Impact of tofacitinib treatment on human B-cells in vitro and in vivo

• Published in: Journal of autoimmunity Vol. 77; pp. 55 - 66
• Main Authors: Rizzi, Marta, Lorenzetti, Raquel, Fischer, Kathleen, Staniek, Julian, Janowska, Iga, Troilo, Arianna, Strohmeier, Valentina, Erlacher, Miriam, Kunze, Mirjam, Bannert, Bettina, Kyburz, Diego, Voll, Reinhard E, Venhoff, Nils, Thiel, Jens
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2017
• Subjects: Allergy and Immunology; Antibody Formation - drug effects; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; B-lymphocytes; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cells, Cultured; Cytidine Deaminase - metabolism; Humans; Immune modulation; Immunoglobulin Class Switching - drug effects; Immunomodulation; Interleukin Receptor Common gamma Subunit - metabolism; JAK inhibitors; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocyte Count; Piperidines - pharmacology; Piperidines - therapeutic use; Plasma Cells - drug effects; Plasma Cells - immunology; Plasma Cells - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Pyrroles - pharmacology; Pyrroles - therapeutic use; Rheumatoid arthritis; Signal Transduction - drug effects; Tofacitinib; tsDMARDs; B-lymphocytes; tsDMARDs; Tofacitinib; Rheumatoid arthritis; Immune modulation; JAK inhibitors
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2016.10.005

Abstract B-cells are pivotal to the pathogenesis of rheumatoid arthritis and tofacitinib, a JAK inhibitor, is effective and safe in its treatment. Tofacitinib interferes with signal transduction via cytokine receptors using the common γ-chain. Despite extensive data on T-lymphocytes, the impact of tofacitinib on B-lymphocytes is poorly understood. In this study we assessed the effect of tofacitinib on B-lymphocyte differentiation and function. Tofacitinib treatment strongly impaired in vitro plasmablast development, immunoglobulin secretion and induction of B-cell fate determining transcription factors, Blimp - 1 , Xbp - 1 , and IRF - 4 , in naïve B-cells. Interestingly, class switch and activation-induced cytidine deaminase ( AICDA ) induction was only slightly reduced in activated naïve B-cells. The effect of tofacitinib on plasmablast formation, immunoglobulin secretion and proliferation was less profound, when peripheral blood B-cells, including not only naïve but also memory B-cells, were stimulated. In line with these in vitro results, the relative distribution of B-cell populations remained stable in tofacitinib treated patients. Nevertheless, a temporary increase in absolute B-cell numbers was observed 6–8 weeks after start of treatment. In addition, B-cells isolated from tofacitinib treated patients responded rapidly to in vitro activation. We demonstrate that tofacitinib has a direct impact on human naïve B-lymphocytes, independently from its effect on T-lymphocytes, by impairing their development into plasmablasts and immunoglobulin secretion. The major effect of tofacitinib on naïve B-lymphocyte development points to the potential inability of tofacitinib-treated patients to respond to novel antigens, and suggests planning vaccination strategies prior to tofacitinib treatment.