Toward Long-Term Prevention of Rheumatoid Arthritis: Are We Closer? Save

As earlier diagnosis and treatment of rheumatoid arthritis (RA) have resulted in greatly improved clinical outcomes, the focus of current research has now shifted to preventing the development of RA altogether. At EULAR 2025 in Barcelona, several oral presentations explored this objective, highlighting data from three key prevention trials: APIPRA, ARIAA, and TREAT EARLIER. Each trial targeted individuals considered to be “at-risk” for developing RA, investigating whether early immunomodulatory interventions could delay or prevent progression to classifiable RA.

APIPRA and ALTO: Initial Efficacy, Long-Term Challenges

The APIPRA trial enrolled individuals who were anti-citrullinated protein antibody (ACPA)-positive and had arthralgia but no clinical synovitis. Participants were randomized to receive either abatacept or placebo for 12 months, followed by an additional year of observation off treatment. During the treatment period, 29% of placebo recipients and only 6% of abatacept-treated individuals developed arthritis, demonstrating a clear short-term benefit of abatacept. However, by the end of the second year, arthritis had developed in 40% of the placebo group and in 30% of the abatacept group, suggesting that the protective effect of abatacept diminished following treatment cessation.

Andrew Cope (OP0004) presented extended follow-up data from the APIPRA Long-Term Outcomes (ALTO) study, which followed participants for up to 6 years. By year 4, arthritis-free survival was similar in both groups, with nearly 60% of participants in each arm having developed arthritis. These findings indicate that, while abatacept delayed disease progression, it did not provide durable prevention. However, a subgroup analysis identified a population of participants with multiple RA-associated autoantibodies in whom abatacept conferred a more sustained protective effect. This observation suggests that individuals with a mature autoantibody profile, but no clinical synovitis, may respond more favorably to T-cell co-stimulation blockade and could be an appropriate target population for preventive intervention with abatacept.

ARIAA and TREAT EARLIER: Targeting Preclinical Synovitis

Both the ARIAA and TREAT EARLIER trials enrolled participants with clinically suspect arthralgia and subclinical joint inflammation identified by magnetic resonance imaging (MRI) of the hands or feet. The ARIAA trial randomized ACPA-positive individuals to receive abatacept or placebo for 6 months, followed by 12 months of observation. TREAT EARLIER included both ACPA-positive and ACPA-negative individuals, who were randomized to receive a one-time intramuscular injection of corticosteroid and oral methotrexate for one year or a matched placebo. Participants were then observed for the subsequent four years.

In the ARIAA trial, at the conclusion of the 18-month evaluation period, RA had developed in 57% of placebo recipients compared with 35% of those treated with abatacept. This corresponded to a delay in progression of approximately 4 months. Koray Tascilar (OP0325) presented 10-year follow-up data, demonstrating that the delay in RA onset persisted for up to 5 years and the duration of this delay increased to an average of 10 months. These findings suggest that the effect of a 6-month course of abatacept on delaying the development of RA appears to be durable and may extend well beyond the treatment window in a subset of “at-risk” individuals.

The TREAT EARLIER trial provided some of the most promising data regarding prevention of the development of RA. In a 5-year subgroup analysis presented by Hanna van Steenbergen (OP0324), outcomes were stratified by ACPA status. ACPA-negative participants treated with methotrexate demonstrated significantly improved arthritis-free survival compared to those who received placebo. Only 9% of ACPA-negative individuals treated with methotrexate progressed to RA over 5 years, compared with 32% in the placebo arm. Furthermore, sustained improvement in physical function was observed in this group. In contrast, ACPA-positive individuals did not experience a reduction in RA development with methotrexate treatment and the initial improvements in physical functioning observed at 2 years had disappeared by year 5. Notably, the number of ACPA-negative individuals needed to treat with 1 year of methotrexate to prevent 1 case of RA was only 4, underscoring the potential clinical utility of early intervention in this subgroup.

Implications for Prevention

While these trials have not yet demonstrated prevention of RA outright, they represent significant progress toward this goal. Collectively, the data suggest:

• Abatacept may delay progression to RA in ACPA-positive individuals, particularly in those with mature autoantibody profiles, although the benefit may not persist after treatment discontinuation.
• Methotrexate, in combination with a single intramuscular injection of corticosteroid, offers durable benefit in ACPA-negative individuals with MRI-confirmed subclinical synovitis, reducing RA incidence and improving long-term function.
• Stratification by biomarker status, particularly ACPA seropositivity and imaging evidence of subclinical inflammation, is critical in identifying individuals most likely to benefit from early intervention.

Future preventive strategies may need to target additional pathogenic pathways, such as citrullination and autoantibody production, to more effectively halt the onset of RA in “at-risk” individuals.