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Introduction
Introduced in the 1950s, methotrexate continues to be one of the most widely used systemic immunosuppressive agents in dermatology [1, 2]. Whilst awareness of important potential adverse events such as hepatotoxicity, myelosuppression, and pulmonary fibrosis are reflected in robust guidelines for dosing and monitoring of treatment [3], other adverse events including cutaneous ulceration remain rarely reported and poorly characterized. Cutaneous ulceration may play a crucial role as an early clinical sign of impending systemic toxicity [4]. Although rare, it is of primary importance that dermatologists remain alert to cutaneous indicators of methotrexate toxicity, are aware of risk factors that may affect drug metabolism and are confident in the management of methotrexate overdose.
We present a case of methotrexate toxicity manifesting with cutaneous ulceration and review the literature, highlighting practice points relevant to dermatology.
Methotrexate
Uses
Methotrexate is licensed for the treatment of severe psoriasis, psoriatic arthritis, rheumatoid arthritis, and a number of malignancies, including: childhood acute lymphoblastic leukemia, lymphoproliferative disorders, choriocarcinoma, and various solid organ tumors. In addition, methotrexate is an abortifacient used in early and ectopic pregnancy and is used off-license in a host of dermatological conditions including atopic eczema [5, 6] and bullous pemphigoid [1], as well as non-dermatological conditions, including: Crohn’s disease, systemic lupus erythematosus, and myositis.
Methotrexate can be used as monotherapy or in combination with other agents including biologic therapies [7, 8]. Combination therapy with methotrexate and infliximab has been reported for the treatment of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) [9], pityriasis rubra pilaris [10], recalcitrant chronic plaque psoriasis [11], and erythrodermic psoriasis [12]. For the treatment of chronic plaque psoriasis, combination therapy of etanercept with methotrexate led to improved disease control in a randomized, double-blinded, placebo-controlled clinical trial [13] as well as in reporting by individual centers [14]. Combination therapy of infliximab with methotrexate led to dose reduction of infliximab when compared with combinations of infliximab and azathioprine [15], increased dosing intervals [12], and appears to be well tolerated when compared with methotrexate monotherapy [16].
It is postulated that the addition of methotrexate to biologic therapy may allow the maintenance of therapeutic benefit through the reduction of formation of anti-infliximab autoantibodies [11]. While this has not been conclusively demonstrated in dermatology patients [17], evidence in...