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

Fumaric Acid Esters

Oral FAE therapy for psoriasis was first reported in 1959 and has become widely used in Northern Europe, particularly in German-speaking countries and the Netherlands.[11,74] Fumaderm® (Fumapharm AG), a specific mixture of dimethylfumarate and monoethylfumarate salts, is registered in Germany for the treatment of patients with severe psoriasis for whom topical therapy is not indicated.[75] Fumaderm® is not approved in the U.K. or the U.S.A. at present. A second-generation fumarate derivative for psoriasis is currently in European clinical trials.

Dimethylfumarate, and its metabolite monomethylfumarate, appear to be the principal active components of Fumaderm®. Treatment with dimethylfumarate and/or monomethylfumarate produces a beneficial shift towards Th2-like cytokine secretion associated with a reduction in peripheral lymphocytes (primarily T cells)[76] and inhibits the proliferation of epidermal keratinocytes in patients with psoriasis.[74]

Current German guidelines recommend a gradual increase in FAE dosage to determine optimal efficacy and tolerability for each patient. During the first week of treatment, patients typically receive one tablet daily of a low-strength 'Fumaderm® initial' formulation (30 mg dimethylfumarate; 75 mg monoethylfumarate as Ca, Mg and Zn salts), increasing over the next 8 weeks to a maximum of six tablets daily of full-strength Fumaderm® (120 mg dimethylfumarate; 95 mg monoethylfumarate as Ca, Mg and Zn salts) taken as a divided dose of two tablets three times daily.[74,75] Clinical benefit is typically observed after 4-6 weeks of treatment.[75] Following psoriasis remission, use of a reduced dose for maintenance should be attempted.[75]

A systematic review of the literature identified five randomized controlled clinical trials of FAE therapy for psoriasis.[11] The efficacy of the registered formulation was demonstrated in two studies in which patients received escalating doses of up to six high-strength tablets daily for 16 weeks.[11,77,78] Nugteren-Huying et al . showed that patients who received the registered FAE formulation ( n = 12) achieved a reduction in mean percentage body surface area of psoriasis from 21% at baseline to 6·7% after 16 weeks, a treatment effect significantly superior to placebo ( n = 12; P < 0·01). Six of the 12 patients treated with FAEs achieved complete clearance of psoriasis. FAE-treated patients also achieved significantly lower mean infiltration and scaling scores compared with the placebo group ( P < 0·01).[77] In a second study in 100 patients with psoriasis insufficiently responsive to topical therapy, Altmeyer et al . showed that FAE-treated patients achieved a reduction in mean PASI from 21·6 at baseline to 10·8 after 16 weeks vs. little or no change in the placebo cohort ( P < 0·0001).[78] The FAE group also showed a significantly superior outcome on a global physician's assessment of change ( P < 0·0001).[78] RD values for the two studies were 0·46 (95% CI 0·17-0·75) and 0·47 (95% CI 0·31-0·63), respectively, with a pooled RD of 0·47 (95% CI 0·33-0·61).[11] The remaining three trials identified in the systematic literature review demonstrated the efficacy of alternative FAE protocols such as dimethylfumarate or monomethylfumarate monotherapy in patients with psoriasis.[11,77,79,80]

Current guidelines recommend combining FAE therapy with topical psoriasis treatments,[74] and a randomized, double-blind, vehicle-controlled study ( n = 143) has shown that the registered FAE formulation combined with topical calcipotriol treatment was more effective than FAE monotherapy in patients with severe psoriasis.[81] The combination produced a more rapid treatment response than FAE treatment alone (50% reduction in PASI after 3 weeks vs. 9 weeks), a greater mean percentage improvement in PASI (76·1% vs. 51·9%, P < 0·001), and superior overall efficacy as assessed by investigators and patients ( P < 0·001).[81] To date, no randomized controlled trials have compared FAE therapy with other systemic therapies for psoriasis,[11] and in the absence of such trials it is difficult to make an accurate evaluation of the place in therapy of FAEs.

Common adverse events associated with FAE therapy for psoriasis are gastrointestinal complaints and flushing.[74] Gastrointestinal adverse events, such as diarrhoea, mild stomach upsets, stomach cramps, fullness and flatulence, occur in more than two-thirds of patients and are most frequently reported between 4 and 12 weeks of treatment.[74,75] Approximately one-third of patients experience flushing, characterized by reddening of the face and a sensation of heat, sometimes associated with headache, lasting minutes to hours. Flushing occurs most often at the onset of treatment and becomes less frequent with further exposure.[74]

Clinical experience has shown that the gastrointestinal adverse effects of FAE therapy may be controlled with aluminium hydroxide, metoclopramide or ranitidine.[82] There is also some evidence that concomitant pentoxifylline therapy may reduce the incidence and severity of gastrointestinal complaints and flushing in patients receiving FAE therapy.[83] FAE dose reduction may also be used to manage symptoms; however, discontinuation should be considered in persistent cases.[75] Gastrointestinal adverse events and flushing together lead to discontinuation of FAE therapy in approximately 7% of patients.[74] Overall, the rate of discontinuation due to adverse events and/or noncompliance with treatment is 30-40%.[34]

Haematological changes, notably leucopenia, lymphopenia and eosinophilia, are frequently observed during FAE therapy.[74,75] These changes are generally reversible following discontinuation of treatment, and to date there has been no evidence of an increased risk of infection.[74,75] Additional laboratory changes noted during FAE therapy include increases in liver enzymes, cholesterol, triglycerides, serum potassium and serum creatinine, and proteinuria.[74,75]

There were several early reports of acute renal failure associated with uncontrolled, concomitant use of oral and topical fumaric acid derivatives,[78,84,85] and a case of chronic renal damage after long-term, high-dose oral FAE therapy.[86] Current guidelines recommend a gradual increase in oral FAE dose to determine each patient's maximum tolerable dose, and advise against concomitant use of topical fumaric acid derivatives to avoid exceeding the maximum dose through percutaneous absorption.[74,75] When used according to these guidelines in controlled clinical trials, no nephrotoxicity has been observed.[74,87] Nevertheless, sufficient fluid intake should be encouraged during FAE therapy,[75,82] and renal function should be monitored throughout treatment.

Current guidelines state that intermittent short-course therapy or continuous maintenance treatment for up to 2 years is possible,[74] and there is clinical experience of up to 14 years of treatment and/or follow-up in a small number of patients. Hoefnagel et al . retrospectively evaluated the safety of prolonged FAE therapy in 66 patients with severe psoriasis treated at a single centre, including patients treated for 1-2 years ( n = 7), 2-5 years ( n = 15), 5-10 years ( n = 7) and 10-14 years ( n = 12).[88] Adverse events and laboratory profiles were consistent with previous clinical experience. Thirty-eight (58%) patients permanently discontinued treatment for a variety of reasons, the most common being lack of efficacy, exacerbation of psoriasis after initial improvement, and adverse events such as flushing, diarrhoea, nausea or tiredness. Several patients also had up to three periods of interruption of treatment on similar grounds.[88] The authors considered that FAE therapy was a relatively safe long-term treatment option in patients with severe psoriasis.[88]

FAE therapy is contraindicated in patients with severe concomitant conditions including severe or chronic gastrointestinal disease or kidney disease, or severe liver disease, and is not considered suitable in patients with abnormal haematology counts. FAE therapy is contraindicated during pregnancy and breastfeeding because of a lack of clinical experience.[74,75] Although there has been no evidence of an increased risk of malignancy in patients receiving FAE therapy for psoriasis, current guidelines advise against treatment of patients with malignant diseases or a history of malignancy.[74]

Patients receiving FAE therapy require regular clinical assessment and monitoring. Full blood counts, including leucocytes and differential, should be performed prior to treatment, every 2 weeks during the first 3 months of treatment and, if no abnormalities are detected, monthly thereafter.[75] Laboratory parameters for renal and hepatic toxicity should be monitored pretreatment, every 2 weeks for the first month, and monthly thereafter. These include alanine and aspartate aminotransferases, γ-glutamyltransferase, alkaline phosphatase, serum creatinine, protein urine and urinary sediment.[75] Blood urea nitrogen should also be monitored regularly.[74] Detection of bone marrow toxicity and/or elevation of serum creatinine above the normal range necessitates immediate discontinuation of treatment.[74,75]

Current guidelines recommend that patients receiving FAE therapy should not receive concomitant methotrexate, retinoids, psoralens, ciclosporin, immunosuppressant agents, cytostatic agents or other drugs known to cause renal dysfunction,[74,75] although such combinations have been reported.[89]

Clinical data and experience in Northern Europe support FAE therapy as an effective and relatively safe treatment option for patients with moderate to severe psoriasis. There appear to be no major toxicities associated with FAE therapy, and the principal limitations are the high incidence of adverse events and high rates of discontinuation due to adverse events and noncompliance.[34] Although gastrointestinal complaints and flushing tend to decline with prolonged treatment, these uncomfortable and potentially embarrassing adverse events may be intolerable for some patients. The inconvenience of taking up to three daily doses, and the requirement for frequent laboratory monitoring, may also represent significant barriers to treatment. Currently, FAE therapy for psoriasis is approved for use only in Germany and issues of availability and reimbursement and lack of clinical experience may limit treatment in other countries. Nevertheless, the relatively favourable benefit/risk profile means that FAE therapy may be a useful alternative for some patients, especially where more toxic therapies are contraindicated.

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