Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers

Abstract

This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation CD4 +, activated naïve CD4 + and effector CD8 + T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4weeks after withdrawal.

Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials

“…The differential effects on NK-cell numbers provide the most striking differences amongst JAK inhibitors. Other JAK inhibitors have decreased NKcell numbers by week 12 of treatment; in contrast, filgotinib relatively spared NK-cell count [14,31,35,36]. The decrease in NK-cell numbers with tofacitinib therapy was also associated with attenuation of functional activity, which was not investigated in our studies [36].…”

“…Total lymphocyte count is also transiently increased by other JAK inhibitors [14,[30][31][32][33]. Sustained B-cell increases of similar magnitude to week 24 have been noted with baricitinib (JAK1/2 inhibitor) [33], while tofacitinib (JAK1/2/3 inhibitor) increased B cells in healthy subjects, and subjects with RA or psoriasis after 12 weeks of therapy, but this effect was not evident at week 24 in longer duration studies in RA [34][35][36]. The numerical increase in B-cell numbers is as of yet unexplained, and our data indicate that B-cell increases are not due to cytokine-driven enhanced survival or expansion, as key factors in these processes were down-regulated (IL-7 and BAFF) with treatment.…”

“…The numerical increase in B-cell numbers is as of yet unexplained, and our data indicate that B-cell increases are not due to cytokine-driven enhanced survival or expansion, as key factors in these processes were down-regulated (IL-7 and BAFF) with treatment. Transient increases in T cells that return to pre-dose levels occur with filgotinib and tofacitinib, in contrast to the progressive reduction of total T-cell count to week 24 with baricitinib [33,35,36]. The differential effects on NK-cell numbers provide the most striking differences amongst JAK inhibitors.…”

“…Other JAK inhibitors have decreased NKcell numbers by week 12 of treatment; in contrast, filgotinib relatively spared NK-cell count [14,31,35,36]. The decrease in NK-cell numbers with tofacitinib therapy was also associated with attenuation of functional activity, which was not investigated in our studies [36]. It is not clear why NK-cell counts were not significantly altered by filgotinib, but the counts likely reflect a balance of JAK selectivity, potency, and duration of inhibition that differs between JAK inhibitors.…”

JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future

“…Treatment with tofacitinib up to six months has been associated with a dose-dependent effect on white blood cells of RA individuals, including a reduction in natural killer (NK) cells (usually at 8–10 weeks of therapy and with a spontaneous reconstitution within 2–6 weeks after the discontinuation of treatment) and an increase in B cell count [ 141 ]. In healthy volunteers, no significant change in T-lymphocyte and their subsets has been reported in the short-medium term, whereas a prolonged treatment (approximately 5 years) has been associated with a reduction in T cells and an increase in NK cells from baseline [ 142 ]. Of note, lymphocyte subsets normalize after the temporary discontinuation of treatment and have not been associated with serious or opportunistic infections or with HZV reactivation.…”