The burden of systemic sclerosis in Switzerland - the Swiss systemic sclerosis EUSTAR cohort.

OBJECTIVES Characteristics of Swiss patients with systemic sclerosis have not been described so far. The aim of the current study was to identify unmet needs in comparison with other European countries that could inform specific interventions to improve the care of systemic sclerosis patients. METHODS We analysed Swiss and other European systemic sclerosis patients registered in European Scleroderma Trials And Research (EUSTAR) and the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) cohort. Demographics, clinical profiles, organ involvement and survival of established, early/mild and very early / very mild systemic sclerosis patients were described and compared between the cohorts. RESULTS We included 679 Swiss and 8793 European systemic sclerosis patients in the analysis. Over 95% of patients in both cohorts were Caucasian, disease subsets were similar, and no age difference was found. The Swiss cohort had more male patients (25% vs 16% European, p = 0.005) and higher prevalence of early/mild and very early / very mild patients (26.1 vs 8.5% European and 14.9% vs 6.7% European, respectively, both p <0.0001). Disease duration in established systemic sclerosis patients at first presentation was numerically shorter but not significant in the Swiss cohort: 5.0 years (1–12) Swiss vs 6.0 years (2–12) years European, p = 0.055). Despite the earlier referral of Swiss patients to systemic sclerosis expert centres, they showed evidence of more severe disease, particularly in the limited cutaneous systemic sclerosis subset, but no differences in overall survival on longitudinal follow-up were observed. CONCLUSION This is the first report of the national Swiss EUSTAR cohort. It identifies earlier referral to systemic sclerosis expert centres, before major organ damage occurs, and when outcome can still be modified, as a priority to improve care of patients with systemic sclerosis

Presence of IgM anti-topoisomerase I antibodies is associated with disease progression in anti-topoisomerase I IgG positive systemic sclerosis

BACKGROUND: Anti-topoisomerase I auto-antibodies (ATA) in systemic sclerosis (SSc) are associated with diffuse skin involvement and interstitial lung fibrosis. Thus far, however, the relations between the ATA response and disease course have not yet been fully evaluated. OBJECTIVES: To gain insight into the relation between characteristics of the ATA immune response and clinical disease course in ATA+ SSc. METHODS: ATA-IgG, -IgM and -IgA levels were assessed in consecutive serum samples of baseline ATA-IgG+ patients from the Leiden Combined Care In Systemic Sclerosis cohort (CCISS). One-year disease progression was defined by a relevant increase in modified Rodnan Skin Score (mRSS), decline in pulmonary function tests, development of digital ulcers, renal crisis, pulmonary hypertension and/or mortality. Validation was performed in ATA+ SSc patients from the Oslo University Hospital and University Hospital Zurich RESULTS: Of 103 ATA-IgG+ patients available in the CCISS cohort, 81 patients had clinical data available to assess one-year disease progression. Of these 81 patients, 23 patients (28%) showed disease progression. At baseline, disease-progressors were significantly more often ATA-IgM+ compared to non-progressors (21/23 [91%] vs 33/58 [57%], p<0.01). This finding was confirmed in the independent validation samples. CONCLUSION: In ATA-IgG+ SSc patients, presence of ATA-IgM, which might be taken as a surrogate for an ongoing auto-reactive B cell immune response, is associated with disease progression

Digital pitting scars are associated with a severe disease course and death in systemic sclerosis: a study from the EUSTAR cohort

Objective Digital pitting scars (DPS) are frequent, but little studied in SSc to date. Methods An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. Results A total of 9671 patients were included with reported DPS at any time point (n = 4924) or 'never' DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud's duration (both P <= 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P <= 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51-24.87), active digital ischaemia: 6.30 (5.34-7.42) and death: 1.86 (1.48-2.36). Conclusion DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy

Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Objective I mmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. Methods We meta-analysed similar to 6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. Results Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. Conclusions We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs