A groundbreaking phase 2b clinical trial published in The Lancet has revealed that abatacept, a T-cell co-stimulation modulator, may significantly reduce the risk of developing rheumatoid arthritis (RA) in individuals who are at high risk. The trial, known as the Arthritis Prevention in the Pre-clinical Phase of Rheumatoid Arthritis with Abatacept (APIPPRA) study, was conducted across 28 hospital-based early arthritis clinics in the UK and three in the Netherlands.
The study found that during the treatment period, only 6% of participants in the abatacept group reached the primary endpoint, compared to 29% in the placebo group. At the 24-month mark, 25% of participants in the abatacept group had progressed to RA, in contrast to 37% in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92.8% for the abatacept group, compared to 69.2% for the placebo group. These results favored abatacept, with significant differences in arthritis-free survival at both 12 and 24 months. In addition to reducing the progression to RA, abatacept was associated with improvements in pain scores, functional well-being, and quality of life during the treatment period. The effects, however, were not sustained at 24 months. The safety profile of abatacept was found to be acceptable, with seven serious adverse events reported in the abatacept group and 11 in the placebo group, including one death in each group, both deemed unrelated to the treatment.
Abatacept (CTLA4Ig) is a fusion protein combining the extracellular domain of CTLA-4 with the Fc portion of human immunoglobulin IgG1, designed to inhibit T cell activation, a critical process in the early stages of RA pathogenesis. T cell activation requires two signals from an antigen-presenting cell (APC): the first is antigen-specific, while the second, known as co-stimulation, involves the interaction between CD80 or CD86 on the APC and CD28 on the T cell. Abatacept binds to CD80 and CD86 with higher affinity than CD28, blocking this crucial second signal, thereby preventing T cell activation and reducing the production of inflammatory mediators and cytokines like TNF-α, interferon-gamma, and interleukin-2. Clinical trials have shown that abatacept effectively slows joint damage progression and improves function in RA patients.
This present study opens up new possibilities for the management of RA. By focusing on prevention rather than treatment of established disease, it could potentially change the approach to this chronic condition. However, researchers caution that larger, longer-term studies are needed to fully understand the long-term benefits and risks of this preventive approach. The findings of this study offer hope to those at high risk of developing RA and could lead to new strategies for managing this debilitating autoimmune disease in the future.
References
- Cope AP, Jasenecova M, Vasconcelos JC, Filer A, Raza K, Qureshi S, D’Agostino MA, McInnes IB, Isaacs JD, Pratt AG, Fisher BA, Buckley CD, Emery P, Ho P, Buch MH, Ciurtin C, van Schaardenburg D, Huizinga T, Toes R, Georgiou E, Kelly J, Murphy C, Prevost AT; APIPPRA study investigators. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial. Lancet. 2024 Mar 2;403(10429):838-849.
- Dubois EA, Cohen AF. Abatacept. Br J Clin Pharmacol. 2009 Oct;68(4):480-1.