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Background: Prevention of rheumatoid arthritis has become a definitive target. However, whether prevention of anti-citrullinated protein antibody (ACPA)-negative rheumatoid arthritis is possible is still unknown. We aimed to assess the efficacy of a 1-year course of methotrexate on the development of rheumatoid arthritis in ACPA-negative people with clinically suspect arthralgia and predicted increased risk of rheumatoid arthritis., Methods: For this follow-up analysis, we used 4-year data from the TREAT EARLIER trial, a randomised, double-blind, placebo-controlled, proof-of-concept trial conducted in the southwest region of the Netherlands from which we analysed data collected between April 16, 2015, and Sept 11, 2023. ACPA-positive and ACPA-negative adults aged 18 years or older with arthralgia and subclinical joint inflammation who were at risk of developing rheumatoid arthritis were eligible for enrolment. For TREAT EARLIER, participants were randomly assigned (1:1) to active treatment or placebo. Active treatment consisted of a single intramuscular glucocorticoid injection (120 mg of methylprednisolone) upon inclusion, then a 1-year course of methotrexate. Placebo consisted of a single placebo injection followed by a 1-year course of placebo tablets. Trial visits occurred every 4 months during the first 2 years, at which clinical and questionnaire data were collected. Total follow-up was 4 years. For this analysis, participants were stratified via a prediction model into low risk, increased risk, and high risk of developing persistent, clinically apparent inflammatory arthritis. The primary outcome was development of rheumatoid arthritis, defined as the presence of clinically apparent inflammatory arthritis and clinical diagnosis of rheumatoid arthritis, and was assessed in all TREAT EARLIER participants. Severity of subclinical joint inflammation, physical functioning, and grip strength in ACPA-negative participants was studied in each risk group over a period of 2 years., Findings: 901 people with clinically suspect arthralgia were assessed for eligibility and 236 were enrolled in TREAT EARLIER. All 236 participants were included in the intention-to-treat analysis and 217 (92%) completed 4-year follow-up. 154 (65%) of 236 participants were women and 82 (35%) were men, 182 (77%) were ACPA-negative and 54 (23%) were ACPA-positive. Of the 182 randomly assigned ACPA-negative participants, none were predicted to be at high risk of developing persistent, clinically apparent inflammatory arthritis, 66 (36%) at increased risk, and 116 (64%) at low risk. Of the 54 ACPA-positive participants, 24 (44%) were predicted to be at high risk, 30 (56%) at increased risk, and none at low risk. After 4 years, 52 (22%) of 236 participants had developed the primary outcome of rheumatoid arthritis (25 [21%] of 119 in the treatment group and 27 [23%] of 117 in the placebo group). Of the 66 ACPA-negative participants predicted to be at increased risk, three (9%) of 35 in the treatment group developed the primary outcome compared with nine (29%) of 31 in the placebo group (hazard ratio 0·27, 95% CI 0·07-0·99; p=0·034). Of the 116 ACPA-negative participants predicted to be at low risk, four (8%) of 53 in the treatment group met the primary outcome compared with six (10%) of 63 in the placebo group (0·79, 0·22-2·80; p=0·71). Thus, after risk stratification, a 1-year course of methotrexate was associated with a reduced rate of development of ACPA-negative rheumatoid arthritis in participants with predicted increased risk of developing the disease. Subclinical joint inflammation, physical functioning, and grip strength persistently improved upon treatment in ACPA-negative participants with increased risk of developing rheumatoid arthritis, but not in those with low risk., Interpretation: Risk stratification can be helpful in trials of ACPA-negative people with clinically suspect arthralgia to identify participants who could benefit from treatment to prevent development of rheumatoid arthritis., Funding: Dutch Research Council-ZonMw, Dutch Arthritis Society., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden., Methods: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (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 investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria 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. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599., Findings: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled 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 vs 21 [18%] of 117 in the placebo group; hazard ratio 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 between-group difference in Health Assessment Questionnaire disability index over 2 years: -0·09, 95% CI -0·16 to -0·03; p=0·0042). Similarly, pain (on scale 0-100, mean between-group difference: -8, 95% CI -12 to -4; p<0·0001), morning stiffness of joints (-12, -16 to -8; p<0·0001), presenteeism (-8%, -13 to -3; p=0·0007), and MRI-detected joint inflammation (-1·4 points, -2·0 to -0·9; p<0·0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate., Interpretation: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo., Funding: Dutch Research Council (NWO; Dutch Arthritis Society)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)