Early treatment with methotrexate alters the course of rheumatoid arthritis


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

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

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

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The primary endpoint was the development of clinical arthritis meeting the 2010 RA classification criteria or involving 2 or more joints and persisting for at least 2 weeks. Secondary endpoints included patient-reported outcomes of physical functioning (measured by Health Assessment Questionnaire Disability Index [HAQ]; range 0-3), symptoms (including joint pain, morning stiffness and fatigue; range 0 [no symptoms] 100 [worst symptoms]) and work productivity (work productivity degradation scale; measured as the percentage decrease in productivity due to joint symptoms in the past week). Magnetic resonance imaging (MRI) was also done to measure joint inflammation and radiographic progression. Adverse events were tracked throughout the study.

A total of 236 patients were included 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 and placebo groups developed the primary endpoint (19% versus 18%, respectively; relative risk [HR]=0.81; 95% CI, 0.45-1.48).

With regard to physical function, the mean difference between groups in the HAQ at 2 years was improved in the treatment group compared to the placebo group and persisted at 2 weeks (-0.09; 95% CI, – 0.16 to -0.03; P =.0042). The mean differences between the groups also showed significant improvements in the treatment group compared to the placebo group in pain (-8; 95% CI, -12 to -14; P P P = 0.0007) and joint inflammation detected by MRI (-1.4 points; 95% CI, -2 0 to -0 9; P <.0001 adverse events were as expected for mtx while serious similar between groups.>

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

The study authors conclude: “This trial showed that a single intramuscular injection of glucocorticoids and a one-year course of methotrexate did not prevent the development of clinically detectable arthritis, but may offer new insights to reduce 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 randomized, double-blind, controlled proof-of-concept trial placebo. Lancet. Published online July 23, 2022. doi:10.1016/S0140-6736(22)01193-X

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