A post-hoc analysis of the AVERT-2 trial, published in The Journal of Rheumatology, found no association between serum exposure levels of subcutaneous (SC) abatacept and infection risk in patients with early rheumatoid arthritis (RA). This analysis was based on data from the Assessing Very Early Rheumatoid Arthritis Treatment-2 (AVERT-2) randomized, placebo-controlled study, which enrolled anti-citrullinated protein antibody (ACPA)-positive patients with early RA. Researchers performed a population pharmacokinetic (PPK) analysis to evaluate the relationship between steady-state abatacept concentration and infection risk.
In the abatacept plus methotrexate (MTX) group, infections occurred in 47.6% of patients (330/693), with 1.6% (11/693) experiencing serious infections. In comparison, 44.5% (134/301) of patients in the placebo plus MTX group developed infections, and 1.3% (4/301) reported serious infections. The exposure–response analysis revealed no correlation between higher abatacept exposure and increased risk of first infection. This finding remained consistent across various subgroups, including patients using concomitant MTX and glucocorticoids (GCs) during the induction period, those with baseline GC use, and those with body weight exceeding 70 kg.
These findings are consistent with broader observational and population-based studies, which have shown that patients with RA are at approximately twice the risk of hospitalization due to infections compared to individuals without RA. They also face a higher risk of infection-related mortality. This elevated risk is multifactorial, likely due to the the immunopathology of RA itself, the presence of comorbidities, and the immunosuppressive effects of corticosteroids and disease-modifying antirheumatic drugs (DMARDs).
The safety profile of abatacept in early RA is further supported by the AGREE trial, a phase IIIb randomized controlled study involving 509 MTX-naïve patients with early, erosive RA. Participants were randomized to receive either abatacept plus MTX or placebo plus MTX for 12 months. The incidence of serious infections was identical in both groups (1.9%), with no reported cases of opportunistic infections or tuberculosis. These results reinforce the conclusion that abatacept does not increase the risk of serious infections when used in early RA.
In summary, both the AVERT-2 and AGREE trials demonstrate that SC abatacept, when used in combination with MTX, is generally well tolerated and not associated with increased infection risk, regardless of drug exposure levels. These findings suggest that infection risk is influenced more by patient-specific factors and background immunosuppression than by abatacept serum concentrations. The authors of the AVERT-2 post-hoc analysis emphasize the need for similar evaluations of exposure–response relationships in other biologic therapies, such as TNF and IL-6 inhibitors, to inform safer, evidence-based treatment strategies in RA.
References
- Emery P, Fleischmann R, Wong R, Lozenski K, Tanaka Y, Bykerk V, Bingham CO 3rd, Huizinga TWJ, Citera G, Perera V, Murthy B, Maxwell KF, Passarell J, Hedrich WD, Williams D. Association Between Abatacept Exposure Levels and Infection Occurrence in Patients With Rheumatoid Arthritis: Post Hoc Analysis of the AVERT-2 Study. J Rheumatol. 2025 May 1;52(5):426-435.
- Westhovens R, Verschueren P. The efficacy and safety of abatacept in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2010 Apr;2(2):89-94.