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Objectives The tuning effects of JAK/TYK2 inhibitors on the imbalance between T follicular helper (Tfh) and T regulatory (Treg) cells, related to systemic lupus erythematosus (SLE) pathogenesis, were investigated using human peripheral blood samples.Methods Peripheral blood mononuclear cells from untreated patients with SLE and healthy controls were analysed. Tfh1 cells were identified in nephritis tissue, and the effect of Tfh1 cells on B-cell differentiation was examined by coculturing naïve B cells with Tfh1 cells.Results Tfh1 cell numbers were increased in the peripheral blood of patients, and activated Treg cell counts were decreased relative to Tfh1 cell counts. This imbalance in the Tfh to Treg ratio was remarkably pronounced in cases of lupus nephritis, especially in types III and IV active nephritis. Immunohistochemistry revealed Tfh1 cell infiltration in lupus nephritis tissues. Co-culture of Tfh1 cells (isolated from healthy individuals) with naïve B cells elicited greater induction of T-bet+ B cells than controls. In JAK/TYK2-dependent STAT phosphorylation assays using memory CD4+ T cells, IL-12-induced STAT1/4 phosphorylation and Tfh1 cell differentiation were inhibited by both JAK and TYK2 inhibitors. However, phosphorylation of STAT5 by IL-2 and induction of Treg cell differentiation by IL-2+TGFβ were inhibited by JAK inhibitors but not by TYK2 inhibitors, suggesting that TYK2 does not mediate the IL-2 signalling pathway.Conclusions Tfh1 cells can induce T-bet+ B cell production and may contribute to SLE pathogenesis-associated processes. TYK2 inhibitor may fine-tune the immune imbalance by suppressing Tfh1 differentiation and maintaining Treg cell differentiation, thereby preserving IL-2 signalling, unlike other JAK inhibitors.

Abstract Introduction The study aimed to optimize medical care for elderly patients with rheumatoid arthritis (RA) by examining the 3-year continuation rate of different molecular targeted therapies across age groups in Japan, which has a significant elderly population. Methods The study included patients with RA who started molecular targeted therapies between 2013 and 2019 and divided them into three age groups. The primary outcome was to assess the 3-year continuation rate of each drug and analyze reasons for treatment discontinuation using inverse probability of treatment weighting. Results Among 2292 patients analyzed, tumor necrosis factor (TNF) inhibitors were most commonly used in those younger than 65 years of age (43.5%), while Janus kinase (JAK) inhibitors were also utilized (17.1%). In contrast, JAK inhibitors were less frequently used in patients aged 75 years and older (7.8%), with cytotoxic T lymphocyte antigen 4 immunoglobulin fusion proteins (CTLA4-Ig) being the most common (39.2%). JAK inhibitors and anti-interleukin-6 receptor (IL-6R) antibodies had higher continuation rates than other drugs in patients under 65 years (p