Lymphocyte modulation by tofacitinib in patients with rheumatoid arthritis.

Tofacitinib is an oral small molecule targeting the intracellular JAK-STAT pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B- and T-cell collagen epitopes in their native and post-translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261-273, B359-369, carT261-273, citB359-369) or with PMA/ionomycin/CD40L in the presence or absence of 100nM tofacitinib for 20 hours and analyzed by FACS. Cultures without brefeldin A were used for cytokine supernatant ELISA analysis. Tofacitinib down-regulated inflammatory cytokines by stimulated B (IL-6 and TNF-α) and T (IFN-γ, IL-17, or TNF-α) cells in the short term while a significant reduction of IL-17 and IL-6 levels in PBMC supernatant was also observed. IL-10 was significantly reduced in collagen-stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self-epitopes in RA. Tofacitinib partially prevented the IL-10 down-modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes.