Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies

Feghali‐Bostwick, Carol; Medsger, Thomas A.; Wright, Timothy M.

doi:10.1002/art.11173

Cited by 275 publications

(167 citation statements)

References 49 publications

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“…Anti-CENP-B antibodies were identified by enzyme-linked immunosorbent assay (ELISA) and anti-CENP by IIF (performed by J-LS) (33). Anti-Th/To antibodies were determined in sera displaying a nucleolar pattern of ANA, using protein A-assisted immunoprecipitation for nucleic acid analysis from nonradiolabeled HeLa cells (performed by MK and GB at the University of Sherbrooke) (34). Anti-topo I antibodies were determined by addressable laser bead immunoassay (ALBIA) and ELISA (35)(36)(37).…”

Section: Methodsmentioning

confidence: 99%

Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: A twenty‐year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis

Koenig

Fritzler

Roussin

et al. 2008

Arthritis & Rheumatism

535

371

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Objective. To identify in patients with Raynaud's phenomenon (RP) independent markers that predict progression to definite systemic sclerosis (SSc) and to determine in patients with progression to SSc the type and sequence of microvascular damage and its relationship to SSc-specific autoantibodies.Methods. Consecutive patients referred for evaluation of RP who had no definite connective tissue disease were evaluated for microvascular damage by nailfold capillary microscopy (NCM) and for anticentromere (anti-CENP-B), anti-Th/To, anti-topoisomerase I, and anti-RNA polymerase III (anti-RNAP III) autoantibodies by specific assays. Patients were studied prospectively.Results. Of the 586 patients who were followed up for 3,197 person-years, 74 (12.6%) developed definite SSc. A characteristic sequence of microvascular damage was identified, starting with enlarged capillaries, followed by capillary loss, and then by capillary telangiectases. Definite SSc was diagnosed in close temporal relationship to capillary loss. Enlarged capillaries, capillary loss, and SSc-specific autoantibodies independently predicted definite SSc. Anti-CENP-B and antiTh/To antibodies predicted enlarged capillaries; these autoantibodies and anti-RNAP III predicted capillary loss. Each autoantibody was associated with a distinct time course of microvascular damage. At followup, 79.5% of patients with 1 of these autoantibodies and abnormal findings on NCM at baseline had developed definite SSc. Patients with both baseline predictors were 60 times more likely to develop definite SSc. The data validated the proposed criteria for early SSc.Conclusion. In RP evolving to definite SSc, microvascular damage is dynamic and sequential, while SScspecific autoantibodies are associated with the course and type of capillary abnormalities. Abnormal findings on NCM at baseline together with an SSc-specific autoantibody indicate a very high probability of devel-

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Section: Methodsmentioning

confidence: 99%

Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: A twenty‐year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis

Koenig

Fritzler

Roussin

et al. 2008

Arthritis & Rheumatism

535

371

View full text Add to dashboard Cite

show abstract

“…In the largest published study of SSc among twin pairs (8), there was no difference in disease concordance rates between monozygotic and dizygotic twins (overall concordance rate of 4.7%), providing evidence against a genetic influence on disease occurrence. However, since that was a cross-sectional study, it is possible that the lifetime concordance for SSc in twins may increase over time.…”

mentioning

confidence: 91%

Clinical, immunologic, and genetic features of familial systemic sclerosis

Assassi¹,

Arnett²,

Reveille³

et al. 2007

Arthritis & Rheumatism

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Objective. To examine whether the affected firstdegree relatives within multicase systemic sclerosis (SSc; scleroderma) families are concordant for autoantibody profile, disease type, and HLA class II haplotypes and whether clinical expression and serologic characteristics of familial SSc differ from those of sporadic SSc.Methods. Seven hundred ten SSc families from the Scleroderma Family Registry and DNA Repository (Scleroderma Registry) were examined, and 18 multicase families were identified. SSc cases and their firstdegree family members underwent serologic testing for different autoantibodies. The disease type and various disease features were abstracted from the available medical records. Additionally, HLA class II typing was performed on the multicase SSc sibpairs.Results. The observed SSc-specific antibody concordance within each multicase SSc family was statistically more common than expected by chance alone (P ‫؍‬ 0.007). The autoantibody profile and disease features of familial and sporadic SSc cases did not differ significantly. The frequency of autoantibody positivity was not different between unaffected first-degree family members of patients from multicase versus singleton SSc families. HLA haplotype sharing between SSc sibpairs was significantly more common than expected (P ‫؍‬ 0.011).Conclusion. The affected members within multicase SSc families tend to be concordant for SSc-specific autoantibodies and HLA haplotypes; familial SSc does not appear to be a unique disease subset.

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“…For instance, the biggest risk factor for SSc is family history (2). On the other hand, concordance for SSc is around 5% in twins and is similar in monozygotic and dizygotic twins, whereas antinuclear antibodies are detected more frequently in the healthy monozygotic twin sibling than in the healthy dizygotic twin sibling of an SSc patient (3). In addition, most SSc susceptibility genes are HLA haplotypes and non-HLA immunerelated genes that are shared by other collagen diseases (4).…”

mentioning

confidence: 99%

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Saigusa

Asano

Taniguchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5−/−) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5−/− mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development.

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Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies

Cited by 275 publications

References 49 publications

Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: A twenty‐year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis

Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: A twenty‐year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis

Clinical, immunologic, and genetic features of familial systemic sclerosis

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

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