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Deutscher Rheumatologiekongress 2023

51. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh)
37. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh)
33. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

30.08. - 02.09.2023, Leipzig

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Impaired B cell function under JAK inhibition recovers quickly after treatment cessation

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  • Natalie Frede - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg
  • Raquel Lorenzetti - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg
  • Janika Hueppe - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg
  • Marei-Theresa Schleyer - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg
  • Ana Cecilia Venhoff - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg
  • Reinhard Voll - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg
  • Jens Thiel - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg; Medizinische Universität Graz, Abteilung für Rheumatologie und klinische Immunologie, Graz
  • Marta Rizzi - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg
  • Nils Venhoff - Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Klinik für Rheumatologie und klinische Immunologie, Freiburg

Deutsche Gesellschaft für Rheumatologie. Deutsche Gesellschaft für Orthopädische Rheumatologie. Gesellschaft für Kinder- und Jugendrheumatologie. Deutscher Rheumatologiekongress 2023, 51. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 37. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 33. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR). Leipzig, 30.08.-02.09.2023. Düsseldorf: German Medical Science GMS Publishing House; 2023. DocET.24

doi: 10.3205/23dgrh043, urn:nbn:de:0183-23dgrh0431

Published: August 30, 2023

© 2023 Frede et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

Introduction: Janus kinase (JAK) inhibitors have been established in the treatment of various immune-mediated diseases (IMIDs), such as rheumatoid arthritis (RA), and are currently under investigation for numerous other IMIDs. JAK-STAT signalling is essential for B cell activation and differentiation and IL-21 signalling through STAT3 is required for the establishment of long-lasting antibody responses [1]. We have previously shown that JAK inhibition has major effects on B cell homeostasis in-vitro with reduced activation and differentiation [2]. JAK inhibition may furthermore lead to reduced vaccination responses [3], [4], [5]. To investigate whether the effects of JAK inhibition on B cell activation and proliferation are reversible, we investigated B cells from RA patients, who are treated with JAK inhibitors, ex-vivo.

Methods: Primary B cells were isolated from peripheral blood of RA patients before and under treatment with JAK inhibitors baricitinib or tofacitinib. B cells were stimulated with CpG (T-cell independent B cell activation) or CD40L+IL21 (T-cell dependent B cell activation) and assessed by flow cytometry on days 0, 3, 6, respectively on days 0, 3, 6, 9. Antibody secretion was measured in supernatants by ELISA.

Results: While JAK inhibition leads to a dose-dependent decrease in total B cell numbers with a profound reduction of switched memory B cell formation in vitro, we observed an increased proliferation of primary B cells from RA patients treated with baricitinib/tofacitinib upon treatment withdrawal ex-vivo. Regarding B cell subpopulations, we observed a relative expansion of switched memory B cells and plasmablasts subsequent to both, T-cell dependent stimulation with CD40L+IL21 as well as T-cell independent stimulation with CpG upon treatment withdrawal. Furthermore, we observed an increased secretion of immunoglobulins (IgG, IgA and IgM) compared to day 0 before start of JAK inhibitor treatment with both, T-cell dependent and T-cell independent stimulation.

Conclusion: These data highlight the reversibility of effects of JAK inhibition on B cells. Drug withdrawal leads to prompt recovery of B-cell function and differentiation within days, which argues for treatment pause in case of e.g. vaccination or infection and is reassuring regarding infections under therapy as it suggests that diminished B cell responses are transient.

Outline

References

1.
Avery DT, Deenick EK, Ma CS, Suryani S, Simpson N, Chew GY, Chan TD, Palendira U, Bustamante J, Boisson-Dupuis S, Choo S, Bleasel KE, Peake J, King C, French MA, Engelhard D, Al-Hajjar S, Al-Muhsen S, Magdorf K, Roesler J, Arkwright PD, Hissaria P, Riminton DS, Wong M, Brink R, Fulcher DA, Casanova JL, Cook MC, Tangye SG. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med. 2010 Jan 18;207(1):155-71. DOI: 10.1084/jem.20091706 External link
2.
Frede N, Lorenzetti R, Hüppe JM, Janowska I, Troilo A, Schleyer MT, Venhoff AC, Voll RE, Thiel J, Venhoff N, Rizzi M. JAK inhibitors differentially modulate B cell activation, maturation and function: A comparative analysis of five JAK inhibitors in an in-vitro B cell differentiation model and in patients with rheumatoid arthritis. Front Immunol. 2023 Jan 26;14:1087986. DOI: 10.3389/fimmu.2023.1087986 External link
3.
Winthrop KL, Silverfield J, Racewicz A, Neal J, Lee EB, Hrycaj P, Gomez-Reino J, Soma K, Mebus C, Wilkinson B, Hodge J, Fan H, Wang T, Bingham CO 3rd. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis. Ann Rheum Dis. 2016 Apr;75(4):687-95. DOI: 10.1136/annrheumdis-2014-207191 External link
4.
Winthrop KL, Bingham CO 3rd, Komocsar WJ, Bradley J, Issa M, Klar R, Kartman CE. Evaluation of pneumococcal and tetanus vaccine responses in patients with rheumatoid arthritis receiving baricitinib: results from a long-term extension trial substudy. Arthritis Res Ther. 2019 Apr 18;21(1):102. DOI: 10.1186/s13075-019-1883-1 External link
5.
Furer V, Eviatar T, Zisman D, Peleg H, Paran D, Levartovsky D, Zisapel M, Elalouf O, Kaufman I, Meidan R, Broyde A, Polachek A, Wollman J, Litinsky I, Meridor K, Nochomovitz H, Silberman A, Rosenberg D, Feld J, Haddad A, Gazzit T, Elias M, Higazi N, Kharouf F, Shefer G, Sharon O, Pel S, Nevo S, Elkayam O. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study. Ann Rheum Dis. 2021 Oct;80(10):1330-8. DOI: 10.1136/annrheumdis-2021-220647 External link