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Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
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2007 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, Vol. 56, no 2, 448-452 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor inhibitors in rheumatoid arthritis (RA).

Methods: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcRIIIA genotypes.

Results: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria.

Conclusion: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.

Place, publisher, year, edition, pages
2007. Vol. 56, no 2, 448-452 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14379DOI: 10.1002/art.22390OAI: oai:DiVA.org:liu-14379DiVA: diva2:23361
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
In thesis
1. Autoantibodies and genetic variation in rheumatoid arthritis: aspects on susceptibility and disease course
Open this publication in new window or tab >>Autoantibodies and genetic variation in rheumatoid arthritis: aspects on susceptibility and disease course
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent destruction of synovial joints. Although its causes remain largely unknown, a substantial genetic contribution is known to exist. During the last decades the benefits of early aggressive treatment have become evident, and more potent therapeutic options have become available. These advances have increased the demands for rapid accurate diagnosis and prognostic markers of disease course and therapy response.

The ‘rheumatoid factor’ (RF) has long been used as a diagnostic and prognostic marker of RA. In this thesis, the utility of measuring antibodies to cyclic citrullinated peptides (CCP) was investigated. In a population-based arthritis incidence study, 69 very early arthritis patients (symptom duration < 3 months) were identified. The anti-CCP test, performed at baseline and related to diagnosis at the 2-year follow-up, had a diagnostic specificity for RA of 96% and a sensitivity of 44%, both of which were superior to RF. In a prospective cohort of 242 incident cases of RA (symptom duration < 1 year), 64% of the patients tested positive for anti-CCP at baseline (equal to RF). Despite receiving more active anti-rheumatic therapy, the anti-CCP-positive patients had a more aggressive disease course during 3 years as compared to those testing negative.

The 158VV genotype of Fcγ Receptor type IIIA (FcγRIIIA), which binds IgG with higher affinity than 158FF, was associated with an increased susceptibility to RA in men, but not in women. Previous studies report conflicting results, and none stratified according to gender. The 158V/F polymorphism of FcγRIIIA was not found to influence outcome of anti-tumour necrosis factor therapy in 282 RA patients, contradicting hints from previous studies. Genetic variation in proteins of the inflammasome, an interleukin-1 (IL-1) regulating intracellular protein complex, is associated with rare autoinflammatory conditions and possibly with Crohn’s disease. In this first study on genetic variation of the inflammasome in RA, we describe a compound polymorphism of the genes CIAS1 and TUCAN that associates both with susceptibility to RA and to the severity of the disease. Hypothetically, these genes may identify a subgroup of RA patients that would benefit from anti-IL-1 therapy.

This thesis work emphasizes the benefits of testing for anti-CCP in the diagnosis and outcome prediction in early arthritis. FcγRIIIA genotype is likely to affect RA susceptibility and further work should apply a gender perspective. Inflammasome genetics may influence the risk of developing RA. Additional studies are warranted to settle whether it also identifies a subgroup of RA patients benefiting from IL-1 targeted therapy.

Place, publisher, year, edition, pages
Institutionen för molekylär och klinisk medicin, 2007. 73 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 990
Keyword
Rheumatoid arthritis, autoantibodies, single-nucleotide polymorphisms, disease course
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-8618 (URN)978-91-85715-39-8 (ISBN)
Public defence
2007-04-20, Berzeliussalen, CampUS, Universitetssjukhuset i Linköping, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31

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Kastbom, AlfSöderkvist, PeterSkogh, Thomas

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