Proportion of T Follicular Helper Cells in Peripheral Blood of Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis

Abstract Objectives: Follicular helper T (Tfh) cells have critical roles in the development and promotion of humoral immune responses. Accumulating evidence points to alterations in the levels and activity of Tfh which may lead to impaired immune tolerance and development of antibody-mediated autoimmune diseases, such as rheumatoid arthritis (RA). To elucidate the status of Tfh cells in patients with RA, we conducted a systematic review and meta-analysis to assess the proportion and types of Tfh cells in the PB of RA patients.Method: We systematically searched databases of Embase, Pubmed, Web of sciences (WOS), and Scopus to identify the eligible articles. We performed meta-analysis to assess the proportion of Tfh cells in PB of RA patients compared to healthy controls (HCs). We also assessed the proportion of Tfh cells based on different parameters including Tfh definition markers, disease activity status, disease stage, treatment status, serum markers, and the geographical location of the included articles. Results: Regardless of definition markers, the proportion of Tfh cells in RA patients was significantly higher than that in HCs (SMD 0.75, [0.56, 0.93], p<0.0001). Based on subgroup analyses, the proportion of Tfh cells with the individual definitions were also significantly higher in PB of RA patients compared to HCs. Tfh cells proportion in untreated-RA and early-RA patients was markedly greater than HCs, when comparisons were made without considering the definition markers, and also when Tfh cells was defined by the specified definition markers. While the proportion of Tfh cells by all definitions was significantly higher in active- and remission-RA compared to HCs, individual analysis of two definitions, CD4+CXCR5+ and CD4+CXCR5+ICOS+, didn’t show significant differences. In addition, higher proportion of Tfh cells defined by all definitions as well as a specified definition (CD4+CXCR5+PD-1high) was observed when S+RA and S-RA patients were compared to the HCs. Higher Tfh cells proportion in RA patients compared with HCs was observed in the Asian populations (SMD 0.89, [0.68, 1.09], p<0.0001), while there was a trend toward significant in the proportion of Tfh between the two groups in non-Asians (SMD 0.29, [-0.003, 0.59], p=0.052).Conclusion: Altogether, our results demonstrate that circulating Tfh are highly elevated in RA patients and are also significantly increased in untreated-, early- and S+-RA patients, underscoring the potential pathogenic role of this cell population in RA and its potential use as a biomarker and a target for RA therapy.