Preface

Systemic sclerosis (scleroderma) is the most enigmatic and challenging of all rheumatic diseases. To date, it is considered incurable and carries the highest cause-specific mortality of all the connective tissue diseases. Despite the advancements in basic, translational, and clinical research that have been made in recent years, the etiology and pathophysiology of this complex and heterogeneous condition remain to be elucidated. The pathogenesis of scleroderma involves an interplay between genetic, epigenetic, and environmental factors that cause alterations in the immune and vascular systems and lead to progressive tissue fibrosis. The heterogeneity, highly variable clinical presentations, multisystemic manifestations, natural history, response to treatment, low prevalence, and level of public awareness or government investment represent some of the reasons for slow progress in the field of systemic sclerosis. Despite the large numbers of clinical trials and the progress made in their design over the last decade, no approved disease-modifying therapies exist for scleroderma to date. Currently available pharmacological therapies predominantly target inflammatory and vascular pathways, have variable and unpredictable clinical efficacy, usually undesirable safety profiles, and only a modest effect on long-term survival. All of these factors contribute to the significant impact of this challenging disease on the quality of life of patients with scleroderma and their families. Nevertheless, life expectancy of scleroderma patients has improved over recent years, mainly because of better disease management and efficacy of available treatment modalities for organ manifestations and complications. However, there is a large unmet need for increasing the awareness of systemic sclerosis among patients, physicians, and allied health professionals, and for comprehensive multidisciplinary care, which should include physical and occupational therapy, and optimization of nutrition, sleep, and sexual or psychological aspects to reduce suffering and disability of scleroderma patients.

This book covers novel insights into the pathogenetic mechanisms, classification, differential diagnosis, diagnostic methods, clinical management, and available treatment approaches of a number of major organ manifestations of scleroderma, including pulmonary hypertension and gastrointestinal and renal involvement. Furthermore, it provides a comprehensive overview of often neglected aspects such as scleroderma-like syndromes, and the impact of sexual and biopsychosocial issues on the ability of patients to participate in society and to work. Contributors include well-established scleroderma experts, rheumatologists, internal medicine specialists, a pathologist and dermatologist, young research fellows, and experienced physiotherapists with an interest in basic, translational, and clinical research in systemic sclerosis. I am indebted to my colleagues for their dedication, expertise, and timely submissions and believe that their contributions reflect the progress made over the last couple of years in understanding and managing systemic sclerosis.

I would like to express my gratitude to all colleagues, research collaborators, my students and mentors in rheumatology, and to all the patients who have taught me about scleroderma and were sources of inspiration over the years.

I gratefully acknowledge Ana Pantar for the kind invitation to become an academic editor of this book and the Author Service Manager Edi Lipović for his dedicated technical assistance, patience, readiness, and helpfulness.

I am deeply grateful and indebted to my family for their ongoing support, encouragement, patience, and love.

*New Insights into Systemic Sclerosis* aims to provide students, residents, trainees, researchers, rheumatologists, and other specialists interested in this fascinating disease with up-to-date knowledge and concepts spanning pathogenesis to the clinical management of scleroderma.

> **Michal Tomčík, MD, PhD** Associate Professor at the Department of Rheumatology, First Faculty of Medicine, Charles University, Institute of Rheumatology, Prague, Czech Republic

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**Chapter 1**

**Abstract**

nitric oxide, prostacyclin

**1. Introduction**

Advances in Management

*John W. Swisher and Shashank Kailash*

of Pulmonary Hypertension

Associated with Systemic Sclerosis

Pulmonary hypertension is a well-known complication of systemic sclerosis. Patients with systemic sclerosis may develop a pulmonary arteriopathy characterized by vascular remodeling, increased pulmonary vascular resistance, and right ventricular failure. Pulmonary hypertension may also arise in systemic sclerosis as a consequence of interstitial lung disease or left ventricular dysfunction. Vascular remodeling is more prevalent than other forms of pulmonary hypertension in systemic sclerosis. The pathogenesis of pulmonary vascular remodeling in this disease state is not completely understood; however, there is evidence of a complex process involving genetic susceptibility, risk factors, vascular injury, and endothelial dysfunction. In those patients with pulmonary arterial hypertension, survival prognosis is extremely poor if the diagnosis is delayed or goes undetected and untreated. In recent years, a number of disease-targeted therapies have been developed that improve functional capacity, hemodynamics, and survival. Early detection and treatment with one or more targeted therapies are essential to improving survival when systemic sclerosis is complicated by pulmonary arterial hypertension.

**Keywords:** pulmonary arterial hypertension, systemic sclerosis, endothelin,

Systemic sclerosis (SSc) is a multisystem, autoimmune disease characterized by excessive collagen deposition and fibrosis of the skin and internal organs. The autoimmune process may affect the lungs with the development of interstitial fibrosis, pulmonary hypertension, or both. Pulmonary hypertension (PH) may result from a pathologic process of remodeling in the pulmonary arteries, in which case it is referred to as pulmonary arterial hypertension (PAH). Pulmonary hypertension may also arise secondary to interstitial fibrosis with chronic hypoxemia or myocardial fibrosis with postcapillary pulmonary hypertension. Pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) represents the second most common cause of PAH after the idiopathic form of the disease (iPAH). Pulmonary arterial hypertension is associated with a progressive rise in pulmonary vascular resistance that can result in right ventricular failure and death. Patients with SSc-PAH have higher mortality than the idiopathic form of PAH or PAH associated with other diseases, such as congenital heart disease. While there is a

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