Adverse Mucocutaneous Events Associated With Low Dose Methotrexate

Alopecia (hair loss) on the head of a 27 year old man. Alopecia can be caused by an autoimmune attack on the hair follicles (alopecia areata), as a result of tightly pulled hairstyles (called traction alopecia) or as a side effect of medication. This patient has developed alopecia due to taking azothioprine, an immunosuppressant drug used to treat his Crohn’s disease (an autoimmune disease that causes chronic inflammation of the intestines).
Researchers assessed the incidence of alopecia and stomatitis with methotrexate in patients with rheumatic diseases.

Before initiating methotrexate (MTX) therapy in patients with rheumatic disease, physicians should discuss the risks and benefits of treatment, including the prevalence of mucocutaneous adverse events (AEs) such as alopecia or stomatitis, according to study results published in Arthritis Care & Research.

Researchers conducted a systematic review and meta-analysis of 20 randomized controlled trials, including 24 MTX monotherapy arms, to examine the prevalence of mucocutaneous AEs.

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The 20 studies analyzed included data from 2331 patients (1113 with alopecia; 2056 with stomatitis). Mean doses of MTX ranged from 10 mg/wk to 25 mg/wk (median, 15 [interquartile range (IQR) 14-19] mg/wk), and administration route included oral (13 studies), subcutaneous (1 study), and intramuscular (1 study).

Thirteen study arms included 5-30 mg/wk of folic acid as an intervention; 2 studies included 1 mg or 2.5 mg folinic acid per week. Median clinical trial duration was 24 (IQR 23-50) weeks. Adverse events were self-reported in 15 study arms and assessed via checklist or questionnaire in 6 study arms. One study used both methods.

A total of 76 cases were reported among the alopecia studies; lower-bound prevalence was 1%, and upper-bound prevalence was 4.9%, making the prevalence of alopecia in 24 studies 1%. The researchers reported significant statistical heterogeneity among the alopecia studies (I² = 84%; P < .01).

A total of 182 cases (8% prevalence) were reported among the stomatitis studies. Overall the prevalence of stomatitis was 5.7%, with significant statistical heterogeneity (I² = 90%; P < .01).

Bias assessment risk was low across most included studies. Among the sensitivity analyses that included assessment by questionnaire only, the incidence of alopecia and stomatitis was 2.8% and 11.8%, respectively. Another sensitivity analysis that only included studies that specified doses of folic or folinic acid found the incidence of alopecia and stomatitis to be 0.6% and 4.6%, respectively. Using the leave-one-out method, the pooled incidence of alopecia and stomatitis was 1% and 5.7%, respectively.

The researchers noted that this review is, to their knowledge, the first to focus on the prevalence of mucocutaneous AEs in patients being treated with low-dose MTX since the advent of widespread folic acid use.

Study limitations included a lack of standardized definitions of stomatitis or oral ulcers and a lack of specificity of the dose of folic or folinic acid.

“This meta-analysis gives more precise estimates of mucocutaneous adverse effects that occur in rheumatic disease patients using MTX,” the researchers of the study concluded. “These estimates will help inform patient decision making regarding MTX.”

Disclosures: Solomon reports relationships with AbbVie Inc.; Amgen Inc.; Bristol Myers Squibb Company; Genentech, Inc.; and Corrona, LLC. He is the chair of the US Food and Drug Administration Arthritis Advisory Committee.


Lalani R, Lyu H, Vanni K, Solomon DH. Low dose methotrexate and mucocutaneous adverse events: results of a systematic literature review and meta-analysis of randomized controlled trials [published online May 31, 2019]. Arthritis Care Res. doi:10.1002/acr.23999