Low‐Dose Methotrexate and Mucocutaneous Adverse Events: Results of a Systematic Literature Review and Meta‐Analysis of Randomized Controlled Trials

Abstract

Objective. Methotrexate (MTX) increases the risk of alopecia and stomatitis, but the prevalence of these adverse events among rheumatic patients taking MTX is poorly defined. We conducted a systematic literature review and meta-analysis to estimate the prevalence of alopecia and stomatitis with MTX in rheumatic diseases.Methods. We searched PubMed, The Cochrane Library, and CINAHL databases for double-blind randomized controlled trials (RCTs) with an MTX monotherapy arm. Alopecia, stomatitis, and oral/mouth ulcers data were extracted. The quality of trials was assessed by 2 authors. We included trials published since 1990 that used at least 10 mg of MTX weekly, coadministered with folic or folinic acid. We estimated the prevalence using randomeffects models because heterogeneity was anticipated. Two estimates of prevalence were included; the lower bound estimate included all trials (assuming no alopecia and stomatitis if not mentioned), and the upper bound estimate included only those that specifically described prevalence estimates of alopecia or stomatitis.Results. Of 3,954 studies identified, 20 RCTs were included, with a total of 24 MTX monotherapy arms, of which 10 reported the prevalence of alopecia (n = 1,113), and 21 reported stomatitis or mouth/oral ulcers (n = 2,056). The prevalence of alopecia was between 1.0% and 4.9%. The prevalence of stomatitis was between 5.7% and 8.0%.Conclusion. This meta-analysis gives more precise estimates of mucocutaneous adverse events that occur in rheumatic disease patients taking MTX. These estimates will help inform patient decision-making regarding MTX.

Stratification of methotrexate‐induced oral ulcers in rheumatoid arthritis patients

“…Mazaud and Fardet 21 pooled data of clinical trials investigating MTX with or without cointervention, and they found that 9.7 % of patients, from 30 studies, developed oral ulcers. Lalani et al 22 pooled data of RCTs investigating monotherapy MTX for RA, and they reported 8% of patients, from 21 studies, developed oral ulcers. In their narrative review, Kalantzis et al 4 reported 14% by pooling the data from 18 studies.…”

Cutaneous Manifestations of “Lupus”: Systemic Lupus Erythematosus and Beyond

“…Gastrointestinal upset, fatigue, hair loss, and oral ulcers are commonly reported adverse effects but may be mitigated by subcutaneous administration, or higher doses of prophylactic folic acid, respectively. Lalani et al recently demonstrated with a meta-analysis relatively low prevalence of stomatitis and alopecia (between 5.7 and 8.0% and between 1.0 and 4.9%, respectively) in patients taking methotrexate [ 122 ]. Bone marrow suppression and hepatotoxicity may occur, and routine lab monitoring is required while on therapy to ensure patient safety [ 6 ].…”

Adverse Oral Reactions Associated with Low Doses of Methotrexate

“…В ряде источников показано, что возникновение НР в полости рта зависит от получаемой дозы МТ незначительно [7,13,14]. Предположительно, это может объясняться секрецией препарата со слюной, повышением его концентрации в ротовой жидкости и развитием местного токсического эффекта даже при использовании минимальных дозировок [11].…”

“…В некоторых исследованиях было показано, что поражения СОПР являлись наиболее частым побочным эффектом при применении низких доз МТ [11]. По данным различных исследований, частота развития стоматита при монотерапии низкими дозами МТ колебалась от 5,7 до 17,0% [10,[13][14][15], в одном исследованиидостигала 60,7% [16]. Такое существенное различие может быть обусловлено разными схемами терапии, сопутствующим приемом фолиевой кислоты.…”

“…В научной литературе имеется небольшое количество описаний случаев НР в полости рта на фоне применения низких доз МТ у пациентов с разными ревматологическими заболеваниями. Опубликованные систематические обзоры объединяют в рамках метаанализа случаи развития поражений СОПР, ассоциированные с приемом МТ у пациентов с РА, псориазом, ПА и другими заболеваниями [13,17]. Описан случай острой слизисто-кожной токсичности у пациента 79 лет с псориазом, получавшего низкие дозы МТ.…”