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.

这项研究评估了托法替尼治疗对外周血白细胞表型和功能的短期影响，以及健康志愿者退出治疗后此类影响的可逆性。巨细胞病毒（CMV）血清反应阳性的受试者接受口服托法替尼10 mg每天两次，持续4周，并在停药后随访4周。托法替尼治疗期间总淋巴细胞和总T细胞计数略有增加，而B细胞计数最多增加26％。粒细胞或单核细胞计数或粒细胞功能无明显变化。治疗期间幼稚和中枢记忆T细胞计数增加，而活化T细胞的所有子集最多减少69％。T细胞亚群，而不是效应物记忆簇的分化（CD）4+，停药后4周，已激活的初生CD4 +和效应CD8 + T细胞计数和B细胞计数恢复正常。下列的离体活化，CMV特异性T细胞反应的测量以及抗原非特异性T细胞介导的细胞毒性和干扰素（IFN）-γ的产生略有下降。这些T细胞功能变化在第15天最明显，在仍使用托法替尼时部分恢复正常，并且在停药后恢复到基线。天然杀手（NK）细胞总数减少了33％，停药后又恢复了基线。托法替尼治疗期间NK细胞功能下降，但在所测参数之间没有一致的时间进程。但是，停药后1个月，NK细胞介导的细胞毒性，抗体依赖性细胞的细胞毒性和IFN-γ产生的标志物降低了42％。在全血中无法检测到CMV DNA，也没有带状疱疹再激活的病例。没有出现新的安全隐患。