Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and CrohnвЂ™s disease (CD), some of which confer susceptibility to both diseases.

Therefore, this article will discuss the possible pathogenesis, treatment strategies, and promising therapeutic interventions in CTD-PAH. Meanwhile, there are more research progresses, novel therapeutic strategies, and updated clinical concepts, including the pivotal role of immunosuppressive therapy, treatment goals of вЂњdual treat-to-targetвЂќ, in the field of CTD-PAH. On the other hand, the role of inflammation underlying the pathogenesis of CTD-PAH should be emphasized, considering the better clinical effectiveness of immunosuppressive therapy for CTD-PAH patients. However, the current treatments fail to be completely curative, and prognosis of PAH patients remains poor. Over the past few decades, effective therapies that targeting key signaling pathways involved in PAH have significantly improved patients' symptoms and quality of life, and CTD-PAH patients are also greatly benefit from them. Pulmonary arterial hypertension (PAH) is a frequent but severe vascular complication of patients with connective tissue diseases (CTDs) and a major cause of significant morbidity and mortality in these patients. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. These include, the B-cell-mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. Current therapies are mainly focused on vasodilative agents to improve prognosis. Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Tocilizumab did not show any consistent treatment effect. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).ДЄdverse events were consistent with the known safety profile of tocilizumab. Inflammatory markers did not predict treatment response. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Tocilizumab was discontinued in 4 patients due to serious adverse events. Twenty-three patients received at least one dose of tocilizumab. Six were withdrawn prior to drug administration. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Twenty-nine patients (M/F 10/19 mean age 54.9) were recruited. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. kg вЃ»В№ ) over 6 months in group 1 pulmonary arterial hypertension.

We conducted an open-label phase-II study of intravenous tocilizumab (8 mg Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling. Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension.

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