Methotrexate intolerance in rheumatoid arthritis

Jack Cush, MD

Feb 02, 2026 10:00 am

A current large Rheumatoid arthritis (RA) cohort study from Cairo assessed methotrexate (MTX) use and found over half were MTX intolerant and a third of patients were noncompliant with MTX.

A total of 355 RA patients on MTX for at least three months were included and assessed using the MTX Intolerance Severity Score (MISS). Drug compliance assessed using the 5-Item Compliance Questionnaire for Rheumatology (CQR5).

Over half of the MTX treated RA population (50.7%) were MTX intolerant, and only two-thirds (66.2%) were compliant on MTX. Predictors of MTX intolerance Included:

Younger age at disease onset (p = 0.006)
Longer disease duration (p = 0.001)
Parenteral MTX administration (IM/oral p < 0.001, OR 3.95, SC/oral p < 0.001, OR 7.73)
fixed morning dosing compared to divided or inconsistent schedule divided/morning p < 0.001, Inconsistent time/morning p = 0.014)
Receiving MTX before meals versus after meals (p = 0.007, OR 5.61)
Concomitant leflunomide use (p = 0.01, OR 1.88)
Higher tender joint count (p = 0.03)
Leflunomide intake (p = 0.002, OR 2.65) and parenteral MTX administration (IM/oral 0.002, OR 6.06, SC/oral < 0.001, OR 14.3) were the only predictors in multivariate logistic regression.
Less tobacco: number of cigarette pack/year (p = 0.007).

Ccaffeine intake, folate adherence/dosage, disease activity, and extra-articular manifestations were not associated with MTX intolerance.

MTX intolerance and noncompliance is common. More so with parenteral use, combined use with LEF and possibly in women.

Methotrexate intolerance in rheumatoid arthritis: Prevalence, risk factors and impact on treatment adherence