Early Methotrexate Did Not Prevent Arthritis Development, Study Found

Among patients with arthralgia, methotrexate initiated at the prearthritis stage of symptoms and subclinical inflammation did not prevent the development of clinical arthritis, according to a study published in The Lancet.

Instead, a 1-year course of methotrexate modified the rheumatoid arthritis (RA) disease course, reflected by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo.

To come to this finding, the study authors conducted a randomized, double-blind, placebo-controlled, proof-of-concept-trial in the Netherlands. Participants were eligible for enrollment if they were 18 years or older, had arthralgia or joint stiffness that was clinically suspected to progress to RA, and had MRI-detected subclinical joint inflammation. A total of 236 adult participants were randomized into the active treatment or placebo group.

The 119 participants in the treatment group received a single intramuscular injection of glucocorticoid 120 mg and a 1-year course of oral methotrexate, taking up to 25 mg per week.The other 117 participants received a single placebo injection and a 1-year course of an oral placebo pill.

Participants were also followed up with for an additional year after completion of the 1-year treatment or placebo course.

After 2 years, the study authors found the participants developed clinical arthritis at similar frequencies between groups, with 19% of participants in the treatment group and 18% in the placebo group developing clinical RA.

However, they also discovered greater and more sustained improvement in physical function among the treatment group, starting within the first 4 months of treatment, compared with the placebo group.

Overall, early treatment improved physical function, pain, morning joint stiffness, MRI-detected joint inflammation, and work productivity. Improvements in these areas were sustained during follow-up.

“A therapeutic window of opportunity in the pre-arthritis stage of rheumatoid arthritis, in which the disease is more susceptible to disease-modifying treatment and biological processes can be halted, is presumed but has not yet been proven,” the authors wrote. “Clinical arthritis was at most delayed in patients who progressed, but it was not prevented.”

The authors also noted the number of serious adverse events was equal between groups, and were consistent with the known safety profile for methotrexate.

Additionally, because the treatment group was receiving both glucocorticoid and methotrexate while the placebo group was receiving neither, the authors cannot confirm which treatment caused these results.

“Whether the effects can be attributed to either methotrexate or the glucocorticoid injection cannot be deduced from these data, and would require a trial in participants at risk of developing rheumatoid arthritis with a study visit after 2–4 weeks after glucocorticoid injection at baseline,” they said. “The cost-effectiveness of a methotrexate course in the pre-arthritis phase also needs to be established, in the context of increasing pressure from society to spend less on health care.”

Although the treatment did not prevent the development of clinical RA, the authors suggested it could potentially offer a new perspective on lowering disease burden.

The authors have extended the follow-up period to 5 years and are currently evaluating longer-term effects.

Reference

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. 2022;400(10348):283-294. doi:10.1016/S0140-6736(22)01193-X