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Autoantibodies and genetic variation in rheumatoid arthritis: aspects on susceptibility and disease course
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.
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 [en]
Rheumatoid arthritis, autoantibodies, single-nucleotide polymorphisms, disease course
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:liu:diva-8618ISBN: 978-91-85715-39-8 (print)OAI: oai:DiVA.org:liu-8618DiVA: diva2:23363
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
List of papers
1. Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity
Open this publication in new window or tab >>Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity
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2004 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, Vol. 33, no 3, 185-188 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To measure serum levels of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and serum cartilage oligomeric matrix protein (COMP) in patients with early joint inflammation, and to study the correlation of these two tests with clinical measurements.

Methods: Adult patients with recent-onset arthritis, of <3 months' duration, were referred from primary healthcare centres to rheumatologists. Serum levels of anti-CCP antibodies and COMP at baseline were analysed by enzyme immunoassay (EIA) and compared with clinical baseline data.

Results: Sixty-nine patients were included. The specificity of the anti-CCP antibody test for RA was 96%, and the sensitivity was 44%. There was a significant difference between the four diagnosis groups in the anti-CCP antibody test, probability (p)<0.001, whereas no significant differences were found concerning COMP. The baseline serum COMP test correlated with age (p=0.0001), joint score for swollen joints (p=0.02), and C-reactive protein (CRP) (p=0.02).

Conclusion: This study confirms the high diagnostic specificity of anti-CCP antibodies for rheumatoid arthritis (RA) in a prospective population-based study of very early arthritis. Raised serum COMP levels were common in all diagnosis groups in this series, indicating cartilage involvement in both self-limiting and non-erosive disease.

Keyword
anti-CCP antibodies, COMP, rheumatoid arthritis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14376 (URN)10.1080/03009740310004856 (DOI)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
2. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)
Open this publication in new window or tab >>Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)
2004 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, Vol. 63, no 9, 1085-1089 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: To evaluate the diagnostic sensitivity of antibodies to cyclic citrullinated peptide (CCP) in recent onset rheumatoid arthritis (RA) at diagnosis and 3 years later, and to evaluate anti-CCP antibody as a predictor of the disease course during 3 years.

Methods: 242 patients with recent onset (≤ 1 year) RA were followed up regularly during 3 years after inclusion in the Swedish multicentre study "TIRA" 1996-98. Anti-CCP antibodies were analysed by an enzyme immunoassay (EIA). Rheumatoid factors (RFs) were analysed by latex agglutination and two isotype-specific (IgM and IgA) EIAs. Disease activity was assessed by plasma CRP, ESR, 28 joint disease activity score, and the physician's global assessment of disease activity. Functional ability was evaluated by the Health Assessment Questionnaire.

Results: Overall, the diagnostic sensitivity of anti-CCP antibodies was 64% and the proportion of positive tests increased with the number of fulfilled classification criteria according to the American College of Rheumatology. The anti-CCP antibody results correlated with RF, but were better than RF as predictor of a more aggressive disease course. After 3 years 5/97 patients had changed anti-CCP status: 2 from negative to positive and 3 from positive to negative. The mean level of anti-CCP antibodies declined by 131 U/ml during the 3 year follow up (95% Cl 34 to 228 U/ml).

Conclusion: The anti-CCP antibody assay has a similar diagnostic sensitivity to that of RF in early RA, but is better as a predictor of the disease course over 3 years. Although the mean serum level declines, anti-CCP antibody positivity remains essentially unaltered 3 years after diagnosis and start of antirheumatic treatment.

Keyword
anti-CCP antibody, rheumatoid factor, early rheumatoid arthritis, inflammation, disease course
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14377 (URN)10.1136/ard.2003.016808 (DOI)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
3. The 158V polymorphism of Fc gamma receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project)
Open this publication in new window or tab >>The 158V polymorphism of Fc gamma receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project)
2005 (English)In: Rheumatology, ISSN 1462-0324, Vol. 44, no 10, 1294-1298 p.Article in journal (Refereed) Published
Abstract [en]

Objectives. To evaluate the influence of Fc receptor IIIA (FcRIIIA) 158V/F polymorphism on susceptibility and disease severity in early rheumatoid arthritis (RA).

Methods. In 181 Swedish patients (128 women, 53 men) with RA of recent onset, disease and disability variables such as erythrocyte sedimentation rate, 28-joint disease activity score (DAS28) and health assessment questionnaire (HAQ) scores were monitored regularly during 3 yr. Three hundred and sixty-two controls were recruited from the same geographical area as the patients. FcRIIIA genotyping was performed using denaturing high-performance liquid chromatography.

Results. In all RA patients, FcRIIIA-158VV was significantly over-represented compared with controls [odds ratio (OR) 1.9, 95% confidence interval (CI) 1.01–3.5, P<0.05]. After stratifying for sex, the difference remained in the male population (OR 3.2, 95%CI 1.03–11, P<0.05) but disappeared among women (OR 1.4, 95%CI 0.7–3.1, P=0.4). In addition, 158VV patients were more likely to exhibit early joint erosions (OR 6.1, 95%CI 1.4–28, P<0.01). At baseline, patients with different FcRIIIA genotypes did not differ with respect to measures of disease activity or functional ability. Thereafter, in male patients with at least one V allele the mean DAS28 and HAQ scores were higher compared with 158FF. In contrast, female patients with at least one 158V allele displayed lower mean DAS28 and HAQ scores compared with those with 158FF.

Conclusions. In a male population, the FcRIIIA-158VV genotype is associated with an increased risk of developing RA, and the 158V allele with more severe disease in early RA.

Keyword
Disease course, Early rheumatoid arthritis, Fc receptor, Single-nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14378 (URN)10.1093/rheumatology/kei010 (DOI)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
4. Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis
Open this publication in new window or tab >>Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14379 (URN)10.1002/art.22390 (DOI)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
5. Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
Open this publication in new window or tab >>Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
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2008 (English)In: Rheumatology, ISSN 1462-0324, Vol. 47, no 4, 415-417 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: The genetic background to RA is incompletely understood.As new cytokine-targeted therapies emerge, early predictorsof disease severity are becoming increasingly important. Theinflammasomes are essential regulators of cytokine production.We investigated whether two polymorphisms in the genes encodingcryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibilityand disease course in RA.

Methods: Genotype frequencies were assessed in 174 Swedish patientswith early RA and 360 population-based controls without rheumaticdisease. Genotypes were categorized according to the presence(+) or absence (–) of two wild-type alleles and comparedbetween patients and controls. In the RA patients, antibodiestowards cyclic citrullinated peptides (anti-CCP) and the ‘sharedepitope’ (SE) were assessed, and medication and measuresof disease activity were monitored regularly during 3 yrs.

Results: The combination of CIAS1/TUCAN/–, ascompared with CIAS1/TUCAN +/+, was significantly more commonamong patients than in controls [odds ratio (OR) 2.2, 95% CI1.03–4.6]. This association was strengthened when patientswere divided into anti-CCP+ [OR 2.8 (1.1–6.7)] or presenceof 1 SE copy [OR 2.8 (1.3–6.2)]. At most time-points duringthe 3-yr follow-up, patients with CIAS1/TUCAN/–showed significantly higher disease activity. Furthermore, CIAS1/TUCAN/– patients proved to be much more likely to receiveTNF-blocking therapy [relative risk 20 (2.6–149)].

Conclusions: Compound polymorphisms in CIAS1 and TUCAN associatewith RA susceptibility and severity. The cryopyrin inflammasomeneeds further attention regarding a possible aetiopathogeneticconnection with RA.

Keyword
Disease course, Genetics, Inflammasome, Rheumatoid arthritis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14380 (URN)10.1093/rheumatology/kem372 (DOI)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31Bibliographically approved

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