A randomized, double-blind, placebo-controlled, proof-of-concept trial depicted that the use of Methotrexate was associated with changes in the course of the illness, as shown by persistent improvement in magnetic resonance imaging (MRI)-detected inflammation, associated symptoms, and deficits compared to placebo. Doortje I. Krijbolder et al. sought to determine if early treatment of arthralgia and subclinical joint inflammation may delay the onset of clinical arthritis or lessen the severity of the condition.

Adult patients ≥ 18 years with arthralgia clinically suspected to proceed to rheumatoid arthritis with MRI-detected subclinical joint inflammation were randomized in a 1:1 ratio to receive a single 120 mg glucocorticoid injection intramuscularly and a 1-year treatment of Methotrexate (up to 25 mg/week) orally, or placebo (single injection and tablets for 1 year). Following the conclusion of the one-year treatment period, follow-up lasted another year.

The development of clinical arthritis that lasted for at least two weeks and met the 2010 rheumatoid arthritis classification criteria or included ≥ 2 joints was the main outcome. Work productivity, symptoms, and patient-reported physical functioning were secondary objectives that were assessed every four months. The development of inflammation detected by MRI was investigated. Intention-to-treat analysis was conducted with all participants.

A total of 236 participants were enrolled and randomized to either active therapy (n = 119) or a placebo (n = 117) after 901 people had been evaluated for eligibility. The incidence of the main endpoint was comparable between the groups at 2 years (hazard ratio: 0.81; 23 [19%] of 119 people in the intervention group vs. 21 [18%] of 117 in the placebo group). During the first four months, the treatment group's physical functioning improved more than the placebo group's, and this difference persisted (mean between-group difference in the Health Assessment Questionnaire disability index over two years: -0.09).

Pain (on a scale of 0-100, mean between-group difference: -8), MRI-detected joint inflammation (-1·4 points, -2·0 to -0·9), presenteeism (-8%, -13 to -3), and morning stiffness of joints (-12, -16 to -8), demonstrated consistent improvement in the treatment group as compared to the placebo group. Both groups experienced the same number of significant adverse events, and these occurrences were in line with Methotrexate's safety profile. Hence, Methotrexate initiated at the pre-arthritis stage of symptoms and subclinical inflammation modified the course of disease in people with arthralgia.