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
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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