Advances in pathogenesis and treatment of systemic sclerosis

Systemic sclerosis is the most severe disease within the scleroderma spectrum and is a major medical challenge with high mortality and morbidity. There have been advances in understanding of pathogenesis that reflect the interplay between immune-inflammatory processes and vasculopathy and fibrosis. It can be regarded as a disease of connective tissue repair and this leads to organ-based complications. However the aetiology and triggering events remain to be elucidated. Treatment is available for many aspects of the disease although the available therapies are not curative and some complications remain very challenging, especially non-lethal manifestations such as fatigue, calcinosis and anorectal dysfunction. Immunosuppression is now established as a beneficial approach but balancing risk and benefit is vital, especially for powerful approaches such as autologous stem cell transplantation

Challenges in systemic sclerosis trial design

Systemic sclerosis (scleroderma; SSc) is an autoimmune rheumatic disease with high clinical burden and unmet need due to connective tissue fibrosis and vascular damage. It has the highest case specific mortality of any rheumatic disease, with approximately half of patients diagnosed eventually dying as a direct result of SSc. There are no approved diseases modifying treatments. This is partly related to the difficulty of conducting clinical trials for regulatory approval. Traditionally skin thickness has been assessed using the modified Rodnan skin score (MRSS) that has been shown to correlate with survival and risk of complications in SSc. However recent trials have highlighted the limitations of MRSS which often improves over time, even on placebo. A new composite measure integrating changes in multiple domains of lung function, skin, patients and physician global and HAQ disability index has been developed, the CRISS (Composite Response Index for Systemic Sclerosis). This measure looks promising and has provisional acceptance by American College of Rheumatology (designated ACR CRISS) but is unlikely to be strongly persuasive to Health Authorities in isolation unless there are also clinically meaningful changes in relevant domains that reflect how patients feel, function or survive

The role of endothelial cells in autoimmune rheumatic disease

Vasculopathy is a generic feature of autoimmune rheumatic disease and there is substantial evidence that endothelial cell dysfunction has a role in pathogenesis and clinical manifestations of this challenging group of diseases. Endothelial cells (EC) are a target for injury and through their essential functional role in vascular homoeostasis, this has significant impact. In addition, the emerging recognition that EC are important regulators of other cell types and can differentiate into other relevant cell types has direct relevance. These aspects are reviewed with a focus on recent published evidence regarding the importance of EC in development, progression and treatment of autoimmune rheumatic disease. The potential role of the adaptive and innate immune system in causing endothelial cell damage, including anti-endothelial cell autoantibodies, will be reviewed. Recent advances in understanding how EC may differentiate into mesenchymal lineages and the interplay between physiological roles in healing or tissue repair and dysfunctional responses in acquired connective tissue disease will be reviewed

Pathogenesis of systemic sclerosis associated interstitial lung disease

Systemic sclerosis is an autoimmune disease leading to vasculopathy and fibrosis of skin and internal organs. Despite likely shared pathogenic mechanisms, the patterns of skin and lung fibrosis differ. Pathogenesis of interstitial lung disease, a major cause of death in systemic sclerosis, reflects the intrinsic disease pathobiology and is associated with distinct clinical phenotypes and laboratory characteristics. The commonest histological pattern of systemic sclerosis–interstitial lung disease is non-specific interstitial pneumonia. Systemic sclerosis–interstitial lung disease pathogenesis involves multiple components, including susceptibility and triggering factors, which could be genetic or environmental. The process is amplified likely through ongoing inflammation and the link between inflammatory activity and fibrosis with IL6 emerging as a key mediator. The disease is driven by epithelial injury, reflected by markers in the serum, such as surfactant proteins and KL-6. In addition, mediators that are produced by epithelial cells and that regulate inflammatory cell trafficking may be important, especially CCL2. Other factors, such as CXCL4 and CCL18, point towards immune-mediated damage or injury response. Monocytes and alternatively activated macrophages appear to be important. Transforming growth factor beta appears central to pathogenesis and regulates epithelial repair and fibroblast activation. Understanding pathogenesis may help to unravel the stages of systemic sclerosis–interstitial lung disease, risks of progression and determinants of outcome. With this article, we set out to review the multiple factors, including genetic, environmental, cellular and molecular, that may be involved in the pathogenesis of systemic sclerosis–interstitial lung disease and the mechanisms leading to sustained fibrosis. We propose a model for the pathogenesis of systemic sclerosis–interstitial lung disease, based on the available literature

Combining datasets as well as therapies shows improved outcome in connective tissue disease associated pulmonary hypertension

The article of Khanna et al [1] is an important summary of more than two decades of progress in management of connective tissue disease (CTD) associated pulmonary hypertension (PH) that provides an important platform for further advances. It also clearly shows the positive impact of current practice with combination therapy introduced early and an emphasis on proactive screening to make an early diagnosis of PH