Activated peripheral blood B cells in rheumatoid arthritis and relationship to anti-TNF treatment and response: randomized clinical trial for anti-TNF effects on B cells.

Objective B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and ectopic GCs in synovium in RA that may be TNF and lymphotoxin (LT) dependent. Here we characterized the peripheral B cell compartment longitudinally during anti-TNF therapy in RA. Methods Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n=43) or adalimumab (n=20) for 24 weeks. Eligible participants met the 1987 ACR criteria for RA, clinically active (DAS28>4.4), and on stable doses of methotrexate. The primary mechanistic endpoint was the change in switched memory B cell fraction from baseline to week 12 in each treatment group. Results B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to TNF blockade alone with adalimumab did not translate into significant differences in clinical response. Multiple activated B cell populations including CD21- double negative memory and activated naive were higher in RA non-responders (NR) at all time points, and CD95+ activated B cells increased with anti-TNF in the NR group. In contrast, transitional B cells- a putative regulatory subset- were lower in the NRs. Conclusions Overall, our results support that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response.