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



Rheumatoid arthritis is the most common autoimmune disease in the world and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We sought to assess whether earlier intervention, in the earlier phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce disease burden.


We conducted a randomized, double-blind, placebo-controlled, proof-of-concept trial at Leiden University Medical Center, Leiden, The Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and subclinical joint inflammation detected by MRI were eligible for enrollment in 13 outpatient rheumatology clinics in the South West region of the Countries -Low and randomly assigned (1:1) to a single intramuscular injection of glucocorticoids (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and interviewers have been hidden for group assignment. Follow-up continued for 1 year after the end of the one-year treatment period. The primary endpoint was the development of clinical arthritis (meeting the 2010 classification criteria for rheumatoid arthritis or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. In addition, the evolution of inflammation detected by MRI was studied. All participants participated in the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599.


Between April 16, 2015 and September 11, 2019, 901 patients were assessed for eligibility and 236 were recruited and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group versus 21 [18%] 117 in the placebo group; relative risk 0 81, 95% CI 0 45 to 1 48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean difference between groups in the Health Assessment Questionnaire Disability Index on 2 years: -0 09, 95% CI -0 16 to –0 03; p=0 0042). Similarly, pain (on a scale of 0 to 100, mean difference between groups: -8, 95% CI -12 to -4; p


Methotrexate, the cornerstone of treatment for rheumatoid arthritis, initiated at the pre-arthritic stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but did alter the course of the disease , as shown by sustained improvement in MRI-detected inflammation, associated symptoms, and impairments compared to placebo.


Dutch Research Council (NWO; Dutch Arthritis Society).

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