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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.)

Competing Interests: We declare no competing interests. This study was carried out in compliance with the Helsinki declaration and all patients provided written informed consent. The study was approved by the medical ethical committee of the Leiden University Medical Centre. The TREAT EARLIER trial is registered with the Netherlands Trials Registry (NTR4853-trial-NL4599). This work was supported by a ZonMW grant (programma translationeel onderzoek), by the European Research Council under the EU's Horizon 2020 research and innovation programme (Starting grant, agreement No 714312), and the Dutch Arthritis Society. The funder had no role in analysis and interpretation of the data, or writing of the manuscript.