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

Clinical Immunology

Volumn 191, Issue , 2018, Pages 10-20

  Weinhold, Kent J ^a   Bukowski, Jack F ^b   Brennan, Todd V ^a   Noveck, Robert J ^a   Staats, Janet S ^a   Lin, Liwen ^a   Stempora, Linda ^a   Hammond, Constance ^b   Wouters, Ann ^b   Mojcik, Christopher F ^b   Cheng, John ^b   Collinge, Mark ^b   Jesson, Michael I ^b   Hazra, Anasuya ^b   Biswas, Pinaki ^b   Lan, Shuping ^b   Clark, James D ^b   Hodge, Jennifer A ^b  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b PFIZER INC   (United States)

Author keywords

Cytotoxicity; Healthy volunteers; Interferon ; Natural killer cells; T cells; Tofacitinib

Indexed keywords

CD4 ANTIGEN; CD8 ANTIGEN; GAMMA INTERFERON; TOFACITINIB; JANUS KINASE INHIBITOR; PIPERIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; PYRROLE DERIVATIVE;

ADULT; ADVERSE EVENT; AGED; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ARTICLE; CD4 LYMPHOCYTE COUNT; CLINICAL ARTICLE; CYTOMEGALOVIRUS INFECTION; CYTOTOXICITY; DRUG EFFECT; DRUG WITHDRAWAL; EX VIVO STUDY; FEMALE; FOLLOW UP; GRANULOCYTE FUNCTION; HUMAN; HUMAN CELL; HUMAN EXPERIMENT; IMMUNOPHENOTYPING; INTERFERON PRODUCTION; LEUKOCYTE FUNCTION; LYMPHOCYTE COUNT; MALE; MEMORY T LYMPHOCYTE; MONOCYTE COUNT; MONOCYTE FUNCTION; NATURAL KILLER CELL; NORMAL HUMAN; OPEN STUDY; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; T LYMPHOCYTE ACTIVATION; T LYMPHOCYTE SUBPOPULATION; TREATMENT DURATION; CLINICAL TRIAL; IMMUNOLOGY; LEUKOCYTE; MIDDLE AGED; PHENOTYPE; RHEUMATOID ARTHRITIS; T LYMPHOCYTE;

ADULT; AGED; ARTHRITIS, RHEUMATOID; FEMALE; HEALTHY VOLUNTEERS; HUMANS; JANUS KINASE INHIBITORS; LEUKOCYTES; LYMPHOCYTE COUNT; MALE; MIDDLE AGED; PHENOTYPE; PIPERIDINES; PYRIMIDINES; PYRROLES; T-LYMPHOCYTES;

EID: 85043764994     PISSN: 15216616     EISSN: 15217035     Source Type: Journal    
DOI: 10.1016/j.clim.2018.03.002     Document Type: Article

References (39)

1. Fleischmann, R., Cutolo, M., Genovese, M.C., Lee, E.B., Kanik, K.S., Sadis, S., et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 64 (2012), 617–629.
2. Kremer, J.M., Bloom, B.J., Breedveld, F.C., Coombs, J.H., Fletcher, M.P., Gruben, D., et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 60 (2009), 1895–1905.
3. Kremer, J.M., Cohen, S., Wilkinson, B.E., Connell, C.A., French, J.L., Gomez-Reino, J., et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 64 (2012), 970–981.
4. Tanaka, Y., Suzuki, M., Nakamura, H., Toyoizumi, S., Zwillich, S.H., Investigators, Tofacitinib Study, Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res. 63 (2011), 1150–1158.
5. Tanaka, Y., Takeuchi, T., Yamanaka, H., Nakamura, H., Toyoizumi, S., Zwillich, S., Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod. Rheumatol. 25 (2015), 514–521.
6. Burmester, G.R., Blanco, R., Charles-Schoeman, C., Wollenhaupt, J., Zerbini, C., Benda, B., et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 381 (2013), 451–460.
7. Fleischmann, R., Kremer, J., Cush, J., Schulze-Koops, H., Connell, C.A., Bradley, J.D., et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 367 (2012), 495–507.
8. Kremer, J., Li, Z.-G., Hall, S., Fleischmann, R., Genovese, M., Martin-Mola, E., et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann. Intern. Med. 159 (2013), 253–261.
9. Lee, E.B., Fleischmann, R., Hall, S., Wilkinson, B., Bradley, J., Gruben, D., et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med. 370 (2014), 2377–2386.
10. van der Heijde, D., Tanaka, Y., Fleischmann, R., Keystone, E., Kremer, J., Zerbini, C., et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 65 (2013), 559–570.
11. van Vollenhoven, R.F., Fleischmann, R., Cohen, S., Lee, E.B., García Meijide, J.A., Wagner, S., et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367 (2012), 508–519.
12. Wollenhaupt, J., Silverfield, J., Lee, E.B., Curtis, J.R., Wood, S.P., Soma, K., et al. Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J. Rheumatol. 41 (2014), 837–852.
13. Wollenhaupt, J., Silverfield, J., Lee, E.B., Terry, K., Kwok, K., Abramsky, S., et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in open-label, long-term extension studies over 8 years. Arthritis Rheum., 68(Suppl. 10), 2016, 1647.
14. Yamanaka, H., Tanaka, Y., Takeuchi, T., Sugiyama, N., Yuasa, H., Toyoizumi, S., et al. Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study. Arthritis Res Ther., 18, 2016, 34.
15. Ghoreschi, K., Jesson, M.I., Li, X., Lee, J.L., Ghosh, S., Alsup, J.W., et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J. Immunol. 186 (2011), 4234–4243.
16. Hodge, J.A., Kawabata, T.T., Krishnaswami, S., Clark, J.D., Telliez, J.B., Dowty, M.E., et al. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin. Exp. Rheumatol. 34 (2016), 318–328.
17. Yoshimura, A., Naka, T., Kubo, M., SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 7 (2007), 454–465.
18. Strober, B., Buonanno, M., Clark, J.D., Kawabata, T., Tan, H., Wolk, R., et al. Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment. Br. J. Dermatol. 169 (2013), 992–999.
19. van Vollenhoven, R., Choy, E., Lee, E.B., Hazra, A., Anisfeld, A., Lazariciu, I., et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: changes in lymphocytes and lymphocyte subset counts and reversibility after up to 8 years of tofacitinib treatment. Ann. Rheum. Dis., 75, 2016, 258.
20. Winthrop, K.L., Silverfield, J., Racewicz, A., Neal, J., Lee, E.B., Hrycaj, P., et al. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis. Ann. Rheum. Dis. 75 (2016), 687–695.
21. Bate, S.L., Dollard, S.C., Cannon, M.J., Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin. Infect. Dis. 50 (2010), 1439–1447.
22. Lauer, F.T., Denson, J.L., Isolation, Burchiel S.W., Cryopreservation, and Immunophenotyping of human peripheral blood mononuclear cells. Curr. Protoc. Toxicol., 74, 2017, 18.
23. Weinberg, A., Song, L.Y., Wilkening, C., Sevin, A., Blais, B., Louzao, R., et al. Optimization and limitations of use of cryopreserved peripheral blood mononuclear cells for functional and phenotypic T-cell characterization. Clin. Vaccine Immunol. 16 (2009), 1176–1186.
24. Murdoch, D.M., Suchard, M.S., Venter, W.D., Mhlangu, P., Ottinger, J.S., Feldman, C., et al. Polychromatic immunophenotypic characterization of T cell profiles among HIV-infected patients experiencing immune reconstitution inflammatory syndrome (IRIS). AIDS Res. Ther., 6, 2009, 16.
25. Maecker, H.T., McCoy, J.P., Nussenblatt, R., Standardizing immunophenotyping for the human immunology project. Nat. Rev. Immunol. 12 (2012), 191–200.
26. Richardson, M.P., Ayliffe, M.J., Helbert, M., Davies, E.G., A simple flow cytometry assay using dihydrorhodamine for the measurement of the neutrophil respiratory burst in whole blood: comparison with the quantitative nitrobluetetrazolium test. J. Immunol. Methods 219 (1998), 187–193.
27. Pajusto, M., Ihalainen, N., Pelkonen, J., Tarkkanen, J., Mattila, P.S., Human in vivo-activated CD45R0(+) CD4(+) T cells are susceptible to spontaneous apoptosis that can be inhibited by the chemokine CXCL12 and IL-2, −6, −7, and −15. Eur. J. Immunol. 34 (2004), 2771–2780.
28. Lurati, A., Laria, A., Gatti, A., Brando, B., Scarpellini, M., Different T cells' distribution and activation degree of Th17 CD4+ cells in peripheral blood in patients with osteoarthritis, rheumatoid arthritis, and healthy donors: preliminary results of the MAGENTA CLICAO study. Open Access Rheumatol. 7 (2015), 63–68.
29. Kubo, S., Yamaoka, K., Kondo, M., Yamagata, K., Zhao, J., Iwata, S., et al. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann. Rheum. Dis. 73 (2014), 2192–2198.
30. Zhou, Y., Leng, X., Luo, S., Su, Z., Luo, X., Guo, H., et al. Tolerogenic dendritic cells generated with tofacitinib ameliorate experimental autoimmune encephalomyelitis through modulation of Th17/Treg balance. J Immunol Res, 2016, 2016, 5021537.
31. Piscianz, E., Valencic, E., Cuzzoni, E., De Iudicibus, S., De Lorenzo, E., Decorti, G., et al. Fate of lymphocytes after withdrawal of tofacitinib treatment. PLoS One, 9, 2014, e85463.
32. Cope, A.P., T cells in rheumatoid arthritis. Arthritis Res Ther., 10(Suppl. 1), 2008, S1.
33. Parrish-Novak, J., Foster, D.C., Holly, R.D., Clegg, C.H., Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J. Leukoc. Biol. 72 (2002), 856–863.
34. Orange, J.S., Natural killer cell deficiency. J. Allergy Clin. Immunol. 132 (2013), 515–525.
35. Meyer, D.M., Jesson, M.I., Li, X., Elrick, M.M., Funckes-Shippy, C.L., Warner, J.D., et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm. (Lond)., 7, 2010, 41.
36. Humblet-Baron, S., Franckaert, D., Dooley, J., Bornschein, S., Cauwe, B., Schönefeldt, S., et al. IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis. J. Allergy Clin. Immunol. 138 (2016), 200–209.
37. Wright, H.L., Moots, R.J., Bucknall, R.C., Edwards, S.W., Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 49 (2010), 1618–1631.
38. Wang, S.P., Iwata, S., Nakayamada, S., Sakata, K., Yamaoka, K., Tanaka, Y., Tofacitinib, a JAK inhibitor, inhibits human B cell activation in vitro. Ann. Rheum. Dis. 73 (2014), 2213–2215.
39. Rizzi, M., Lorenzetti, R., Fischer, K., Staniek, J., Janowska, I., Troilo, A., et al. Impact of tofacitinib treatment on human B-cells in vitro and in vivo. J. Autoimmun. 77 (2017), 55–66.