Best outcomes with broad autoantibody profiles in ‘very promising’ long-term follow-up, showing potential of immune reset in RA.
A finite course of abatacept can meaningfully delay the onset of clinically apparent disease in people at high risk of developing rheumatoid arthritis while maintaining a reassuring safety profile, according to a new Lancet paper.
The findings come from the ALTO study, an extension of the Arthritis Prevention in the Preclinical Phase of Rheumatoid arthritis with Abatacep (APIPPRA) phase 2b randomised controlled trial.
They provide some of the clearest evidence to date on the durability of disease interception strategies in preclinical rheumatoid arthritis. Results have been published in The Lancet Rheumatology, and follow on from the initial results of the APIPPRA study that were published in The Lancet in 2024 and reported in Rheumatology Republic.
“In this at-risk population, one-year treatment with abatacept delayed progression to rheumatoid arthritis for up to four years,” the researchers wrote.
“Those at highest risk of progression have a broad autoantibody profile but are more responsive to abatacept treatment.”
APIPPRA originally enrolled 213 adults with inflammatory arthralgia who were positive for anti-citrullinated protein antibodies, a population known to have a substantially elevated risk of progressing to rheumatoid arthritis.
Participants were randomised to receive weekly subcutaneous abatacept or placebo for one year, followed by a further year of observation.
The ALTO (APIPPRA Long-Term Outcome) extension study followed a subset of these participants for between four and eight years after randomisation, with both participants and assessors remaining masked to treatment allocation.
This allowed investigators to examine whether early immunomodulation translated into sustained clinical benefit or unforeseen long-term harm.
Over a median follow-up of just under five years, progression events accumulated steadily in both treatment groups, but the timing differed.
Individuals who had received abatacept experienced a significant delay in progression to clinical synovitis, classification as rheumatoid arthritis, or initiation of disease-modifying antirheumatic drug therapy.
At four years, the restricted mean arthritis-free survival time was almost five months longer in the abatacept group than in the placebo group, indicating that the benefit seen during the original trial period persisted well beyond cessation of therapy, albeit with diminishing magnitude over time.
By later follow-up, the cumulative incidence curves converged, indicating that abatacept delayed rather than permanently prevented disease onset.
The most clinically informative findings emerged from prespecified analyses stratified by baseline autoantibody profiles.
Participants with very high titres of IgG anti-citrullinated protein antibodies, or with a broad autoantibody repertoire including rheumatoid factor, IgA anti-citrullinated protein antibodies and antibodies to carbamylated and acetylated proteins, were at greatest risk of progression overall.
However, this same group derived the most pronounced and durable benefit from abatacept. In those with an extended autoantibody serotype, the separation between abatacept and placebo groups in arthritis-free survival was substantial at two years and remained evident for up to six years, suggesting that individuals with a more mature autoimmune response may be particularly sensitive to T-cell co-stimulation blockade.
The ALTO data strengthened the rationale for a risk-stratified approach to rheumatoid arthritis prevention.
While it demonstrated that short-term intervention with abatacept could delay disease onset for several years, with the greatest benefit seen in those at highest immunological risk, it also highlighted that a minority of at-risk individuals did not progress at all, regardless of intervention.
Professor Ranjeny Thomas, a rheumatologist and researcher at the University of Queensland Translational Research Institute, said while the findings were important, “finding everyone who’s at risk in the population is almost impossible” and it was still early days.
“We certainly see people with clinically suspicious arthralgia coming through our clinics, and in private practice, and generally, we don’t do anything,” she told Rheumatology Republic.
“I think the paper is important because it helps us understand that those with early symptoms, you know, arthralgia, difficulty making a fist, warning, stiffness, hand symptoms and antibodies, are a high risk group and we should follow them more rigorously, until there’s the possibility to treat them with something that might delay the onset.
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“But if we were to try to give immunotherapy… we can’t give it to everyone in the population. It’s not like a vaccine.
“It’s more that you might get a further indication beyond treating people with disease who are in remission, you might get a further indication to prevent in people at high risk.”
Professor Thomas said it was “very promising” to see the identification of a serotype that could help identify who best to treat when aiming for prevention.
“We’ve got some drugs that potentially work so we can build on that,” she told RR.
Professor Thomas is currently leading the Reset Rheumatoid Arthritis project, working on a treatment known as an antigen-specific tolerising immunotherapy, which instructs the immune system to tolerate joint proteins.
The work that began in 2000 has progressed through two proof-of-concept trials, and early-stage clinical trials of the world first “immune-reset” therapy for RA are expected to start this year.
The project is funded by an $11.54 million federal grant through the Medical Research Future Fund.
Arthritis Australia and the Australian Rheumatology Associations are key partners in the Reset RA project, along with teams at Monash University, Macquarie University, Flinders University, University of Sydney, Queensland Health, Kings College London, Newcastle University and Leiden University Medical Center.
The researchers hope to create prolonged remission in patients with recent onset who are already in remission on csDMARDS [conventional synthetic disease modifying antirheumatic drugs].
Professor Thomas said the findings from the abatacept study reinforced the importance of refining predictive tools to identify who is most likely to benefit from interception, and framed future research questions around optimal treatment duration, alternative immune targets and the balance between delaying disease and long-term patient-centred outcomes.
Beyond the prevention endpoint in the abatacept study, longer-term assessments of disease activity, pain, functional status and quality of life showed no meaningful differences between groups once treatment had stopped.
This aligned with earlier observations that abatacept improved symptoms during active treatment in at-risk individuals, but that these symptomatic benefits were not sustained after withdrawal.
“Indeed, the benefit of study drug on patient reported outcomes was short-lived and confined to the treatment period, indicating that continuous treatment is required to suppress symptoms such as fatigue, pain, and impaired physical and mental wellbeing,” the researchers wrote.
“This outcome suggests that adaptive immune responses underpin symptom complexes associated with the at-risk state. Applying disease activity assessments validated for established rheumatoid arthritis revealed low scores and modest effect sizes for study drug.
“Likewise, low erosion and joint space narrowing scores, while reassuring, precluded meaningful analysis of any long-term benefit of abatacept based on radiographic changes alone. These findings highlight the need to develop more sensitive assessment tools that capture the disease burden of at-risk individuals, as well as the response to intervention.”
They noted that further in-depth studies of individuals at risk of rheumatoid arthritis should also uncover a wider range of therapeutic targets extending beyond the existing armamentarium of disease modifying therapies used to treat established rheumatoid arthritis.
Importantly, for clinicians considering preventive strategies, extended safety surveillance did not reveal new concerns. Serious adverse events were infrequent and balanced between groups, and none were judged to be related to study drug exposure.
Rates of infections, cardiovascular events, malignancies and other events of special interest were comparable between abatacept and placebo, supporting the longer-term safety of a one-year course of therapy in this at-risk population.
