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Significance HLA alleles have previously been implicated with scleroderma risk, but, in this study, using a European American ancestral cohort and a newly recruited large cohort of African Americans, we comprehensively define the HLA alleles and amino acid residues associated with scleroderma. Scleroderma is characterized by mutually exclusive and specific autoantibodies. We demonstrated ancestry-predominant HLA alleles that were much more strongly associated with autoantibody subsets of scleroderma than with the overall risk of SSc. We bioinformatically predicted immunodominant peptides of self-antigens and demonstrated homology of these peptides with viral protein sequences from Mimiviridae and Phycodnaviridae families. Our findings suggest the hypothesis that scleroderma-specific autoantibodies may arise through molecular mimicry, driven by the interaction of specific viral antigens with corresponding HLA α/β heterodimers., Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10−6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

OBJECTIVE Latino patients are overrepresented among cases of coronavirus disease 2019 (COVID-19) and are at an increased risk of severe disease. Prevalence of COVID-19 in Latinos with rheumatic diseases is poorly reported. This study was undertaken to characterize COVID-19 clinical features and outcomes in Latino patients with rheumatic diseases. METHODS We conducted a retrospective study of Latino patients with rheumatic diseases from an existing observational cohort in the Washington, DC area. Patients seen between April 1, 2020 and October 15, 2020 were analyzed in this study. We reviewed demographic characteristics, body mass index (BMI), comorbidities, and use of immunomodulatory therapies. An exploratory classification and regression tree (CART) analysis along with logistic regression analyses were performed to identify risk factors for COVID-19 and rheumatic disease flare. RESULTS Of 178 Latino patients with rheumatic diseases, 32 (18%) were identified as having COVID-19, and the incidence rate of infection was found to be 3-fold higher than in the general Latino population. No patients required intensive care unit-level care. A CART analysis and multivariable logistic regression analysis identified a BMI of >30.35 as a risk factor for COVID-19 (odds ratio [OR] 3.37 [95% confidence interval (95% CI) 1.5-7.7]; P = 0.004). COVID-19 positivity was a risk factor for rheumatic disease flare (OR 4.57 [95% CI 1.2-17.4]; P = 0.02). CONCLUSION Our findings indicate that Latino patients with rheumatic diseases have a higher rate of COVID-19 compared with the general Latino population. Obesity is a risk factor for COVID-19, and COVID-19 is a risk factor for rheumatic disease flare. Latino patients with risk factors should be closely followed up, especially post-COVID-19 in anticipation of disease flare.

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated while iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in 7 subjects; no causative mutation was found in the eighth. Biopsies from 4 subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in 1 subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the 2 subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and peri-lesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation.

Objective.To identify differentially expressed genes in peripheral blood cells (PBC) of patients with ankylosing spondylitis (AS) relative to healthy controls and controls with systemic inflammation.Methods.We investigated PBC samples of 16 patients with AS and 14 matched controls, in addition to systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) samples utilizing Illumina Human Ref-8 BeadChips. Candidate genes were confirmed using quantitative PCR. Subsequently, these genes were also validated in a separate sample of 27 patients with AS [before and after anti-tumor necrosis factor (anti-TNF) treatment] and 27 matched controls.Results.We identified 83 differentially expressed transcripts between AS patients and controls. This gene list was filtered through the lists of differentially expressed transcripts in SLE and SSc, which resulted in identification of 52 uniquely dysregulated transcripts in AS. Many of the differentially expressed genes belonged to Toll-like receptor (TLR) and related pathways.TLR4andTLR5were the only dysregulated TLR subtypes among AS patients. We confirmed the overexpression ofTLR4andTLR5in AS patients in comparison to controls (p = 0.012 and p = 0.006, respectively) and SLE (p = 0.002, p = 0.008) using quantitative PCR in the same sample. Similarly,TLR4(p = 0.007) andTLR5(p = 0.012) were significantly upregulated among the AS patients before anti-TNF treatment in the confirmatory sample.TLR4(p = 0.002) andTLR5(p = 0.025) decreased significantly after anti-TNF treatment.Conclusion.PBC gene expression profiling in AS shows an upregulation ofTLR4andTLR5.This supports the importance of TLR subtypes in the pathogenesis of AS that are responsible for the immune response to Gram-negative bacteria.

Systemic sclerosis (SSc) is a multisystem autoimmune disease of connective tissue characterized by immune dysregulation, obliterative vasculopathy, and fibrosis of skin and internal organs (1–3). Using microarrays, 4 previous studies have investigated the transcript profiles of SSc peripheral blood (PB) cells or their subpopulations. We first reported that, compared with PB cells from controls, PB cells from patients with early SSc have a distinct transcript pattern that includes dysregulation of interferon (IFN)–inducible genes (4). This observation was replicated by other investigators in PB mononuclear cells (PBMCs) (5), monocytes, and CD4+ T cells (6) and PB cells (7) from SSc patients. None of those studies found a correlation between the IFN signature and the clinical or serologic subtypes of SSc. Due to the heterogeneity of SSc, those studies may not have been sufficiently powered to assess subtle clinical and serologic differences in the transcript profile. However, Bos et al (7) reported that the expression levels of 5 IFN-inducible gene transcripts measured by quantitative polymerase chain reaction (PCR) in an extended group of 43 SSc patients were higher in patients without anticentromere antibodies (ACAs). Several studies have shown a striking pattern of up-regulated type I IFN–inducible genes in PBMCs from patients with systemic lupus erythematosus (SLE) (8–10). In particular, the presence of anti-Ro, anti–U1 RNP, anti-Sm, and anti–double-stranded DNA (anti-dsDNA) is significantly associated with a high IFN score in SLE (11). SSc shares several similarities with SLE, such as autoantibodies directed against nuclear antigens, and in some patients, overlapping clinical features. At the gene level, there is emerging evidence that SSc and SLE share common genetic associations, such as IRF5 (12–14) and PTPN22 (15–17). The risk alleles of the IRF5 and PTPN22 genes have been linked to higher serum levels of IFNα in SLE patients (18,19). Despite the evidence of similarities between SSc and SLE, a direct comparison of the transcript profiles of patients with the 2 diseases has not been undertaken. We now report the results of such a comparative study of a large number of SSc patients with SLE patients and controls. We analyzed our results using conventional methods and a newly described modular analysis framework (10). We examined whether SSc patients with certain genetic, clinical, or serologic features are more likely to have a transcript profile that is similar to that of SLE. The results place a subset of SSc patients alongside SLE in the continuum of IFN-mediated autoimmune diseases.

Contains fulltext : 88471.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets. 01 april 2010

Objective Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility. Methods We tested SNPs in TBX21 and STAT4 for association with SSc in 2 independent cohorts, the SSc Registry cohort (880 SSc cases and 507 controls) and the University of Texas SSc cohort (522 cases and 531 controls). Additional white control genotypes were obtained from public repositories. We also investigated for gene–gene interactions. Plasma cytokines and whole blood gene expression profiles were examined to determine functional effects of these SNPs. Results Multiple SNPs in TBX21 and STAT4 were found to be associated with SSc. In a combined analysis of 902 SSc patients and 4,745 controls, TT genotyping of the TBX21 rs11650354 variant revealed a recessive pattern for disease susceptibility (Pcorr = 1.4 × 10−15, odds ratio 3.37, 95% confidence interval 2.4–4.6). In an analysis of 1,039 SSc patients and 3,322 controls, the A allele of the STAT4 variant rs11889341 was associated with increased SSc susceptibility in a dominant pattern (Pcorr = 2.4 × 10−5, odds ratio 1.29, 95% confidence interval 1.2–1.5). Furthermore, we identified gene–gene interaction among the TBX21 and STAT4 variants, such that the STAT4 genotype increased the risk of SSc only in the TBX21 CC genotype group. SSc patients carrying the TBX21 CC genotype had higher interleukin-6 (IL-6) and tumor necrosis factor α levels, and those with the TT genotype had elevated IL-2, IL-5, IL-4, and IL-13 (Th2) levels, compared with controls. Whole blood expression profiles revealed dysregulation of type I interferon pathways in the CC group and T cell pathways in the TT group of the TBX21 SNP. Conclusion The present results, from studies of 2 independent cohorts, indicate that SNPs in TBX21 and STAT4 contribute uniquely and interactively to SSc susceptibility, leading to altered cytokine balance and immune dysregulation.

Objective To investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort. Methods GENISOS is a prospective, observational study of a multiethnic early systemic sclerosis (SSc) cohort. To date, a total of 250 patients have been enrolled. In addition to clinical and laboratory data, electrocardiograms (EKGs), chest radiographs, and pulmonary function tests have been obtained from each patient. A modified Rodnan skin thickness score, HLA class II genotyping, and a Medsger Damage Index also have been collected. We performed multivariable analyses utilizing the Cox regression following a purposeful model building strategy. Results The study analyzed 122 white, 47 African American, and 71 Hispanic SSc patients with an average disease duration of 2.6 years at enrollment. At the time of analysis, 52 (20.8%) of the 250 patients had died. In the final multivariable model excluding HLA genes, 7 variables emerged as significant predictors of mortality: age ≥65 years at enrollment, forced vital capacity

ObjectiveIt is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.MethodsA total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls.ResultsCase-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, pFDR=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, pFDR=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, pFDR=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, pFDR=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility.ConclusionsPolymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.

Objective To examine whether the affected first-degree 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 first-degree 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.

OBJECTIVE To obtain a global view of the immunological alterations occurring in early systemic sclerosis (SSc) by transcriptional profiling of peripheral blood cells (PBCs). METHODS Oligonucleotide microarrays were used to compare PBC gene expression profiles in 18 SSc cases (

Objective.Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk.Methods.Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry.Results.Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12–1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15–1.54) and TT genotype p = 0.00046; OR 2.02 (1.36–2.98)].Conclusion.We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.

Systemic sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that is driven by a combination of genetic risk factors and environmental events1. Accumulating data have demonstrated shared autoimmunity pathways and genetic susceptibility factors among various autoimmune diseases. Most of these genetic susceptibility factors are frequently replicated in different diseases such as insulin-dependent diabetes mellitus, multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis, celiac disease, and others2. Regarding SSc, recent data have shown that the main shared genetic factors that contribute the most to susceptibility are the major histocompatibility complex (MHC), IRF5, STAT4, BANK1, PTPN22, and TNFAIP33,4. These genes and pathways are, strikingly, all known to contribute to susceptibility to SLE. In SLE, some new risk loci have recently been identified. Among these, ITGAM and ITGAX were identified first in association studies performed in large cohorts. Proteins encoded by these latter genes all belong to the integrin family. Among integrin molecules, very late antigen-4 (VLA-4) and lymphocyte function associated-1 (LFA-1) have been implicated in both SLE and SSc5,6. Some hypotheses suggest their participation in maintaining the pathogenic cells in targeted tissues, thereby promoting tissue damage7. ITGAM, also known as CD11b, is located in chromosome 16p11.2 and encodes for the α-chain of the αMβ2– integrin. This leukocyte-specific integrin regulates cell activation and adhesion of neutrophils and monocytes, permitting endothelium stimulation and phagocytosis of complement-coated particles. Particular involvement in immune complex clearance can be linked to the demonstrated impairment of this function in SLE8. Indeed, a deficiency of ITGAM leads to enhanced production of interleukin 6 by antigen-presenting cells9. rs9937837 and other genetic variants located on chromosome 16p11.12 near the gene ITGAM were found to contribute to SLE susceptibility in a genome-wide association study (OR 1.28, p = 7 × 10−7)10. At the same time, another strong genetic variant of ITGAM rs1143679 was reported to be associated with SLE (OR 1.78, p = 1.7 × 10−17)11. A metaanalysis strengthened these results and a strong association of ITGAM rs9937837 (OR 0.47) and rs1143679 (OR 3.04) was shown to influence disease severity12,13,14. This latter finding was convincingly reported as the putative causal variant15. ITGAX encodes the integrin α-X chain protein, which forms by association with β-chain, another leukocyte-specific integrin that overlaps the properties of ITGAM. ITGAM variants have been found to be associated with SLE (OR 1.3). However, linkage disequilibrium data with ITGAM have questioned its role as an independent signal10. This assumption was emphasized by the role of rs114367915. MS and RA also share genetic susceptibility factors with other autoimmune diseases. Another new risk locus shown to be associated with MS is CD58, also known as LFA-3. It encodes a member of the immunoglobulin superfamily, a ligand of the T lymphocyte CD2 protein, and has been implicated in adhesion and activation of T lymphocytes. The rs12044852 variant of CD58 was found to be associated in a large genome-wide association study (OR 1.48)16 in MS and was independently replicated17. Another CD58 variant was also found to be associated with RA (OR 1.14)18. Taking into account (1) the autoimmune background of SSc; (2) the contribution of shared autoimmunity in this condition; (3) the recent report of new autoimmune susceptibility risk factors belonging to integrin genes for autoimmune diseases10; and (4) implication of integrins in SSc, we investigated whether ITGAM, ITGAX, and CD58 variants may confer susceptibility to SSc.

Item does not contain fulltext OBJECTIVE: Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc. METHODS: Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain. RESULTS: The "T" allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P = 6.8 x 10(-5), OR 1.27, 95% CI 1.1-1.4). The "A" allele at rs13277113 variant was associated with SSc in the U.S. series only (P = 3.6 x 10(-4), OR 1.32, 95% CI 1.1-1.6) and was significant in the combined analyses of the two series (P = 2.0 x 10(-3); OR 1.20, 95% CI 1.1-1.3). Both variants demonstrated an association with the anti-centromere antibody (P = 2.2 x 10(-6) and P = 5.5 x 10(-4), respectively) and limited SSc (P = 3.3 x 10(-5) and P = 2.9 x 10(-3), respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFkappaB signaling are dysregulated based on the risk haplotype of these variants. CONCLUSION: We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes. 01 maart 2010

4 páginas, 2 figuras, 2 tablas.-- Spanish Scleroderma Group., Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22–23, rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 × 10−18), IRF5 (P = 1.86 × 10−13) and STAT4 (P = 3.37 × 10−9) gene regions as SSc genetic risk factors., This work was supported by the following grants: T.R.D.J.R. was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). J.M. was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain and in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain (J.M.). R.B. is supported by the I3P Consejo Superior de Investigaciones Científicas program funded by the 'Fondo Social Europeo'. B.Z.A. is supported by the Netherlands Organization for Health Research and Development (ZonMW grant 016.096.121). B.K. is supported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). Genotyping of the Dutch control samples was sponsored by US National Insitutes of Mental Health funding, R01 MH078075 (R.O.A.). The German controls were from the PopGen biobank (to B.K.).

Objective.IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.Methods.We tested 9 single-nucleotide polymorphisms (SNP) in IL23R for association with SSc in a cohort of 1402 SSc cases and 1038 controls. IL23R SNP tested were previously identified as SNP showing associations with inflammatory bowel disease.Results.Case-control comparisons revealed no statistically significant differences between patients and healthy controls with any of the IL23R polymorphisms. Analyses of subsets of SSc patients showed that rs11209026 (Arg381Gln variant) was associated with anti-topoisomerase I antibody (ATA)-positive SSc (p = 0.001)) and rs11465804 SNP was associated with diffuse and ATA-positive SSc (p = 0.0001, p = 0.0026, respectively). These associations remained significant after accounting for multiple comparisons using the false discovery rate method. Wild-type genotype at both rs11209026 and rs11465804 showed significant protection against the presence of pulmonary hypertension (PHT). (p = 3×10−5, p = 1×10−5, respectively).Conclusion.Polymorphisms in IL23R are associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc.

Objective To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case–control association study. Patients and methods 1300 SSc cases (961 white, 178 black and 161 Hispanic subjects) characterised for clinical skin forms (limited vs diffuse), SSc-specific autoantibodies (anticentromere (ACA), anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 ribonucleoprotein (fibrillarin)) and others were studied using molecular genotyping. Statistical analyses in SSc itself by ethnicity, gender, skin type and autoantibodies were performed using exact logistic regression modelling for dominant, additive and recessive effects from HLA. Results The strongest positive class II associations with SSc in white and Hispanic subjects were the DRB1*1104, DQA1*0501, DQB1*0301 haplotype and DQB1 alleles encoding a non-leucine residue at position 26 (DQB1 26 epi), while the DRB1*0701, DQA1*0201, DQB1*0202 haplotype and DRB1*1501 haplotype were negatively correlated and possibly protective in dominant and recessive models, respectively. These associations did not discriminate between limited and diffuse SSc. SSc in black subjects was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles. DPB1*1301 showed the highest odds ratio for ATA (OR = 14). Moreover, it showed no linkage disequilibrium or gene interaction with DR/DQ. ACA was best explained by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and DQB1*03 alleles in white and Hispanic subjects but DRB1*08 in black subjects. Conclusion These data indicate unique and multiple HLA-class II effects in SSc, especially on autoantibody markers of different subphenotypes.

Objective To identify genetic associations between allograft inflammatory factor 1 (AIF1) and systemic sclerosis (SSc), or its subsets, using a single nucleotide polymorphism (SNP) in a replicate case-control study. Methods The frequencies of alleles and genotypes of an SNP, rs2269475, for the AIF1 gene were examined in two large independent cohorts of SSc patients (n = 1015 total), and compared with two groups of normal controls (n = 893 total). Both cases and controls were stratified by ethnicity (Caucasian, African American and Hispanic) and by autoantibody status [anti-centromere antibodies (ACA) and anti-topoisomerase I antibody (ATA)]. Results The minor T allele and CT/TT genotype frequencies of the AIF1 SNP were not observed more frequently in SSc patients of the three ethnic groups (individually or combined) when compared with controls. On the other hand, T and CT/TT frequencies were significantly increased in ACA-positive Caucasian SSc patients, and all ACA-positive SSc patients (the three ethnic groups combined), when compared with ACA-negative SSc patients and with normal controls, with odds ratios of approximately 1.5. Conclusion The data demonstrate a genetic association between AIF1 and the ACA-positive subset of SSc. This polymorphism is a non-synonymous substitution and therefore likely to represent an important functional change in AIF1. Since vascular pathology is a prominent feature in ACA-positive SSc patients, the observed association with a vasculotrophic inflammatory gene is biologically plausible and warrants further research.

Objective To determine any associations of the PTPN22 R620W single-nucleotide polymorphism (SNP) with systemic sclerosis (SSc) or with anticentromere antibody (ACA)–positive or anti–topoisomerase I (anti–topo I) antibody–positive SSc, in a case–control study of US white, black, Hispanic, and Choctaw Indian individuals. Methods A total of 850 white, 130 black, 120 Hispanic, and 20 Choctaw Indian patients with SSc were compared with 430 white, 164 black, 146 Hispanic, and 76 Choctaw Indian control subjects, respectively. All subjects were living in the US. PTPN22 SNP (rs2476601) genotyping was performed by TaqMan 5′ allelic discrimination assay and pyrosequencing. Results The PTPN22 CT/TT genotype showed significant association with anti–topo I antibody–positive SSc in white patients (odds ratio [OR] 2.21, 95% confidence interval [95% CI] 1.3–3.7) and with ACA-positive white patients with SSc (OR 1.70, 95% CI 1.1–2.7). Frequency of the PTPN22*T allele also showed significant association with anti–topo I antibody–positive SSc in white patients (OR 2.03, 95% CI 1.3–3.2). When data for patients in the 3 ethnic groups (black, white, and Hispanic) were combined, a significant association with both genotype and allele frequencies was observed, suggesting a trend toward association in ACA-positive and anti–topo I antibody–positive SSc. Stepwise logistic regression analysis (controlled for the confounding effects of sex and race) showed that the PTPN22 CT/TT genotype was associated with a significantly higher risk of SSc compared with the CC genotype (for patients with SSc, OR 1.64, 95% CI 1.2–2.2; for ACA-positive patients with SSc, OR 1.63, 95% CI 1.0–2.6; for anti–topo I antibody–positive SSc, OR 2.33, 95% CI 1.5–3.7). Conclusion Our results indicate that the PTPN22 R620W polymorphism is associated with ACA-positive and anti–topo I antibody–positive subsets of SSc and represents a risk factor in both white patients and black patients. The association of subsets of SSc with the PTPN22 R620W polymorphism further strengthens the classification of SSc within the spectrum of autoimmune diseases and strongly suggests the involvement of common susceptibility genes and similarly disordered immunoregulatory pathways.

Nat. Genet. 42, 426–429 (2010); published online 11 April 2010; corrected after print 23 March 2011 In the version of this article initially published, incorrect affiliations were published for Lorenzo Beretta and Rafaella Scorza. The correct affiliation for Lorenzo Beretta and Rafaella Scorza is “Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan”.

Aim Pre-B cell colony-enhancing factor (PBEF) is intricately involved in inflammation and fibrosis, functional polymorphisms of PBEF have been previously shown to influence PBEF expression and pulmonary damage. Systemic sclerosis (SSc) is a disease in which inflammation, fibrosis and pulmonary deterioration are prominent hallmarks. Therefore the authors here investigate the role of the PBEF -1001T>G and PBEF -1543C>T polymorphisms in the genetic predisposition to SSc susceptibility and pulmonary involvement. Patients and methods The authors genotyped DNA from 2737 SSc patients and 1913 matched healthy controls, both from eight different ethnic populations. Genotyping was performed using custom Taqman 59 allelic discrimination assays. In addition, PBEF serum expression levels were measured by ELISA and correlated with genotypes. Results In two separate populations and in a meta-analysis, the combined PBEF -1543CC -1001TT genotype , hence carrying no minor alleles, was found associated with SSc susceptibility (p=0.009 OR 1.20 (95% CI 1.05 to 1.37)). In addition, these subjects showed an increased decline in forced vital capacity over 15 years follow-up (p=0.02) (HR 1.64, 95% CI 1.02 to 2.64) and a higher PBEF serum concentration (p PBEF -1001TT were at lower risk for PAH development within 15 years of disease onset compared to the carriers with genotypes PBEF -1001GG and PBEF -1001TG (p Conclusions This data identify PBEF as a novel candidate gene that influences SSc susceptibility, pulmonary function and the development of PAH.

Introduction Systemic sclerosis (SSc) (scleroderma) is a complex autoimmune disease that clinically manifests as progressive fibrosis of the skin and internal organs. Anti-centromere antibodies (ACAs), anti-topoisomerase antibodies (ATAs), and anti-RNA polymerase III antibodies (ARAs) are three mutually exclusive SSc-associated autoantibodies that correlate with distinct clinical subsets characterized by extent of cutaneous involvement and pattern of organ involvement. The current report sought to determine whether plasma cytokine profiles differ in SSc patients grouped according to these SSc-associated autoantibody subsets. Methods Plasma from 444 SSc patients and 216 healthy controls was obtained from the Scleroderma Family Registry and University of Texas Rheumatology Division. Patients were classified according to the presence of ACAs, ATAs, ARAs, or none of the above (antibody-negative). Levels of 13 cytokines were determined using multiplex assays. Results Compared with females, healthy control males had higher plasma levels of IL-2 (P = 0.008), IL-5 (P = 0.01) and IL-8 (P = 0.01). In addition, in controls, IL-6 (P = 0.02) and IL-17 (P = 0.01) levels increased with advancing age. After adjusting for age and gender, SSc patients had higher circulating levels of TNFα (P < 0.0001), IL-6 (P < 0.0001), and IFNγ (P = 0.05) and lower IL-17 (P = 0.0005) and IL-23 (P = 0.014). Additional analyses demonstrated that disease duration also influenced these cytokine profiles. IL-6 was elevated in ATA-positive and ARA-positive patients, but not in ACA-positive patients. IL-8 was uniquely increased in the ATA-positive subset while both ATA-positive and ACA-positive subsets had elevated IFNγ and IL-10. IL-5 was only significantly increased in the ACA-positive subset. Lastly, patients with interstitial lung disease had elevated IL-6 and patients with pulmonary hypertension had elevated IL-6 and IL-13. Conclusions Plasma cytokine profiles differ in SSc patients based on the presence of SSc-associated autoantibodies. Plasma cytokine profiles in SSc patients may also be affected by disease duration and the pattern of internal organ involvement.

2 páginas.-- Póster presentado al 5º European Workshop on Immune-Mediated Inflammatory Diseases celebrado en Sitges (Barcelona, España) del 1 al 3 de Diciembre de 2010.-- et al.