Shared epitopes and rheumatoid arthritis: Disease associations in Greece and meta-analysis of Mediterranean European populations

doi:10.1053/sarh.2002.31725

Seminars in Arthritis and Rheumatism

Volume 31, Issue 6, June 2002, Pages 361-370

https://doi.org/10.1053/sarh.2002.31725 Get rights and content

Abstract

Objectives: To assess the strength of the associations between HLA shared epitopes (SE) and rheumatoid arthritis (RA) susceptibility, articular disease severity, and extra-articular features in Mediterranean European populations. Methods: One hundred and seventy-four Greek RA patients and 103 controls were evaluated. Data were then included in a meta-analysis of 9 studies of Mediterranean European populations (959 RA patients and 1,405 controls). Results: In our study population, SE alleles were significantly more common in RA patients than in controls (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.4-4.3). Larsen radiologic score was predicted by SE and disease duration. SE did not increase the risk of any extra-articular manifestation. The meta-analysis showed a pooled OR of 3.7 (95% CI, 2.6-5.2) for susceptibility to RA conferred by SE (OR, 3.4 v 3.9 in Greek v non-Greek populations). Conclusions: SE determine articular destruction without increasing the risk of extra-articular manifestations. The immunogenetic associations of RA susceptibility are consistent, but their strength may depend on the SE prevalence in different ethnic groups. Semin Arthritis Rheum 31:361-370. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Patients and controls

A total of 174 patients with RA were enrolled in this study. Patients were observed at the Rheumatology Clinic of the University Hospital, University of Ioannina (n = 96) and at the Department of Pathophysiology, University of Athens (n = 78). Patients enrolled at the 2 sites were expected to have fairly similar genetic backgrounds. All patients fulfilled at least 4 of the American College of Rheumatology Criteria for RA ⁽¹⁵⁾ and had a disease duration of more than 1 year. One hundred and three

Study population

A total of 174 patients with RA (26 men, 148 women) were typed, 131 of whom had RF. The mean disease duration was 10.5 years (median, 9.5 years; interquartile range [IQR], 5-13). The mean and median age at RA onset was 47.5 and 48 years, respectively (IQR, 40-57). The median Larsen scores were 52 (IQR, 32-75) for total score, 36 (IQR, 21-55) for hands (including wrists), and 14 (IQR, 8-21) for feet. Rheumatoid nodules were recorded in 20 patients, secondary SS in 57 patients, ACD in 45

Discussion

Our study is the largest study of HLA associations of RA conducted in Greece and one of the largest worldwide. It confirms that SE alleles are observed in about half of Greek patients with RA. SE dose is associated with the development of articular damage, and there is an interesting interaction between SE dose and disease duration. In our population in which RA was remarkably mild, SE alleles were not related to the frequency of any carefully defined extra-articular manifestations among

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Rheumatoid arthritis
2010, Best Practice and Research: Clinical Rheumatology
Citation Excerpt :
However, more than half of the heritability of this disease remains without explanation [81,82]. Aetiological hypotheses related to gene-environment interactions are far more plausible [83–85], and may underlie the association of different genotypes in different geographical and cultural settings [86]. Other risk factors may be held in common with other auto-immune diseases.
Rheumatoid arthritis (RA) is a complex disease that affects approximately 0.5% of the adult population worldwide, and occurs in 20–50 cases per 100 000 annually, mainly in women after their 40s. The onset of the disease has important diagnostic, prognostic and therapeutic implications and is yet to be defined. The distribution of the disease, in terms of both occurrence and clinical expression, has unclear geographical borders that may reflect differences in genetic admixture, environmental factors and socio-demographic determinants. Some diseases co-occur more frequently than expected with RA, as it is the case of cardiovascular disease, infections or lymphoma, but others in lower frequency than expected, such as cancer or schizophrenia. RA is associated with increased mortality rates compared with the general population in the majority of cohorts published, and the expected survival of RA patients is likely to decrease 3–10 years. As in the general population, the leading cause of death among patients with RA is cardiovascular disease, and deaths due to malignancy occur at a comparable incidence; however, patients with RA are at greater risk of mortality due to infection. Many genes have been implicated in the susceptibility of RA, all of which with a modest effect on isolation. Gene-environment interactions appear as the most plausible underlying cause of RA. Age, sex, smoking, shared epitope and others correlate with its RA. The most important determinants of prognosis in RA are the severity at presentation and the management of the disease, both of which are subject to inequalities.
Extra-articular manifestations and complications of rheumatoid arthritis
2007, Best Practice and Research: Clinical Rheumatology
Citation Excerpt :
A higher risk of vasculitis was reported in RA patients who carried two HLA DRB1 susceptibility genes [odds ratio (OR) 3].29 In contrast to this, a meta-analysis of Mediterranean European populations concluded that shared epitope (SE) alleles determine articular destruction without increasing the risk of ExRA manifestations.34 In one study, cervical spine subluxation was related to HLA DR2 and HLA B2735, and this feature of RA was more likely but not exclusive to patients with peripheral erosive disease.36
Rheumatoid arthritis (RA) is a systemic inflammatory disease that can involve other tissues and organs as well as synovial joints. This chapter reviews the clinical aspects of extra-articular RA, from the early descriptions in rheumatology texts to reports from more recent cross-sectional and inception cohort studies. There is no agreed classification for these manifestations and, because criteria and definitions vary so much, this report includes not only the classic extra-articular features but also the non-articular complications of RA, for example normochromic normocytic anaemia and chronic leg ulcers, and the important disease-associated comorbidities, including non-Hodgkin's lymphoma, ischaemic heart disease and osteoporosis.
Incidence and frequency figures for extra-articular RA vary according to study design. Nodules are the most common extra-articular feature, and are present in up to 30%; many of the other classic features occur in 1% or less in normal clinic settings. Sjögren's syndrome, anaemia of chronic disease and pulmonary manifestations are relatively common – in 6–10% – are frequently present in early disease and are all related to worse outcomes measures of rheumatoid disease, in particular functional impairment and mortality.
Currently, there are no reliable predictors for these features in early RA, although they are associated with men, smokers, more severe joint disease, worse function, high levels of inflammatory markers, and the presence of rheumatoid factor (RF), antinuclear antibodies (ANA) and the RA HLA-related shared epitope.
Many of these manifestations are related to the more active and severe RA, so early and more aggressive RA drug therapies are being employed and, although evidence from randomised studies is not available, this approach would seem appropriate in view of the adverse effect of extra-articular manifestations on RA outcomes. Unfortunately, specific therapies for extra-articular manifestations of RA are largely disappointing or unavailable, except for steroids and cyclophosphamide for vasculitis. The place for biological therapies is still not clear. Pulmonary fibrosis in RA has a poor prognosis whether treated with large doses of steroids, cytotoxic or disease modifying drugs like cyclosporine, or biologics.
In summary, extra-articular features and non-articular complications of RA are common and are generally related to worse disease. They need to be recognised early and managed promptly.
Incidence and Prevalence of Rheumatoid Arthritis, Based on the 1987 American College of Rheumatology Criteria: A Systematic Review
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In addition, some of these studies are based on relatively small sample sizes. It has been suggested that RA in southern Europe has a particular genetic, epidemiological, and clinical profile (35-39). Some studies indicate that RA is milder, with less extra-articular and radiological manifestations in south European populations.
To conduct a systematic review of incidence and prevalence studies of rheumatoid arthritis (RA), based on the 1987 revised American College of Rheumatology (ACR) criteria, to compare their methodologies and summarize their results, and to investigate the possible geographic variations and changes over time in the frequency of the disease.
We conducted a Medline search between January 1988 and December 2005. Studies reporting the incidence and prevalence of RA in adult populations (16 to 20 years and over), based on 1987 ACR criteria, were eligible for inclusion. From each study included, we extracted the country, year of publication, type of study (retrospective, prospective, or cross-sectional), and incidence or prevalence rates. The study areas were grouped into (a) North American countries; (b) north European countries; (c) south European countries; and (d) developing countries. We examined the geographical differences of prevalence and incidence rates using the Mann–Whitney and the Kruskall–Wallis tests.
A total of 28 studies were identified meeting the inclusion criteria. Nine were incidence studies, 17 were prevalence studies, and 2 estimated both prevalence and incidence rates. Incidence studies were not available from developing countries. There is a significant difference of prevalence estimates between northern European and American countries and developing countries. South European countries have lower median incidence rates than North American and north European countries. As concerning the time trends of RA occurrence, only 3 incidence studies provided secular data from the same study area, based on ACR criteria, using the same methods of case ascertainment. Two of these studies indicate a decreasing incidence of RA in Finland and United States of America.
The occurrence of RA varies among countries and areas of the world. A decreasing trend has been observed in countries characterized by high rates of RA incidence and prevalence. However, the relatively small number of studies for most areas of the world and the lack of incidence studies for the developing countries limits the understanding of worldwide RA epidemiology.
Epidemiology of adult rheumatoid arthritis
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^*: Supported by a grant from E.C. concerted action BIOMED 2 (No. BMHH-CT96-0087 [DG 12-SS MA]).

^**: Address reprint requests to Alexandros A. Drosos, MD, FACR, Professor of Medicine/Rheumatology, Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina, Greece. E-mail: [email protected]

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Shared epitopes and rheumatoid arthritis: Disease associations in Greece and meta-analysis of Mediterranean European populations*,**

Abstract

Section snippets

Patients and controls

Study population

Discussion

Hum Immunol

Clin Immunol

Lancet

Hum Immunol

J Clin Epidemiol

Hum Immunol

The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

Arthritis Rheum

The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis

Ann Intern Med

The genetics revolution and the assault on rheumatoid arthritis

Arthritis Rheum

Rheumatoid arthritis in Greek and British patients

Arthritis Rheum

Rheumatoid arthritis in Greece: Clinical, serological and genetic considerations

Clin Exp Rheumatol

Epidemiology of adult rheumatoid arthritis in Northwest Greece 1987-1995

J Rheumatol

HLA class II sequence polymorphisms and susceptibility to rheumatoid arthritis in Greeks

Arthritis Rheum

Examination of HLA-DR4 as a severity marker for rheumatoid arthritis in Greek patients

Ann Rheum Dis

Association of HLA-DR4-Dw15 and DR10 with rheumatoid arthritis in a Spanish population

Arthritis Rheum

HLA-DRB1 alleles associated with rheumatoid arthritis in southern France. Absence of extraarticular disease despite expression of the shared epitope

J Rheumatol

HLA-DRB1 alleles in Greek rheumatoid arthritis patients and their association with clinical characteristics

Eur J Immunogenet

HLA-DRB1 alleles associated with rheumatoid arthritis in Northern Italy: Correlation with disease severity

Br J Rheumatol

Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films

Acta Radiol Diagn

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

Arthritis Rheum