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Background Recent evidence has highlighted a potential role of interleukin 1β (IL-1β) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1β. In addition, variants were found to confer susceptibility to autoimmune disorders. Objective To study a possible association of the rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. Methods single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. Results Conditional analyses revealed a significant association for the rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of rs2004640, rs7574865 and rs8182352 risk alleles on SSc-related FA. Conclusions Our results establish as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease. [ABSTRACT FROM PUBLISHER]

Objective Two functional single nucleotide polymorphisms (SNP) in the gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes. Methods 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these polymorphisms in SSc. Results The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1). Conclusion The study suggests that the R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases. [ABSTRACT FROM PUBLISHER]

Background encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between variants and autoimmune diseases have been reported. Objective To investigate the association of polymorphisms with systemic sclerosis (SSc). Methods Three single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in intron 2, rs5029939, were selected. The rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel–Haenszel meta-analysis. Results The rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16×10), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91×10), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2×10), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5×10) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3×10). Conclusion These results suggest that is a genetic susceptibility factor for SSc. [ABSTRACT FROM PUBLISHER]

Objective To investigate the possible association of the 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 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 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 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 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets. [ABSTRACT FROM PUBLISHER]

Objectives: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc). Methods: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression. Results: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction. Conclusion: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective. [ABSTRACT FROM PUBLISHER]

Objectives: This study investigated the long-term effects of bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, in patients with pulmonary arterial hypertension (PAH) exclusively related to connective tissue diseases (CTD).Methods: A total of 53 patients with PAH related to connective tissue diseases (PAH-CTD) in World Health Organization (WHO) functional class III received bosentan 62.5 mg twice a day for 4 weeks and then 125 mg twice a day for 44 weeks in this open non-comparative study. Assessments at weeks 16 and 48 included WHO class, clinical worsening, quality of life (Short-Form Health Survey (SF-36) and health assessment questionnaire (HAQ) modified for scleroderma), and survival (week 48 only). Safety and tolerability were monitored throughout the study.Results: At week 48, WHO class improved in 27% of patients (95% CI 16-42%) and worsened in 16% (95% CI 7-29%). Kaplan-Meier estimates were 68% (95% CI 55-82%) for absence of clinical worsening and 92% (95% CI 85-100%) for survival. Overall changes in quality of life were minimal. There were no unexpected side effects observed during the study.Conclusions: In most patients, bosentan was associated with improvement or stability of clinical status. The 92% estimate for survival at 48 weeks is a significant achievement in this patient population. [ABSTRACT FROM AUTHOR]

Background: The SmD1(83-119) peptide is a major target of the B cell response in patients with systemic lupus erythematosus (SLE).Objective: To investigate the T cell response directed against this peptide, its disease specificity, and possible impact on SLE pathogenesis.Methods: Peripheral blood mononuclear cells derived from 28 patients with SLE and 29 healthy and disease controls were stimulated by the SmD1(83-119) and the recombinant (r)SmD1 protein, and [3H]thymidine incorporation was measured. Patients with SLE were simultaneously tested for autoantibodies, disease activity, clinical symptoms, and medical treatments.Results: T cell reactivity against the SmD1(83-119) peptide was detected in 11/28 (39%) patients with SLE and against the rSmD1 protein in 10/28 (36%) patients. In contrast, only 2/29 (7%) controls exhibited SmD1 reactivity. An analysis of proliferation kinetics showed that SmD1 reactive T cells are activated in vivo, as additionally confirmed by cytometric analysis. Addition of mammalian dsDNA to rSmD1 enhanced the rSmD1-specific T cell response. SmD1(83-119)-specific T cell reactivity was significantly more common in patients with cardiac and pulmonary symptoms. No correlation between T and B cell responses and disease activity was seen.Conclusion: SmD1(83-119) is a major T cell epitope of SmD1, commonly recognised by T cells from patients with SLE and much less commonly found by healthy or disease controls. This strong T cell reactivity as well as the high frequency and specificity of anti-SmD1(83-119) antibodies in SLE suggest a possible role in SLE pathogenesis, at least in a subset of patients. [ABSTRACT FROM AUTHOR]

Objective: To conduct a replication study to investigate whether the -945 CTGF genetic variant is associated with systemic sclerosis (SSc) susceptibility or specific SSc phenotype.Methods: The study population comprised 1180 patients with SSc and 1784 healthy controls from seven independent case-control sets of European ancestry (Spanish, French, Dutch, German, British, Swedish and North American). The -945 CTGF genetic variant was genotyped using a Taqman 5' allelic discrimination assay.Results: An independent association study showed in all the case-control cohorts no association of the CTGF -945 polymorphism with SSc susceptibility. These findings were confirmed by a meta-analysis giving a pooled OR = 1.12 (95% CI 0.99 to 1.25), p = 0.06. Investigation of the possible contribution of the -945 CTGF genetic variant to SSc phenotype showed that stratification according to SSc subtypes (limited or diffuse), selective autoantibodies (anti-topoisomerase I or anticentromere) or pulmonary involvement reached no statistically significant skewing.Conclusion: The results do not confirm previous findings and suggest that the CTGF -945 promoter polymorphism does not play a major role in SSc susceptibility or clinical phenotype. [ABSTRACT FROM AUTHOR]

Objective: To conduct a replication study to investigate whether the −945 genetic variant is associated with systemic sclerosis (SSc) susceptibility or specific SSc phenotype. Methods: The study population comprised 1180 patients with SSc and 1784 healthy controls from seven independent case–control sets of European ancestry (Spanish, French, Dutch, German, British, Swedish and North American). The −945 genetic variant was genotyped using a Taqman 5′ allelic discrimination assay. Results: An independent association study showed in all the case–control cohorts no association of the −945 polymorphism with SSc susceptibility. These findings were confirmed by a meta-analysis giving a pooled OR = 1.12 (95% CI 0.99 to 1.25), p = 0.06. Investigation of the possible contribution of the −945 genetic variant to SSc phenotype showed that stratification according to SSc subtypes (limited or diffuse), selective autoantibodies (anti-topoisomerase I or anticentromere) or pulmonary involvement reached no statistically significant skewing. Conclusion: The results do not confirm previous findings and suggest that the −945 promoter polymorphism does not play a major role in SSc susceptibility or clinical phenotype. [ABSTRACT FROM PUBLISHER]

Background Systemic sclerosis (SSc) is characterised by autoimmunity, vasculopathy and fibrosis. The functional link between these three pathophysiological components is still missing. Recent research suggests an involvement of the vasoconstrictive soluble peptides endothelin-1 and angiotensin II, and of the activation of their receptors by the natural ligands and agonistic autoantibodies against these receptors in SSc–associated vasculopathy. Objectives We could identify auto-antibodies against the angiotensin receptor type 1 (AT1R) and the endothelin receptor type A (ETAR) in SSc patients. The pathophysiological effects of these antibodies on immune cells and their association with clinical data have not been studied so far. Materials and methods Peripheral blood mononuclear cells (PBMC) from healthy donors were isolated by gradient centrifugation and stimulated in vitro by affinity-purified IgG from SSc patients containing anti-AT1R and anti-ETAR antibodies as well as by IgG from healthy donors. After stimulation the expression of several markers and cytokines were measured by flow cytometry or ELISA. Results Stimulation of PBMC from healthy donors by SSc patient IgG resulted in a significantly increased expression of IL-8 compared to the stimulation by IgG of healthy donors. This effect can be blocked by commercial AT1R and ETAR blockers. In contrast, expression of soluble CD14 as well as of the surface marker CD14 was significantly decreased. Correlation analysis of the IL-8 expression with clinical data of the SSc patients whose IgGs were used revealed an association of the high IL-8 expression with the early stage of disease, in fact in vitro stimulation of PBMC with IgG of patients who were within the first 8 years after onset of the disease caused a significantly higher IL-8 secretion in comparison to the stimulation with IgG of patients at a later stage. Conclusion SSc patient IgGs containing anti-AT1R and anti-ETAR antibodies seem to have effects on inflammation and immune regulation. Especially the release of IL-8, which is a strong inflammatory cytokine mainly secreted by monocytes among the immune cells, may play an important role in the early stage of disease contributing to vascular inflammation and injury, which are regarded to be the first events leading to tissue damage and fibrosis. [ABSTRACT FROM PUBLISHER]

Background and objectives Systemic lupus erythematosus is a severe systemic chronic autoimmune disease and New Zealand black × New Zealand white (NZB/W) F1 mice are commonly used to study this disease. The role of interleukin 10 (IL-10) in lupus is controversial and needs to be clarified, especially in regard to the different cell types, which can produce IL-10. Here the authors analysed whether IL-10 producing CD4 T cells have a beneficial effect in murine lupus. Materials and methods Lupus-prone NZB/W F1 mice were repeatedly high-dose tolerised with SmD1(83–119) and analysed for SmD1(830119)-specific CD4 cells producing IL-10. Function of IL-10 on autoantibody production was analysed in an in vitro assay based on ELISA. Young, healthy NZB/W F1 mice were preventively treated with whole CD4 T cells from SmD1(83–119)- tolerised NZB/W F1 mice. And finally old, diseased NZB/W F1 were treated with polyclonal CD4 IL-10+ T cells generated in vitro. Results First, the authors detected SmD1(83–119)-specific CD4 IL-10+ T cells after their previously published SmD1(83–119) high dose tolerisation protocol and the authors were able to increase the number of these cells by an additional booster immunisation with SmD1(83–119), second, the authors showed that IL-10 has a suppressive effect on anti-dsDNA autoantibody production at least in vitro, third, the authors achieved a temporary beneficial effect on proteinuria course and autoantibody development by transfer of CD4 T cells containing up to 0.04% SmD1(83–119)-specific CD4 IL-10+ T cells from SmD1(83–119) high dose tolerised NZB/W F1 mice into untreated NZB/W F1 mice, and fourth, the authors were able to treat full blown lupus disease in old female NZB/W F1 mice with in vitro generated polyclonal CD4 IL-10+ T cells improving significantly the survival of these mice in contrast to a control transfer of in vitro generated polyclonal CD4 interferon γ+ T cells or phosphate-buffered saline treated control mice. Conclusions The authors conclude that IL-10 produced by CD4 T cells has a beneficial effect in murine lupus, even in full-blown disease in old, severely ill lupus-prone NZB/W F1 mice. Therefore, treatment of lupus prone mice with this cell type is an interesting new approach. [ABSTRACT FROM PUBLISHER]

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 and 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 5' 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 , 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<0.01), compared to carriers of minor alleles. On the other hand, patients with genotype were at lower risk for PAH development within 15 years of disease onset compared to the carriers with genotypes and (p<0.001) (HR 3.29, 95% CI 1.52 to 7.12). Conclusions This data identify PBEF as a novel candidate gene that influences SSc susceptibility, pulmonary function and the development of PAH. [ABSTRACT FROM PUBLISHER]

Aim Polymorphisms in the interleukin 4 (IL-4), IL-13 and their corresponding receptors have previously been found associated with systemic sclerosis (SSc). In this study the authors aim to validate these previous observations and scrutinise their effects on gene expression. Patients and methods The authors genotyped a cohort consisting of 2488 SSc patients and 2246 healthy controls, derived from The Netherlands, Spain, UK, Italy, Germany and France. Taqman assays were used for genotyping two single-nucleotide polymorphisms (SNPs) within (/rs1801275) and the (/rs2243250). In the gene two SNPs were genotyped (rs20541) and (rs1800925.) In the gene, the (rs6646259) variant was genotyped. In addition, the authors investigated the effect of these polymorphisms on corresponding gene expression with RT-PCR in B cells, T cells, plasmacytoid dendritic cells, monocytes and myeloid dendritic cells. Results None of these polymorphisms was found to be enriched in the SSc population or in any SSc clinical subtype and there was no influence of these polymorphisms on development of either pulmonary arterial hypertension and declineer of forced vital capacity in 15 years of follow-up. In addition, the authors did not observe an effect on expression levels in the cell subtypes. Conclusions This data show that these polymorphisms do not play a role in SSc and do not influence gene expression levels. [ABSTRACT FROM PUBLISHER]