Early Treatment With Methotrexate Modifies Rheumatoid Arthritis Disease Course

methotrexate syringe
Researchers evaluated either early intervention with methotrexate for rheumatoid arthritis could prevent the development of clinical arthritis or reduce disease burden.

Methotrexate (MTX) therapy for pre-rheumatoid arthritis (RA) does not prevent clinical arthritis, but improves inflammation, symptoms, and impairment compared with placebo, according to study findings published in Lancet.

Researchers sought to evaluate whether treatment with MTX for pre-RA could delay development of arthritis and patient-reported outcomes of disease burden. They conducted a randomized, double-blind, placebo-controlled, proof-of-concept trial at a single center in the Netherlands between April 16, 2015, and September 11, 2019 (EU Clinical Trials Register Identifier: 2014-004472-35).

Patients aged years 18 and older with arthralgia at risk for developing RA and subclinical joint inflammation were randomly assigned to receive either a single intramuscular glucocorticoid injection plus 1 year of treatment with methotrexate or placebo. Study visits occurred every 4 months for the first year. Follow-up continued for 1 year following the treatment period.

The primary endpoint was the development of clinical arthritis that fulfilled the 2010 RA classification criteria or involved 2 or more joints and persisted for at least 2 weeks. Secondary endpoints included patient-reported outcomes in physical functioning (measured by the Health Assessment Questionnaire disability index [HAQ]; range of 0 to 3), symptoms (including joint pain, morning stiffness, and fatigue; range of 0 [no symptoms] to 100 [worst symptoms]), and work productivity (Work Productivity Impairment Scale; measured as the percentage of impairment in productivity due to joint symptoms in the last week). Magnetic resonance imaging (MRI) was also performed to measure joint inflammation and radiographical progression. Adverse events were tracked throughout the study.

A total of 236 patients were enrolled in the study, including 119 in the treatment group and 117 in the placebo group. After 2 years, a similar proportion of patients in the treatment group and the placebo group developed the primary endpoint (19% vs 18% respectively; hazard ratio [HR]=0.81; 95% CI, 0.45-1.48).

Regarding physical function, the mean between-group difference in HAQ at 2 years was improved in the treatment group compared with the placebo group and persisted at 2 weeks (-0.09; 95% CI, -0.16 to -0.03; P =.0042). The mean between-group differences also showed significant improvements in the treatment group compared with the placebo group in pain (-8; 95% CI, -12 to -14; P <.0001), morning stiffness of joints (-12; 95% CI, -16 to -8; P <.0001), presenteeism (-8%; 95% CI, -13 to -3; P =.0007), and MRI-detected joint inflammation (-1.4 points; 95% CI, -2·0 to -0·9; P <.0001). Adverse events were as expected for MTX, while serious adverse events were similar between groups.

Limitations of the study include the inability to determine effects of the glucocorticoid injection vs the course of methotrexate and unknown cost-effectiveness of treatment for pre-RA.

The study authors conclude, “This trial showed that a single intramuscular glucocorticoid injection and a 1-year course of methotrexate did not prevent the development of detectable clinical arthritis, but could offer new perspectives on lowering the burden of disease.”


Krijbolder DI, Verstappen M, van Dijk BT, et al. Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet. Published online July 23, 2022. doi:10.1016/S0140-6736(22)01193-X