Investigators noted that methotrexate cutaneous ulceration, a rare complication of methotrexate use, has only been characterized in case reports and case series. They conducted a meta-analysis to determine general characteristics of methotrexate cutaneous ulceration and found that it frequently presented after dosage mistakes, absence of folic acid supplementation, and concurrent nephrotoxic medication use.

Their report, published in the American Journal of Clinical Dermatology, further described that renal impairment, pancytopenia, and absence of folic acid supplementation were key risk factors of mortality for this adverse reaction.

The analysis enrolled 114 patients with methotrexate cutaneous ulceration from case reports and case series published to the PubMed and Embase databases. The most common indications leading to methotrexate use were psoriasis (69.3%), rheumatoid arthritis (18.4%), and mycosis fungoides (6.1%).

Morphological presentations included erosions localized to psoriatic plaques (33.3%), epidermal necrosis, necrolysis (35.1%), localized ulceration (16.7%), and skin-fold erosions (5.3%). Notably, methotrexate dosing prior to adverse reaction was highly varied with a median of 20 mg/wk, interquartile range of 15-40 mg/wk, and range of 5-150 mg/wk. The majority of patients had risk factors for serum toxicity, including baseline renal dysfunction (37.8%), concurrent NSAID use (28.1%), and inadequate folic acid supplementation (89.1%).

Approximately 30% of cases involved mistakenly high doses of methotrexate. In total, 14 patients died. Absence of folic acid use (69% vs 100%; P<.001), pancytopenia (33% vs 86%; P<.001), and renal dysfunction at presentation (47% vs 92%; P<.001) were associated with increased mortality.

The authors cautioned that providers should maintain high suspicion for methotrexate cutaneous ulceration given the variable presentations and high rate of mortality. They advised monitoring dosing adherence and drug-to-drug interactions, as well as routine laboratory evaluations.

Reference: Berna R, Rosenbach M, Margolis DJ, Mitra N, Baumrin E. Methotrexate Cutaneous Ulceration: A Systematic Review of Cases [published online ahead of print, 2022 Apr 29]. Am J Clin Dermatol. 2022;10.1007/s40257-022-00692-1. doi:10.1007/s40257-022-00692-1