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 (CD)4+, 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 4 weeks after withdrawal.

Keywords: Cytotoxicity; Healthy volunteers; Interferon-γ; Natural killer cells; T cells; Tofacitinib.

Fig. 1

Cell subtypes identified via flow cytometry. CCR7 is also designated as CD197. CCR, CC-chemokine receptor; CD, cluster of differentiation; CM, central memory; DCs, dendritic cells; E, effector; EM, effector memory; HLA-DR, human leukocyte antigen - antigen D related; NK, natural killer; PBMC, peripheral blood mononuclear cell.

Fig. 2

Frequencies of activated EM CD4 + and CD8 + cell subsets from a single, representative participant from baseline through Day 57 post-treatment. The value in the upper right quadrant of each plot represents the percentage of CD4 + or CD8 + cells that co-expressed CD38 and HLA-DR. CD, cluster of differentiation; EM, effector memory; HLA-DR, human leukocyte antigen - antigen D related antigen.