Original article
Methotrexate-induced epidermal necrosis: A case series of 24 patients

https://doi.org/10.1016/j.jaad.2017.02.021Get rights and content

Background

Methotrexate-induced epidermal necrosis (MEN) is a rare but life-threatening cutaneous reaction that mimics Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Objectives

To investigate the clinicopathology, risk factors, and prognostic factors of MEN.

Methods

We enrolled 24 patients with MEN and 150 controls and analyzed the demographics, pathology, and plasma concentrations of methotrexate (MTX).

Results

Patients with MEN showed extensive skin necrosis (mean, 33.2% total body surface area) but no target lesions. The histopathology displayed keratinocyte dystrophy. Early signs of MEN included painful skin erosions, oral ulcers, and leukopenia/thrombocytopenia. Although 79.2% patients received leucovorin treatment, there was 16.7% mortality. Risk factors for MEN included older age (>60 years), chronic kidney disease, and high initial dosage of MTX without folic acid supplementation. Renal insufficiency delayed MTX clearance. Severe renal disease and leukopenia predicted poor prognosis in MEN, but none of the SCORe of Toxic Epidermal Necrosis criteria were associated with mortality of MEN.

Limitations

The study was limited by the small sample size.

Conclusion

MEN exhibited distinct clinicopathologic features from SJS/TEN. Recognition of the early signs and prognostic factors is important, because the rapid institution of leucovorin may be helpful. To reduce the risk of MEN, physicians should avoid prescribing MTX to high-risk patients and titrate the dosage slowly upward with folic acid supplementation.

Section snippets

Study participants

Patients with epidermal necrosis after taking MTX were enrolled from Chang Gung Memorial Hospital (CGMH) system and Wan Fang Hospital between 2007 and 2016. This study was approved by the institutional review board of the study site. Written informed consent was obtained from each participant. All cases were evaluated by at least 2 dermatologists. The diagnosis of epidermal necrosis was made by the clinical presentation or histopathologic findings. Drug causality was determined by the Naranjo

Demographic characteristics of patients with MEN and controls

We enrolled 24 MEN cases and 150 MTX-tolerant controls (Table I). The detailed demographic data of 24 cases are listed in Supplemental Table I (available at http://www.jaad.org), and representative clinical photographs of patients are shown in Fig 1. Four of the 24 patients with MEN died from this episode, and the overall mortality was 16.7% (Table I). Twenty-two (91.7%) patients with MEN received MTX for treating psoriasis or psoriatic arthritis, 1 for bullous pemphigoid, and 1 for rheumatoid

Discussion

To our knowledge, this is the largest study comparing patients with MEN and controls to investigate the clinicopathologic features, risks, and prognostic factors of MEN. The early signs of MEN include painful skin erosions, oral ulcers, leukopenia, and thrombocytopenia. The risks of MEN included older age (>60 years), CKD, and high initial dosage without folic acid supplement. Poor renal function delayed the clearance of plasma MTX. We found that severe renal disease and leukopenia were linked

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    Drs T-J. Chen and Chung contributed equally to this work.

    Supported by the grants from the Ministry of Science and Technology, Taiwan (NSC101-2320-B-010-072-MY3, NSC101-2321-B-010-027, NSC101-2628-B-182-001-MY3, NSC101-2321-B-182-008, NSC102-2314-B-010-014-MY3, and NSC104-2320-B-010-036-MY3) and grants from Chang Gung Memorial Hospital (BMRPG290011, CMRPG-290051∼3, OMRPG2C0011, OMRPG2C0021, and CLRPG340599).

    Conflicts of interest: None declared.

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