A one-year course of abatacept can delay progression to rheumatoid arthritis (RA) for several years in people at increased risk, according to a long-term extension study, with the greatest benefit observed among those with high-risk autoantibody profiles.

RA is associated with substantial physical, psychological and societal burden. Preventing or delaying disease onset in individuals at high risk has become a key research priority.

The APIPPRA Long-Term Outcome (ALTO) study aimed to evaluate the long-term efficacy and safety of abatacept in delaying progression to RA after treatment cessation. It is the longest follow-up to date of a disease-interception strategy using abatacept in people at risk of developing the condition.

Extending follow-up of participants from the Arthritis Prevention In the Preclinical Phase of Rheumatoid arthritis with Abatacept (APIPPRA) phase 2b randomised controlled trial – which was conducted across 28 hospital-based early arthritis clinics in the UK and three centres in the Netherlands – the ALTO follow-up period spanned four to eight years after randomisation.

Long-term abatacept follow-up

APIPPRA initially enrolled 213 adults with inflammatory arthralgia who were positive for anti-citrullinated protein antibodies (ACPA), placing them at high risk of RA. Participants were randomised to receive weekly subcutaneous abatacept 125 mg (n=110) or placebo (n=103) for 52 weeks, followed by 52 weeks of observation.

Of these, 143 participants (71 abatacept; 72 placebo) consented to long-term follow-up in ALTO. The mean age was 48.2 years, 78% were female and 81% were White. Median follow-up from randomisation was 55 months (interquartile range 23–74).

Over combined APIPPRA and ALTO follow-up, 119 participants developed the primary outcome of clinical synovitis in at least three joints, RA according to American College of Rheumatology–European Alliance of Associations for Rheumatology 2010 criteria, or initiation of disease-modifying anti-rheumatic drugs.

At four years, restricted mean arthritis-free survival was significantly longer in the abatacept group than in the placebo group, with a difference of 4.9 months (95% CI 0.1–9.6; P=0.044).

This confirmed that a one-year course of abatacept delayed progression to RA for up to four years, although it did not provide permanent prevention.

Risk-stratification analyses showed that participants with high ACPA titres (≥340 IU/mL) or a broad autoantibody profile were at greatest risk of progression but also derived the greatest sustained benefit.

In those with all five measured autoantibodies, arthritis-free survival at two years was 88% with abatacept compared with 47% with placebo, with separation of survival curves maintained up to six years.

Disease activity scores, patient-reported outcomes and radiographic progression did not differ significantly between groups beyond the treatment period. Safety findings were also reassuring, with 18 serious adverse events in the abatacept group and 13 in the placebo group, none of which were considered related to the study drug.

However, the authors noted that not all original APIPPRA participants enrolled in ALTO, and the interval between APIPPRA completion and ALTO recruitment limited precise ascertainment of primary endpoints. Radiographic progression was minimal, limiting the ability to detect differences between groups, they added.

Early intervention has lasting benefits

The ALTO study showed that even after six years of follow-up, 29% of at-risk individuals enrolled in APIPPRA had not progressed to RA. The findings support a ‘predict and prevent’ approach in RA, demonstrating that early immune modulation with abatacept can meaningfully delay disease onset, particularly in those patients at highest risk.

Reflecting on the findings, lead ALTO investigator Professor Andrew Cope, professor of rheumatology and head of the Centre for Rheumatic Diseases at King’s College London, said: ‘Intervening early in people at high risk of RA can have lasting benefits. We have shown that this approach is safe and can prevent disease while patients are on treatment as well as substantially relieve symptoms.

‘Importantly, it can also delay the onset of RA for several years, even after treatment has stopped. This could reduce how long people live with symptoms and complications, drastically improving their quality of life.’

Reference
Cope AP 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 2026;Jan 20:S2665-9913(25)00371-6.