Risk Factors for Oral Methotrexate Failure Identified in Inflammatory Polyarthritis

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Investigators sought to evaluate the rate and predictors of oral methotrexate failure.

Oral methotrexate (MTX) failure because of inefficacy is associated with rheumatoid factor positivity, younger age at symptom onset, and higher baseline disease activity, according to new study data published in Arthritis Research & Therapy.

A total of 431 patients with inflammatory polyarthritis who received MTX as their first disease-modifying antirheumatic drug (DMARD) were recruited for the study. Follow-up assessments were conducted to collect demographic and clinical data, and blood draws were performed at baseline to determine C-reactive protein concentration, measure rheumatoid factor, and detect anticitrullinated protein antibodies. Researchers used these figures to calculate baseline disease activity for each patient.

During the study period, MTX therapy failed because of adverse events in 67 patients (16%) and because of inefficacy in 143 patients (33%). Of the adverse events, gut symptoms were most commonly reported (42%). The probability of patients remaining on MTX at 2 and 5 years was 82% (95% CI, 0.79-0.86) and 72% (95% CI, 0.67-0.76), respectively. Rheumatoid factor positivity was protective against early MTX failure caused by an adverse event but was independently associated with later MTX failure (HR, 0.34; 95% CI, 0.20-0.59). To explain the former trend, researchers suggested that patients positive for rheumatoid factor who have higher disease activity may be more likely to persist with MTX despite side effects compared with those without rheumatoid factor.

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In the final model, rheumatoid factor positivity (HR, 1.67; 95% CI, 1.13-2.48), younger age (HR, 0.97; 95% CI, 0.96-0.99) and higher baseline disease activity (HR, 1.23; 95% CI, 1.05-1.43) were each associated with earlier MTX failure because of inefficacy.

These data support the continued blood monitoring of patients taking MTX to screen for risk factors and efficacy potential. Patients at a higher risk for MTX inefficacy, investigators concluded, may require combination therapy and a more tailored treatment approach.


Bluett J, Sergeant JC, MacGregor AJ, et al. Risk factors for oral methotrexate failure in patients with inflammatory polyarthritis: results from a UK prospective cohort study. Arthritis Res. Ther. 2018;20(1):50.