Journal of Scleroderma and Related Disorders

Involving patients and health care professionals in research has been shown to be a useful strategy to generate program development ideas and establish research priorities. Online surveys can be used to identify patient research priorities. The Scleroderma Patient-centered Intervention Network is an international collaboration dedicated to researching problems important to people with scleroderma and developing, testing, and disseminating educational, self-management, rehabilitation, and psychological tools to support coping within the disease. The objectives of the Scleroderma Patient-centered Intervention Network Scleroderma Research Topics Survey were to (1) obtain input on online programs that Scleroderma Patient-centered Intervention Network could develop, (2) identify research topics important to members of the scleroderma community that could be addressed via the Scleroderma Patient-centered Intervention Network Cohort, and (3) identify potentially understudied groups. Eligible survey respondents included individuals with scleroderma and their caregivers, health care professionals, and patient organization representatives. Responses were evaluated separately for online programs, possible research questions, and understudied groups. In each category, thematic analysis was used to group responses into themes. A total of 125 participants (100 patients, 24 health care professionals, and 1 caregiver) completed the survey, and responses from patients and health care professionals were reported. For online programs, frequent recommendations included Interactive Platforms to facilitate communication between patients, as well as interventions targeting physical activity, and emotions and stress. Common responses for possible research questions were related to calcinosis, accessing health care, and quality of life. The most common suggestions for understudied groups were young patients, minority patients, and patients with calcinosis. Research topic suggestions provided in the survey will inform Scleroderma Patient-centered Intervention Network priorities and can be considered by other researchers.

Peer-facilitated support groups are an important source for receiving disease-related information and support for people with systemic sclerosis (or scleroderma). A recent survey explored reasons for attending systemic sclerosis support groups in Europe and Australia and used exploratory factor analysis to group reasons for attendance into three main themes: (1) interpersonal and social support, (2) disease treatment and symptom management strategies, and (3) other aspects of living with systemic sclerosis. The objective of the present study was to replicate this study in a sample of patients from North America using confirmatory factor analysis. A 30-item survey was used to assess reasons for attendance and organizational preferences among systemic sclerosis patients in Canada and the United States. In total, 171 members completed the survey. In the confirmatory factor analysis, the three-factor model showed good fit to the data (χ²(399) = 646.0, p < 0.001, Tucker–Lewis index = 0.97, comparative fit index = 0.97, root mean square error approximation = 0.06). On average, respondents rated 22 (73%) of 30 items as “important” or “very important” reasons for attending support groups. Among organizational preferences, respondents emphasized the importance of the ability to share feelings and concerns, as well as educational aspects. Findings of our study suggest that reasons for attending support groups are similar for patients from Europe, Australia, and North America and that support groups should facilitate social support as well as disease education. These results inform the development of training programs for current and future systemic sclerosis support group leaders across the globe.

Patients with systemic sclerosis often seek information regarding complementary and nutrition-based therapy. Some study results have shown that vitamins D and E, probiotics, turmeric, l-arginine, essential fatty acids, broccoli, biofeedback, and acupuncture may be beneficial in systemic sclerosis care. However, large randomized clinical trials have not been conducted. This review summarizes current data regarding various complementary therapies in systemic sclerosis and concludes with recommendations.

Capillaroscopy is a unique method for morphological evaluation of the nailfold capillaries that plays a crucial role for early diagnosis of systemic sclerosis. The first description of the pathological capillaroscopic changes in systemic sclerosis was made by Brown and O’Leary in 1925. Several decades later they have been validated and accepted as a diagnostic criterion in the current 2013 EULAR/ACR classification criteria. This article summarizes the evolving knowledge about the use of nailfold capillaroscopy in systemic sclerosis. Initially, Maricq et al. suggested two major categories of capillaroscopic findings in systemic sclerosis – an ‘active’and ‘slow’ capillaroscopic pattern. Their description and terminology suggested a correlation between capillaroscopic changes and disease activity and progression. In the later classification of Cutolo et al., three phases were defined, i.e. ‘early’, ‘active’ and ‘late’ that reflect the time-related evolution of the capillaroscopic changes suggesting their association with disease duration. Current knowledge about the microvascular changes in systemic sclerosis supports both associations with disease activity and disease duration. The general opinion about the association of capillaroscopic findings with clinical involvement and disease activity in systemic sclerosis is not uniform. This is supposedly because the phase changes of systemic sclerosis–related microangiopathy are almost a universal feature in scleroderma and are not specific for a certain type of an accompaning clinical manifestation. Thus, the speed of progression of microvascular alterations might be a decisive criterion, and in cases of rapid dynamics of capillaroscopic findings, it could be considered as an indicator of disease activity. Interestingly, vascular ‘recovery’ has been observed after treatment with immunosuppressive drugs, haematopoietic stem cell transplantation, and the endothelin receptor antagonist – bosentan. The evolving knowledge about nailfold capillaroscopy in systemic sclerosis will further spread its application from a mainly diagnostic tool to an established, reliable method for evaluation of disease activity, prognosis and therapeutic response.

Interstitial lung disease is a common manifestation of systemic sclerosis. Systemic sclerosis–associated interstitial lung disease is characterized by progressive pulmonary fibrosis and a reduction in pulmonary function. Effective treatments for systemic sclerosis–associated interstitial lung disease are lacking. In addition to clinical similarities, systemic sclerosis–associated interstitial lung disease shows similarities to idiopathic pulmonary fibrosis in the pathophysiology of the underlying fibrotic processes. Idiopathic pulmonary fibrosis and systemic sclerosis–associated interstitial lung disease culminate in a self-sustaining pathway of pulmonary fibrosis in which fibroblasts are activated, myofibroblasts accumulate, and the excessive extracellular matrix is deposited. Nintedanib is a tyrosine kinase inhibitor that has been approved for the treatment of idiopathic pulmonary fibrosis. In patients with idiopathic pulmonary fibrosis, nintedanib slows disease progression by decreasing the rate of lung function decline. In this review, we summarize the antifibrotic, anti-inflammatory, and attenuated vascular remodeling effects of nintedanib demonstrated in in vitro studies and in animal models of aspects of systemic sclerosis. Nintedanib interferes at multiple critical steps in the pathobiology of systemic sclerosis–associated interstitial lung disease, providing a convincing rationale for its investigation as a potential therapy. Finally, we summarize the design of the randomized placebo-controlled SENSCIS^® trial that is evaluating the efficacy and safety of nintedanib in patients with systemic sclerosis–associated interstitial lung disease.

Pulmonary vascular disease represents one of the most frequent complications in systemic sclerosis leading to increased mortality. The recognition and appropriate clinical management of early pulmonary vascular disease could significantly improve the prognosis of affected patients. Early pulmonary vascular disease is characterized by the histological signs of pulmonary vascular remodeling, mildly increased mean pulmonary arterial pressure (21–24 mmHg) at rest, abnormal pulmonary hemodynamics during exercise, decreased exercise capacity, and a high risk for development of pulmonary arterial hypertension. Pulmonary hemodynamics can be investigated during exercise by echocardiography or by right heart catheterization both representing important clinical tools for the screening and confirmation of early pulmonary vascular disease. Further studies are needed to better understand the clinical course of systemic sclerosis patients with early pulmonary vascular disease and to define the characteristics of patients that will or will not profit from pulmonary arterial hypertension treatment.

In general, pulmonary vascular disease has important negative prognostic implications, regardless of the associated condition or underlying mechanism. In this regard, systemic sclerosis is of particular interest as it is the most common connective tissue disease associated with pulmonary hypertension, and a well-recognized at-risk population. In the setting of systemic sclerosis and unexplained dyspnea, the concept of using exercise to probe for underlying pulmonary vascular disease has acquired significant interest. In theory, a diagnosis of systemic sclerosis–associated exercise pulmonary hypertension may allow for earlier therapeutic intervention and a favorable alteration in the natural history of the pulmonary vascular disease. In the context of underlying systemic sclerosis, the purpose of this article is to provide a comprehensive review of the evolving definition of exercise pulmonary hypertension, the current role and methodologies for non-invasive and invasive exercise testing, and the importance of the right ventricle.

Scleroderma or systemic sclerosis is thought to result from the interplay between environmental or non-genetic factors in a genetically susceptible individual. Epigenetic modifications are influenced by genetic variation and environmental exposures, and change with chronological age and between populations. Despite progress in identifying genetic, epigenetic, and environmental risk factors, the underlying mechanism of systemic sclerosis remains unclear. Since epigenetics provides the regulatory mechanism linking genetic and non-genetic factors to gene expression, understanding the role of epigenetic regulation in systemic sclerosis will elucidate how these factors interact to cause systemic sclerosis. Among the cell types under tight epigenetic control and susceptible to epigenetic dysregulation, immune cells are critically involved in early pathogenic events in the progression of fibrosis and systemic sclerosis. This review starts by summarizing the changes in DNA methylation, histone modification, and non-coding RNAs associated with systemic sclerosis. It then discusses the role of genetic, ethnic, age, and environmental effects on epigenetic regulation, with a focus on immune system dysregulation. Given the potential of epigenome editing technologies for cell reprogramming and as a therapeutic approach for durable gene regulation, this review concludes with a prospect on epigenetic editing. Although epigenomics in systemic sclerosis is in its infancy, future studies will help elucidate the regulatory mechanisms underpinning systemic sclerosis and inform the design of targeted epigenetic therapies to control its dysregulation.