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Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF alpha
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
2005 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, no 3, 403-407 p.Article in journal (Refereed) Published
Abstract [en]

Background: Research on autoantibody formation in patients treated with TNFα inhibitors has produced contradictory results.

Objective: To study the prevalence of autoantibodies in patients with rheumatoid arthritis treated with the TNFα inhibitor infliximab.

Methods: 53 patients (48 female, 11 male) treated with infliximab for rheumatoid arthritis were followed for autoantibody production before treatment and after 14, 30, and 54 weeks. Six patients treated with etanercept were studied for comparison. The analyses included antibodies against nuclear antigens (ANA), extractable nuclear antigens, double stranded (ds)DNA (by ELISA, IIF on Crithidia luciliae for IgM and IgG, and Farr assay), nucleosomes, cardiolipin, smooth muscle, mitochondria, proteinase 3, and myeloperoxidase antigens.

Results: The number of patients treated with infliximab who developed antibodies against dsDNA of both IgG and IgM class (tested by IIF) increased significantly. The prevalence of patients positive for IgG class increased to 66% at 30 weeks and 45% at 54 weeks, and of IgM class to 85% and 70%, respectively. The titre and number of patients expressing antibodies against nucleosomes and ANA also increased significantly. The number of rheumatoid factor or anticardiolipin positive patients was stable and there was no increase in antibodies against the other antigens. A lupus-like syndrome was seen in one patient. No patient treated with etanercept developed any of these autoantibodies.

Conclusions: Patients treated with infliximab may develop anti-dsDNA antibodies of both IgM and IgG class, anti-nucleosome antibodies, and ANA, with a gradual increase until 30 weeks.

Place, publisher, year, edition, pages
2005. Vol. 64, no 3, 403-407 p.
Keyword [en]
Adult, Aged, Antibodies; Antinuclear/biosynthesis, Antibodies; Monoclonal/adverse effects/*immunology/therapeutic use, Antirheumatic Agents/adverse effects/*immunology/therapeutic use, Arthritis; Rheumatoid/drug therapy/*immunology, Autoantibodies/*biosynthesis, DNA/immunology, Drug Hypersensitivity/etiology, Drug Therapy; Combination, Female, Humans, Immunoglobulin G/biosynthesis, Immunoglobulin M/biosynthesis, Male, Middle Aged
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
Identifiers
URN: urn:nbn:se:umu:diva-12934DOI: 10.1136/ard.2004.024182PubMedID: 15297281OAI: oai:DiVA.org:umu-12934DiVA: diva2:152605
Available from: 2007-04-25 Created: 2007-04-25 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Immunological mechanisms in systemic autoimmunity: autoantibodies and chemokines in systemic lupus erythematosus and during treatment with TNF inhibitors in rheumatoid arthritis
Open this publication in new window or tab >>Immunological mechanisms in systemic autoimmunity: autoantibodies and chemokines in systemic lupus erythematosus and during treatment with TNF inhibitors in rheumatoid arthritis
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease that, without powerful treatment, may lead to irreversible joint damage. During the past decade, anti-cytokine therapy has become available, e.g., infliximab, a chimeric antibody targeting the pro-inflammatory cytokine TNF that has a central role in the inflammatory process in RA patients. Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that may affect all organs and is characterized by a massive antibody production. Chemokines, chemokine receptors and lipoprotein receptor-related protein 1(CD91) are regulators of inflammation in autoimmune diseases and T-cell migration.

Objectives. The aim of this study was to get a deeper understanding how TNF blocking treatment influences inflammatory mechanisms and autoantibody formation in RA with special reference to similarities and differences with SLE.

Methods. In patients with RA treated with anti-TNF, and in SLE patients (ACR criteria) clinical evaluation was performed and blood samples analyzed. Autoantibodies were analyzed using indirect immunofluorescence, ELISA and multiplex flow cytometry in samples from anti-TNF treated RA patients (n=59) followed longitudinally for 54 weeks, in pre-diseased samples from SLE patients (n=38) and matched population-based controls (n=152). T-cell expression of chemokine receptors and CD91 was analyzed by flow cytometry, whilst serum levels of chemokines were determined using ELISA in anti-TNF treated RA-patients (n=24) followed longitudinally (30 weeks), and cross-sectionally in SLE-patients (n=23). Expression of mRNA for chemokines was analyzed in T-cells from SLE-patients (n=10) using PCR.

Results. After treatment with infliximab, RA patients produced ANA, anti-dsDNA and anti-nucleosome antibodies, but not anti-ENA antibodies. Although these antibodies are considered typical for SLE only one patient developed a transient lupus-syndrome. Antibodies against cell nuclear antigens, including ENA, were detected several years before the first clinical symptom of SLE; anti-SSA was the earliest detectable antibody.

In RA-patients before infliximab treatment, the T-cell expression of several chemokine receptors was elevated compared with healthy controls. In contrast, only one soluble chemokine, IP-10 was elevated. After treatment the levels of soluble MIP-1β, MCP-1 and IP-10, and the T-cell expression of CCR2 were decreased. In SLE-patients MIP-1β, MCP-1, SDF-1, IP-10 and RANTES in blood were elevated, whilst expression of CXCR5 and CCR6 on T-cells was lower than in healthy controls. T-cell expression of CXCR2 and CCR1 was elevated in active disease (measured as SLEDAI index), whereas the CXCR5 and CCR2 expression was lower in inactive SLE. In SLE patients with nephritis IP-10 was lower and T-cell expression of CXCR3 and CCR3 elevated compared with patients without nephritis. The expression of CD91 was higher on T-cells from patients not responsive to infliximab treatment compared with responders.

Conclusion. These findings indicate that anti-TNF (infliximab) treatment in RA-patients has a major impact on the production of autoantibodies and chemokines. The autoantibody profile in infliximab-treated patients was similar to that predating disease onset in SLE patients with the exception of anti-ENA being detectable in SLE, but the development of lupus-syndromes was rare. The expression of CD91 on T-cells may predict responsiveness to infliximab. The expression of chemokine receptors in SLE- patients seemed to be related to disease activity. Anti-nuclear antibodies were detectable years before clinical disease onset in patients who developed SLE suggesting a gradual pathogenic process.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2011. 68 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1401
Keyword
autoimmunity, chemokines, T-cells, autoantibodies, CD91
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-42954 (URN)978-91-7459-143-9 (ISBN)
Public defence
2011-05-12, Betula, Norrlands universitetssjukhus, by 6M, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2011-04-20 Created: 2011-04-15 Last updated: 2011-04-20Bibliographically approved

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