acitretin + PUVA combination was more effective than PUVA alone.4 It reduced the overall number of PUVA treatments.6 This, in conjunction with acitretin’s demonstrated preventative action against carcinogenesis, allows for theoretical advantages.1,7 Acitretin and Ultraviolet B (UVB)

One RCT, two open studies, along with one retrospective investigation demonstrated better outcomes and sparing of UVB in the combination group.20-25

Acitretin and Calcipotriol Ointment

Two RCTs showed additive benefits of acitretin and calcipotriol ointment in combination.26 In one study, the 'clear' or 'almost clear' success rate increased to 67% with the addition of calcipotriol (vs. 41% with acitretin monotherapy).27 In the second study, patients' complete clearance increased from 15% to 40% after 12 weeks.28

Palmoplantar Pustulosis

Two RCTs compared acitretin with placebo.29-30 Acitretin produced a five-fold reduction in pustules after 4 weeks and a ten-fold reduction in pustules after 12 weeks.30

Nail Psoriasis

In one open study, patients (N = 36) with nail psoriasis were treated with acitretin doses of 0.2-0.3mg/kg given daily for 6 months.31 The findings showed a 41% mean improvement on the Nail Psoriasis Severity Index (NAPSI). In addition, 25% of patients were cleared or almost cleared.

Review of Indications and Level of Evidence1

Table 1 and Table 2 provide brief overviews of studies investigating the use of acitretin in various skin disorders and their quality of supporting evidence.

Indications Comments and Recommendations
Psoriasis Acitretin is the retinoid of choice for treating psoriasis that has severe effects on quality of life and require systematic therapy, is resistant to topical therapy and phototherapy, or is unstable for these treatments. It is recommended in combination with PUVA or narrowband phototherapy, as well as in combination with calcipotriol ointments. Acitretin is effective in palmoplantar pustular psoriasis.
Lichen planus In severe lichen planus, improvement was seen in 64% of patients on acitretin (30mg daily) vs. 13% in placebo.32 In the further open 8 week experiment, 83% of the initial placebo patients subsequently responded to acitretin. It has been suggested that acitretin should be a possible first-line therapy in cutaneous lichen planus, particularly in hyperkeratotic form.20
Darier disease Researchers comparing actitretin with etretinate in 26 patients with Darier disease showed similar rates of marked improvement or remission in both groups with 10 of 13 patients responding.33 Lower doses are required (10-25mg/day) in the treatement of Darier disease.1
Hand eczema A RCT of 29 patients showed a 51% reduction of hyperkeratotic hand eczema.34
Malignancy prevention There have been numerous reports of retinoid use as malignancy prophylaxis in organ transplant recipients. This has recently been reviewed in Skin Therapy Letter.35 Data from a small number of randomized controlled trials suggest that acitretin may have a beneficial role in high risk organ transplant recipients.43 Other retinoids have been anecdotally shown to prevent malignancy in xeroderma pigmentosum (isotretinoin) and basal cell nevus syndrome.36
Cutaneous lupus erythematosus In one RCT of 58 patients comparing acitretin 50mg daily for 8 weeks with hydroxychloroquine 400mg daily, researchers found improvement in 46% for acitretin and 50% for hydroxychloroquine.37 Moreover, in an open trial of 20 subjects, 15 patients experienced total clearing or marked reduction of all lesions.38

Table 1: Acitretin use in cutaneous disorders supported by studies categorized as A/1+ level of evidence

A = at least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results; 1+ = well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias

Indications Comments and Recommendations Level of Evidence
Pityriasis rubra pilaris In a single retrospective study of 14 patients (9 treated with acitretin or etretinate), researchers showed partial or complete clearing in 7 of 9 patients without major side-effects.39 The authors considered retinoids to be first-line treatment for pityriasis rubra pilaris.39 anecdotal
Lichen sclerosus Another RCT randomized 78 patients, however, only 46 subjects were measured for efficacy per protocol. More than half of the patients (14 of 22) on acitretin responded, compared with 6 of 24 in the placebo group.40 Due to the high drop-out rate and the high risk of bias the British Journal of Dermatology declined to make a recommendation in this area.1 1-
Congenital ichthyoses Evidence for efficacy is based on anecdotal reports with several open studies combining numerous conditions (lamellar ichthyosis, non-bullous ichthyosiform erythroderma, bullous ichthyosiform erythroderma, Sjogren-Larsson syndrome, and Papillon-Lefèvre syndrome).41-43 Patients generally showed improvement, however, one patient tested with acitretin therapy who suffered from Netherton syndrome showed marked worsening.42 D, 3
Keratodermas Evidence is based on open study anecdotal reports for efficacy and again combining multiple conditions, including Vohwinkel syndrome, keratitis-ichthyosis-deafness (KID) syndrome, hereditary punctate keratoderma, and Papillon-Lefèvre syndrome. It was reported that acitretin therapy successfully helped disease symptoms.42,44,45 D, 3

Table 2: Dermatologic conditions with less evidence in the literature1
1- = meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias ; 3 = nonanalytical studies (e.g. case reports, case series); D = evidence 3 or 4, or extrapolated evidence from studies rated as 2+, or formal consensus

Safety and Tolerability

Acitretin has a side-effect profile similar to other systemic retinoids. Many of the reported adverse effects (Table 3) have occurred in patients using higher doses (>25mg/day) of acitretin and are less prevalent in low doses of acitretin (<25mg/day).

Prescribing

Therapy should be initiated only under the responsibility of a supervising dermatologist.1 It is recommended that capsules be taken once daily with fatty foods.46 Therapeutic and toxic doses of acitretin are dose-dependent, and individual adjustments of dosage is necessary. Effective doses are typically around 25-50mg/day.47,48 Researchers state that a gradual escalation approach is most effective.48 Acitretin dosages are recommended to start at 25mg/day and increase by 10-25mg every 2-4 weeks to achieve the maximally tolerated dose.1 It is important to note that the response to acitretin is gradual, typically requiring 3-6 months to reach peak effectiveness.1 In Darier disease a starting dose of 10mg daily may be appropriate.1

Monitoring

Patients taking acitretin require monthly monitoring for the first 3 months, then every 3 months thereafter. A complete blood count (CBC) is required as well as a fasting lipid profile (TG, cholesterol). Liver function (AST, ALT) and blood sugar levels of diabetic patients must also be monitored.1 Radiological investigation for skeletal changes need not be done routinely.1

Prevalence Type Side-effect/Description
Serious common Teratogenic
  • Teratogenic regardless of dose or duration of treatment
  • US FDA Pregnancy Category X
  • Should only be used in men, postmenopausal women, or females not desiring to achieve pregnancy for 3 years
Serious rare Bone
  • Diffuse idiopathic skeletal hyperostosis (DISH)
  • Osteophyte formation
  • Premature epiphyseal closure
Gastrointestinal
  • Pancreatitis
  • Possible trigger of inflammatory bowel disease
Hematologic
  • Leukopenia
  • Agranulocytosis
Hepatic
  • Transaminitis
  • Toxic hepatitis
  • Hyperlipidemia
Musculoskeletal
  • Myopathy
Neurologic
  • Pseudotumor cerebri
  • Depression/suicidal ideation
Ocular
  • Reduced night vision
Common Gastrointestinal
  • Nausea
  • Diarrhea
  • Abdominal pain
Mucocutaneous
  • Cheilitis
  • Xerosis
  • Skin peeling
  • Photosensitivity
  • Alopecia
  • Sticky sensation
Musculoskeletal
  • Myalgias
  • Arthralgias
Nails
  • Paronychia
  • Fragility
Neurologic
  • Headache
Ocular
  • Dry eyes

Table 3: Summary of adverse effects associated with acitretin therapy

Conclusion

The use of acitretin over the last 20 years has proven to be an effective treatment and adjunct in a number of dermatological conditions. A thorough understanding of the drug, its efficacy, and potential side-effects is important for yielding a beneficial therapeutic outcome for patients.

References

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In this issue:

  1. Acitretin Revisited
  2. Overview of Treatment of Vulvovaginal Disease
  3. Update on Drugs and Drug News - March 2011