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Pfeffer LK, Fischbach F, Heesen C, Friese MA. Current state and perspectives of CAR T cell therapy in central nervous system diseases. Brain 2025; 148:723-736. [PMID: 39530593 DOI: 10.1093/brain/awae362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 10/03/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
B cell-directed CAR T cell therapy has fundamentally changed the treatment of haematological malignancies, and its scope of application is rapidly expanding to include other diseases such as solid tumours or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include the limited access current therapies have to the CNS, as well as enormous inter- and intra-individual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option for overcoming this problem and tackling pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has recently revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further prospect, preclinical data reveal the potential benefits of CAR T cell therapy in the treatment of primary neurodegenerative diseases such as Alzheimer's disease. Considering the biotechnological optimizations in the field of T cell engineering, such as extension to target different antigens or variation of the modified T cell subtype, new and promising fields of CAR T cell application are rapidly opening up. These innovations offer the potential to address the complex pathophysiological properties of CNS diseases. To use CAR T cell therapy optimally to treat CNS diseases in the future while minimizing therapy risks, further mechanistic research and prospective controlled trials are needed to assess seriously the disease and patient-specific risk-benefit ratio.
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Affiliation(s)
- Lena Kristina Pfeffer
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Felix Fischbach
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Christoph Heesen
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Manuel A Friese
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
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Minopoulou I, Wilhelm A, Albach F, Kleyer A, Wiebe E, Schallenberg S, Fleischmann A, Frick M, Damm F, Gogolok J, Serve S, Locher BN, Borie D, Casteleyn V, Biesen R, Dörner T, Alexander T, Zernicke J, Movassaghi K, Hütter-Krönke ML, Schrezenmeier E, Schreiber A, Schneider U, Bullinger L, Krönke G, Penack O, Simon D. Anti-CD19 CAR T cell therapy induces antibody seroconversion and complete B cell depletion in the bone marrow of a therapy-refractory patient with ANCA-associated vasculitis. Ann Rheum Dis 2025; 84:e4-e7. [PMID: 39893102 DOI: 10.1016/j.ard.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/25/2024] [Accepted: 12/10/2024] [Indexed: 02/04/2025]
Affiliation(s)
- Ioanna Minopoulou
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Artur Wilhelm
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany
| | - Fredrik Albach
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Arnd Kleyer
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Edgar Wiebe
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Schallenberg
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität Berlin, Berlin, Germany
| | - Anja Fleischmann
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Mareike Frick
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Frederik Damm
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Julia Gogolok
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Sebastian Serve
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Benjamin Nick Locher
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | | | - Vincent Casteleyn
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Robert Biesen
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Dörner
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany
| | - Tobias Alexander
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany
| | - Jan Zernicke
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Kamran Movassaghi
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Marie Luise Hütter-Krönke
- Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, Campus Steglitz, Berlin, Germany
| | - Eva Schrezenmeier
- Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin, Berlin, Germany
| | - Adrian Schreiber
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin, Berlin, Germany
| | - Udo Schneider
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Lars Bullinger
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany; Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Gerhard Krönke
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany; Department of Internal Medicine 3, University of Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), University of Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Olaf Penack
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - David Simon
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Department of Internal Medicine 3, University of Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), University of Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany.
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Fiore NT, Willcox KF, Dayani D, Zuberi YA, Heijnen CJ, Grace PM. Reducing IgG accumulation via neonatal Fc receptor (FcRn) blockade relieves neuropathic pain. Brain Behav Immun 2025; 125:371-387. [PMID: 39870199 PMCID: PMC11903150 DOI: 10.1016/j.bbi.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 01/16/2025] [Accepted: 01/21/2025] [Indexed: 01/29/2025] Open
Abstract
Preclinical and clinical studies have established that autoreactive immunoglobulin G (IgG) can drive neuropathic pain. We recently demonstrated that sciatic nerve chronic constriction injury (CCI) in male and female mice results in the production of pronociceptive IgG, which accumulates around the lumbar region, including within the dorsal root ganglia (DRG) and spinal cord, facilitating the development of neuropathic pain. These data raise the intriguing possibility that neuropathic pain may be alleviated by reducing the accumulation of IgG. To this end, we tested whether biologic inhibition or genetic deletion of the neonatal Fc receptor (FcRn) would attenuate mechanical hypersensitivity (allodynia) and IgG deposition induced by CCI. FcRn are prominently expressed on myeloid and endothelial cells and extend the half-life of IgG via pinocytosis and recycling into the extracellular milieu. We show here that administration of the FcRn blocker efgartigimod either 7- or 28-days post-CCI relieved allodynia among both male and female mice, compared to the Fc fragment control. Efgartigimod, administered systemically (intraperitoneal) or to the lumbar region (intrathecal), attenuated mechanical allodynia for at least one month. CCI-induced allodynia was similarly reduced in FcRn-deficient (FcRn-) mice compared to wild-type mice. Biologic inhibition or genetic deletion of FcRn also reduced CCI-induced accumulation of IgG on macrophages and neurons in lumbar DRG, as well as microglia in the lumbar dorsal spinal cord. Expression of the Fc receptor γ subunit (FcRγ) was reduced in efgartigimod-treated or FcRn- mice post-CCI compared to controls. The FcRγ subunit is a key component of Fc gamma receptors (FcγRs), which are activated by IgG immune complexes. In macrophage cultures stimulated by IgG immune complexes, FcRn blockade also dampened FcγR-dependent production of proinflammatory cytokines. Collectively, our study demonstrates that FcRn blockade or deletion alleviates mechanical allodynia and reduces IgG accumulation after CCI, attenuating pronociceptive IgG-FcγR signaling around the lumbar region. Strategies to block FcRn and reduce IgG recycling warrant further investigation as potential treatments for IgG-mediated neuropathic pain.
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Affiliation(s)
- Nathan T Fiore
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Kendal F Willcox
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Dorsa Dayani
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Younus A Zuberi
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Cobi J Heijnen
- Department of Psychological Sciences, Rice University, Houston, USA
| | - Peter M Grace
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA.
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Kartnig F, Bonelli M, Goldmann U, Mészáros N, Krall N, Aletaha D, Heinz LX, Superti-Furga G. Ex vivo imaging-based high content phenotyping of patients with rheumatoid arthritis. EBioMedicine 2025; 111:105522. [PMID: 39729885 PMCID: PMC11732195 DOI: 10.1016/j.ebiom.2024.105522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 11/18/2024] [Accepted: 12/10/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND High content imaging-based functional precision medicine approaches have been developed and successfully applied in the field of haemato-oncology. For rheumatoid arthritis (RA), treatment selection is still based on a trial-and-error principle, and biomarkers for patient stratification and drug response prediction are needed. METHODS A high content, high throughput microscopy-based phenotyping pipeline for peripheral blood mononuclear cells (PBMCs) was developed, allowing for the quantification of cell type frequencies, cell type specific morphology and intercellular interactions from patients with RA (n = 65) and healthy controls (HC, n = 33). Samples were exposed to a curated set of RA-specific small molecules, biologicals and reference stimuli for 24 h to assess ex vivo drug effects. Data on ex vivo PBMC phenotypes were integrated with information on patients' in vivo medication and disease activity. FINDINGS The unbiased data from in total 6.9e8 individual cells were collected and allowed for the identification of PBMC phenotypes specific to disease activity as well as in vivo and ex vivo treatment. The arrayed ex vivo drug perturbation enabled the systematic characterization of drug effects, clustering by mode of action and uncovered morphologic alterations associated with biologic disease-modifying anti-rheumatic drug (DMARD) treatment. Individual in vivo treatment regimens translated into altered immune cell abundances in patients with a comedication of conventional synthetic DMARDs when compared to HCs. Global integration of PBMC characteristics led to clustering of patients according to disease activity and correlation with clinical data. INTERPRETATION The application of the developed screening tool demonstrates a technical proof-of-concept for feasibility of a functional precision medicine approach to the ex vivo immunophenotypic characterisation of patients with RA. FUNDING This work was supported by the Austrian Academy of Sciences, the Medical University of Vienna and a grant (RMG2235 to L.X.H.) from the European Alliance of Associations for Rheumatology (EULAR).
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Affiliation(s)
- Felix Kartnig
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Internal Medicine III, Division of Rheumatology, Medical University Vienna; Vienna, Austria
| | - Michael Bonelli
- Department of Internal Medicine III, Division of Rheumatology, Medical University Vienna; Vienna, Austria
| | - Ulrich Goldmann
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Noemi Mészáros
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Nikolaus Krall
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Daniel Aletaha
- Department of Internal Medicine III, Division of Rheumatology, Medical University Vienna; Vienna, Austria
| | - Leonhard X Heinz
- Department of Internal Medicine III, Division of Rheumatology, Medical University Vienna; Vienna, Austria.
| | - Giulio Superti-Furga
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Centre for Physiology and Pharmacology, Medical University of Vienna; Vienna, Austria.
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5
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Pathak GN, Agarwal P, Wolfe SM, Patel KH, Dhillon J, Rao BK. Pemphigus relapse: Mechanisms, risk factors, and agents associated with disease recurrence. J Dermatol 2024; 51:1533-1546. [PMID: 39460496 PMCID: PMC11624153 DOI: 10.1111/1346-8138.17505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/20/2024] [Accepted: 09/26/2024] [Indexed: 10/28/2024]
Abstract
Pemphigus represents a spectrum of potentially life-threatening autoimmune-mediated skin blistering conditions caused by antibody production against desmoglein 1 and 3 (anti-DSG 1 and 3) in keratinocytes. Greater than 50% of pemphigus patients experience relapse, which complicates long-term medical management, including risks associated with re-treatment and complications such as infection and dehydration. This review aims to elucidate mechanisms, risk factors, and medications associated with pemphigus relapse. Mechanisms of relapse include the persistence of auto-reactive B-cell populations post-treatment and CD20- B-cell populations that reactivate after B-cell depletion therapy. Risk factors for relapse include high body surface area (BSA) of pemphigus involvement, high body mass index, high severity according to the Pemphigus Disease Area Index (PDAI) at onset, treatment delay, and high anti-DSG1 and DSG3 titers post-treatment. Targeted B-cell localization is associated with better clinical outcomes, including less frequent relapses. Rituximab is currently the gold standard of treatment for moderate-severe pemphigus and has relapse rates of 11%-44% in selected studies, with a mean time to relapse of 5.8 months to 36 months following treatment. Relapse rates across lymphoma dosing (375 mg/m2) versus rheumatoid arthritis dosing (1 g dosing weekly) was inconsistent; however, more frequent dosing, earlier treatment, and higher cumulative dosing were associated with lower relapse rates. Alternative agents that have clinical efficacy include corticosteroid monotherapy, mycophenolate mofetil, azathioprine, and intravenous immunoglobulin. Future studies should include head-to-head comparators over long follow-up periods to identify the best treatment agents associated with the least relapse risk.
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Affiliation(s)
- Gaurav N. Pathak
- Department of DermatologyRutgers Robert Wood Johnson Medical SchoolSomersetNew JerseyUSA
| | - Priya Agarwal
- Department of DermatologyRutgers Robert Wood Johnson Medical SchoolSomersetNew JerseyUSA
| | - Sydney M. Wolfe
- Department of DermatologyRutgers Robert Wood Johnson Medical SchoolSomersetNew JerseyUSA
| | - Kush H. Patel
- Department of DermatologyRutgers Robert Wood Johnson Medical SchoolSomersetNew JerseyUSA
| | - Jimmy Dhillon
- Department of DermatologyRutgers Robert Wood Johnson Medical SchoolSomersetNew JerseyUSA
| | - Babar K. Rao
- Department of DermatologyRutgers Robert Wood Johnson Medical SchoolSomersetNew JerseyUSA
- Department of DermatologyRao DermatologyAtlantic HighlandsNew JerseyUSA
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He Z, Glass MC, Venkatesan P, Feser ML, Lazaro L, Okada LY, Tran NTT, He YD, Zaim SR, Bennett CE, Ravisankar P, Dornisch EM, Arishi NA, Asamoah AG, Barzideh S, Becker LA, Bemis EA, Buckner JH, Collora CE, Criley MAL, Demoruelle MK, Fleischer CL, Garber J, Genge PC, Gong Q, Graybuck LT, Gustafson CE, Hattel BC, Hernandez V, Heubeck AT, Kawelo EK, Krishnan U, Kuan EL, Kuhn KA, LaFrance CM, Lee KJ, Li R, Lord C, Mettey RR, Moss L, Musgrove B, Nguyen K, Ochoa A, Parthasarathy V, Pebworth MP, Pedrick C, Peng T, Phalen CG, Reading J, Roll CR, Seifert JA, Siedschlag MD, Speake C, Striebich CC, Stuckey TJ, Swanson EG, Takada H, Thai T, Thomson ZJ, Trieu N, Tsaltskan V, Wang W, Weiss MDA, Westermann A, Zhang F, Boyle DL, Goldrath AW, Bumol TF, Li XJ, Holers VM, Skene PJ, Savage AK, Firestein GS, Deane KD, Torgerson TR, Gillespie MA. Systemic inflammation and lymphocyte activation precede rheumatoid arthritis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.25.620344. [PMID: 39554042 PMCID: PMC11565773 DOI: 10.1101/2024.10.25.620344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical 'at-risk' state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity. We provide a suite of tools at https://apps.allenimmunology.org/aifi/insights/ra-progression/ to facilitate exploration and enhance accessibility of this extensive dataset.
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Affiliation(s)
- Ziyuan He
- Allen Institute for Immunology, Seattle WA 98109, USA
| | | | | | - Marie L. Feser
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | | | | | | | - Yudong D. He
- Allen Institute for Immunology, Seattle WA 98109, USA
| | | | | | | | | | - Najeeb A. Arishi
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | - Ashley G. Asamoah
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | - Saman Barzideh
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | | | | | - Jane H. Buckner
- BRI Center for Interventional Immunology, Seattle WA 98101, USA
| | | | | | | | | | | | | | - Qiuyu Gong
- Allen Institute for Immunology, Seattle WA 98109, USA
| | | | | | - Brian C. Hattel
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | | | | | | | | | - Emma L. Kuan
- Allen Institute for Immunology, Seattle WA 98109, USA
| | - Kristine A. Kuhn
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | | | - Kevin J. Lee
- Allen Institute for Immunology, Seattle WA 98109, USA
| | - Ruoxin Li
- Allen Institute for Immunology, Seattle WA 98109, USA
| | - Cara Lord
- Allen Institute for Immunology, Seattle WA 98109, USA
| | | | - LauraKay Moss
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | | | | | - Andrea Ochoa
- University of California, San Diego, CA 92093, USA
| | | | | | - Chong Pedrick
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | - Tao Peng
- Allen Institute for Immunology, Seattle WA 98109, USA
| | | | | | | | | | | | - Cate Speake
- BRI Center for Interventional Immunology, Seattle WA 98101, USA
| | | | | | | | - Hideto Takada
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | - Tylor Thai
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | | | - Nguyen Trieu
- University of California, San Diego, CA 92093, USA
| | | | - Wei Wang
- University of California, San Diego, CA 92093, USA
| | | | | | - Fan Zhang
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | | | | | | | - Xiao-jun Li
- Allen Institute for Immunology, Seattle WA 98109, USA
| | - V. Michael Holers
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
| | | | | | | | - Kevin D. Deane
- University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
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Markmann JF, Burrell BE, Bromberg JS, Hartono C, Kaufman DB, Possselt AM, Naji A, Bridges ND, Breeden C, Kanaparthi S, Pardo J, Kopetskie H, Mason K, Lim N, Chandran S. Immunosuppression withdrawal in living-donor renal transplant recipients following induction with antithymocyte globulin and rituximab: Results of a prospective clinical trial. Am J Transplant 2024; 24:1193-1204. [PMID: 38467375 DOI: 10.1016/j.ajt.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 02/19/2024] [Accepted: 03/05/2024] [Indexed: 03/13/2024]
Abstract
Durable tolerance in kidney transplant recipients remains an important but elusive goal. We hypothesized that adding B cell depletion to T cell depletion would generate an immune milieu postreconstitution dominated by immature transitional B cells, favoring tolerance. The Immune Tolerance Network ITN039ST Research Study of ATG and Rituximab in Renal Transplantation was a prospective multicenter pilot study of live donor kidney transplant recipients who received induction with rabbit antithymocyte globulin and rituximab and initiated immunosuppression (IS) withdrawal (ISW) at 26 weeks. The primary endpoint was freedom from rejection at 52 weeks post-ISW. Six of the 10 subjects successfully completed ISW. Of these 6 subjects, 4 restarted immunosuppressive medications due to acute rejection or recurrent disease, 1 remains IS-free for over 9 years, and 1 was lost to follow-up after being IS-free for 42 weeks. There were no cases of patient or graft loss. CD19+ B cell frequencies returned to predepletion levels by 26 weeks posttransplant; immunoglobulin D+CD27--naïve B cells predominated. In contrast, memory cells dominated the repopulation of the T cell compartment. A regimen of combined B and T cell depletion did not generate the tolerogenic B cell profile observed in preclinical studies and did not lead to durable tolerance in the majority of kidney transplant recipients.
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Affiliation(s)
- James F Markmann
- Massachusetts General Hospital, Center for Transplantation Sciences, Boston, Massachusetts, USA
| | - Bryna E Burrell
- Biomarker Discovery Group, Immune Tolerance Network, Bethesda, Maryland, USA
| | - Jonathan S Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Choli Hartono
- Rogosin Institute, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA
| | - Dixon B Kaufman
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Andrew M Possselt
- Department of Surgery, University of California-San Francisco Medical Center, San Francisco, California, USA
| | - Ali Naji
- Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
| | - Nancy D Bridges
- Division of Allergy, Immunology and Transplantation, The National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Cynthia Breeden
- Immune Tolerance Network, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - Sai Kanaparthi
- Immune Tolerance Network, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - Jorge Pardo
- Immune Tolerance Network, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | | | | | - Noha Lim
- Immune Tolerance Network, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - Sindhu Chandran
- Immune Tolerance Network, Clinical Trials Group at the University of California- San Francisco, San Francisco, California, USA.
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8
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Shah K, Leandro M, Cragg M, Kollert F, Schuler F, Klein C, Reddy V. Disrupting B and T-cell collaboration in autoimmune disease: T-cell engagers versus CAR T-cell therapy? Clin Exp Immunol 2024; 217:15-30. [PMID: 38642912 PMCID: PMC11188544 DOI: 10.1093/cei/uxae031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 02/07/2024] [Accepted: 04/18/2024] [Indexed: 04/22/2024] Open
Abstract
B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T-cell collaboration toward overcoming rituximab-resistant AID.
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Affiliation(s)
| | - Maria Leandro
- Centre for Rheumatology, UCLH, London,UK
- Department of Rheumatology, University College London Hospital, London, UK
| | - Mark Cragg
- University of Southampton Faculty of Medicine, Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton, Southampton, UK
| | - Florian Kollert
- Roche Innovation Center Basel, Early Development Immunology, Infectious Diseases & Ophthalmology, Basel, Switzerland
| | - Franz Schuler
- Roche Innovation Center Basel, Roche Pharma Research and Early Development, Schlieren, Switzerland
| | - Christian Klein
- Roche Innovation Center Zurich, Cancer Immunotherapy Discovery, Oncology Discovery & Translational Area, Schlieren, Switzerland
| | - Venkat Reddy
- Centre for Rheumatology, UCLH, London,UK
- Department of Rheumatology, University College London Hospital, London, UK
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9
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Ünlü S, Sánchez Navarro BG, Cakan E, Berchtold D, Meleka Hanna R, Vural S, Vural A, Meisel A, Fichtner ML. Exploring the depths of IgG4: insights into autoimmunity and novel treatments. Front Immunol 2024; 15:1346671. [PMID: 38698867 PMCID: PMC11063302 DOI: 10.3389/fimmu.2024.1346671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/29/2024] [Indexed: 05/05/2024] Open
Abstract
IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.
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Affiliation(s)
- Selen Ünlü
- Koç University Research Center for Translational Medicine (KUTTAM), İstanbul, Türkiye
- Koç University School of Medicine, Istanbul, Türkiye
| | - Blanca G. Sánchez Navarro
- Department of Neurology with Experimental Neurology, Integrated Myasthenia Gravis Center, Neuroscience Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Elif Cakan
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
| | - Daniel Berchtold
- Department of Neurology with Experimental Neurology, Integrated Myasthenia Gravis Center, Neuroscience Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Rafael Meleka Hanna
- Department of Neurology with Experimental Neurology, Integrated Myasthenia Gravis Center, Neuroscience Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Secil Vural
- Koç University Research Center for Translational Medicine (KUTTAM), İstanbul, Türkiye
- Department of Dermatology and Venereology, Koç University School of Medicine, İstanbul, Türkiye
| | - Atay Vural
- Koç University Research Center for Translational Medicine (KUTTAM), İstanbul, Türkiye
- Department of Neurology, Koç University School of Medicine, İstanbul, Türkiye
| | - Andreas Meisel
- Department of Neurology with Experimental Neurology, Integrated Myasthenia Gravis Center, Neuroscience Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Miriam L. Fichtner
- Koç University Research Center for Translational Medicine (KUTTAM), İstanbul, Türkiye
- Department of Neurology with Experimental Neurology, Integrated Myasthenia Gravis Center, Neuroscience Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany
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10
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Wu KY, Kulbay M, Daigle P, Nguyen BH, Tran SD. Nonspecific Orbital Inflammation (NSOI): Unraveling the Molecular Pathogenesis, Diagnostic Modalities, and Therapeutic Interventions. Int J Mol Sci 2024; 25:1553. [PMID: 38338832 PMCID: PMC10855920 DOI: 10.3390/ijms25031553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/21/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Nonspecific orbital inflammation (NSOI), colloquially known as orbital pseudotumor, sometimes presents a diagnostic and therapeutic challenge in ophthalmology. This review aims to dissect NSOI through a molecular lens, offering a comprehensive overview of its pathogenesis, clinical presentation, diagnostic methods, and management strategies. The article delves into the underpinnings of NSOI, examining immunological and environmental factors alongside intricate molecular mechanisms involving signaling pathways, cytokines, and mediators. Special emphasis is placed on emerging molecular discoveries and approaches, highlighting the significance of understanding molecular mechanisms in NSOI for the development of novel diagnostic and therapeutic tools. Various diagnostic modalities are scrutinized for their utility and limitations. Therapeutic interventions encompass medical treatments with corticosteroids and immunomodulatory agents, all discussed in light of current molecular understanding. More importantly, this review offers a novel molecular perspective on NSOI, dissecting its pathogenesis and management with an emphasis on the latest molecular discoveries. It introduces an integrated approach combining advanced molecular diagnostics with current clinical assessments and explores emerging targeted therapies. By synthesizing these facets, the review aims to inform clinicians and researchers alike, paving the way for molecularly informed, precision-based strategies for managing NSOI.
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Affiliation(s)
- Kevin Y. Wu
- Department of Surgery, Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada; (K.Y.W.)
| | - Merve Kulbay
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 0A4, Canada
| | - Patrick Daigle
- Department of Surgery, Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada; (K.Y.W.)
| | - Bich H. Nguyen
- CHU Sainte Justine Hospital, Montreal, QC H3T 1C5, Canada
| | - Simon D. Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
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11
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Carpenter MC, Souter SC, Zipkin RJ, Ackerman ME. Current Insights Into K-associated Fetal Anemia and Potential Treatment Strategies for Sensitized Pregnancies. Transfus Med Rev 2024; 38:150779. [PMID: 37926651 PMCID: PMC10856777 DOI: 10.1016/j.tmrv.2023.150779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/21/2023] [Accepted: 09/27/2023] [Indexed: 11/07/2023]
Abstract
K-associated anemic disease of the fetus and newborn (K-ADFN) is a rare but life-threatening disease in which maternal alloantibodies cross the placenta and can mediate an immune attack on fetal red blood cells expressing the K antigen. A considerably more common disease, D-associated hemolytic disease of the fetus and newborn (D-HDFN), can be prophylactically treated using polyclonal α-D antibody preparations. Currently, no such prophylactic treatment exists for K-associated fetal anemia, and disease is usually treated with intrauterine blood transfusions. Here we review current understanding of the biology of K-associated fetal anemia, how the maternal immune system is sensitized to fetal red blood cells, and what is understood about potential mechanisms of prophylactic HDFN interventions. Given the apparent challenges associated with preventing alloimmunization, we highlight novel strategies for treating sensitized mothers to prevent fetal anemia that may hold promise not only for K-mediated disease, but also for other pathogenic alloantibody responses.
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Affiliation(s)
| | | | | | - Margaret E Ackerman
- Thayer School of Engineering, Dartmouth College, Hanover, NH, USA; Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
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12
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Ocadlikova D, Lussana F, Fracchiolla N, Bonifacio M, Santoro L, Delia M, Chiaretti S, Pasciolla C, Cignetti A, Forghieri F, Grimaldi F, Corradi G, Zannoni L, De Propris S, Borleri GM, Tanasi I, Vadakekolathu J, Rutella S, Guarini AR, Foà R, Curti A. Blinatumomab differentially modulates peripheral blood and bone marrow immune cell repertoire: A Campus ALL study. Br J Haematol 2023; 203:637-650. [PMID: 37700538 DOI: 10.1111/bjh.19104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 08/04/2023] [Accepted: 08/30/2023] [Indexed: 09/14/2023]
Abstract
Blinatumomab is the first bi-specific T-cell engager approved for relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (B-ALL). Despite remarkable clinical results, the effects of blinatumomab on the host immune cell repertoire are not fully elucidated. In the present study, we characterized the peripheral blood (PB) and, for the first time, the bone marrow (BM) immune cell repertoire upon blinatumomab treatment. Twenty-nine patients with B-ALL received blinatumomab according to clinical practice. Deep multiparametric flow cytometry was used to characterize lymphoid subsets during the first treatment cycle. Blinatumomab induced a transient redistribution of PB effector T-cell subsets and Treg cells with a persistent increase in cytotoxic NK cells, which was associated with a transient upregulation of immune checkpoint receptors on PB CD4 and CD8 T-cell subpopulations and of CD39 expression on suppressive Treg cells. Of note, BM immune T-cell subsets showed a broader post-treatment subversion, including the modulation of markers associated with a T-cell-exhausted phenotype. In conclusion, our study indicates that blinatumomab differentially modulates the PB and BM immune cell repertoire, which may have relevant clinical implications in the therapeutic setting.
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Affiliation(s)
- Darina Ocadlikova
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
| | - Federico Lussana
- Department of Oncology and Hematology, Università degli Studi di Milano, Milan, Italy
- Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Nicola Fracchiolla
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UO Ematologia, Milan, Italy
| | - Massimiliano Bonifacio
- Dipartimento di Medicina, UOC Ematologia, Università di Verona and AOUI Verona, Verona, Italy
| | | | - Mario Delia
- UO Ematologia con Trapianto - Azienda Ospedaliero-Universitaria-Consorziale Policlinico di Bari, Bari, Italy
| | - Sabina Chiaretti
- Dipartimento di Medicina Traslazionale e di Precisione, Università "Sapienza", Roma, Italy
| | | | | | - Fabio Forghieri
- Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Università di Modena e Reggio Emilia, AOU di Modena, Modena, Italy
| | | | - Giulia Corradi
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
| | - Letizia Zannoni
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
| | - Stefania De Propris
- Dipartimento di Medicina Traslazionale e di Precisione, Università "Sapienza", Roma, Italy
| | - Gian Maria Borleri
- Department of Oncology and Hematology, Università degli Studi di Milano, Milan, Italy
- Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Ilaria Tanasi
- Dipartimento di Medicina, UOC Ematologia, Università di Verona and AOUI Verona, Verona, Italy
| | - Jayakumar Vadakekolathu
- John van Geest Cancer Research Centre, College of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Sergio Rutella
- John van Geest Cancer Research Centre, College of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Anna Rita Guarini
- Dipartimento di Medicina Molecolare, Università "Sapienza", Roma, Italy
| | - Robin Foà
- Dipartimento di Medicina Traslazionale e di Precisione, Università "Sapienza", Roma, Italy
| | - Antonio Curti
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
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13
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Lim MJ, Jung KH, Kwon SR, Park W. Inflammation is responsible for systemic bone loss in patients with seropositive rheumatoid arthritis treated with rituximab. Korean J Intern Med 2023; 38:912-922. [PMID: 37867140 PMCID: PMC10636556 DOI: 10.3904/kjim.2023.080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/15/2023] [Accepted: 05/23/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND/AIMS We investigated the effect of rituximab on systemic bone metabolism in patients with seropositive rheumatoid arthritis (RA). METHODS Twenty seropositive patients with RA were enrolled and administered one cycle of rituximab. If RA became active for > 6 months after the first rituximab cycle, a second cycle was initiated; otherwise, no additional treatment was administered. Patients were divided into two groups according to the number of rituximab treatment cycles. RESULTS In patients treated with a second cycle, the total hip bone mineral density (BMD) was clinically low, whereas the serum levels of receptor activator of nuclear factor kappa-B ligand (RANKL) were increased at 12 months. BMD in patients treated with one cycle did not change at 12 months, whereas serum RANKL levels decreased at all time points. DAS28 activity improved in both groups from baseline to 4 months; however, from 4 to 12 months, DAS28 activity worsened in the develgroup with the second cycle but remained stable in the group with one cycle. CONCLUSION Systemic inflammation, reflected by increased disease activity, may be responsible for the increase in RANKL levels, which causes systemic bone loss in rituximab-treated patients with RA. Although rituximab affects inflammation, it does not seem to alter systemic bone metabolism in RA.
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Affiliation(s)
- Mie Jin Lim
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, Inha University, Incheon, Korea
| | - Kyong-Hee Jung
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, Inha University, Incheon, Korea
| | - Seong-Ryul Kwon
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, Inha University, Incheon, Korea
| | - Won Park
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, Inha University, Incheon, Korea
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14
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Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients. Transplant Direct 2023; 9:e1436. [PMID: 36700064 PMCID: PMC9851678 DOI: 10.1097/txd.0000000000001436] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/18/2022] [Accepted: 11/28/2022] [Indexed: 01/27/2023] Open
Abstract
The THEORY study evaluated the effects of single and multiple doses of obinutuzumab, a type 2 anti-CD20 antibody that induces antibody-dependent cell-mediated cytotoxicity and direct cell death, in combination with standard of care in patients with end-stage renal disease. Methods We measured B-cell subsets and protein biomarkers of B-cell activity in peripheral blood before and after obinutuzumab administration in THEORY patients, and B-cell subsets in lymph nodes in THEORY patients and an untreated comparator cohort. Results Obinutuzumab treatment resulted in a rapid loss of B-cell subsets (including naive B, memory B, double-negative, immunoglobulin D+ transitional cells, and plasmablasts/plasma cells) in peripheral blood and tissue. This loss of B cells was associated with increased B cell-activating factor and decreased CXCL13 levels in circulation. Conclusions Our data further characterize the mechanistic profile of obinutuzumab and suggest that it may elicit greater efficacy in indications such as lupus where B-cell targeting therapeutics are limited by the resistance of pathogenic tissue B cells to depletion.
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15
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Al-Janabi A, Ra A, Littlewood Z, Foulkes AC, Hunter HJA, Chinoy H, Moriarty CA, Hyrich KL, Limdi JK, Yiu ZZN, Griffiths CEM, Warren RB. The effect of immunomodulators on seroconversion after BNT162b2 and AZD1222 vaccines in patients with immune-mediated inflammatory diseases: a prospective cohort study. Br J Dermatol 2022; 188:542-551. [PMID: 36695406 DOI: 10.1093/bjd/ljac109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/18/2022] [Accepted: 11/28/2022] [Indexed: 01/22/2023]
Abstract
BACKGROUND Biologic and nonbiologic immunomodulators, used to treat immune-mediated inflammatory diseases (IMIDs), could impair the immune response to COVID-19 vaccines and thus vaccine effectiveness. OBJECTIVES Our objective was to investigate the association between biologic and nonbiologic immunomodulators and seroconversion following the first and second dose of COVID-19 vaccines in patients with IMIDs. METHODS Serum samples were collected following the first or second dose of the BNT162b2 or AZD1222 vaccines from patients receiving biologic and/or nonbiologic immunomodulators for one or more of psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease or systemic lupus erythematosus. Seroconversion was defined as a positive Roche Elecsys® Anti-SARS-CoV-2 S (spike protein subunit S1/receptor binding domain) immunoassay (≥ 0.8 U mL-1). Association between immunomodulator exposure and seroconversion was assessed using logistic regression, adjusting for age and sex. RESULTS After excluding those with prior COVID-19, post-first vaccine dose samples from 193 participants and post-second dose samples from 312 participants were included in the analysis. Following the first vaccine dose, 17.6% (n = 34) of participants did not seroconvert. Seroconversion was reduced for those on nonbiologic [adjusted odds ratio (OR) 0.29, 95% confidence interval (CI) 0.12-0.69] or combined nonbiologic and biologic treatment (adjusted OR 0.14, 95% CI 0.045-0.45) compared with those on biologic monotherapy. Subgroup analysis demonstrated reduced odds of seroconversion in those on methotrexate (adjusted OR 0.097, 95% CI 0.19-0.49) or prednisolone treatment (adjusted OR 0.044, 95% CI 0.002-1.00) relative to tumour necrosis factor-α inhibitor monotherapy. No participants receiving rituximab (n < 5) seroconverted after the first vaccine dose. Following the second vaccine dose, 1.6% of all participants did not seroconvert. Non-seroconversion was associated with receiving rituximab (n = 3 of 4) compared with those receiving other therapies (n = 2 of 308, P < 0.001). Post hoc analyses demonstrated that non-seroconversion was associated with age [adjusted OR 0.18, 95% CI 0.037-0.93 for those aged 60 years and over (reference category age 18-39 years)], but not sex, ethnicity or vaccine type. CONCLUSIONS Treatment with nonbiologics, particularly methotrexate, is associated with impaired seroconversion following two BNT162b2 or AZD1222 vaccine doses, in patients with IMIDs. These findings are consistent with those of other published studies. While this could indicate reduced protection against COVID-19, the immunological parameters that correlate most closely with vaccine effectiveness need to be defined to reach this conclusion.
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Affiliation(s)
- Ali Al-Janabi
- Centre for Dermatology Research, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
| | - Amelle Ra
- Centre for Dermatology Research, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
| | - Zoe Littlewood
- Centre for Dermatology Research, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
| | - Amy C Foulkes
- Centre for Dermatology Research, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
| | - Hamish J A Hunter
- Centre for Dermatology Research, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
| | - Hector Chinoy
- National Institute of Health Research, Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester NHS Foundation Trust, Manchester, UK
- Department of Rheumatology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK
- Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Christopher A Moriarty
- Affinity Biomarker Labs, Translation & Innovation Hub Building, Imperial College London White City Campus, London W12 0BZ, UK
| | - Kimme L Hyrich
- National Institute of Health Research, Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester NHS Foundation Trust, Manchester, UK
- Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Jimmy K Limdi
- Section of IBD, Division of Gastroenterology, Northern Care Alliance NHS Trust, Manchester, UK
- Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Zenas Z N Yiu
- Centre for Dermatology Research, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
| | - Christopher E M Griffiths
- Centre for Dermatology Research, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
| | - Richard B Warren
- Centre for Dermatology Research, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
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16
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Blincoe A, Labrosse R, Abraham RS. Acquired B-cell deficiency secondary to B-cell-depleting therapies. J Immunol Methods 2022; 511:113385. [PMID: 36372267 DOI: 10.1016/j.jim.2022.113385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 09/26/2022] [Accepted: 10/17/2022] [Indexed: 11/13/2022]
Abstract
The advantage of the newer biological therapies is that the immunosuppressive effect is targeted, in contrast, to the standard, traditional immunomodulatory agents, which have a more global effect. However, there are unintended targets and consequences, even to these "precise" therapeutics, leading to acquired or secondary immunodeficiencies. Besides depleting specific cellular immune subsets, these biological agents, which include monoclonal antibodies against biologically relevant molecules, often have broader functional immune consequences, which become apparent over time. This review focuses on acquired B-cell immunodeficiency, secondary to the use of B-cell depleting therapeutic agents. Among the many adverse consequences of B-cell depletion is the risk of hypogammaglobulinemia, failure of B-cell recovery, impaired B-cell differentiation, and risk of infections. Factors, which modulate the outcomes of B-cell depleting therapies, include the intrinsic nature of the underlying disease, the concomitant use of other immunomodulatory agents, and the clinical status of the patient and other co-existing morbidities. This article seeks to explore the mechanism of action of B-cell depleting agents, the clinical utility and adverse effects of these therapies, and the relevance of systematic and serial laboratory immune monitoring in identifying patients at risk for developing immunological complications, and who may benefit from early intervention to mitigate the secondary consequences. Though these biological drugs are gaining widespread use, a harmonized approach to immune evaluation pre-and post-treatment has not yet gained traction across multiple clinical specialties, because of which, the true prevalence of these adverse events cannot be determined in the treated population, and a systematic and evidence-based dosing schedule cannot be developed. The aim of this review is to bring these issues into focus, and initiate a multi-specialty, data-driven approach to immune monitoring.
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Affiliation(s)
- Annaliesse Blincoe
- Department of Paediatric Immunology and Allergy, Starship Child Health, Auckland, NZ, New Zealand
| | - Roxane Labrosse
- Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, Canada
| | - Roshini S Abraham
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
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17
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Mischlinger J, Jaeger VK, Ciurea A, Gabay C, Hasler P, Mueller RB, Siegrist CA, Villiger P, Walker UA, Hatz C, Bühler S. Long-term persistence of antibodies after diphtheria/tetanus vaccination in immunosuppressed patients with inflammatory rheumatic diseases and healthy controls. Vaccine 2022; 40:4897-4904. [PMID: 35810064 DOI: 10.1016/j.vaccine.2022.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 05/16/2022] [Accepted: 06/02/2022] [Indexed: 10/17/2022]
Abstract
Many vaccines demonstrate high effectiveness for years. This prospective multicentre study was conducted in Switzerland to assess the long-term persistence of antibodies to the diphtheria/tetanus (dT)-vaccine in adult patients with rheumatic diseases (PRDs). 163 PRDs and 169 controls were included in the study. The median age of all participants was 50 years (range: 18-83 years) and 56% were female. After a median time interval of 16 years after vaccination, the median anti-vaccine antibody concentrations were lower in PRDs than in controls for tetanus (1.68 vs 2.01; p = 0.049) and diphtheria (0.05 vs 0.22; p = 0.002). Based on the currently accepted seroprotection threshold (antibody concentration ≥ 0.1 IU/ml), PRDs had lower proportions of short-term tetanus and diphtheria protection as demonstrated by crude odds ratios (OR) of 0.30 (p = 0.017) and OR: 0.52 (p = 0.004), respectively. After adjusting for 'age' and 'time since last dT vaccination', the strength of associations became weaker; for tetanus, borderline evidence remained for a true difference between PRDs and controls (OR: 0.36 [p = 0.098]), however, not for diphtheria (OR: 0.86 [p = 0.58]). We hypothesize that in the presence of rheumatic diseases and its immunosuppressive treatment, vaccine-specific long-lived plasma cells (LLPCs) may be diminished or competitively displaced by rheumatism-specific LLPCs, a process which may decrease the persistence of vaccine-specific antibodies. Novel studies should be designed by incorporating methodologies allowing to determine the attributable fraction of immunosuppressive/immunomodulatory medications and rheumatic disease itself on long-lasting vaccine-specific antibody persistence, as well as, further study the role of LLPCs.
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Affiliation(s)
- Johannes Mischlinger
- Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine & I. Department of Medicine University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Veronika K Jaeger
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland; Institute of Epidemiology and Social Medicine, University of Münster, Germany
| | - Adrian Ciurea
- Department of Rheumatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Cem Gabay
- Division of Rheumatology, University Hospital of Geneva, Geneva, Switzerland
| | - Paul Hasler
- Division of Rheumatology, University Department of Medicine, University of Basel Medical Faculty, Cantonal Hospital Aarau, Aarau, Switzerland
| | - Ruediger B Mueller
- Division of Rheumatology, University Department of Medicine, University of Basel Medical Faculty, Cantonal Hospital Aarau, Aarau, Switzerland; Division of Rheumatology, Department of Internal Medicine, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; Division of Rheumatology and Clinical Immunology, Department of Internal Medicine Ludwig-Maximilians-University Munich, Germany
| | - Claire Ann Siegrist
- Center for Vaccinology, University Hospital and Faculty of Medicine, Geneva, Switzerland
| | - Peter Villiger
- Department of Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland
| | - Ulrich A Walker
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland
| | - Christoph Hatz
- Department of Public Health / Division of Infectious Diseases, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland; Department of Medicine and Diagnostics, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Switzerland; Division of Infectious Diseases & Hospital Epidemiology, Kantonsspital St. Gallen, Switzerland
| | - Silja Bühler
- Department of Public Health / Division of Infectious Diseases, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland; Division of Hygiene and Infectious Diseases, Institute for Hygiene and Environment, Hamburg, Germany.
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18
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Hu C, Wu D, Yu J, Xu J, Liu L, Zhang M, Jiao W, Chen G. Dihydroarteannuin Ameliorates Collagen-Induced Arthritis Via Inhibiting B Cell Activation by Activating the FcγRIIb/Lyn/SHP-1 Pathway. Front Pharmacol 2022; 13:883835. [PMID: 35592412 PMCID: PMC9111742 DOI: 10.3389/fphar.2022.883835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Dihydroarteannuin (DHA), which is extracted from the traditional Chinese herb Artemisia annua L, exhibits potent immunosuppressive activity in rheumatoid arthritis (RA). Strong evidence indicates that B cells act as an essential factor in the pathogenesis of RA, but research on the immunosuppressive function of DHA in regulating B cells is limited. Objective: To investigate the modulatory effects of DHA on joint destruction, proinflammatory cytokine production, activation, apoptosis and proliferation of B cells and to explore the possible associated mechanism in RA treatment. Methods: Collagen-induced arthritis (CIA) model was established. Weight and joint oedema were record weekly, and joint damage was detected by micro-CT scan. Human Burkitt B lymphoma cells lacking endogenous Fc gamma receptor b (FcγRIIb) gene were transfected with a 232Thr loss-of-function mutant to construct a mutant cell model ST486. The proliferation of ST486 cells was assessed with Cell Counting Kit-8. Apoptosis and activation were tested by flow cytometry. The effects of DHA on the activation of FcγRIIb, protein tyrosine kinases (Lyn), and SH2-containing tyrosine phosphatase-1 (SHP-1) signaling pathways were determined by western blotting. Results: In comparison to model group, bone volume/tissue volume (BV/TV) and bone mineral density (BMD) were increased, whereas joint oedema was decreased in both of the DHA and MTX group. The mRNA and protein expression levels of Interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNF-α) were decreased after treatment with DHA. In addition, DHA treatment promoted the apoptosis, inhibited the activation and proliferation of ST486 cells. Furthermore, the protein expression levels of FcγRIIb, SHP-1, and Lyn were increased after treatment with DHA. Moreover, the expression of phosphorylated CD19 was also inhibited by DHA. Conclusion: We provide the first evidence that DHA may alleviate collagen-induced arthritis by activating the FcγRIIb/Lyn/SHP-1 signaling pathway in B cell, indicating that DHA is a novel and valuable candidate for RA therapy.
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Affiliation(s)
- Congqi Hu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Danbin Wu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiahui Yu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China.,Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jia Xu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China.,Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lijuan Liu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mingying Zhang
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Jiao
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China.,Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangxing Chen
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Baiyun Hospital of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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19
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Baker D, MacDougall A, Kang AS, Schmierer K, Giovannoni G, Dobson R. Seroconversion following COVID-19 vaccination: can we optimize protective response in CD20-treated individuals? Clin Exp Immunol 2022; 207:263-271. [PMID: 35553629 PMCID: PMC9113152 DOI: 10.1093/cei/uxab015] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/28/2021] [Accepted: 11/05/2021] [Indexed: 12/14/2022] Open
Abstract
Although there is an ever-increasing number of disease-modifying treatments for relapsing multiple sclerosis (MS), few appear to influence coronavirus disease 2019 (COVID-19) severity. There is concern about the use of anti-CD20-depleting monoclonal antibodies, due to the apparent increased risk of severe disease following severe acute respiratory syndrome corona virus two (SARS-CoV-2) infection and inhibition of protective anti-COVID-19 vaccine responses. These antibodies are given as maintenance infusions/injections and cause persistent depletion of CD20+ B cells, notably memory B-cell populations that may be instrumental in the control of relapsing MS. However, they also continuously deplete immature and mature/naïve B cells that form the precursors for infection-protective antibody responses, thus blunting vaccine responses. Seroconversion and maintained SARS-CoV-2 neutralizing antibody levels provide protection from COVID-19. However, it is evident that poor seroconversion occurs in the majority of individuals following initial and booster COVID-19 vaccinations, based on standard 6 monthly dosing intervals. Seroconversion may be optimized in the anti-CD20-treated population by vaccinating prior to treatment onset or using extended/delayed interval dosing (3-6 month extension to dosing interval) in those established on therapy, with B-cell monitoring until (1-3%) B-cell repopulation occurs prior to vaccination. Some people will take more than a year to replete and therefore protection may depend on either the vaccine-induced T-cell responses that typically occur or may require prophylactic, or rapid post-infection therapeutic, antibody or small-molecule antiviral treatment to optimize protection against COVID-19. Further studies are warranted to demonstrate the safety and efficacy of such approaches and whether or not immunity wanes prematurely as has been observed in the other populations.
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Affiliation(s)
- David Baker
- The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Amy MacDougall
- Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
| | - Angray S Kang
- The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
- Centre for Oral Immunobiology and Regenerative Medicine, Dental Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Klaus Schmierer
- The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
- Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Gavin Giovannoni
- The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
- Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Ruth Dobson
- Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK
- Preventive Neurology Unit, Wolfson Institute of Population Health, Queen Mary University of London, Barts and The London School of Medicine & Dentistry, London, UK
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20
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Asplund Högelin K, Ruffin N, Pin E, Månberg A, Hober S, Gafvelin G, Grönlund H, Nilsson P, Khademi M, Olsson T, Piehl F, Al Nimer F. Development of humoral and cellular immunological memory against SARS-CoV-2 despite B cell depleting treatment in multiple sclerosis. iScience 2021; 24:103078. [PMID: 34490414 PMCID: PMC8410640 DOI: 10.1016/j.isci.2021.103078] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 06/17/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022] Open
Abstract
B cell depleting therapies (BCDTs) are widely used as immunomodulating agents for autoimmune diseases such as multiple sclerosis. Their possible impact on development of immunity to severe acute respiratory syndrome virus-2 (SARS-CoV-2) has raised concerns with the coronavirus disease 2019 (COVID-19) pandemic. We here evaluated the frequency of COVID-19-like symptoms and determined immunological responses in participants of an observational trial comprising several multiple sclerosis disease modulatory drugs (COMBAT-MS; NCT03193866) and in eleven patients after vaccination, with a focus on BCDT. Almost all seropositive and 17.9% of seronegative patients on BCDT, enriched for a history of COVID-19-like symptoms, developed anti-SARS-CoV-2 T cell memory, and T cells displayed functional similarity to controls producing IFN-γ and TNF. Following vaccination, vaccine-specific humoral memory was impaired, while all patients developed a specific T cell response. These results indicate that BCDTs do not abrogate SARS-CoV-2 cellular memory and provide a possible explanation as to why the majority of patients on BCDTs recover from COVID-19.
BCDT might blunt antibody responses after COVID-19 infection or vaccination Patients with no detectable B cells in the blood might still produce antibodies A majority of patients that do not develop antibodies still display a T cell response SARS-CoV-2 T-cells produce Th1 cytokines both in patients on BCDT and untreated
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Affiliation(s)
- Klara Asplund Högelin
- Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:04, 171 76 Stockholm, Sweden
| | - Nicolas Ruffin
- Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:04, 171 76 Stockholm, Sweden
| | - Elisa Pin
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, 17165 Stockholm, Sweden
| | - Anna Månberg
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, 17165 Stockholm, Sweden
| | - Sophia Hober
- Division of Protein Technology, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, 17165 Stockholm, Sweden
| | - Guro Gafvelin
- Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:02, 171 76 Stockholm, Sweden
| | - Hans Grönlund
- Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:02, 171 76 Stockholm, Sweden
| | - Peter Nilsson
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, 17165 Stockholm, Sweden
| | - Mohsen Khademi
- Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:04, 171 76 Stockholm, Sweden
| | - Tomas Olsson
- Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:04, 171 76 Stockholm, Sweden
| | - Fredrik Piehl
- Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:04, 171 76 Stockholm, Sweden
| | - Faiez Al Nimer
- Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:04, 171 76 Stockholm, Sweden
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21
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Habal MV. Current Desensitization Strategies in Heart Transplantation. Front Immunol 2021; 12:702186. [PMID: 34504489 PMCID: PMC8423343 DOI: 10.3389/fimmu.2021.702186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/26/2021] [Indexed: 01/03/2023] Open
Abstract
Heart transplant candidates sensitized to HLA antigens wait longer for transplant, are at increased risk of dying while waiting, and may not be listed at all. The increasing prevalence of HLA sensitization and limitations of current desensitization strategies underscore the urgent need for a more effective approach. In addition to pregnancy, prior transplant, and transfusions, patients with end-stage heart failure are burdened with unique factors placing them at risk for HLA sensitization. These include homograft material used for congenital heart disease repair and left ventricular assist devices (LVADs). Moreover, these risks are often stacked, forming a seemingly insurmountable barrier in some cases. While desensitization protocols are typically implemented uniformly, irrespective of the mode of sensitization, the heterogeneity in success and post-transplant outcomes argues for a more tailored approach. Achieving this will require progress in our understanding of the immunobiology underlying the innate and adaptive immune response to these varied allosensitizing exposures. Further attention to B cell activation, memory, and plasma cell differentiation is required to establish methods that durably abrogate the anti-HLA antibody response before and after transplant. The contribution of non-HLA antibodies to the net state of sensitization and the potential implications for graft longevity also remain to be comprehensively defined. The aim of this review is to first bring forth select issues unique to the sensitized heart transplant candidate. The current literature on desensitization in heart transplantation will then be summarized providing context within the immune response. Building on this, newer approaches with therapeutic potential will be discussed emphasizing the importance of not only addressing the short-term pathogenic consequences of circulating HLA antibodies, but also the need to modulate alloimmune memory.
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Affiliation(s)
- Marlena V. Habal
- Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, Columbia University, New York, NY, United States
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22
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Ghilardi N, Pappu R, Arron JR, Chan AC. 30 Years of Biotherapeutics Development-What Have We Learned? Annu Rev Immunol 2021; 38:249-287. [PMID: 32340579 DOI: 10.1146/annurev-immunol-101619-031510] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Since the birth of biotechnology, hundreds of biotherapeutics have been developed and approved by the US Food and Drug Administration (FDA) for human use. These novel medicines not only bring significant benefit to patients but also represent precision tools to interrogate human disease biology. Accordingly, much has been learned from the successes and failures of hundreds of high-quality clinical trials. In this review, we discuss general and broadly applicable themes that have emerged from this collective experience. We base our discussion on insights gained from exploring some of the most important target classes, including interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), IL-6, IL-12/23, IL-17, IL-4/13, IL-5, immunoglobulin E (IgE), integrins and B cells. We also describe current challenges and speculate about how emerging technological capabilities may enable the discovery and development of the next generation of biotherapeutics.
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Affiliation(s)
- Nico Ghilardi
- Department of Immunology, Genentech, South San Francisco, California 94080, USA; , ,
| | - Rajita Pappu
- Department of Immunology, Genentech, South San Francisco, California 94080, USA; , ,
| | - Joseph R Arron
- Department of Immunology, Genentech, South San Francisco, California 94080, USA; , ,
| | - Andrew C Chan
- Research-Biology, Genentech, South San Francisco, California 94080, USA;
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23
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Markmann C, Bhoj VG. On the road to eliminating long-lived plasma cells-"are we there yet?". Immunol Rev 2021; 303:154-167. [PMID: 34351644 DOI: 10.1111/imr.13015] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 01/19/2023]
Abstract
Central to protective humoral immunity is the activation of B cells and their terminal differentiation into antibody-secreting plasma cells. Long-lived plasma cells (LLPC) may survive for years to decades. Such long-lived plasma cells are also responsible for producing pathogenic antibodies that cause a variety of challenges such as autoimmunity, allograft rejection, and drug neutralization. Up to now, various therapeutic strategies aimed at durably eliminating pathogenic antibodies have failed, in large part due to their inability to efficiently target LLPCs. Several antibody-based therapies have recently gained regulatory approval or are in clinical phases of development for the treatment of multiple myeloma, a malignancy of plasma cells. We discuss the exciting potential of using these emerging cancer immunotherapies to solve the antibody problem.
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Affiliation(s)
- Caroline Markmann
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.,Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
| | - Vijay G Bhoj
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.,Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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24
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Vaccine response following anti-CD20 therapy: a systematic review and meta-analysis of 905 patients. Blood Adv 2021; 5:2624-2643. [PMID: 34152403 PMCID: PMC8216656 DOI: 10.1182/bloodadvances.2021004629] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/23/2021] [Indexed: 11/20/2022] Open
Abstract
The objective of this study was to perform a systematic review of the literature on vaccine responsiveness in patients who have received anti-CD20 therapy. PubMed and EMBASE were searched up to 4 January 2021 to identify studies of vaccine immunogenicity in patients treated with anti-CD20 therapy, including patients with hematologic malignancy or autoimmune disease. The primary outcomes were seroprotection (SP), seroconversion (SC), and/or seroresponse rates for each type of vaccine reported. As the pandemic influenza vaccine (2009 H1N1) has standardized definitions for SP and SC, and represented a novel primary antigen similar to the COVID-19 vaccine, meta-analysis was conducted for SC of studies of this vaccine. Pooled estimates, relative benefit ratios (RBs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-eight studies (905 patients treated with anti-CD20 therapy) were included (19 studies of patients with hematologic malignancies). Patients on active (<3 months since last dose) anti-CD20 therapy had poor responses to all types of vaccines. The pooled estimate for SC after 1 pandemic influenza vaccine dose in these patients was 3% (95% CI, 0% to 9%), with an RB of 0.05 (95% CI, 0-0.73) compared with healthy controls and 0.22 (95% CI, 0.09-0.56) compared with disease controls. SC compared with controls seems abrogated for at least 6 months following treatment (3-6 months post anti-CD20 therapy with an RB of 0.50 [95% CI, 0.24-1.06] compared with healthy and of 0.44 [95% CI, 0.23-0.84] compared with disease controls). For all vaccine types, response to vaccination improves incrementally over time, but may not reach the level of healthy controls even 12 months after therapy.
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25
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Stable HLA antibodies following sustained CD19+ cell depletion implicate a long-lived plasma cell source. Blood Adv 2021; 4:4292-4295. [PMID: 32915973 DOI: 10.1182/bloodadvances.2020002435] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 08/12/2020] [Indexed: 11/20/2022] Open
Abstract
Key Points
HLA-specific alloantibodies can be maintained despite profound CD19+ cell aplasia, likely due to production by CD19− plasma cells.
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26
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Bonek K, Roszkowski L, Massalska M, Maslinski W, Ciechomska M. Biologic Drugs for Rheumatoid Arthritis in the Context of Biosimilars, Genetics, Epigenetics and COVID-19 Treatment. Cells 2021; 10:323. [PMID: 33557301 PMCID: PMC7914976 DOI: 10.3390/cells10020323] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/24/2021] [Accepted: 01/30/2021] [Indexed: 01/08/2023] Open
Abstract
Rheumatoid arthritis (RA) affects around 1.2% of the adult population. RA is one of the main reasons for work disability and premature retirement, thus substantially increasing social and economic burden. Biological disease-modifying antirheumatic drugs (bDMARDs) were shown to be an effective therapy especially in those rheumatoid arthritis (RA) patients, who did not adequately respond to conventional synthetic DMARD therapy. However, despite the proven efficacy, the high cost of the therapy resulted in limitation of the widespread use and unequal access to the care. The introduction of biosimilars, which are much cheaper relative to original drugs, may facilitate the achievement of the therapy by a much broader spectrum of patients. In this review we present the properties of original biologic agents based on cytokine-targeted (blockers of TNF, IL-6, IL-1, GM-CSF) and cell-targeted therapies (aimed to inhibit T cells and B cells properties) as well as biosimilars used in rheumatology. We also analyze the latest update of bDMARDs' possible influence on DNA methylation, miRNA expression and histone modification in RA patients, what might be the important factors toward precise and personalized RA treatment. In addition, during the COVID-19 outbreak, we discuss the usage of biologicals in context of effective and safe COVID-19 treatment. Therefore, early diagnosing along with therapeutic intervention based on personalized drugs targeting disease-specific genes is still needed to relieve symptoms and to improve the quality of life of RA patients.
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Affiliation(s)
- Krzysztof Bonek
- Department of Rheumatology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (K.B.); (L.R.)
| | - Leszek Roszkowski
- Department of Rheumatology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (K.B.); (L.R.)
| | - Magdalena Massalska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (M.M.); (W.M.)
| | - Wlodzimierz Maslinski
- Department of Pathophysiology and Immunology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (M.M.); (W.M.)
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (M.M.); (W.M.)
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27
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Hu C, Peng S, Zhao L, Li M, Liu M, Xu Y, Chen G. Yishen-tongbi decoction inhibits excessive activation of B cells by activating the FcγRIIb/Lyn/SHP-1 pathway and attenuates the inflammatory response in CIA rats. Biomed Pharmacother 2021; 134:111166. [PMID: 33373915 DOI: 10.1016/j.biopha.2020.111166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/17/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease. Strong evidence supports that excessive activation of B cells plays a critical role in the pathogenesis of RA. Fc gamma receptor b (FcγRIIb) is the B cell inhibitory receptor and inhibits BCR (B cell receptor) signalling in part by selectively dephosphorylating CD19 which is considered a co-receptor for BCR and is essential for B cell activation. Our previous study demonstrated that a FcγRIIb I232T polymorphism presented a strong genetic link to RA and may lead to the excessive activation of B cells. Therefore, novel therapeutic strategies and drugs that can effectively inhibit the excessive activation of B cells by regulating the FcγRIIb are necessary for the treatment of RA. Therefore, we used Burkitt's lymphoma ST486 human B cells (lacking endogenous FcγRIIb) transfected with the 232Thr loss-of-function mutant to construct a FcγRIIb mutant cell line (ST486), and we demonstrated that YSTB treatment not only reduced proliferation and promoted apoptosis in ST486 cells but also did so in a dose-dependent manner. Furthermore, the intracellular Ca2+ flux of ST486 cells was decreased after treatment with YSTB, inhibiting the excessive activation of ST486 cells, and these effects correlated with the CD19/FcγRIIb-Lyn-SHP-1 pathways. Our data showed that YSTB treatment inhibited the expression of phosphorylated CD19 and upregulated the protein expression of FcγRIIb, Lyn, and SHP-1. Additionally, the CIA model was established to explore the anti-inflammatory and inhibitory effects of YSTB on bone destruction, and we found that YSTB decreased the paw oedema and arthritis index (AI) in CIA rats. It is worth mentioning that YSTB clearly decreased the AI earlier than methotrexate (MTX) (day 10 vs 16). Moreover, synovial hyperplasia, inflammatory cell infiltration and cartilage surface erosion in CIA rats were noticeably reduced after treatment with YSTB as evidenced by histopathological examination. Finally, we found that YSTB treatment suppressed bone erosion and joint space score (JNS) in CIA rats as evidenced by radiographic assessment. In summary, these data suggest that YSTB has great therapeutic potential for RA treatment.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Apoptosis/drug effects
- Arthritis, Experimental/chemically induced
- Arthritis, Experimental/immunology
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/prevention & control
- B-Lymphocytes/drug effects
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Collagen Type II
- Drugs, Chinese Herbal/pharmacology
- Female
- Humans
- Joints/drug effects
- Joints/immunology
- Joints/metabolism
- Joints/pathology
- Lymphocyte Activation/drug effects
- Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism
- Rats, Wistar
- Receptors, IgG/genetics
- Receptors, IgG/metabolism
- Signal Transduction
- src-Family Kinases/genetics
- src-Family Kinases/metabolism
- Rats
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Affiliation(s)
- Congqi Hu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shanqin Peng
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lianyu Zhao
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Meilin Li
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Muqiu Liu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanping Xu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangxing Chen
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Baiyun Hospital of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, China.
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28
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Jiang R, Fichtner ML, Hoehn KB, Pham MC, Stathopoulos P, Nowak RJ, Kleinstein SH, O'Connor KC. Single-cell repertoire tracing identifies rituximab-resistant B cells during myasthenia gravis relapses. JCI Insight 2020; 5:136471. [PMID: 32573488 DOI: 10.1172/jci.insight.136471] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/11/2020] [Indexed: 12/19/2022] Open
Abstract
Rituximab, a B cell-depleting therapy, is indicated for treating a growing number of autoantibody-mediated autoimmune disorders. However, relapses can occur after treatment, and autoantibody-producing B cell subsets may be found during relapses. It is not understood whether these autoantibody-producing B cell subsets emerge from the failed depletion of preexisting B cells or are generated de novo. To further define the mechanisms that cause postrituximab relapse, we studied patients with autoantibody-mediated muscle-specific kinase (MuSK) myasthenia gravis (MG) who relapsed after treatment. We carried out single-cell transcriptional and B cell receptor profiling on longitudinal B cell samples. We identified clones present before therapy that persisted during relapse. Persistent B cell clones included both antibody-secreting cells and memory B cells characterized by gene expression signatures associated with B cell survival. A subset of persistent antibody-secreting cells and memory B cells were specific for the MuSK autoantigen. These results demonstrate that rituximab is not fully effective at eliminating autoantibody-producing B cells and provide a mechanistic understanding of postrituximab relapse in MuSK MG.
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Affiliation(s)
| | - Miriam L Fichtner
- Department of Immunobiology and.,Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Kenneth B Hoehn
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Panos Stathopoulos
- Department of Immunobiology and.,Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Richard J Nowak
- Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Steven H Kleinstein
- Department of Immunobiology and.,Interdepartmental Program in Computational Biology & Bioinformatics, Yale University, New Haven, Connecticut, USA.,Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Kevin C O'Connor
- Department of Immunobiology and.,Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
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29
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Biswas M, Palaschak B, Kumar SRP, Rana J, Markusic DM. B Cell Depletion Eliminates FVIII Memory B Cells and Enhances AAV8-coF8 Immune Tolerance Induction When Combined With Rapamycin. Front Immunol 2020; 11:1293. [PMID: 32670285 PMCID: PMC7327091 DOI: 10.3389/fimmu.2020.01293] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 05/21/2020] [Indexed: 01/19/2023] Open
Abstract
Hemophilia A is an inherited coagulation disorder resulting in the loss of functional clotting factor VIII (FVIII). Presently, the most effective treatment is prophylactic protein replacement therapy. However, this requires frequent life-long intravenous infusions of plasma derived or recombinant clotting factors and is not a cure. A major complication is the development of inhibitory antibodies that nullify the replacement factor. Immune tolerance induction (ITI) therapy to reverse inhibitors can last from months to years, requires daily or every other day infusions of supraphysiological levels of FVIII and is effective in only up to 70% of hemophilia A patients. Preclinical and recent clinical studies have shown that gene replacement therapy with AAV vectors can effectively cure hemophilia A patients. However, it is unclear how hemophilia patients with high risk inhibitor F8 mutations or with established inhibitors will respond to gene therapy, as these patients have been excluded from ongoing clinical trials. AAV8-coF8 gene transfer in naïve BALB/c-F8e16−/Y mice (BALB/c-HA) results in anti-FVIII IgG1 inhibitors following gene transfer, which can be prevented by transient immune modulation with anti-mCD20 (18B12) and oral rapamycin. We investigated if we could improve ITI in inhibitor positive mice by combining anti-mCD20 and rapamycin with AAV8-coF8 gene therapy. Our hypothesis was that continuous expression of FVIII protein from gene transfer compared to transient FVIII from weekly protein therapy, would enhance regulatory T cell induction and promote deletion of FVIII reactive B cells, following reconstitution. Mice that received anti-CD20 had a sharp decline in inhibitors, which corresponded to FVIII memory B (Bmem) cell deletion. Importantly, only mice receiving both anti-mCD20 and rapamycin failed to increase inhibitors following rechallenge with intravenous FVIII protein therapy. Our data show that B and T cell immune modulation complements AAV8-coF8 gene therapy in naïve and inhibitor positive hemophilia A mice and suggest that such protocols should be considered for AAV gene therapy in high risk or inhibitor positive hemophilia patients.
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Affiliation(s)
- Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Brett Palaschak
- Department of Pediatrics, University of Florida, Gainesville, FL, United States
| | - Sandeep R P Kumar
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Jyoti Rana
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - David M Markusic
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
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30
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García-Rivas G, Castillo EC, Gonzalez-Gil AM, Maravillas-Montero JL, Brunck M, Torres-Quintanilla A, Elizondo-Montemayor L, Torre-Amione G. The role of B cells in heart failure and implications for future immunomodulatory treatment strategies. ESC Heart Fail 2020; 7:1387-1399. [PMID: 32533765 PMCID: PMC7373901 DOI: 10.1002/ehf2.12744] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/10/2020] [Accepted: 04/20/2020] [Indexed: 12/17/2022] Open
Abstract
Despite numerous demonstrations that the immune system is activated in heart failure, negatively affecting patients' outcomes, no definitive treatment strategy exists directed to modulate the immune system. In this review, we present the evidence that B cells contribute to the development of hypertrophy, inflammation, and maladaptive tissue remodelling. B cells produce antibodies that interfere with cardiomyocyte function, which culminates as the result of recruitment and activation of a variety of innate and structural cell populations, including neutrophils, macrophages, fibroblasts, and T cells. As B cells appear as active players in heart failure, we propose here novel immunomodulatory therapeutic strategies that target B cells and their products.
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Affiliation(s)
- Gerardo García-Rivas
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Cátedra de Cardiología y Medicina Vascular, Monterrey, Nuevo León, Mexico.,Tecnologico de Monterrey, Hospital Zambrano Hellion, TecSalud, Centro de Investigación Biomédica, San Pedro Garza García, Nuevo León, Mexico
| | - Elena Cristina Castillo
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Cátedra de Cardiología y Medicina Vascular, Monterrey, Nuevo León, Mexico
| | - Adrian M Gonzalez-Gil
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Cátedra de Cardiología y Medicina Vascular, Monterrey, Nuevo León, Mexico
| | - José Luis Maravillas-Montero
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Marion Brunck
- Tecnologico de Monterrey, School of Engineering and Science, FEMSA Biotechnology Center, Monterrey, Nuevo León, Mexico
| | - Alejandro Torres-Quintanilla
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Cátedra de Cardiología y Medicina Vascular, Monterrey, Nuevo León, Mexico
| | - Leticia Elizondo-Montemayor
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Cátedra de Cardiología y Medicina Vascular, Monterrey, Nuevo León, Mexico.,Tecnologico de Monterrey, Hospital Zambrano Hellion, TecSalud, Centro de Investigación Biomédica, San Pedro Garza García, Nuevo León, Mexico
| | - Guillermo Torre-Amione
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Cátedra de Cardiología y Medicina Vascular, Monterrey, Nuevo León, Mexico.,Tecnologico de Monterrey, Hospital Zambrano Hellion, TecSalud, Centro de Investigación Biomédica, San Pedro Garza García, Nuevo León, Mexico.,Weill Cornell Medical College, Methodist DeBakey Heart & Vascular Center, The Methodist Hospital, Houston, TX, USA
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31
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Anti-CD20–mediated B-cell depletion in autoimmune diseases: successes, failures and future perspectives. Kidney Int 2020; 97:885-893. [DOI: 10.1016/j.kint.2019.12.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/09/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022]
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32
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Ramwadhdoebe TH, van Baarsen LGM, Boumans MJH, Bruijnen STG, Safy M, Berger FH, Semmelink JF, van der Laken CJ, Gerlag DM, Thurlings RM, Tak PP. Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis. Rheumatology (Oxford) 2020; 58:1075-1085. [PMID: 30649469 PMCID: PMC6532448 DOI: 10.1093/rheumatology/key428] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 11/21/2018] [Indexed: 11/25/2022] Open
Abstract
Objectives The exact underlying mechanism of rituximab treatment in patients with RA is poorly defined and knowledge about the effect of B cell depletion on immune cells in secondary lymphoid organs is lacking. We analysed lymphoid tissue responses to rituximab in RA patients. Methods Fourteen RA patients received 2 × 1000 mg rituximab intravenously, and lymph node (LN) biopsies were obtained before and 4 weeks after the first infusion. Tissues were examined by flow cytometry, immunohistochemistry and quantitative PCR. LN biopsies from five healthy individuals (HC) served as controls. Results LN biopsies of RA patients showed increased frequencies of CD21+CD23+IgDhighIgMvariable follicular B cells and CD3+CD25+CD69+ early activated, tissue resident T cells when compared with HCs. After treatment, there was incomplete depletion of LN B cells. There was a significant decrease in CD27−IgD+ naïve B cells, and CD27+IgD+ unswitched memory B cells including the CD27+IgD+IgM+ subset and follicular B cells. Strikingly, CD27+IgD− switched memory B cells persisted in LN biopsies after rituximab treatment. In the T cell compartment, a significant decrease was observed in the frequency of early activated, tissue resident T cells after rituximab treatment, but late activated T cells persisted. B cell proliferation inducing cytokine IL-21 was higher expressed in LN biopsies of RA patients compared with HC and expression was not affected by rituximab treatment. Conclusion Rituximab does not cure RA, possibly due to persistence of switched memory B cells in lymphoid tissues suggesting that factors promoting B cell survival and differentiation need to be additionally targeted.
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Affiliation(s)
- Tamara H Ramwadhdoebe
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center (ARC), Netherlands.,Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Netherlands
| | - Lisa G M van Baarsen
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center (ARC), Netherlands.,Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Netherlands
| | - Maria J H Boumans
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center (ARC), Netherlands
| | - Stefan T G Bruijnen
- Department of Rheumatology and Clinical Immunology, ARC, Amsterdam UMC, Vrije Universiteit Amsterdam, Netherlands
| | - Mary Safy
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center (ARC), Netherlands
| | - Ferco H Berger
- Department of Radiology & Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Johanna F Semmelink
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center (ARC), Netherlands.,Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Netherlands
| | - Conny J van der Laken
- Department of Rheumatology and Clinical Immunology, ARC, Amsterdam UMC, Vrije Universiteit Amsterdam, Netherlands
| | - Danielle M Gerlag
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center (ARC), Netherlands.,Clinical Unit Cambridge, GlaxoSmithKline, UK
| | - Rogier M Thurlings
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center (ARC), Netherlands
| | - Paul P Tak
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center (ARC), Netherlands.,University of Cambridge, Cambridge, UK.,Ghent University, Ghent, Belgium
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33
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Davis JM, Crowson CS, Knutson KL, Achenbach SJ, Strausbauch MA, Therneau TM, Matteson EL, Gabriel SE, Wettstein PJ. Longitudinal relationships between rheumatoid factor and cytokine expression by immunostimulated peripheral blood lymphocytes from patients with rheumatoid arthritis: New insights into B-cell activation. Clin Immunol 2020; 211:108342. [PMID: 31926330 PMCID: PMC7045286 DOI: 10.1016/j.clim.2020.108342] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/20/2019] [Accepted: 01/04/2020] [Indexed: 01/16/2023]
Abstract
To identify associations between immunostimulated cytokine production and disease characteristics, peripheral blood lymphocytes were collected from 155 adult patients with rheumatoid arthritis (RA) before and after a 5-year interval. The lymphocytes were activated in vitro with T-cell stimulants, cytosine-phosphate-guanine (CpG) oligonucleotide, and medium alone (negative control). Expression of 17 cytokines was evaluated with immunoassays, and factor analysis was used to reduce data complexity and identify cytokine combinations indicative of cell types preferentially activated by each immunostimulant. The findings showed that the highest numbers of correlations were between cytokine levels and rheumatoid factor (RF) positivity and between cytokine levels and disease duration. Scores for cytokines driven by CpG and medium alone were negatively associated with RF positivity and disease duration at baseline but positively associated with both at 5 years. Our findings suggest that RF expression sustained over time increases activation of B cells and monocytes without requirements for T-cell functions.
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Affiliation(s)
- John M Davis
- Division of Rheumatology, Mayo Clinic, Rochester, MN, United States of America.
| | - Cynthia S Crowson
- Division of Rheumatology, Mayo Clinic, Rochester, MN, United States of America; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America
| | - Keith L Knutson
- Department of Immunology, Mayo Clinic, Jacksonville, FL, United States of America
| | - Sara J Achenbach
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America
| | - Michael A Strausbauch
- Immunochemical Core Laboratory, Mayo Clinic, Rochester, MN, United States of America
| | - Terry M Therneau
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America
| | - Eric L Matteson
- Division of Rheumatology, Mayo Clinic, Rochester, MN, United States of America
| | - Sherine E Gabriel
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America
| | - Peter J Wettstein
- Department of Surgery, Mayo Clinic, Rochester, MN, United States of America
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34
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Sidiropoulos P, Sfikakis PP, Boumpas DD, Vassilopoulos D. Twenty Years of Targeted Treatment in Rheumatoid Arthritis in the Greek Databases: Achievements and Unmet Needs. Mediterr J Rheumatol 2019; 30:141-146. [PMID: 32185356 PMCID: PMC7045862 DOI: 10.31138/mjr.30.3.141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 06/05/2019] [Accepted: 06/22/2019] [Indexed: 11/25/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with substantial morbidity and mortality especially in difficult to treat cases. Biologic agents were introduced 20 years ago in Greece and RA management has paralleled the European experience. Several publications from the country have captured important aspects of the disease from its epidemiology to the clinical use of biologics and management of comorbidities. In this communication we review the management of RA and its evolution over the last 20 years in Greece, discussing the major achievements and the unmet needs of the disease in an effort to put this into a perspective. We conclude that introduction of biologic therapy has substantially changed the treatment of difficult to treat rheumatoid arthritis in-spite of the multiple unmet needs. While striving for even better outcomes, we cannot lose sight of the major impact of biologic therapies on the lives of patients with rheumatoid arthritis.
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Affiliation(s)
- Prodromos Sidiropoulos
- Department of Rheumatology and Clinical Immunology, School of Medicine, University of Crete, Greece
- Laboratory of Rheumatology, Inflammation and Autoimmunity, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece
| | - Petros P. Sfikakis
- First Department of Propaedeutic and Internal Medicine & Rheumatology Unit, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Joint Rheumatology Program, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimitrios D. Boumpas
- 4th Department of Internal Medicine, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
- Joint Rheumatology Program, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
- Laboratory of Immune Regulation and Tolerance, Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Dimitrios Vassilopoulos
- 2nd Department of Medicine and Laboratory, Hippokration General Hospital, Medical School, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
- Joint Rheumatology Program, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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35
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Tavakolpour S, Alesaeidi S, Darvishi M, GhasemiAdl M, Darabi-Monadi S, Akhlaghdoust M, Elikaei Behjati S, Jafarieh A. A comprehensive review of rituximab therapy in rheumatoid arthritis patients. Clin Rheumatol 2019; 38:2977-2994. [PMID: 31367943 DOI: 10.1007/s10067-019-04699-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 07/09/2019] [Accepted: 07/15/2019] [Indexed: 12/15/2022]
Abstract
Rituximab (RTX) is an approved treatment for rheumatoid arthritis (RA) patients that do not respond adequately to disease-modifying antirheumatic drugs. However, different new concerns, such as efficacy, optimum dose, safety issues, prediction of response to RTX, and pregnancy outcomes have attracted a lot of attention. The PubMed database was systematically reviewed for the last published articles, new findings, and controversial issues regarding RTX therapy in RA using "Rheumatoid arthritis" AND "rituximab" keywords, last updated on June 18, 2019. From 1812 initial recorders, 162 studies met the criteria. Regarding the optimum dose, low-dose RTX therapy (2 × 500 mg) seems as effective as standard dose (2 × 1000 mg), safer, and more cost-effective. The most common reported safety challenges included de novo infections, false negative serologic tests of viral infections, reactivation of chronic infections, interfering with vaccination outcome, and development of de novo psoriasis. Other less reported side effects are infusion reactions, nervous system disorders, and gastrointestinal disorders. Lower exposure to other biologics, presence of some serological markers (e.g., anti-RF, anti-CCP, IL-33, ESR), specific variations in FCGR3A, FCGR2A, TGFβ1, IL6, IRF5, BAFF genes, and also EBV-positivity could be used to predict response to RTX. Although there is no evidence of the teratogenic effect of RTX, it is recommended that women do not expose themselves to RTX at least 6 months before the conception. Only a reversible reduction of B cell-count in the offspring may be the pregnancy-related outcome. Although RTX is an effective therapeutic option for RA, more studies on optimum doses, prevention of RTX-related side effects, prediction of RTX response, and safety during the pregnancy are required.
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Affiliation(s)
- Soheil Tavakolpour
- Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Rheumatology and Internal Medicine, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Samira Alesaeidi
- Rheumatology and Internal Medicine, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), department of aerospace and subaquatic medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Mojtaba GhasemiAdl
- Rheumatology and Internal Medicine, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Meisam Akhlaghdoust
- Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Jafarieh
- Amir'Alam Hospital, Tehran University of Medical Sciences, Tehran, Iran
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36
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Baker D, Pryce G, Amor S, Giovannoni G, Schmierer K. Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis. Brain 2019; 141:2834-2847. [PMID: 30212896 DOI: 10.1093/brain/awy239] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/01/2018] [Indexed: 12/15/2022] Open
Abstract
Although many suspected autoimmune diseases are thought to be T cell-mediated, the response to therapy indicates that depletion of B cells consistently inhibits disease activity. In multiple sclerosis, it appears that disease suppression is associated with the long-term reduction of memory B cells, which serves as a biomarker for disease activity in many other CD20+ B cell depletion-sensitive, autoimmune diseases. Following B cell depletion, the rapid repopulation by transitional (immature) and naïve (mature) B cells from the bone marrow masks the marked depletion and slow repopulation of lymphoid tissue-derived, memory B cells. This can provide long-term protection from a short treatment cycle. It seems that memory B cells, possibly via T cell stimulation, drive relapsing disease. However, their sequestration in ectopic follicles and the chronic activity of B cells and plasma cells in the central nervous system may drive progressive neurodegeneration directly via antigen-specific mechanisms or indirectly via glial-dependent mechanisms. While unproven, Epstein-Barr virus may be an aetiological trigger of multiple sclerosis. This infects mature B cells, drives the production of memory B cells and possibly provides co-stimulatory signals promoting T cell-independent activation that breaks immune tolerance to generate autoreactivity. Thus, a memory B cell centric mechanism can integrate: potential aetiology, genetics, pathology and response to therapy in multiple sclerosis and other autoimmune conditions with ectopic B cell activation that are responsive to memory B cell-depleting strategies.
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Affiliation(s)
- David Baker
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Gareth Pryce
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Sandra Amor
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Pathology Department, Free University Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Gavin Giovannoni
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Klaus Schmierer
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK
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37
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Berkani N, Joly P, Golinski ML, Colliou N, Lim A, Larbi A, Riou G, Caillot F, Bernard P, Bedane C, Delaporte E, Chaby G, Dompmartin A, Hertl M, Calbo S, Musette P. B-cell depletion induces a shift in self antigen specific B-cell repertoire and cytokine pattern in patients with bullous pemphigoid. Sci Rep 2019; 9:3525. [PMID: 30837635 PMCID: PMC6401188 DOI: 10.1038/s41598-019-40203-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 02/04/2019] [Indexed: 11/08/2022] Open
Abstract
Bullous Pemphigoid is the most common auto-immune bullous skin disease. It is characterized by the production of auto-antibodies directed against 2 proteins of the hemi-desmosome (BP180 and BP230). We assessed the efficacy and mechanisms of action of rituximab, an anti-CD20 monoclonal antibody, in 17 patients with severe and relapsing type of bullous pemphigoid. The phenotype, cytokine gene expression, and rearrangement of BP180-specific B-cell receptor genes were performed over 2 years following treatment. At the end of the study, 5 patients had died, 3 had withdrawn from the study, and 9 patients were in complete remission. The one- and two-year relapse rates were 44.1% (95% Confidence Interval (CI): 21.0-76.0%) and 66.5%, (95% CI: 38.4-91.4%), respectively. Phenotypic analyses confirmed dramatic B-cell depletion, which lasted for 9 to 12 months. The ELISA values of serum anti-BP180 antibodies and the frequency of BP180-specific circulating B cells decreased dramatically following treatment, which paralleled the improvement of skin lesions. During B-cell reconstitution, a polyclonal IgM repertoire appeared and a shift in the rearrangement of the B-cell receptor genes of BP180-specific circulating B cells was observed. Concurrently, we observed a decrease of IL-15, IL-6 and TNFα expressing BP180-specific B cells, and the emergence of IL-10 and IL-1RA-expressing BP180-specific IgM+ B cells in patients in complete remission off therapy, suggesting the functional plasticity of BP180-specific auto-immune B cells after rituximab treatment.
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Affiliation(s)
| | - Pascal Joly
- Normandie University, UNIROUEN, INSERM U1234, Rouen, France
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Dermatology, French reference center for autoimmune bullous diseases, F76000, Rouen, France
| | - Marie-Laure Golinski
- Normandie University, UNIROUEN, INSERM U1234, Rouen, France
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Dermatology, French reference center for autoimmune bullous diseases, F76000, Rouen, France
| | | | - Annick Lim
- Immunoscope plateform, Pasteur Institute, Paris, France
| | - Anis Larbi
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Gaetan Riou
- Normandie University, UNIROUEN, INSERM U1234, Rouen, France
| | | | - Philippe Bernard
- Department of Dermatology, Reims University Hospital, Reims, France
| | - Christophe Bedane
- Department of Dermatology, Limoges University Hospital, Limoges, France
| | | | - Guillaume Chaby
- Department of Dermatology, Amiens University Hospital, Amiens, France
| | - Anne Dompmartin
- Department of Dermatology, Caen University Hospital, Caen, France
| | - Michael Hertl
- Department of Dermatology and Allergology, Philipps University, Marburg, Germany
| | | | - Philippe Musette
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Dermatology, French reference center for autoimmune bullous diseases, F76000, Rouen, France.
- INSERM U976, Saint Louis Hospital, Paris, France.
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Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia. JAMA Netw Open 2018; 1:e184169. [PMID: 30646343 PMCID: PMC6324375 DOI: 10.1001/jamanetworkopen.2018.4169] [Citation(s) in RCA: 234] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
IMPORTANCE Rituximab is an anti-CD20 chimeric antibody used in a wide variety of clinical indications. There has not been widespread adoption of consistent immune monitoring before and after rituximab therapy. However, there is a subset of patients who develop prolonged, symptomatic hypogammaglobulinemia following rituximab, and monitoring before and after rituximab therapy could help to identify these patients and initiate measures to prevent excess morbidity and mortality. OBJECTIVE To determine the current levels of screening for hypogammaglobulinemia (specifically, low immunoglobulin G), infectious risks associated with hypogammaglobulinemia, and variables associated with an increased risk of mortality. DESIGN, SETTING, AND PARTICIPANTS A cohort study was conducted of 8633 patients receiving rituximab from January 1, 1997, to December 31, 2017, at a large, tertiary referral center (Partners HealthCare System). EXPOSURES Rituximab administration. MAIN OUTCOMES AND MEASURES The primary outcome measures were immunoglobulin measurements, infectious complications, and mortality. Cox regression analysis was used to examine the results of infectious complications on survival, adjusted for age, sex, and indication for rituximab use. RESULTS Of the 8633 patients who received rituximab in the large, academic, health care system, 4479 satisfied inclusion criteria, with a mean (SD) age of 59.8 (16.2) years; 2280 patients (50.9%) were women. Most patients (3824 [85.4%]) did not have immunoglobulin levels checked before rituximab therapy. Of those who had levels determined, hypogammaglobulinemia was noted in 313 (47.8%) patients before initiation of rituximab. Following rituximab administration, worsening hypogammaglobulinemia was noted. There was an increase in severe infections after rituximab use in the study cohort (from 17.2% to 21.7%; P < .001). In the survival analysis, increased mortality was associated with increasing age (hazard ratio [HR], 1.02; 95% CI, 1.01-1.02; P < .001), male sex (HR, 1.14; 95% CI, 1.02-1.28; P = .02), and severe infectious complications in the 6 months before (HR, 3.14; 95% CI, 2.77-3.55; P < .001) and after (HR, 4.97; 95% CI, 4.41-5.60; P < .001) the first rituximab infusion. A total of 201 patients (4.5%) received immunoglobulin replacement following rituximab, and among these patients, higher cumulative immunoglobulin replacement dose was associated with a reduced risk of serious infectious complications (HR, 0.98; 95% CI, 0.96-0.99; P = .002). CONCLUSIONS AND RELEVANCE Many patients are not being screened or properly identified as having hypogammaglobulinemia both before and after rituximab administration. Monitoring of immunoglobulin levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from immunoglobulin replacement, which may in turn help to avoid excess morbidity and mortality.
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Affiliation(s)
- Sara Barmettler
- Allergy and Clinical Immunology Unit, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Boston
| | - Mei-Sing Ong
- Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care, Boston, Massachusetts
| | - Jocelyn R. Farmer
- Allergy and Clinical Immunology Unit, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Boston
| | - Hyon Choi
- Rheumatology Unit, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Boston
| | - Jolan Walter
- Division of Allergy & Immunology, Department of Pediatrics, Massachusetts General Hospital, Boston
- Division of Pediatric Allergy/Immunology, Department of Pediatrics, University of South Florida, Johns Hopkins All Children’s Hospital, St Petersburg
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Ahmed AR, Kaveri S. Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin. Front Immunol 2018; 9:1189. [PMID: 30072982 PMCID: PMC6058053 DOI: 10.3389/fimmu.2018.01189] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 05/14/2018] [Indexed: 12/14/2022] Open
Abstract
In this concept paper, the authors present a unique and novel protocol to treat autoimmune diseases that may have the potential to reverse autoimmunity. It uses a combination of B cell depletion therapy (BDT), specifically rituximab (RTX) and intravenous immunoglobulin (IVIg), based on a specifically designed protocol (Ahmed Protocol). Twelve infusions of RTX are given in 6–14 months. Once the CD20+ B cells are depleted from the peripheral blood, IVIg is given monthly until B cells repopulation occurs. Six additional cycles are given to end the protocol. During the stages of B cell depletion, repopulation and after clinical recovery, IVIg is continued. Along with clinical recovery, significant reduction and eventual disappearance of pathogenic autoantibody occurs. Administration of IVIg in the post-clinical period is a crucial part of this protocol. This combination reduces and may eventually significantly eliminates inflammation in the microenvironment and facilitates restoring immune balance. Consequently, the process of autoimmunity and the phenomenon that lead to autoimmune disease are arrested, and a sustained and prolonged disease and drug-free remission is achieved. Data from seven published studies, in which this combination protocol was used, are presented. It is known that BDT does not affect check points. IVIg has functions that mimic checkpoints. Hence, when inflammation is reduced and the microenvironment is favorable, IVIg may restore tolerance. The authors provide relevant information, molecular mechanism of action of BDT, IVIg, autoimmunity, and autoimmune diseases. The focus of the manuscript is providing an explanation, using the current literature, to demonstrate possible pathways, used by the combination of BDT and IVIg in providing sustained, long-term, drug-free remissions of autoimmune diseases, and thus reversing autoimmunity, albeit for the duration of the observation.
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Affiliation(s)
- A Razzaque Ahmed
- Department of Dermatology, Tufts University School of Medicine, Boston, MA, United States.,Center for Blistering Diseases, Boston, MA, United States
| | - Srinivas Kaveri
- INSERM U1138 Centre de Recherche des Cordeliers, Paris, France
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El Qashty RMN, Mohamed NN, Radwan LRS, Ibrahim FMM. Effect of bone marrow mesenchymal stem cells on healing of temporomandibular joints in rats with induced rheumatoid arthritis. Eur J Oral Sci 2018; 126:272-281. [PMID: 29952027 DOI: 10.1111/eos.12533] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2018] [Indexed: 12/15/2022]
Abstract
The healing capacity of bone marrow mesenchymal stem cells (BMMSCs) has been evaluated in various studies. This study aimed to evaluate the effect of BMMSCs on the healing of temporomandibular joints (TMJs) with induced rheumatoid arthritis. Fifty healthy male Sprague Dawley rats were divided into three groups: group I (n = 10), negative control; group II (n = 20), positive control (induction of arthritis by adjuvant followed by intravenous injection of 0.1 ml of PBS); and group III (n = 20), intervention (as for group II but injected intravenously with 1 × 106 cells ml-1 of BMMSCs suspended in PBS). Half of the rats in each group were euthanized 3 wk after the start of the experiment and the other half was euthanized after 5 wk. Group I revealed normal TMJ features. Group II showed thickening of disc, thinning of cartilage, disordered bone trabeculae, and decreased in mean % area staining positive of collagen fibers at 3 wk, while at 5 wk these effects were more aggravated. Group III showed nearly normal thickness of disc and condylar cartilage, nearly normal arrangement of bone trabeculae and regenerated collagen fibers at 3 wk, while after 5 wk the TMJ features were almost normal. Two-way anova revealed statistically significant differences between groups. Thus, treatment of induced rheumatoid arthritis with BMMSCs shows promising results that need to be further investigated in humans.
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Affiliation(s)
- Rana M N El Qashty
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Nesreen N Mohamed
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Lobna R S Radwan
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt.,Department of Oral Biology, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Gamasa, Egypt
| | - Fatma M M Ibrahim
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
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Demoersman J, Pochard P, Framery C, Simon Q, Boisramé S, Soueidan A, Pers JO. B cell subset distribution is altered in patients with severe periodontitis. PLoS One 2018; 13:e0192986. [PMID: 29447240 PMCID: PMC5814041 DOI: 10.1371/journal.pone.0192986] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 02/01/2018] [Indexed: 01/10/2023] Open
Abstract
Several studies have recently highlighted the implication of B cells in physiopathogenesis of periodontal disease by showing that a B cell deficiency leads to improved periodontal parameters. However, the detailed profiles of circulating B cell subsets have not yet been investigated in patients with severe periodontitis (SP). We hypothesised that an abnormal distribution of B cell subsets could be detected in the blood of patients with severe periodontal lesions, as already reported for patients with chronic inflammatory diseases as systemic autoimmune diseases. Fifteen subjects with SP and 13 subjects without periodontitis, according to the definition proposed by the CDC periodontal disease surveillance work group, were enrolled in this pilot observational study. Two flow cytometry panels were designed to analyse the circulating B and B1 cell subset distribution in association with the RANKL expression. A significantly higher percentage of CD27+ memory B cells was observed in patients with SP. Among these CD27+ B cells, the proportion of the switched memory subset was significantly higher. At the same time, human B1 cells, which were previously associated with a regulatory function (CD20+CD69-CD43+CD27+CD11b+), decreased in SP patients. The RANKL expression increased in every B cell subset from the SP patients and was significantly greater in activated B cells than in the subjects without periodontitis. These preliminary results demonstrate the altered distribution of B cells in the context of severe periodontitis. Further investigations with a larger cohort of patients can elucidate if the analysis of the B cell compartment distribution can reflect the periodontal disease activity and be a reliable marker for its prognosis (clinical trial registration number: NCT02833285, B cell functions in periodontitis).
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Affiliation(s)
- Julien Demoersman
- UMR1227, Université de Brest, Inserm, Brest, France
- LabEx IGO, Brest, France
| | - Pierre Pochard
- UMR1227, Université de Brest, Inserm, Brest, France
- LabEx IGO, Brest, France
| | | | - Quentin Simon
- UMR1227, Université de Brest, Inserm, Brest, France
- LabEx IGO, Brest, France
| | | | - Assem Soueidan
- Department of Periodontology, CHU de Nantes, Nantes, France
- Rmes Inserm U1229/UIC11, Université de Nantes, Nantes, France
| | - Jacques-Olivier Pers
- UMR1227, Université de Brest, Inserm, Brest, France
- LabEx IGO, Brest, France
- Service d’odontologie, CHU Brest, Brest, France
- * E-mail:
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Hall V, Johnson D, Torresi J. Travel and biologic therapy: travel-related infection risk, vaccine response and recommendations. J Travel Med 2018; 25:4934912. [PMID: 29635641 DOI: 10.1093/jtm/tay018] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 03/01/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Biologic therapy has revolutionized the management of refractory chronic autoimmune and auto-inflammatory disease, as well as several malignancies, providing rapid symptomatic relief and/or disease remission. Patients receiving biologic therapies have an improved quality of life, facilitating travel to exotic destinations and potentially placing them at risk of a range of infections. For each biologic agent, we review associated travel-related infection risk and expected travel vaccine response and effectiveness. METHODS A PUBMED search [vaccination OR vaccine] AND/OR ['specific vaccine'] AND/OR [immunology OR immune response OR response] AND [biologic OR biological OR biologic agent] was performed. A review of the literature was performed in order to develop recommendations on vaccination for patients in receipt of biologic therapy travelling to high-risk travel destinations. RESULTS There is a paucity of literature in this area, however, it is apparent that travel-related infection risk is increased in patients on biologic therapy and when illness occurs they are at a higher risk of complication and hospitalization. Patients in receipt of biologic agents are deemed as having a high level of immunosuppression-live vaccines, including the yellow fever vaccine, are contraindicated. Inactivated vaccines are considered safe; however, vaccine response can be attenuated by the patient's biologic therapy, thereby resulting in reduced vaccine effectiveness and protection. CONCLUSIONS Best practice requires a collaborative approach between the patient's primary healthcare physician, relevant specialist and travel medicine expert, who should all be familiar with the immunosuppressive and immunomodulatory effects resulting from the biologic therapies. Timing of vaccines should be carefully planned, and if possible, vaccination provided well before established immunosuppression.
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Affiliation(s)
- Victoria Hall
- Department of Infectious Diseases, Austin Health, Heidelberg, VIC, Australia
| | - Douglas Johnson
- Department of Infectious Diseases, Austin Health, Heidelberg, VIC, Australia.,Department of General Medicine, Austin Health, Heidelberg, VIC, Australia.,Department of Medicine, University of Melbourne, Parkville, VIC, Australia
| | - Joseph Torresi
- Department of Medicine, University of Melbourne, Parkville, VIC, Australia.,Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.,Eastern Infectious Diseases and Travel Medicine, Knox Private Hospital, Boronia, VIC, Australia
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Romão VC, Vital EM, Fonseca JE, Buch MH. Right drug, right patient, right time: aspiration or future promise for biologics in rheumatoid arthritis? Arthritis Res Ther 2017; 19:239. [PMID: 29065909 PMCID: PMC5655983 DOI: 10.1186/s13075-017-1445-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Individualising biologic disease-modifying anti-rheumatic drugs (bDMARDs) to maximise outcomes and deliver safe and cost-effective care is a key goal in the management of rheumatoid arthritis (RA). Investigation to identify predictive tools of bDMARD response is a highly active and prolific area of research. In addition to clinical phenotyping, cellular and molecular characterisation of synovial tissue and blood in patients with RA, using different technologies, can facilitate predictive testing. This narrative review will summarise the literature for the available bDMARD classes and focus on where progress has been made. We will also look ahead and consider the increasing use of 'omics' technologies, the potential they hold as well as the challenges, and what is needed in the future to fully realise our ambition of personalised bDMARD treatment.
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Affiliation(s)
- Vasco C. Romão
- Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
- Department of Rheumatology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Professor Egas Moniz, 1649-035 Lisboa, Portugal
| | - Edward M. Vital
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - João Eurico Fonseca
- Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
- Department of Rheumatology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Professor Egas Moniz, 1649-035 Lisboa, Portugal
| | - Maya H. Buch
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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Nasonov EL, Mazurov VI, Zonova EV, Knyazeva LA, Marusenko IM, Nesmeyanova OB, Plaksina TV, Shapovalova YS, Ilivanova EP, Krechikova DG, Petrochenkova NA, Reshetko OV, Denisov LN, Gordeev IG, Davydova AF, Eremina NA, Zemerova EV, Ivanova TB, Kastanayan AA, Pokrovskaya TG, Smakotina SA, Smolyarchuk EA, Artemyeva AV, Ivanov RA, Usacheva YV, Chernyaeva EV. THE EFFICACY AND SAFETY OF RITUXIMAB BIOSIMILAR (ACELLBIA®) IN RHEUMATOID ARTHRITIS AS THE FIRST BIOLOGICAL AGENT: RESULTS OF PHASE III (ALTERRA) CLINICAL TRIAL. RHEUMATOLOGY SCIENCE AND PRACTICE 2017. [DOI: 10.14412/1995-4484-2017-351-359] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The Russian biotechnological company «BIOCAD» has designed a chimeric monoclonal antibody against CD20 (BCD-020, Acellbia®) that is a biosimilar of rituximab (RTM; MabThera®, F. Hoffmann-La Roche Ltd., Switzerland). In recent years, there has been evidence that RTM can be used at lower doses than those given in the standard recommendations and instructions for the use of this drug. This serves as the basis for the BCD-020-4/ALTERRA (ALTErnative Rituximab regimen in Rheumatoid Arthritis) trial, the objective of which was to investigate the efficiency and safety of using Acellbia® (at a dose of 600 mg twice at a 2-week interval) as the first biological agent (BA) for methotrexate (MTX)-resistant active rheumatoid arthritis (RA). The investigation enrolled 159 patients aged 18 to 80 years with active RA. After 24 weeks 65.7 and 29.4% of patients achieved 20% improvement by the American College of Rheumatology (ACR) criteria in the Acellbia® + MTX and placebo (PL) + MTX groups, respectively (p<0.0001). The differences in the ACR20 response rate in the two groups were 36.3% (95% CI, 19.27–53.28%). There were significant differences between the groups in the ACR50 response rates: 28.4% and 5.9% (p=0.001) and in the ACR70 ones: 12.8% and only 2.0%, respectively (p=0.036). Analysis of all recorded adverse events (AE) frequency showed no significant differences between the patients in the study and control groups and demonstrates its equivalence with that of RTM (MabThera®); all the AE were expectable. It is noted that antibodies to RTM with binding and neutralizing activities had no impact on the efficiency and safety of therapy.
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Affiliation(s)
- E. L. Nasonov
- V.A. Nasonova Research Institute of Rheumatology
I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - V. I. Mazurov
- I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia
| | | | | | - I. M. Marusenko
- V.A. Baranov Republican Hospital, Ministry of Health of the Republic of Karelia
| | | | - T. V. Plaksina
- N.A. Semashko Nizhny Novgorod Regional Clinical Hospital
| | | | | | | | | | | | | | | | - A. F. Davydova
- Professor S.V. Ochapovsky Territorial Clinical Hospital One
| | - N. A. Eremina
- Railway Clinical Hospital at the Gorky Station, OAO «RZhD»
| | | | | | | | | | - S. A. Smakotina
- Kemerovo State Medical Academy, Ministry of Health of Russia
| | - E. A. Smolyarchuk
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia
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Viecceli D, Garcia MP, Schneider L, Alegretti AP, Silva CK, Ribeiro AL, Brenol CV, Xavier RM. Correlação entre expressão celular de proteínas reguladoras do complemento com a depleção e repopulação de linfócitos B no sangue periférico de pacientes com artrite reumatoide tratada com rituximabe. REVISTA BRASILEIRA DE REUMATOLOGIA 2017. [DOI: 10.1016/j.rbr.2016.07.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Liu D, Yuan N, Yu G, Song G, Chen Y. Can rheumatoid arthritis ever cease to exist: a review of various therapeutic modalities to maintain drug-free remission? Am J Transl Res 2017; 9:3758-3775. [PMID: 28861167 PMCID: PMC5575190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 05/20/2017] [Indexed: 06/07/2023]
Abstract
Therapies for rheumatoid arthritis (RA) were mostly aimed at reducing the pain, stiffness and further progression of joint destruction. However, with the advent of biologic agents that act against specific inflammatory cytokines contributing to RA pathogenesis (treat-to-target strategy), the degree of remission achieved has been remarkably impressive. In particular, inhibition of tumor necrosis factor α (TNFα), interleukins-1 and -6 and receptor-activator of nuclear kappa B ligand by neutralizing antibodies in early diagnosed RA patients has resulted in lowering of disease activity to levels that enable them to function as in the pre-disease stage. There are other biologic approaches such as depletion of B cells and blocking T-cell co-stimulators that have been included successfully in RA therapy under the class of disease-modifying anti-rheumatic drugs (DMARD). Given the excellent clinical outcomes of biologic DMARDs when initiated early in RA, discontinuation or dose tapering is practised. Because biologic DMARDs are expensive and also known to make users vulnerable to viral infections, dose reduction and drug holiday are reasonable steps when sustained good clinical response has been achieved. Majority clinical studies have been done with TNF inhibitors and data suggest that sustained remission of RA is achieved in several multi-centric studies carried out worldwide. However, high flare rate and reappearance of disease has been reported in several cases. This review critically discusses response predictors of biologic DMARDs, the case for treatment relaxation, strategizing drug tapering considering patient eligibility and timing in light of available clinical practice guidelines of RA.
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Affiliation(s)
- Di Liu
- Department of Rheumatology, The Affiliated Hospital to Changchun University of Chinese MedicineChangchun, China
| | - Na Yuan
- Department of Rheumatology, The Affiliated Hospital to Changchun University of Chinese MedicineChangchun, China
| | - Guimei Yu
- Department of Rheumatology, The Affiliated Hospital to Changchun University of Chinese MedicineChangchun, China
| | - Ge Song
- Department of Neurology, The First Hospital of Jilin UniversityJilin, China
| | - Yan Chen
- Department of Hematology, The First Clinical Hospital of Jilin Province Academy of Traditional Chinese MedicineJilin, China
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Cho A, Bradley B, Kauffman R, Priyamvada L, Kovalenkov Y, Feldman R, Wrammert J. Robust memory responses against influenza vaccination in pemphigus patients previously treated with rituximab. JCI Insight 2017; 2:93222. [PMID: 28614800 PMCID: PMC5470882 DOI: 10.1172/jci.insight.93222] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 05/16/2017] [Indexed: 12/21/2022] Open
Abstract
Rituximab is a therapeutic anti-CD20 monoclonal antibody widely used to treat B cell lymphoma and autoimmune diseases, such as rheumatic arthritis, systemic lupus erythematosus, and autoimmune blistering skin diseases (AIBD). While rituximab fully depletes peripheral blood B cells, it remains unclear whether some preexisting B cell memory to pathogens or vaccines may survive depletion, especially in lymphoid tissues, and if these memory B cells can undergo homeostatic expansion during recovery from depletion. The limited data available on vaccine efficacy in this setting have been derived from rituximab-treated patients receiving concomitant chemotherapy or other potent immunosuppressants. Here, we present an in-depth analysis of seasonal influenza vaccine responses in AIBD patients previously treated with rituximab, who generally did not receive additional therapeutic interventions. We found that, despite a lack of influenza-specific memory B cells in the blood, patients mount robust recall responses to vaccination, comparable to healthy controls, both at a cellular and a serological level. Repertoire analyses of plasmablast responses suggest that they likely derive from a diverse pool of tissue-resident memory cells, refractory to depletion. Overall, these data have important implications for establishing an effective vaccine schedule for AIBD patients and the clinical care of rituximab-treated patients in general and contribute to our basic understanding of maintenance of normal and pathogenic human B cell memory.
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Affiliation(s)
- Alice Cho
- Department of Pediatrics, Division of Infectious Disease.,Emory Vaccine Center, and
| | - Bridget Bradley
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Robert Kauffman
- Department of Pediatrics, Division of Infectious Disease.,Emory Vaccine Center, and
| | - Lalita Priyamvada
- Department of Pediatrics, Division of Infectious Disease.,Emory Vaccine Center, and
| | - Yevgeniy Kovalenkov
- Department of Pediatrics, Division of Infectious Disease.,Emory Vaccine Center, and
| | - Ron Feldman
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Jens Wrammert
- Department of Pediatrics, Division of Infectious Disease.,Emory Vaccine Center, and
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Discovery and evaluation of 1 H -pyrrolo[2,3- b ]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis. Bioorg Med Chem Lett 2017; 27:1867-1873. [DOI: 10.1016/j.bmcl.2017.02.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 02/03/2017] [Accepted: 02/13/2017] [Indexed: 01/07/2023]
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Baharlou R, Ahmadi-Vasmehjani A, Faraji F, Atashzar MR, Khoubyari M, Ahi S, Erfanian S, Navabi SS. Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis: Regulatory effects on peripheral blood mononuclear cells activation. Int Immunopharmacol 2017; 47:59-69. [PMID: 28364628 DOI: 10.1016/j.intimp.2017.03.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 03/11/2017] [Accepted: 03/13/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Mesenchymal stem cells (MSCs) are multipotent adult stem cells with immunomodulatory properties. The mechanisms by which MSCs inhibit the proliferation of pro-inflammatory T cells have not been fully elucidated yet. It is assumed that pro-inflammatory T-cells play an important role in the development of autoimmune diseases. We investigated the potential therapeutic effects of human adipose tissue derived (Ad)-MSCs on the peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients and healthy individuals, with a particular focus on Th17-associated cytokines. MATERIALS AND METHODS PBMCs from RA patients and healthy donors were co-cultured with Ad-MSCs and HeLa with or without Phytohemagglutinin (PHA). Finally, IL-6, IL-17, IL-21, IL-23 and TGF-β levels were determined by ELISA and quantitative real-time RT-PCR on co-culture supernatants and PBMCs, respectively. RESULTS In co-culture interaction, Ad-MSCs inhibited IL-17 secretion by PBMCs compared to unstimulated PBMCs cultured alone. In addition, IL-21 expressions in PBMCs of the patient group, and IL-17 and IL-21 in healthy group were inhibited by Ad-MSCs compared to PBMCs cultured alone. TGF-β expression in healthy individuals remarkably increased in both MSC-treated groups with and without PHA in comparison to PHA-stimulated and -unstimulated PBMCs. CONCLUSIONS This study demonstrates that human Ad-MSCs act as key regulators of immune tolerance by inhibiting the inflammation. Therefore, they can be attractive candidates for immunomodulatory cell-based therapy in RA.
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Affiliation(s)
- Rasoul Baharlou
- Department of Immunology and Microbiology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Abbas Ahmadi-Vasmehjani
- Department of Immunology and Microbiology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.
| | - Fatemeh Faraji
- Department of Immunology and Microbiology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Mohammad Reza Atashzar
- Department of Immunology and Microbiology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Mahshid Khoubyari
- Department of Student Research Committee, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Salma Ahi
- Department of Internal Medicine, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Saiedeh Erfanian
- Research Center for Non-Communicable Diseases, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Shadi-Sadat Navabi
- Department of Immunology and Microbiology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
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The role of anticitrullinated protein antibodies in the early stages of rheumatoid arthritis. Curr Opin Rheumatol 2016; 28:275-81. [PMID: 26945334 DOI: 10.1097/bor.0000000000000277] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW This review provides an update on the recent discoveries on the role of anticitrullinated protein antibodies (ACPA) in early rheumatoid arthritis (RA). RECENT FINDINGS RA is characterized by an immune response against posttranslationally modified proteins, in particular citrullinated proteins. Recent studies have found that the ACPA response matures shortly before clinical disease manifests itself and is characterized by an increase in titre, isotype switching, antigen-recognition profile, and a change in the Fc-glycosylation pattern. To date, many citrullinated autoantigens have been identified and novel studies suggest that the human leucocyte antigen class II locus may directly influence the maturation of the ACPA response via antigen-specific T cells. Clinical studies have demonstrated that effective treatment of arthritis can lead to reduced ACPA levels or a change in composition of ACPA. In addition to ACPA, autoantibodies targeting other posttranslational modifications have been identified and may be associated with disease prognosis. SUMMARY Key studies have demonstrated that autoimmunity against citrullinated proteins is already present in preclinical RA and matures over time. Future studies are required to reveal whether autoantibodies and the B cells that produce them play a role in disease development or can function as biomarkers for disease maturation.
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