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Objective: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes., Methods: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed., Results: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E-03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10(-05))., Conclusions: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown cause., Objective: To assess the prevalence, pattern and severity of interstitial lung disease (ILD) in a cross-sectional study of the nationwide, Norwegian MCTD cohort., Methods: 126 patients with MCTD were systematically examined for ILD by high-resolution CT (HRCT), pulmonary function tests (PFT), 6 min walk test (6MWT) and by the New York Heart Association (NYHA) functional classification of dyspnoea. The extent and type of HRCT lung abnormalities were scored according to the CT criteria of ILD recommended by the Fleischner Society., Results: All 126 patients were Caucasian, 75% women. At the time of the cross-sectional ILD study, the patients had a mean disease duration of 9.0 years. 52% of the patients had abnormal HRCT findings, most commonly reticular patterns consistent with lung fibrosis (35%). Lung fibrosis was quantified as minor in 7%, moderate in 9% and severe in 19% of the patients. Fibrosis was uniformly concentrated in the lower parts of the lungs and was not associated with smoking. Patients with severe lung fibrosis had lower PFT values, shorter 6MWT and a higher mean NYHA functional class. After a mean 4.2 years' follow-up, overall mortality was 7.9%. Mortality in patients with normal HRCT was 3.3%, as compared with 20.8% in patients with severe lung fibrosis (p<0.01)., Conclusions: Severe lung fibrosis is common in MCTD, has an impact on pulmonary function and overall physical capacity and is associated with increased mortality.

Objectives: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features., Methods: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers., Results: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively)., Conclusions: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.