Early methotrexate treatment can modify the disease course of RA

The findings of TREAT EARLIER proof of concept study, published in the recent issue of Annals of the Rheumatic Disease, have concluded that the use of methotrexate in the pre-arthritis stage may help in altering the disease course of clinical arthritis. However, this early treatment does not prevent the disease development.

Through this study, Krijbolder and a team of colleagues evaluated the hypothesis whether the therapeutic intervention in the pre-arthritis phase of arthralgia and subclinical joint inflammation helps in preventing/reducing the RA burden. The two-year, randomized, double-blind, trial involved 236 adult patients with clinically suspected RA and MRI-detected sub-clinical joint inflammation, who presented to the outpatient rheumatology clinics in the south-west Netherlands. The subjects were randomized in 1:1 ratio to receive single 120 mg intramuscular glucocorticoid injection and a 1-year course of oral methotrexate up to 25 mg per week or placebo injection and placebo pills.

The 2- year follow-up revealed that the arthritis-free survival was comparable in both groups (80% vs. 82%, HR 0.81). Physical functioning was found to be significantly improved in the treatment group during the first few months and its persistence in the following months (P=0.004). Further analysis demonstrated sustained improvement in pain (p <0·001), morning stiffness (p <0·001), and presenteeism (p=0·001) compared to placebo. MRI-based evaluation of joint inflammation also reported sustained improvement in joint inflammation (95%CI -2·0,-0.9;p<0·001). A delay in clinical arthritis development was noted in high-risk subjects, but frequencies of episodes were comparable at 24 months (67% in both groups). Similar delay was observed in ACPA-positive subjects. The number of serious adverse events was comparable between the groups.

A previous review by Emery and Quinn has also advocated early intervention to alter the disease process, thereby to prevent the disability and irreversible damage. The findings of radiological outcome studies also corroborate the need for early intervention. Such studies have demonstrated the occurrence of damage by the end of 2 years in majority of RA patients.

The current study is expected to open-up newer avenues to develop early intervention modalities targeting the pre-arthritis phase of RA.


  1. Krijbolder D, Verstappen M, van Dijk B, et al. OP0070 Intervention with methotrexate in arthralgia at risk for rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a double-blind, randomised, placebo-controlled trial. Annals of the Rheumatic Diseases 2022;81:48-49.
  1. Quinn MA, Emery P. Window of opportunity in early rheumatoid arthritis: possibility of altering the disease process with early intervention. Clin Exp Rheumatol. 2003;21(5 Suppl 31):S154-S157.