Anti-citrullinated protein antibodies (ACPA), linked to a severe form of rheumatoid arthritis, lack effective treatments for halting autoantibody production and re-establishing immune tolerance. rituximab, targeting B cells, and abatacept, targeting T cells, have demonstrated ACPA level reduction and occasional seroconversion.

The TOLERA trial (EudraCT: 2018-003877-91) is a phase II randomized-controlled open-label clinical study, aiming to evaluate sequential rituximab/abatacept therapy in ACPA + active RA disease. Twenty patients received rituximab treatment, followed by randomization into two groups (rituximab/abatacept and control). 

The data showed that none of the participants experienced seroconversion, indicating no significant impact on autoantibody production. The rituximab/abatacept group showed higher anti-CCP2 antibody levels at 52 weeks compared to the control group, with no significant difference after adjusting for baseline levels. Disease activity, measured by DAS-28 ESR, did not significantly differ between the groups at 52 weeks (RTX/ABA: 3.21 [1.30], Control: 3.32 [0.88]) with an adjusted mean difference (95% CI) of -0.07 (-1.13 to 0.99, p=0.90).  Nine patients in the rituximab/abatacept group and six in the control group remained flare-free. However, there were more serious adverse events in the control group.

KOL Insights

“TOLERA trial in rheumatoid arthritis rituximab/abatacept sequence versus rituximab alone 10 patients each group Primary outcome was ambitious: ACPA seroconversion with no seroconversion, no difference in disease activity, and no difference in ACPA change with Week 52.” – Expert Opinion

Conclusion

Rheumatoid arthritis is more common in women, and about 75% of rheumatoid arthritis patients are women. Around 1 to 3% of women may get rheumatoid arthritis in their lifetime. The disease most often begins between the ages of 30 and 50. For the past few years, a lot of drug failure has been seen in the rheumatoid arthritis space. Rituximab is the only B-cell inhibitor approved for rheumatoid arthritis. 

This small-size study was carried out in order to identify a significant impact, which would need more research into sequential therapy if favorable results were found. However, the sequential therapy of rituximab followed by abatacept did not result in a decrease in anti-CCP antibody levels nor a reduction in these antibodies compared to rituximab treatment alone. Surprisingly, there was no significant variation in disease activity or an increase in serious adverse events. Overall, the study's findings do not provide much optimism for the rituximab/abatacept sequence because they are not significantly positive.