Traditional Therapies in the Management of Moderate to Severe Chronic Plaque Psoriasis: An Assessment of the Benefits and Risks

L. Naldi; C.E.M. Griffiths

Disclosures

The British Journal of Dermatology. 2005;152(4):597-615. 

In This Article

Oral Retinoids

Several systemic retinoids (derivatives of vitamin A) have been developed for the treatment of psoriasis; however, acitretin (Neotigason®, Soriatane®) is currently the only oral retinoid approved for this indication registered in most European countries and the U.S.A.[67] The exact mechanism of acitretin therapy in psoriasis has not been elucidated; however, systemic retinoids are known to have immunosuppressive and anti-inflammatory activity, and to modulate epidermal proliferation and differentiation.[60,68]

Interindividual variation in the pharmacokinetic, efficacy, and adverse event profiles of acitretin has been reported; therefore, the dosage must be adjusted for each patient to achieve an optimal clinical outcome while minimizing toxicity.[67] It is currently recommended that acitretin therapy should be initiated at a single daily dose of 25-50 mg (or 0·25-0·5 mg kg-1 daily).[67,69] Depending upon the patient's response to induction therapy, acitretin may be continued at maintenance doses of 25-50 mg daily.[67]

The clinical data suggest that acitretin monotherapy may be somewhat less effective than other systemic agents in the short-term treatment of psoriasis. A systematic review of the literature identified several clinical trials of oral retinoid therapy for psoriasis.[11] Interpretation of the data was limited by marked heterogeneity in baseline disease severity, oral retinoid dose, duration of retinoid therapy, concomitant topical steroid use and treatment success criteria. The short duration of treatment (8-16 weeks) and small number of patients (two to 49 patients per arm) in placebo-controlled clinical trials probably contributed to the variability in results reported. Overall, oral retinoid (etretinate or acitretin) therapy was found to be 'only modestly' effective against psoriasis at doses of 75 mg daily or 1 mg kg-1 daily based on calculated RD values.[11] Clinical data indicate that acitretin produces good responses in patients with pustular or erythrodermic/exfoliative psoriasis, but is less effective in patients with common plaque psoriasis.[39]

As mentioned previously, clinical data suggest that combination retinoid-PUVA therapy may be more effective than either treatment alone, and may minimize the toxicities associated with each modality through dose-sparing or independent chemopreventive effects.[11,70] For example, one follow-up study of 135 patients with psoriasis treated with PUVA showed that the incidence of cutaneous squamous cell carcinoma was significantly reduced during years with substantial concomitant oral retinoid use compared with years without oral retinoid use (196 vs. 302 tumours per 1000 patient-years, P = 0·002; incidence rate ratio 0·79), although the incidence of basal cell carcinoma was not significantly different.[71] There is evidence that combination acitretin plus UVB may also be an effective therapeutic strategy for psoriasis.[11,70,72]

Acitretin is a suppressive therapy associated with gradual clearance of psoriasis lesions, and researchers have suggested that it may be best suited for longer-term maintenance therapy, for example as part of a sequential treatment regimen.[20,39] One proposed sequential regimen involves ciclosporin treatment to achieve rapid psoriasis clearance, followed by acitretin maintenance therapy incorporating PUVA or UVB therapy as necessary.[39]

Perhaps the most important safety issue associated with acitretin is its long-lasting teratogenicity ( Table 2 ). Acitretin can cause major fetal abnormalities and is therefore contraindicated in pregnant women.[67] Although the terminal elimination half-life of acitretin (49 h) is relatively short, acitretin may transform within the body, either spontaneously or as a result of concurrent ingestion of alcohol, into its nonacid form metabolite (etretinate), which has a much longer elimination half-life. Based on the longest known etretinate elimination half-life (168 days), it is estimated that it may take up to 3 years for 98% of the etretinate to be eliminated. Therefore, acitretin therapy is contraindicated in women who intend to become pregnant, or who may fail to use effective contraception during and for at least 2-3 years following discontinuation of therapy. Neotigason® labelling indicates that women should not attempt pregnancy within 2 years after discontinuation of therapy,[73] while U.S. guidelines recommend waiting a period of 3 years after discontinuation of acitretin.[67] Of note, acitretin is known to interfere with the contraceptive effect of some oral progestin preparations ( Table 4 ); therefore, careful consideration of contraceptive methods is required.[67] To lower the risk of etretinate formation, female patients of childbearing potential should not drink alcohol during or for at least 2 months following discontinuation of acitretin.[67]

Oral retinoid therapy frequently causes reversible changes in liver function and serum lipids. For example, acitretin causes elevations in liver function tests in approximately one-third of patients and, in rare cases, has been associated with severe liver damage.[67] During clinical trials of acitretin, 66% of patients developed hypertriglyceridaemia, 33% developed hypercholesterolaemia, and 40% experienced a reduction in high-density lipoproteins.[67] Consequently, acitretin is contraindicated in patients with pre-existing severe liver or kidney damage, or chronically elevated blood lipids ( Table 2 ), and regular monitoring of liver function, serum lipids and blood glucose is recommended during acitretin treatment ( Table 3 ).[67]

Other adverse effects commonly associated with acitretin therapy resemble chronic hypervitaminosis A syndrome.[60,68] Retinoid therapy almost invariably causes mucocutaneous toxicity, in particular cheilitis, xerosis and pruritus.[20,44,68,69] Up to 75% of retinoid-treated patients experience dose-related hair loss, which is reversible upon discontinuation of therapy.[44] Less frequently, patients receiving acitretin may experience arthralgia, myalgia or paraesthesia, as well as possible worsening of pre-existing bone disorders during long-term therapy.[20,69] In general, adverse effects associated with acitretin therapy do not lead to serious end-organ damage, and may be monitored by standard laboratory evaluation. A review of the literature revealed that adverse effects led to discontinuation of treatment in 10%-20% of patients receiving acitretin therapy for psoriasis.[34]

As oral retinoid therapy may be less effective than other systemic agents in the short-term treatment of psoriasis, the benefit/risk ratio may be greatest when oral retinoids are used for maintenance treatment in patients who have already achieved clearance with other therapeutic modalities.[39] Indeed, oral retinoid therapy is comparatively safe for maintenance administration as, with the exception of poorly established skeletal effects, there are no cumulative toxicities.[39] Furthermore, the lack of immunosuppressant activity makes oral retinoid therapy one of the few therapeutic options suitable for immunosuppressed patients, such as human immunodeficiency virus-positive patients with severe plaque-type psoriasis.[39,68]

Regrettably, however, the prolonged teratogenic effects associated with oral retinoid therapy limit its utility in female patients of childbearing potential,[69] particularly among patients who may fail to use reliable contraception and/or comply with alcohol limitations. Although not life-threatening, the common adverse effects of oral retinoid therapy may also be intolerable for some patients. For example, hair loss may be particularly distressing.[39]

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