Skin Therapy Letter HOME
Written for dermatologists by dermatologists. Indexed by the US National Library of Medicine.
Skin Information
NETWORK
Skin Therapy Letter About STL Subscribe Today SkinCareGuide Network Site Map
CUSTOM DERMATOLOGY SEARCH:
Loading


Efficacy of Acitretin in Severe Psoriasis

J.M. Geiger, MD, Pharm D

Université Louis Pasteur, Strasbourg, France

ABSTRACT

Acitretin (SORIATANE®, Roche Pharmaceuticals) is an aromatic retinoid, effective in the treatment of severe psoriasis. This study highlights data from two existing clinical trials to capture PASI 50 and PASI 75 responder rates which represent a common metric used in current psoriasis clinical trials. A review of pharmacokinetics, safety and a discussion of relapse rate establish acitretin as an efficacious, convenient, oral treatment for initial and maintenance therapy of severe psoriasis.
Key Words: acitretin, aromatic retinoid, psoriasis, PASI

Acitretin (SORIATANE®) is an aromatic retinoid which is used in the symptomatic treatment of severe psoriasis.

Mechanism of action

The efficacy of acitretin in psoriasis is mainly explained by the fact that this compound acts on a pathological epidermis to reduce proliferation and stimulate differentiation. It also decreases inflammation in the epidermis and dermis by interfering with various cytokines. However, in contrast to other systemic antipsoriatic drugs, acitretin is neither cytotoxic nor immunosuppressive.
The cellular mechanisms underlying the pharmacological effects of acitretin are not well characterized. Acitretin appears to interfere with the intracellular metabolism of natural retinoids. It also competes with retinoic acid for CRABP (Cellular Retinoic Acid Binding Protein) binding and activates retinoic acid nuclear receptors (RARs).

Pharmacokinetics

Acitretin exists in the form of 10mg and 25mg capsules, administered once daily during a meal, since the concomitant intake with food increases the bioavailability of the drug. After treatment discontinuation, the terminal elimination half-life of acitretin is approximately 50 hours and that of its 13-cis isomer around 90 hours.1 This is much shorter than that of its more lipophilic ester, etretinate, which has been previously marketed for the same indications.

However, measurable levels of etretinate, have been detected in plasma samples of some patients taking acitretin. Experimental data indicate that etretinate is formed when acitretin is taken concomitantly with ethanol. This has been confirmed in a clinical study.2 No etretinate was found in patients who reported that they never drink alcohol while it was detected in all patients with an average weekly alcohol consumption of more than 200g ethanol (this corresponds to around 15 pints of beer or glasses of wine).

For the treatment of psoriasis

The recommended initial dose for acitretin therapy is 25-30mg/day. Maintenance doses of 25-50mg/day may be given after initial response to treatment (12-16 weeks). The maintenance dose should be based on clinical efficacy and tolerability. The best clinical responses are obtained in localized or generalized (Zumbusch type) pustular psoriasis and in erythrodermic psoriasis. Acitretin markedly improves plaque-type psoriasis and complete remission is obtained in around one-third of patients.

In some patients, an initial worsening of the disease may be observed with an increase in erythema and in the extent of lesions. A therapeutic scheme that initially uses low doses and is progressively increased (up to 50mg/day) seems to avoid this undesirable effect and may allow optimization of the therapeutic effect. After 12-16 weeks initial therapy, efficacy can be safely maintained in a long term treatment with acitretin.

PASI 50 and PASI 75 response rates

Acitretin has been shown in extensive clinical trials to be effective in the treatment of severe psoriasis. In clinical trials, the efficacy of psoriasis therapy is typically measured using the Psoriasis Area Severity Index (PASI), which quantifies the severity of a patient’s condition based on both the percentage of body surface area affected and the lesion severity. PASI 50 and PASI 75, which refer to the percentage of patients achieving a 50% or 75% improvement in baseline PASI score, are increasingly used as efficacy endpoints.

A retrospective analysis was undertaken to determine PASI 50 and PASI 75 response rates for two previously published acitretin clinical trials, study A3 and study B4. In both studies, efficacy was measured by PASI scores and Physician’s Global Assessment (PGA) at the end of treatment.

In study A3, a multicenter Canadian trial, a total of 63 patients (42 men, 21 women) with severe psoriasis were enrolled. Treatment with acitretin was initiated at 50 mg/day for 4 weeks, followed by dosage adjustment according to therapeutic response for up to 12 months. After 12 weeks of treatment, PASI 50 response rate was 66% and PASI 75 response rate was 34%. For the 37 patients who completed the 12-month course of therapy, 89% were found to be PASI 50 responders, and 78.4% PASI 75 responders. Among the 63 patients enrolled, 76% achieved a PASI 50 response and 46% a PASI 75 response by the end of treatment (average duration: 267 days; mean daily dose: 41mg). PGA evaluations found 52.4% of patients to show “marked improvement”, 31.7% “moderate or slight improvement 15.9% “no change or worsening”. Of the patients showing “marked improvement”, 79% were PASI 75 responders.

Study B4 was a multicenter, double-blind trial comparing acitretin and etretinate that was conducted in the four European Nordic countries. Treatment for the acitretin group consisted of 4 weeks of therapy at 40mg/day followed by an 8-week phase of dosage adjustment according to therapeutic response. A total of 127 patients received acitretin (median daily dose: 40 mg) and 41 patients received etretinate (median daily dose: 49.7mg). After 8 weeks of treatment, PASI 50 and 75 response rates were 57% and 24% for acitretin, and 40% and 17% for etretinate, respectively. In patients who completed the 12 week treatment, PASI 50 and PASI 75 response rates were 85% and 52% for acitretin, and 80% and 45% for etretinate, respectively.

The high percentage of patients achieving a 50% or 75% reduction in PASI score during treatment with acitretin confirms the therapeutic efficacy of this drug. Although responder rates were slightly higher in study B than in study A at week 12, responder rates at the end of treatment were found to be similar in both trials, with around 75% of patients showing a PASI 50 response rate, and 50% demonstrating a PASI 75 response rate.

Relapse rate

The differences in the duration of response between various psoriasis therapies is not well established, since the definitions of relapse used in various clinical studies differ. In a double-blind study comparing acitretin with etretinate, patients were followed for 6-months after a 12-week treatment course.5 Relapse was defined as a marked or continuous deterioration of psoriasis that has required an active specific treatment, as judged by the physician or requested by the patient. At the end of the 6-month follow up period, 59% of acitretin and 53% of etretinate treated patients did not relapse.

Contraindications

There is an extremely high risk that major fetal abnormalities will occur if pregnancy occurs during treatment with acitretin. Effective contraceptive measures must be used for at least one month before starting treatment, during treatment and for at least 3 years after discontinuation of treatment. This post-therapy contraception period is based on the potential formation of etretinate in presence of alcohol (see pharmacology).

Adverse events

Mucocutaneous reactions
Undesirable dose-related effects on the skin and mucous membranes are almost always observed during treatment with acitretin. Dry lips (or cheilitis) is the earliest and most frequent sign appearing after treatment starts. Other reactions frequently observed include xerosis of the skin, pruritus, peeling of the palms and soles, epistaxis, conjunctivitis and hair loss. All these reactions are dosedependant and rapidly reversible after drug discontinuation.

Systemic toxic effects
The most common clinical adverse effects include headache, arthralgia, myalgia, and fatigue. Skeletal changes after long-term use have been attributed to retinoids. However, a prospective study has failed to document new spurs or other bone changes.6 Transitory abnormal elevations in liver enzymes are reported in approximately 33% of patients in US trials. Serum lipid changes (increase
in triglycerides, in VLDL and LDL) are common.

Conclusion

Acitretin (SORIATANE®) is a convenient oral treatment of severe psoriasis, with a well-established efficacy and safety profile. Due to its long-term safety, acitretin can be used both as an initial and a maintenance treatment.

References



  1. Efficacy of Acitretin in Severe Psoriasis
  2. Nonablative Laser and Light Therapy: An Approach to Patient and Device Selection