The effect of B-cell depletion therapy on serological evidence of B-cell and plasmablast activation in patients with rheumatoid arthritis over multiple cycles of rituximab treatment
| Autor: | Guy Serre, J. C. W. Edwards, H.C. Perry, I. de la Torre, Leonor Nogueira, M.C. Dickson, Maria J. Leandro, HM Parsons, Geraldine Cambridge |
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| Přispěvatelé: | University College of London [London] (UCL), GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Rok vydání: | 2013 |
| Předmět: |
MESH: B-Cell Activating Factor / genetics
Gene Expression MESH: Lymphocyte Depletion Lymphocyte Activation Serology Arthritis Rheumatoid Antibodies Monoclonal Murine-Derived MESH: Aged 80 and over MESH: Arthritis Rheumatoid / genetics MESH: Arthritis Rheumatoid / immunology [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases Recurrence MESH: Arthritis Rheumatoid / pathology B-Cell Activating Factor Immunology and Allergy Medicine MESH: Aged Aged 80 and over MESH: Middle Aged biology B-cell depletion MESH: B-Lymphocyte Subsets / drug effects Remission Induction CD23 Cell Differentiation Middle Aged medicine.anatomical_structure Rheumatoid arthritis MESH: Receptors IgE / genetics Antirheumatic Agents BAFF Rituximab MESH: Rituximab Antibody MESH: B-Lymphocyte Subsets / pathology medicine.drug MESH: Cell Differentiation Adult MESH: Gene Expression MESH: Receptors IgE / immunology Immunology Plasma Cells MESH: Plasma Cells / drug effects B-Lymphocyte Subsets Lymphocyte Depletion MESH: Immunoglobulin M / immunology Humans B-cell activating factor MESH: Lymphocyte Activation MESH: Plasma Cells / immunology MESH: Autoantibodies / blood B cell MESH: B-Cell Activating Factor / immunology Aged Autoantibodies MESH: Humans MESH: Arthritis Rheumatoid / therapy business.industry Receptors IgE MESH: Immunoglobulin M / genetics Autoantibody MESH: Adult medicine.disease MESH: Antibodies Monoclonal Murine-Derived / therapeutic use MESH: Recurrence Tumor Necrosis Factor Receptor Superfamily Member 7 MESH: Plasma Cells / pathology MESH: Tumor Necrosis Factor Receptor Superfamily Member 7 / immunology MESH: Biomarkers / metabolism Immunoglobulin M MESH: Tumor Necrosis Factor Receptor Superfamily Member 7 / genetics MESH: B-Lymphocyte Subsets / immunology biology.protein MESH: Antirheumatic Agents / therapeutic use business Biomarkers |
| Zdroj: | Journal of Autoimmunity Journal of Autoimmunity, Elsevier, 2014, 50, pp.67-76. ⟨10.1016/j.jaut.2013.12.002⟩ |
| ISSN: | 1095-9157 0896-8411 |
| DOI: | 10.1016/j.jaut.2013.12.002⟩ |
| Popis: | International audience; B-cell depletion therapy (BCDT) based on rituximab (RTX) induces clinical remission in a majority of seropositive patients with Rheumatoid arthritis (RA). However, all patients eventually relapse. The aim of this study was to determine whether dynamic changes in combinations of serological measures of B-cell activation were associated over up to three cycles of BCDT. We included only RA patients who gave an adequate clinical response, as measured by DAS28. Twenty three patients were studied over 1 cycle, 21 over 2, and 15 over 3 cycles of BCDT. Serum analytes including isotypes of Rheumatoid factors (RhF) and anti-citrullinated protein/peptide antibodies (ACPA), B-cell activating factor (BAFF), serum free light chains (SFLC), soluble CD23 (sCD23), antibodies to tetanus toxoid (TT) and to pneumococcal capsular polysaccharide (PCP) were measured by ELISA at 4 key points in each cycle, namely: Baseline (pre-RTX in each cycle); when B-cell depleted (CD19+B-cells < 5/μl); at B-cell return (CD19+B-cells ≥ 5/μl); and at clinical relapse (ΔDAS28 > 1.2). SFLC were used as a measure of plasmablast activity. As sCD23 is cleaved from naïve B-cells coincident with attaining CD27 expression, levels were used as a novel measure of maturation of B-cells to CD27+. The most consistent changes between baseline and B-cell depletion within all 3 cycles were in SFLC, sCD23 and IgM-RhF which fell and in BAFF levels which rose. After 3 complete cycles of BCDT, both IgM autoantibodies and IgG-CCP had decreased, BAFF levels were higher (all p < 0.05); other analytes remained unchanged compared with baseline. Dynamic changes in λSFLC, sCD23, IgM-RhF and BAFF were also consistently associated with relapse in patients with longer clinical responses after B-cell return. Incremental rises in sCD23 levels in cycles 2 and 3 were correlated with time to relapse. Repopulation of the periphery after BCDT is initiated by naïve B-cells and precedes relapse. Our study showed that differentiation into plasmablasts, attended by sCD23 and SFLC production and IgM-RhF specificity may be required to precipitate relapse in patients experiencing longer responses after RTX. These studies also provide novel information related to the resumption of autoimmune responses and their association with B-cell kinetics following BCDT. |
| Databáze: | OpenAIRE |
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