Therapeutic interception in individuals at risk of rheumatoid arthritis to prevent clinically impactful disease.

Multiple clinical trials for rheumatoid arthritis (RA) prevention have been completed. Here, we set out to report on the lessons learnt from these studies. Researchers who conducted RA prevention trials shared the background, rationale, approach and outcomes and evaluated the lessons learnt to inform the next generation of RA prevention trials. Individuals at risk of RA can be identified through population screening, referrals to musculoskeletal programmes and by recognition of arthralgia suspicious for RA. Clinical trials in individuals at risk for future clinical RA have demonstrated that limited courses of corticosteroids, atorvastatin and hydroxychloroquine do not alter incidence rates of clinical RA; however, rituximab delays clinical RA onset, and methotrexate has transient effects in individuals who are anticitrullinated protein antibody-positive with subclinical joint inflammation identified by imaging. Abatacept delays clinical RA onset but does not fully prevent onset of RA after treatment cessation. Additionally, subclinical joint inflammation and symptoms appear responsive to interventions such as methotrexate and abatacept. To advance prevention, next steps include building networks of individuals at risk for RA, to improve risk stratification for future RA and to understand the biological mechanisms of RA development, including potential endotypes of disease, which can be targeted for prevention, thus adopting a more precision-based approach. Future trials should focus on interceptions aimed at preventing clinical RA onset and which treat existing symptoms and imaging-defined subclinical inflammation. These trials may include advanced designs (eg, adaptive) and should be combined with mechanistic studies to further define pathophysiological drivers of disease development.

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Competing interests: KDD has received honoraria from BMS, ThermoFisher and Werfen, and in-kind research supplies from Inova Diagnostics; VMH has received equity and funds from Q32 Bio unrelated to this work; PE has received funds for consulting from AnaptysisBio, BMS, Boehringer Ingelheim, Galapagos, Gilead, Janssen, MSD, Lilly, Novartis and support for clinical trials from Abbvie, BMS, Lilly, Novartis and Samsung; KM has received honoraria and/or consulting fees from Abbvie, Lilly, Galapagos, Serac Healthcare, Deepcure, UCB, Zura Bio and research grants from Astra Zeneca, Lilly, Gilead, Serac Healthcare and Deepcure. GS has received funds for consulting from BMS, Janssen and Novartis; JAS has received research support from Boehringer Ingelheim and Bristol Myers Squibb unrelated to this work. He has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi and UCB unrelated to this work; RT has received funds for consulting from CSL, AbbVie, Nextera, Sandoz, Viela Bio and Janssen-Cilag and received research contracts from CSL and Viela Bio; APC has received consulting and speaker bureau fees from Abbvie, BMS, Galapagos, UCB, Galvani, Janssen, Roche and Arthrogen, and research grant support from BMS, UCB and Janssen, with funds administered by King’s College London.