Andrew Cope, Marianna Jasenecova, Joana Carvalho Vasconcelos, Andrew Filer, Karim Raza, Sumera Qureshi, Maria Antonietta D’Agostino, Iain McInnes, John Isaacs, Arthur Pratt, Benjamin Fisher, C. D. Buckley, Paul Emery, Pauline Ho, Maya H. Buch, Coziana Ciurtin, Thomas Huizinga, Dirkjan van Schaardenburg, Caroline Murphy, Toby Prevost

Research output: Contribution to journalMeeting Abstract


While genetic and epidemiological factors have been used traditionally to evaluate the risk of developing rheumatoid arthritis (RA), the definition of higher risk states has been refined in more recent years through inclusion of serum autoantibodies and symptom complexes, such as inflammatory joint pain. Data from at risk cohorts have reported rates of progression to RA in excess of 50% over 24 months. These combined features have provided a framework for the design of interception studies, aimed at delaying or preventing RA.

We evaluated the feasibility, efficacy and acceptability of T-cell co-stimulation modulation with abatacept in individuals at risk of developing RA in the Arthritis Prevention In the Pre-clinical Phase of RA with Abatacept (APIPPRA) study.

APIPPRA is a Phase IIB randomised, double blind, placebo-controlled trial recruiting ACPA+RF+ or ACPAhi (≥3 x ULN) RF- individuals with arthralgia. Consenting participants were randomised, stratified by gender, smoking status and country, to receive 52 weekly subcutaneous injections of placebo or 125mg abatacept, and followed up for a further 52 weeks after stopping treatment. Exclusion criteria included previous episodes of clinical synovitis, prior corticosteroids or DMARDs. The primary endpoint was the time to development of either clinical synovitis in ≥3 joints, or RA according to ACR/EULAR 2010 criteria, whichever was met first, where joint involvement required swelling. Joint synovitis was confirmed by ultrasonography. The study was powered to detect a 50% reduction in progression in those receiving abatacept. Secondary endpoints included multiple disease activity assessments, the time to commencing DMARDs and/or corticosteroids, X-ray and ultrasound scores, as well as safety data. The main ITT analysis was repeated in a per-protocol population of participants who did not take forbidden medication, and who, in the first year or up to a primary event, had 90% adherence to treatment.

Between December 2014 and January 2019, 280 individuals were evaluated for eligibility across 31 study sites, 28 in the UK and 3 in the Netherlands. Two hundred and thirteen were randomised, 103 to placebo and 110 to abatacept. Mean age was 49 and 77% were female. Ninety-three percent of individuals were ACPAhi. Ultrasonography at baseline suggested modest levels of active sub-clinical synovitis (73% of participants with power Doppler score of 0). In total, there were 65 primary outcome events. After stopping treatment at 52 weeks there were 30 events (29%) in the placebo arm and 7 (6%) in the abatacept arm. By the end of the study there were 38 (37%) and 27 (25%) events, respectively, resulting in differences in mean arthritis-free survival time between arms of 99.2 days (95% CI 37.5 – 160.9; p-value=0.002), in favour of abatacept. The respective log-rank test for difference in the survival distribution was p=0.044, reflecting a large effect in the first year and convergence over the second year (see Figure 1). The per protocol analysis showed similar results. The cumulative proportion of arthritis-free participants at 52 weeks was 0.692 (SE 0.047) in the placebo arm and 0.928 (SE 0.026) for the abatacept arm, and 0.585 (SE 0.054) for placebo and 0.704 (SE 0.048) for abatacept at 104 weeks. Post hoc analysis revealed that individuals with an extended autoantibody profile at baseline were more likely to remain arthritis-free following abatacept therapy. Those treated with abatacept had lower tender joint counts and pain scores during the treatment period, when compared to placebo. There were 4 serious adverse events in the abatacept group and 10 in the placebo group, including two deaths, one in each arm, none deemed attributable to study drug.

Therapeutic intervention during the RA at risk phase is feasible, with acceptable safety profiles. T cell co-stimulation modulation with abatacept for 52 weeks showed a reduction in the development of RA over two years. There were no new safety signals.
Original languageEnglish
Pages (from-to)86
Number of pages1
JournalAnnals of the Rheumatic Diseases
Issue numberIssue Suppl 1
Early online date30 May 2023
Publication statusPublished - 30 May 2023
EventEULAR 2023 European Congress of Rheumatology - Italy, Milan, Italy
Duration: 31 May 20233 Jun 2023

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