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

Methotrexate

Methotrexate is approved in most European countries and the U.S.A.[51] for the treatment of psoriasis ( Table 1 ). The mechanism of action of methotrexate in psoriasis is not fully understood; however, it is believed to act primarily as an immunosuppressant.[44] Methotrexate treatment schedules should be adjusted for each patient in order to control psoriasis symptoms at the lowest possible dose and thus minimize toxicity.[52] For adult patients of average weight, methotrexate therapy may be started as a single weekly oral, intramuscular or intravenous dose of 2·5-25 mg. The dose may be gradually increased to achieve optimal control of psoriasis symptoms; in general, however, a total weekly dose of 30 mg should not be exceeded with either treatment schedule.[51,52]

Over the past four decades, methotrexate has been used extensively for the treatment of psoriasis, despite the lack of rigorous clinical data supporting its use in this regard. A systematic review of the literature found no well-designed randomized controlled trials of methotrexate for psoriasis.[11] Based on available clinical data, primarily derived from retrospective studies, case studies and case reports, the authors suggested that methotrexate may reduce the severity of psoriasis by at least 50% in at least 75% of patients.[11] However, in the absence of well-designed, comparative clinical trials it is difficult to assess accurately the efficacy of methotrexate.

Recently, three small studies have demonstrated symptomatic improvement in patients with psoriasis receiving methotrexate. Preliminary data have been obtained from an open-label study of methotrexate therapy in 25 patients with moderate to severe psoriasis. An interim analysis showed that 15 patients completed 24 weeks of therapy with a mean methotrexate dose of 19 mg weekly. The mean improvement in PASI at 24 weeks was approximately 50%, and 10 of 15 patients (67%) achieved a PASI-50 response.[53] The study by Heydendael et al. described above, comparing the efficacy of methotrexate and ciclosporin in 85 patients with moderate to severe plaque psoriasis,[41] showed that methotrexate administered at a dosage of at least 15 mg weekly for 16 weeks effectively cleared psoriasis, with a 64% reduction in mean PASI relative to baseline after 16 weeks. Overall, data from these two trials suggest that patients with moderate to severe psoriasis achieve a 50-60% improvement in mean PASI during the first 4-6 months of methotrexate therapy (15-19 mg weekly). In contrast, the study by Sandhu et al. comparing methotrexate and ciclosporin in 30 consecutive patients with severe psoriasis, showed a more rapid clinical response, with a 69·4% improvement in mean PASI after 1 month of methotrexate therapy (mean dose 27·7 mg weekly).[42]

Methotrexate therapy may be associated with a range of potentially serious toxicities, and rare deaths among patients with psoriasis have been reported ( Table 2 ).[20,51] Serious methotrexate-induced toxicities may include acute haematological toxicity, acute and chronic hepatotoxicity including potentially serious fibrosis and cirrhosis, lung disease, severe skin reactions, severe opportunistic infection and lymphoproliferative disorders and severe gastrointestinal toxicity.[20,51,54,55] The risk and severity of methotrexate toxicity may be related to the dose or frequency of dosing; however, toxic effects can occur at any time during treatment.[51,55] In one retrospective study, 31 of 156 (20%) patients with psoriasis treated with low-dose methotrexate for an average of 237 weeks were required to discontinue treatment due to adverse events, including liver toxicity (14%) and bone marrow suppression (6%).[56] In the small prospective study by Heydendael et al . mentioned above, 12 (28%) of 43 patients receiving methotrexate were required to discontinue treatment prematurely due to mild elevation of liver enzymes, which returned to normal within 4-8 weeks following discontinuation of methotrexate.[41]

Notably, research has shown that in patients with rheumatoid arthritis, folate supplementation lowers the incidence of liver function test abnormalities, thus improving methotrexate continuation without an apparent reduction in efficacy.[57,58] Supplemental folate also appears to reduce hyperhomocysteinaemia associated with methotrexate therapy in patients with rheumatoid arthritis, reducing the associated increase in cardiovascular risk.[58] Although little is known about the effects of folate supplementation in patients with psoriasis, a survey of 153 British dermatologists revealed that 75% of them used supplemental folate with methotrexate for psoriasis, either routinely or when low folate levels were detected.[59]

Due to the risk of serious cumulative toxicity, it has been recommended that methotrexate be reserved for patients with severe, 'life-ruining' psoriasis that cannot adequately be controlled by topical therapies, and that methotrexate treatment regimens should include dose reductions and periods off treatment 'to the greatest extent possible'.[55] Methotrexate therapy is contraindicated in psoriasis patients with significantly impaired renal or liver function, and may be unsuitable for patients with bone marrow insufficiency, immunodeficiency, active infection or hypersensitivity ( Table 2 ).[51,54] Patients with delayed drug clearance may be at increased risk of toxicity, and dose reduction or discontinuation of treatment may be required in these patients.[51] Methotrexate is both a teratogen and an abortifacient; therefore, it is contraindicated in pregnancy and should be used with extreme caution in women of childbearing potential. Pregnancy should be avoided during treatment and for one ovulation cycle after discontinuation in female patients; partners of male patients taking methotrexate should not become pregnant for at least 3 months after discontinuation of treatment.[51,52] Methotrexate is also contraindicated during breastfeeding due to the potential for serious adverse effects in the infant.[51]

Patients treated with methotrexate may experience a range of acute adverse reactions such as hypersensitivity, nausea or fatigue.[60] With methotrexate at doses used to treat psoriasis, the most common adverse events include malaise, gastrointestinal effects, headaches and leucopenia.[55] Most adverse events are reversible with early detection and management, which may include dose reduction or discontinuation.[51]

Frequent monitoring of renal, hepatic and haematological parameters is necessary for all patients with psoriasis receiving methotrexate ( Table 3 ).[51,52] Not all cases of methotrexate-induced hepatotoxicity may be detected by liver function tests,[52,60] and liver biopsy is still considered the most reliable method of detecting hepatotoxicity in patients treated with methotrexate. It has been recommended that, in general, biopsies should first be conducted at a cumulative methotrexate dose of 1·0-1·5 g, and repeated at cumulative dose intervals of 1·5 g thereafter.[51,52] For patients at increased risk of hepatotoxicity, liver biopsy may be justified earlier during therapy.[52] The presence of pathological changes detected by the liver biopsy will direct the decision of whether or not to continue methotrexate therapy.[61] Patients with grade I or II histological changes can continue to receive methotrexate; patients with grade IIIA changes (e.g. mild fibrosis) can continue methotrexate therapy with a repeat liver biopsy performed after approximately 6 months; patients with grade IIIB changes (e.g. moderate to severe fibrosis) or grade IV changes (e.g. cirrhosis) should discontinue methotrexate therapy.[52] However, liver biopsy is an invasive procedure, which itself may cause liver damage.[52] Due to the cost and morbidity associated with liver biopsy and the relatively low incidence of serious methotrexate-induced liver toxicity, the British Association of Dermatologists has questioned the appropriateness of routine liver biopsy.[20] Research has shown that patients with consistently normal serum type III procollagen aminopeptide (PIIINP) levels in serial measurements are at low risk of developing substantial liver fibrosis,[62,63,64] and this alternative, noninvasive test has been accepted by clinicians in the U.K. and some parts of Europe. It is still considered wise to evaluate liver biopsies early for high-risk patients; however, serial PIIINP measurement may replace subsequent repeat biopsies for patients with normal initial biopsy results.[64] In the event of a persistently elevated PIIINP level (i.e. > 4·2 ng mL-1; Orion assay), liver biopsy is required.[63,64] As discussed previously, the extent of pathological changes detected by liver biopsy will direct the decision of whether or not to continue methotrexate. Limitations of PIIINP monitoring identified by researchers include the inability to detect pre-existing liver damage, lack of organ specificity, and possible PIIINP elevation due to arthritis.[64] Further work is required to address these specific issues.

Several drugs may influence methotrexate metabolism and/or potentiate methotrexate-induced toxicity, including some nonsteroidal anti-inflammatory drugs and salicylic acid ( Table 4 ).[51,55] Therefore, careful consideration of concomitant medication is required. Indeed, avoidance of drug interactions has been identified as an important requirement for safe long-term methotrexate treatment.[56,65] Particular caution is warranted for patients who may be at increased risk of methotrexate-induced toxicity due to impaired renal function or folate deficiency,[55] and patients with psoriatic arthritis, many of whom use nonsteroidal anti-inflammatory drugs.[54]

Given the potentially serious toxicities associated with methotrexate and the need for regular and invasive monitoring, the benefits and risks of methotrexate therapy for psoriasis must be carefully evaluated for each patient.[52] Provided that strict patient selection and monitoring guidelines are followed, clinical experience has shown that methotrexate can be reasonably safe and well tolerated.[56,65,66] Methotrexate may be suitable for practical reasons such as low cost and the convenience of oral administration.[20]

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