Abatacept May Delay RA Onset for Up to 4 Years in At-Risk Individuals, With Andrew Cope, MD, PhD

A single year of abatacept (Orencia) treatment in individuals at high risk of rheumatoid arthritis (RA) delayed disease progression for up to 4 years after treatment cessation in the overall at-risk population — and may have conferred durable benefit extending to 6 years in those with the most extensive autoantibody profile at baseline, according to long-term follow-up data from the ALTO study.

Andrew P. Cope, MD, PhD, professor of rheumatology and head of the Centre for Rheumatic Diseases at King's College London and honorary consultant rheumatologist at Guy's and St Thomas' NHS Foundation Trust, served as chief investigator of the original APIPPRA trial and the ALTO extension, and sat down to talk with RheumatologyLive about the latest findings from the follow-up.

Results were published in The Lancet Rheumatology in March 2026. The APIPPRA (Arthritis Prevention In the Preclinical Phase of Rheumatoid Arthritis with Abatacept) trial randomized at-risk individuals to 1 year of subcutaneous abatacept or placebo; the ALTO (APIPPRA Long-Term Outcome) study enrolled 143 APIPPRA participants — 71 in the abatacept group and 72 in the placebo group — between April 2021 and January 2023, following them for a median of 55 months (IQR, 23–74) from randomization. The primary outcome was time to meeting any of 3 indicators of RA: development of clinical synovitis in at least 3 joints, classification as RA per 2010 ACR/EULAR criteria, or initiation of DMARD therapy. Participants had a mean age of 48.2 years (SD, 11.2) and were 78% female.

Cope described the at-risk population targeted in APIPPRA as defined by 2 key features: the presence of anti-citrullinated protein antibodies (ACPA, also known as anti-CCP) with or without rheumatoid factor, and inflammatory-sounding arthralgia — typically symmetrical joint pain affecting the small joints of the hands and feet — in the absence of clinically detectable synovitis. Individuals who are both anti-CCP and rheumatoid factor positive carry the highest progression risk within this group. The biological rationale for abatacept, a selective T cell costimulation modulator, in this setting is that the autoimmune process — reflected by high circulating autoantibody titers — is already active during the pre-clinical phase, and targeting T cell activation at that stage may interrupt the cascade before structural damage is established.

The initial APIPPRA results, published in The Lancet, demonstrated that abatacept nearly abolished RA progression during the 1-year treatment period and that Kaplan-Meier survival curves for time to RA did not converge immediately after drug cessation — prompting the ALTO extension to determine how long that separation would persist. In ALTO, the between-group difference in restricted mean arthritis-free survival time that was significant at 2 years in APIPPRA remained statistically significant at 4 years (4.9 months; 95% CI, 0.1–9.6; P = .044), though differences between arms narrowed and were no longer significant beyond that point. By 6 years of follow-up, 29% of all enrolled APIPPRA participants had not progressed to RA. Cope noted that among participants with the broadest autoantibody profile at baseline — those carrying ACPA targeting multiple post-translational modifications in addition to rheumatoid factor — Kaplan-Meier survival curves remained separated through 6 years, suggesting that the highest-risk patients, paradoxically, may be the best responders and derive the most durable benefit from T cell costimulation blockade.

The symptom burden of the pre-clinical phase is a dimension Cope emphasized that is sometimes underappreciated. At-risk individuals experience a broad constellation of systemic symptoms — fatigue, diffuse achiness, cognitive and physical health impairment — that resolved substantially on abatacept during the treatment period but returned after drug cessation. This on-treatment symptom benefit, while not durable off drug, reinforces the clinical relevance of identifying and treating this population even before RA is formally diagnosable, particularly given the quality-of-life burden imposed during this phase. Safety outcomes across the extended follow-up were reassuring: 18 serious adverse events were recorded in the abatacept group and 13 in the placebo group, with none attributed to study drug.

Cope acknowledged the questions that remain: whether periodic retreatment — for example, guided by ACPA titer trajectories — could extend the protective window; whether abatacept-exposed patients who ultimately progress to RA will experience a milder disease course; and how to refine the definition of the at-risk state with sufficient precision to enable cost-effective preventive treatment. He called for future research to more precisely characterize the high-risk autoantibody-positive population and to expand the investigation of preventive approaches beyond the established DMARD armamentarium used in established disease.

“We have had a growing appreciation of individuals who are not only at risk of developing RA, but are at high risk. I think that's the first thing, and probably the commonest features of this is the presence of an auto antibody,” Cope said.

Cope reported no relevant disclosures.

References

1. Cope AP, Jasenecova M, Vasconcelos JC, et al. Long-term outcomes of abatacept in individuals at risk of developing rheumatoid arthritis (ALTO): a randomised, double-blind, placebo-controlled trial. Lancet Rheumatol. Published online January 20, 2026. Accessed January 21, 2026. DOI: 10.1016/S2665-9913(25)00371-6

2. Early treatment can delay rheumatoid arthritis for years. News release. King’s College London. January 20, 2026. Accessed January 21, 2026. https://www.eurekalert.org/news-releases/1113191