Background/Purpose: Autoreactive memory B cells and T cells contribute to the pathogenesis of rheumatoid arthritis (RA) through production of antibodies and cytokines that activate monocytes and joint stromal cells.  Memory B cells and T cells react to similar citrullinated joint proteins, and have been shown to decrease in response to therapy with TNF inhibitors.  However, interactions between these cells have not been interrogated in the same RA patients in relation to disease activity and therapy response.

Methods: We obtained RA PBMC samples from the Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry.  26 subjects were selected based on disease activity (19 patients with active disease (Clinical Disease Activity Index (CDAI) > 2.8) and 7 patients in remission (CDAI ≤ 2.8)).  Subjects were treated with methotrexate (MTX) (n = 14) or with a TNF inhibitor plus MTX (n = 12).  Nine healthy subjects served as controls.  We performed flow cytometry on PBMC to analyze monocyte and T and B cell subsets.  Mann-Whitney tests were used for unpaired comparisons of T and B cell populations from RA subjects and healthy controls.  Spearman’s rho was determined for correlations of T and B cell populations with disease activity.

Results: The frequencies of peripheral blood classical, non-classical and intermediate monocytes were not different between RA subjects and healthy controls, and were not associated with disease activity or therapy.  Of CD4+ T helper (Th) subsets, CXCR5^high T follicular helper (TFh)-like cell subsets that co-expressed CCR6 (CXCR5^highTh17) were increased in RA compared to healthy controls (p = 0.0082), and there was a trend towards increased frequencies of CXCR5^highTh17 cells in patients with active disease compared to remission.  In contrast, CXCR3⁺TFh cells (CXCR5^highTh1) showed the opposite pattern, and were decreased in RA patients with active disease (p < 0.0004), but unchanged between those in remission and healthy controls.  This resulted in significantly higher CXCR5⁺Th17:CXCR5⁺Th1 ratios in active RA patients compared to healthy controls (p < 0.01) or to patients in remission (p < 0.05).  For these T cell populations, there was no association with treatment or between T helper subsets and memory B cell subsets.  However, the proportion of isotype-switched memory B cells was positively correlated with disease activity in the MTX group (rho = 0.54, p = 0.05) but not TNF inhibitor plus MTX group (rho = 0.37, p = 0.24).

Conclusion: TFh/Th17 cells and memory B cells were both increased in RA while TFh/Th1 cells were decreased in active RA.  Disease activity correlated with class-switched memory B cells in subjects treated with MTX but not with TNF antagonists. Although TNF inhibitors have been reported to decrease Th17 cell populations, our results suggest that disease activity rather than therapy may have a greater effect on frequencies of TFh/Th17 and TFh/Th1 cells.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-t-follicular-helper-th17-t-cell-and-memory-b-cell-populations-in-rheumatoid-arthritis-with-disease-activity-and-therapy-with-tnf-antagonists/