Autoimmune diseases and autoantibodies in the first degree relatives of patients with systemic sclerosis☆
Introduction
Systemic sclerosis (SSc) is a chronic multi-system autoimmune disease of unknown etiology. Familial recurrence has been shown to be greater than expected by chance. A positive family history is the strongest risk factor yet identified for SSc [1].
Diverse autoimmune diseases may coexist in the same individual and in families, implying a common etiology. The presence of antinuclear antibodies (ANA) is the serological hallmark of connective tissue diseases, and the majority of patients with SSc and other connective tissue diseases have ANAs. Two previous studies have examined ANA positivity in family members and/or spouses of SSc patients with contradicting results. Maddison et al. reported higher frequency of ANA positivity among FDRs and spouses of patients with SSc [2] while Barnett et al. did not find an increased frequency of ANAs among family members or spouses of SSc patients [3]. A study, investigating the spectrum of polyautoimmunity and familial autoimmunity in a cross-sectional population of 719 SSc patients from two cohorts (Canada and Columbia) reported that 273 (38%) patients with SSc had another autoimmune disease. Furthermore, 260 patients reported FDRs with autoimmune disease. The prevalence of autoimmune diseases was determined by self- or other report. The reported diagnoses were confirmed by medical record review or patient interview only in the Columbian cohort. The prevalence rates of rheumatoid arthritis (RA) (3.4% vs. 28.7%), autoimmune thyroid disease (1.4% vs. 14%) and systemic lupus erythematosus (SLE) (0.7 vs. 4.9%) were significantly lower in the Columbian cohort than in the Canadian sample. This difference might be explained by the different methods of case confirmation in these two populations [4].
The hypothesis of a common origin for different autoimmune diseases is supported by results of genetic studies showing that several susceptibility loci may overlap in different autoimmune diseases, and by gene microarray expression studies disclosing a similar transcriptional pattern in different autoimmune diseases. For example, the PTPN22 gene has been associated with the development of rheumatoid arthritis, SLE, type I diabetes mellitus, Hashimoto's thyroiditis and SSc [5], [6], [7], [8], [9], [10]. Similarly, STAT4 has been implicated in susceptibility to RA, SLE, primary biliary cirrhosis (PBC), and SSc [11], [12], [13].
The aims of this study were to examine the aggregation of autoimmune diseases in the FDR's of SSc patients as verified by physicians or medical record review and to investigate the prevalence of antinuclear antibodies in these individuals in comparison to healthy controls and spouses of patients with SSc.
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Study participants
We investigated 1071 unrelated patients with SSc (probands), 4612 FDRs (parents and siblings only) of SSc patients, and 637 controls (including spouses). All SSc probands and controls in addition to a portion of FDR's were enrolled in the Scleroderma Family Registry and DNA Repository (Registry). The SSc probands either met the 1980 American College of Rheumatology preliminary criteria for the classification of SSc [14] or had at least three of the five CREST syndrome features (calcinosis,
Demographic characteristics of SSc probands and their families
Of the 1071 SSc probands, 614 (57.3%) had limited and 961 (89.7%) were female. The mean age of the SSc probands was 58.1 ± 13.8 (±SD) years. The majority of probands (76.7%, n = 821) were Caucasians, whereas the remainder of patients were 10.7% (n = 115) Hispanic, 8.8% (n = 94) African American, and 3.8% (n = 41) other. A total of 4612 FDR's were investigated. As expected, the FDR cohort had an approximately equal proportion of females to males and had an ethnic composition similar to the SSc probands.
Discussion
The current study investigated the prevalence of autoimmune diseases in FDRs of a large sample of SSc patients. Compared with the prevalence in controls families (17), SLE, hypothyroidism and hyperthyroidism were significantly increased in our families with SSc. We attempted to confirm all the reported autoimmune diseases. Furthermore, we investigated the presence of ANA and more specific autoantibodies in FDRs and spouses of patients with SSc in addition to unrelated controls.
We report the
Acknowledgements
The authors thank Mr. Julio Charles, Ms. Yasamin Salehi and Mr. William Babu for conducting the laboratory studies.
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Grant Support: National Institute of Arthritis/Musculoskeletal and Skin diseases: NIH/NIAMS N01-AR-02251 (M.D. Mayes) and R01 AR055258 (M.D. Mayes); NIH/NIAMS P50-AR054144 (F.C. Arnett); NIH/CTSA, 1U54 RR 23417-01; American College of Rheumatology/Clinical Investigator Fellowship Award (S. Assassi) and NIH-KL2RR024149-04 (S. Assassi).
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These two authors contributed equally to this study.