The majority of research studies in systemic sclerosis focus largely on addressing skin and cardiopulmonary manifestations. Fewer studies assess the pathogenesis and treatment of gastrointestinal tract involvement in systemic sclerosis, despite the fact that the majority of patients with systemic sclerosis have gastrointestinal manifestations and these manifestations are a leading cause of death in systemic sclerosis. The present review provides a comprehensive update on morbidity and mortality outcomes related to gastrointestinal involvement in systemic sclerosis. This review also describes conventional and emerging approaches to managing gastrointestinal symptoms in systemic sclerosis. Recent developments in systemic sclerosis-gastrointestinal research efforts have revealed promising treatment targets, including specific auto-antibodies and microbiota alterations. This review will conclude with an overview of future research directions that may improve our understanding of systemic sclerosis-gastrointestinal involvement and ultimately help to alleviate suffering from this devastating dimension of systemic sclerosis.

The fears associated with being diagnosed with a disease unfamiliar to many, systemic sclerosis, is described by a patient living with systemic sclerosis. The patient, a coauthor, also describes the challenges of being a young person diagnosed with a chronic and, at times, debilitating disease. Despite initially being told that she had 6 months to live, she has embraced life and has become a fierce advocate for others living with systemic sclerosis. The physician perspective is provided by two rheumatologists who specialize in systemic sclerosis and work at a scleroderma center of excellence. This section details the current challenges in diagnosing systemic sclerosis early and the dangers of a delayed diagnosis. It also reviews the importance of multi-disciplinary specialty centers in the care of patients with systemic sclerosis as well as empowering patients through education.

Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

Systemic sclerosis, also known as scleroderma, is a rare and complex autoimmune connective-tissue disease. Once considered an untreatable and unpredictable condition, research advancements have improved our understanding of its disease pathogenesis and clinical phenotypes and expanded our treatment armamentarium. Early and accurate diagnosis is essential, while ongoing efforts to risk stratify patients have a central role in predicting both organ involvement and disease progression. A holistic approach is required when choosing the optimal therapeutic strategy, balancing the side-effect profile with efficacy and tailoring the treatment according to the goals of care of the patient. This Seminar reviews the multiple clinical dimensions of systemic sclerosis, beginning at a precursor very early stage of disease, with a focus on timely early detection of organ involvement. This Seminar also summarises management considerations according to the pathological hallmarks of systemic sclerosis (eg, inflammation, fibrosis, and vasculopathy) and highlights unmet needs and opportunities for future research and discovery.

Systemic sclerosis (SSc) is a rare, systemic autoimmune disease of unknown etiology. Among the systemic rheumatic diseases, SSc carries the highest mortality, in part due to the historical lack of disease modifying therapies. Recently, landmark randomized controlled trials (RCTs) have been conducted that have illustrated the heterogeneous nature of SSc and furthered our understanding of the key inflammatory and fibrotic pathways involved in SSc pathogenesis. Although SSc affects various organ systems, RCTs have focused on investigating treatments for diffuse cutaneous sclerosis (dcSSc) and interstitial lung disease (ILD). While recent RCTs for dcSSc have failed to demonstrate a treatment benefit, the outcomes of two RCTs led to the approval of two novel therapies for SSc-ILD: nintedanib and tocilizumab. This review summarizes the salient outcome data from recent SSc trials within a practical clinical framework and points out gaps in knowledge that may help inform the design of future SSc studies.

INTRODUCTION: Systemic sclerosis (SSc) is a multi-dimensional connective tissue disease of unknown etiology. Given the immense clinical complexity of SSc, the treatment of this condition is not standardized and considerable heterogeneity exists in SSc management approaches. The purpose of this article is to highlight novel therapeutic strategies and new medications under development for the treatment of systemic sclerosis (SSc). AREAS COVERED: Herein, the authors focus primarily on recently completed clinical trials and phase 3 and 4 clinical trials of therapeutic agents that show promise in SSc. This review is organized by the clinical complications that occur in SSc, for which novel treatment strategies are under study. EXPERT OPINION: Combining therapies to address the individual manifestations of SSc is a cornerstone to the comprehensive management of this condition. Therapeutic strategies must take into account the organs involved, the level of disease activity in each area, and the disease stage. Controlling the complex biological network, progressive vasculopathy and fibrosis, as well as manifestations of end-organ dysfunction are all critical considerations when determining the best treatment approach for SSc.

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease with distinct pathological hallmarks (ie, inflammation, vasculopathy, fibrosis) that may predominate at different stages in the disease course with varying severity. Initial efforts to classify patients with SSc identified a subset of patients with very early SSc. These patients possessed signs of SSc (eg, Raynaud phenomenon, SSc specific autoantibodies and/or nailfold capillary abnormalities) without fulfilling complete SSc classification criteria. Recognizing the inherent value in early diagnosis and intervention in SSc, researchers have endeavored to identify risk factors for progression from very early SSc to definite SSc. The present review summarizes the clinical phenotype of patients with very early and early SSc. Through a scoping review of recent literature, this review also describes risk factors for progression to definite SSc with a focus on the specific clinical features that arise early in the SSc disease course (eg, diffuse cutaneous sclerosis, interstitial lung disease, esophageal dysfunction, renal crisis, cardiac involvement). In addition to clinical risk factors, this review provides evidence for how biological data (ie, serological, genomic, proteomic profiles, skin bioengineering methods) can be integrated into risk assessment models in the future. Furthering our understanding of biological features of very early SSc will undoubtedly provide novel insights into SSc pathogenesis and may illuminate new therapeutic targets to prevent progression of SSc.

Contemporary studies of systemic sclerosis (SSc) consistently demonstrate that interstitial lung (ILD) is a leading cause of disease-related death. This review summarizes morbidity and mortality outcomes in SSc-ILD patients from high-quality observational and interventional studies over the last 50 years. The data presented suggest a trend for improved morbidity and mortality outcomes among present day SSc-ILD patients. Specifically, SSc-ILD patients appear to be living longer from the time of the initial diagnosis. Despite improved survival, the number one cause of death for most SSc-ILD patients remains respiratory failure from ILD. This review describes the most important demographic, clinical, and biological factors, which affect mortality in SSc-ILD, and could be used to help stratify patients for closer monitoring and more aggressive initial treatment. The review concludes with an overview of future research needed to (1) understand how to personalize the care of SSc-ILD patients to improve morbidity and mortality outcomes; and (2) investigate whether novel therapeutic interventions (e.g., anti-fibrotics, hematopoetic stem-cell transplantation) offer any meaningful long-term survival advantage over the current standard of care.

Objective

The aim of this study is to examine validity, reliability, and responsiveness to change of Patient-Reported Outcomes Measurement Information System Self-Efficacy for Managing Chronic Conditions in persons with systemic sclerosis.

Methods

We conducted a post hoc analysis of the Patient-Reported Outcomes Measurement Information System Self-Efficacy measure and other quality-of-life measures from systemic sclerosis participants from a 16-week randomized control trial. The trial compared an Internet-based self-management program to a control condition where participants were provided an educational book. All participants completed outcome measures at baseline and following the 16-week trial period.

Results

The mean age of participants was 53.7 years, 91% were female and systemic sclerosis subtype included 44.9% limited/sine and 43.1% diffuse; mean disease duration was 9.0 years. All self-efficacy subscales (Managing Emotions, Symptoms, Daily Activities, Social Interactions, and Medications/Treatment) demonstrated good internal consistency (.92-.96). All subscales showed statistically significant correlations with other validated measures of depressive symptoms and quality of life (.20-.86) but were not associated with satisfaction nor with appearance. The subscales appropriately discriminated between those with and without depressive symptoms and demonstrated responsiveness to change over the 16-week period for those who had a corresponding increase in reported quality of life.

Conclusion

The Patient-Reported Outcomes Measurement Information System Self-Efficacy measure is valid, reliable, and responsive to change for persons with systemic sclerosis.