Best of 2025: Methotrexate intolerance in rheumatoid arthritis Save

Editor's note: This article was originally published August 26, 2025, and is being shared again as part of RheumNow's 'Best of 2025' series as we close out the year. Enjoy!

Methotrexate (MTX) is the most commonly used DMARD in rheumatoid arthritis (RA); however, there is significant intolerance to this drug among adult RA patients - especially at doses above 15 mg per week. 

A cross-sectional, single center study from India included RA patients on regular oral or subcutaneous MTX for a lease three months. Patients were surveyed using the methotrexate intolerance severity score (MISS) questionnaire. Patients with a MISS score ≥ 6 were considered MTX intolerant. Intolerance was correlated with clinical variables and disease activity (DAS-28 CRP). 

Among a total of 200 adult RA patients (86% female), the average duration of MTX use was 46 months. 

• MTX intolerance was observed in nearly 35% - Nausea (85.5%) and GI discomfort (59.42%) were the most prevalent symptoms.
  • nausea was a predominant symptom not only after MTX administration but also as an anticipatory and associative symptom
• MTX intolerance was correlated with female gender, disease severity, and MTX dose. 42-48% were MTX intolerant with the DAS28-CRP > 3.2

MTX doses of 15 mg/week or greater may be associated with intolerance. 

This study did not evaluate the effects of folate supplementation on intolerance.