Abstract Text: Janus kinase (JAK) inhibitors have been established for the treatment of various immune-mediated diseases (IMIDs), such as rheumatoid arthritis (RA), and are currently under investigation for numerous other IMIDs. Nonetheless, comprehensive studies to examine the impact of various JAK inhibitors on B cells are lacking. This study thus aimed to explore the effect of JAK inhibition on the B cell compartment by comparing the specific outcomes of different JAK inhibitors, including tofacitinib (pan-JAK), baricitinib (JAK1/2), ruxolitinib (JAK1/2), upadacitinib (JAK1/2), and filgotinib (selective JAK1), on B cell activation, proliferation, class switch recombination, and involved pathways in vitro.
In an in-vitro model of T-cell-independent B cell activation we observed a dose-dependent decrease in total B cell numbers as well as an altered B cell differentiation under JAK inhibition with a profound reduction of switched memory B cell formation, especially with JAK1/2 inhibition, as well as a significant increase in MZ-like B cells. Additionally, JAK inhibition resulted in reduced STAT3 expression and phosphorylation and altered cytokine secretion.
To investigate whether the effects of JAK inhibition on B cell activation and proliferation were durable, we investigated B cells from RA patients treated with JAK inhibitors ex-vivo. Here, we observed increased switched memory and plasmablast development as well as increased antibody secretion upon drug withdrawal, highlighting the reversibility of the observed effects.
The results showed that JAK inhibition has a significant but reversible effect on B cell activation and differentiation. The study further highlights the differential effects of different JAK inhibitors on B cell homeostasis.
