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Methotrexate Cutaneous Ulceration: A Systematic Review of Cases

  • Systematic Review
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American Journal of Clinical Dermatology Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 17 April 2023

A Letter to the Editor to this article was published on 17 April 2023

Abstract

Background

Methotrexate cutaneous ulceration is a rare methotrexate complication, and has only been described in case reports and case series.

Objective

To document patient characteristics, morphologic features, and mortality risk factors for methotrexate cutaneous ulceration.

Methods

A systematic literature review of PubMed and Embase (last date 1 November 2021) was performed with data collected from case reports and case series. This study was limited to cases of cutaneous ulceration; presence of oral ulceration was collected from within these cases.

Results

114 cases (men = 57.9%, mean age = 61 years) of methotrexate cutaneous ulceration met inclusion criteria. Psoriasis (69.3%), rheumatoid arthritis (18.4%), and mycosis fungoides (6.1%) were the most common indications for methotrexate use. Morphologies included erosions localized to psoriatic plaques (33.3%), epidermal necrosis/necrolysis (35.1%), localized ulceration (16.7%), and skin-fold erosions (5.3%). Methotrexate dose preceding toxicity varied greatly; median 20 mg/week, interquartile range 15–40 mg/week, range 5–150 mg/week. Most patients had risk factors for serum toxicity (baseline renal dysfunction = 37.8%, concurrent NSAID use = 28.1%, inadequate folic acid use = 89.1%). Thirty percent of cases involved mistakenly high methotrexate doses. Fourteen patients (12%) died. Absence of folic acid use (69% vs. 100%, p value < 0.001), pancytopenia (33% vs. 86%, p value < 0.001), and renal dysfunction at presentation (47% vs. 92%, p value < 0.001) were associated with increased mortality.

Limitations

Selection bias present due to abstraction from case reports and case series.

Conclusion

Methotrexate cutaneous ulceration is commonly preceded by dosage mistakes, absence of folic acid supplementation, and concurrent use of nephrotoxic medications. Renal impairment, pancytopenia, and absence of folic acid supplementation are key risk factors for mortality from this adverse medication reaction. Providers should regularly monitor methotrexate dosing adherence, drug–drug interactions, and perform routine laboratory evaluation. Index of suspicion for this toxicity should remain high given the varied clinical presentation and high mortality.

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Author information

Authors and Affiliations

  1. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, South Tower, 7th floor, Philadelphia, PA, 19104, USA

    Ronald Berna, Misha Rosenbach, David J. Margolis, Nandita Mitra & Emily Baumrin

  2. Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    David J. Margolis & Nandita Mitra

Authors
  1. Ronald Berna
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  2. Misha Rosenbach
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  3. David J. Margolis
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  4. Nandita Mitra
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  5. Emily Baumrin
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Corresponding author

Correspondence to Emily Baumrin.

Ethics declarations

Funding

None.

Conflict of interest

None.

Institutional review board approval

This study involved only data that are publicly available, and thus was not reviewed by the University of Pennsylvania Institutional Review Board.

Data availability

Data are readily accessible from the individual case reports.

Consent to participate/publish

Not applicable.

Code availability

R code available upon request from the corresponding author.

Author contributions

Conceived and designed the analysis: RB, DJM, EB. Collected the data: RB, EB. Performed the analysis: RB. Statistical guidance and technical support: NM. Writing and revision of manuscript: RB, MR, DJM, NM, EB. Project administration and support: DJM, EB.

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Berna, R., Rosenbach, M., Margolis, D.J. et al. Methotrexate Cutaneous Ulceration: A Systematic Review of Cases. Am J Clin Dermatol 23, 449–457 (2022). https://doi.org/10.1007/s40257-022-00692-1

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