Abatacept delays onset of RA long-term in at-risk individuals

medwireNews: Treating individuals at high risk for developing rheumatoid arthritis (RA) with abatacept for 12 months may delay the rheumatic condition beyond the initial treatment period, the ALTO study investigators say.

“The results show that abatacept reduces the symptom burden and prevents progression to rheumatoid arthritis during the treatment period, while delaying disease onset for up to 4 years,” Andrew Cope (King’s College London, UK) and co-investigators summarize in The Lancet Rheumatology.

ALTO was the long-term follow-up study of the previously reported APIPPRA trial, a randomized, double-blind, multicenter phase 2b trial of adults considered to be at risk for developing RA based on having inflammatory arthralgia without clinical synovitis. The patients were also positive for both anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), or had a high ACPA titer without RF positivity.

APIPPRA was conducted in the UK and the Netherlands between 2014 and 2019, randomly allocating participants to receive either 52 weekly subcutaneous injections of abatacept 125 mg or placebo, followed by an additional 1 year of follow-up. Results showed that significantly fewer participants treated with abatacept than placebo progressed to having RA (25.0 vs 37.0%), most notably while the treatment was being given (92.8 vs 69.2%).

Participants who completed APIPPRA were later invited to enroll in ALTO, with 143 (67%) of the original 213 APIPPRA participants recruited between 2021 and 2023; 71 had been treated with abatacept and 72 with placebo.

The researchers point out that earlier recruitment into ALTO had not been possible due to restrictions in the UK during the COVID pandemic. To mitigate any bias, however, they scrutinized the medical records of participants to capture any primary outcomes or adverse events that had occurred in the interval between the two trials.

Delayed RA progression

The mean age of the re-enrolled participants was 48.2 years, the majority (78%) were women, and of White ethnicity (81%). The median follow-up was 55 months, with participants seen in-person or remotely at 6-month intervals up to January 2023.

The primary outcome was the time from randomization to the development of clinical synovitis in at least three joints, onset of RA as defined by the 2010 joint American College of Rheumatology and European Alliance of Associations for Rheumatology criteria, or first treatment with a disease modifying anti-rheumatic drug, whichever occurred first.

The cumulative proportions of abatacept-treated participants progressing to RA at 3, 4, 5, and 6 years were a respective 50%, 59%, 65%, and 73%. While the respective cumulative proportions of placebo-receiving patients diagnosed with RA were 54%, 61%, 65%, and 70%.

At 4 years, abatacept treatment was associated with a restricted mean arthritis-free survival time of 34.0 months, which was a significant 4.9 months longer than the 29.1 months with placebo.

This indicates “a significant delay in arthritis development, and longer than the 2-year difference of 3.2 months,” highlight the study authors.

As for safety, “1-year treatment of at-risk individuals with abatacept is well tolerated; the trial did not reveal any untoward safety signals appearing after extended follow-up,” say the researchers. There were 95 events of special interest that occurred in 53 participants (28 in the abatacept group and 25 in the placebo group), with the majority “considered mild and unlikely to be related to study drug,” they note.

High ACPA level linked to being arthritis-free with abatacept

In a prespecified exploratory analysis, participants with ACPA titers of 340 IU/mL or higher were significantly more likely to be arthritis-free at 2 years if they had been treated with abatacept than placebo (73 vs 51%). This effect was still apparent after 4 years (41 vs 33%). In comparison, there was no difference between the abatacept and placebo groups after 18 months in those with lower ACPA titers. 

These findings are perhaps hypothesis generating, Janet Pope (University of Western Ontario, London, Ontario, Canada) comments in a related editorial.

“One could conclude that only strongly ACPA positive patients benefited from the intervention,” she writes, suggesting that future trials could look at these individuals further.

“We have learned that when the treatment is stopped, the preventive effects wear off, but what we don’t know is whether abatacept-exposed patients who eventually develop rheumatoid arthritis will in the future have a milder disease or not,” Pope observes.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2026 Springer Healthcare Ltd, part of Springer Nature

Lancet Rheumatol 2026; doi:10.1016/S2665-9913(25)00371-6
Lancet Rheumatol 2026; doi:10.1016/S2665-9913(26)00006-8