RA B-Cell Depletion

Abstract 726: TNF Inhibitors in Rheumatoid Arthritis Patients Previously Treated with Rituximab

Treatment with rituximab results in a rapid and profound depletion of B cells, from the pre-B to early plasma cell lineage, which may be long lasting even after one treatment course. Though effective in significantly improving the clinical signs and symptoms of RA, a substantial number will not achieve an acceptable level of response with rituximab. These patients may go on to receive other biologics which, in combination with B cell depletion, may introduce unrecognized safety risks, particularly in regard to an increased susceptibility to infection. Here, Genovese et al investigate the safety of using TNF inhibitors in patients previously exposed to rituximab.

Methods: Subjects withdrawing from randomized clinical trials of rituximab were followed for safety monitoring for 48 weeks after their last infusion of rituximab, or until peripheral B cell counts returned to normal levels or the subject’s pre-infusion level. For this analysis, safety data were described for subjects beginning TNF inhibitor therapy at the discretion of their treating rheumatologist in the period before peripheral B cell repletion after rituximab was complete.

Results: Of the 1039 subjects enrolled in randomized clinical trials of rituximab, 78 had received at least one TNF inhibitor in the period after withdrawal from the trial before B cell repletion was complete. Of the 78 subjects, 23 received etanercept, 23 received infliximab, 25 received adalimumab, and 7 received more than 1 TNF inhibitor as successive monotherapy. The time between last exposure to rituximab and initiation of a TNF inhibitor ranged from 23 to 694 days (mean 223).
During the study interval, 10 serious adverse events were reported, 4 of which were classified as serious infections (erysipelas, cellulitis, bacterial septic arthritis, and aseptic meningitis). The range of time between exposure to TNF inhibition and incident infection was 17 to 275 days, with two of the serious infections occurring more than 6 months after initiation of TNF inhibitor therapy. No deaths were reported. Two of the four serious infections occurred in etanercept treated subjects, 1 in an infliximab treated subject and 1 in an adalimumab treated subject. There were no significant predictors of infection, including low CD19 count, which did not distinguish the subjects with infection from those without infection.

The rate of serious infections for the group prior to the receipt of a TNF inhibitor was 5.2 per 100 patient years compared to 7.6 per 100 patient years after initiation of a TNF inhibitor, a difference that was not found to be statistically significant.

Conclusion: The risk of serious infection was not increased over baseline in patients receiving TNF inhibitors before rituximab-induced peripheral B cell depletion had resolved. Low CD19 count was not successful in identifying subjects at risk for serious infection.

Editorial Comment: The subject of this investigation is a clinically important question that will become more of an issue as rituximab becomes more widely used in clinical practice. These results are extremely preliminary, but at the least do not reveal any strong signals for an increased infection risk. Importantly, no studies have yet examined the safety of concomitant rituximab and TNF inhibitor use.

Though it is possible that this may be a viable combination, no combinations of biologics have, to date, proved safe enough for clinical application. Because of the long lasting effects of rituximab, particular care may be required when using any agent after rituximab. A greater number of subjects with longer term follow-up is required to validate these results. In particular, the risk of subsequent infection may accumulate depending on the number of prior rituximab infusions, or based on the level of suppression of circulating immunoglobulin, each of which will require separate investigation.

On a minor issue, one might question the inclusion of aseptic meningitis as a serious infection, as presumably no infectious agent is involved. If omitted, the pre and post-TNF inhibitor infection rates in this sample would equalize still further.

All information contained within the Johns Hopkins Arthritis Center website is intended for educational purposes only. Physicians and other health care professionals are encouraged to consult other sources and confirm the information contained within this site. Consumers should never disregard medical advice or delay in seeking it because of something they may have read on this website.