title: Impact of tofacitinib treatment on human B-cells in vitro and in vivo.
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.
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: marta.rizzi@uniklinik-freiburg.de.
authors: Marta
authors: M
authors: Rizzi
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Raquel
authors: R
authors: Lorenzetti
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Kathleen
authors: K
authors: Fischer
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Julian
authors: J
authors: Staniek
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Iga
authors: I
authors: Janowska
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Arianna
authors: A
authors: Troilo
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Valentina
authors: V
authors: Strohmeier
authors: Clinic for Pediatrics and Juvenile Medicine, University Medical Center Freiburg, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
authors: Miriam
authors: M
authors: Erlacher
authors: Department of Gynaecology, University Medical Center Freiburg, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
authors: Mirjam
authors: M
authors: Kunze
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Rheumatology, University of Basel, Faculty of Medicine, University of Basel, Switzerland.
authors: Bettina
authors: B
authors: Bannert
authors: Department of Rheumatology, University of Basel, Faculty of Medicine, University of Basel, Switzerland.
authors: Diego
authors: D
authors: Kyburz
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Reinhard E
authors: RE
authors: Voll
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Nils
authors: N
authors: Venhoff
authors: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Jens
authors: J
authors: Thiel
mesh_terms: D000917:Antibody Formation / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D056747:Immunomodulation; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: B-lymphocytes; Immune modulation; JAK inhibitors; Rheumatoid arthritis; Tofacitinib; tsDMARDs