Tackling systemic sclerosis from all angles

Abstract

Systemic sclerosis (SSc) remains among the deadliest of the rheumatic diseases. Despite decades of research, only one disease-modifying drug is approved for severe lung complications of the disease, and no effective treatment exists that combats the disease across organ systems. In this issue, The Lancet Rheumatology teams up with The Lancet Respiratory Medicine to present a Series of articles focused on recent successes and failures in SSc. The Series—published to coincide with the 6th World Systemic Sclerosis Congress (March 5–7, 2020, in Prague, Czech Republic)—also tackles the key hurdles that must be overcome to develop more effective therapies and treatment approaches for patients with this debilitating disease. Although a rare disease, patients with SSc often have severe disability, fibrosis-related organ failure, and die prematurely; up to half develop interstitial lung disease (ILD), the most common cause of mortality in these patients. The disease has a severe impact on patients' lives, causing a variable constellation of symptoms including Raynaud's phenomenon, arthritis, painful ulcers on the fingers and toes, thickening and scarring of the skin, shortness of breath, hypertension, and severe fatigue. Patients with SSc have a decreased quality of life, with substantial direct and indirect costs to patients and health-care systems. A recent study from Australia estimated that the total health-care utilisation cost for patients with SSc exceeded US$43 million per year between 2011 and 2015. As with many rheumatic and musculoskeletal conditions, the clinical heterogeneity of SSc presents a major challenge for the treatment of disease and the design of clinical trials. There are two main subsets of the disease—diffuse cutaneous SSc (affecting roughly a third of patients) and limited cutaneous SSc—but there is substantial clinical variability therein. Indeed, the heterogeneity of the disease, along with its rarity, is one of the key reasons for the many failed trials of new and potentially useful therapeutic agents for SSc. Reversing this trend will require a focus on novel and innovative trial designs, improved patient stratification approaches, and more robust (possibly composite) outcome measures, as discussed in a Review by Francesco Del Galdo and colleagues and a Viewpoint by Janet Pope. Perhaps the biggest recent successes have been seen in patients with SSc-related ILD, as comprehensively reviewed by Apostolos Perelas and colleagues. Notably, in the SENSCIS trial of patients with SSc-related ILD, the tyrosine kinase inhibitor nintedanib was shown to reduce the decline in forced vial capacity, leading to its 2019 approval by the US Food and Drug Administration. Another milestone in SSc-related ILD was the 2020 publication of the first evidence-based expert consensus statements for its identification and management, which stressed the importance of screening all patients with SSc for ILD using high-resolution CT, and the need to use multiple measures of disease severity. A notable omission in the development of these consensus statements was the lack of patient involvement, particularly given the growing emphasis on shared decision making and importance of patient-reported outcomes and treatment satisfaction. With regard to patient priorities, we also urgently need more research on fatigue. Fatigue is arguably the most intractable aspect of SSc—perhaps explaining the dearth of research on the topic—but it invariably tops the list of complaints among patients living with the disease. Many patients feel that fatigue is overlooked in the clinical management of their disease. To effectively change this situation will require a multifaceted approach that includes improved patient and physician education, health-care system reform, outcomes research, and improved efforts toward shared decision making. The importance of these issues for patient care is discussed in two Comments from Tanja Stamm and colleagues and from Julia Spierings and Jacob van Laar. Finally, improving therapy for patients with SSc will ultimately require a better understanding of the biology of the disease, and improved predictors of clinical course and therapeutic response. As such, there is a clear need for more translational research, including studies of disease drivers and risk factors, and studies identifying robust, validated biomarkers of disease severity, clinical progression, and therapeutic response. With an all-angles approach—from translational research to innovative trial design and an increased focus on patient priorities—we are optimistic that the field will continue to progress toward new and better therapies for patients with SSc. For the Systemic sclerosis Series see https://www.thelancet.com/series/systemic-sclerosisFor the SENSCIS trial see N Engl J Med 2019; 380: 2518–28 For the Systemic sclerosis Series see https://www.thelancet.com/series/systemic-sclerosis For the SENSCIS trial see N Engl J Med 2019; 380: 2518–28 Randomised controlled trials in systemic sclerosis: patient selection and endpoints for next generation trialsThe heterogeneity in the natural history of systemic sclerosis is a major issue in both clinical management and trial design and is dictated by the complex and multifactorial pathogenesis of the disease. Systemic sclerosis is an autoimmune disease and therefore many trials for the disease have targeted immune activation pathways; however, the phase 3 trials that have been positive have targeted pathways directly linked to tissue damage rather than systemic immune activation. On one hand, these results represent enormous progress that has led to the first approved drugs for this extremely challenging condition. Full-Text PDF The future of treatment in systemic sclerosis: can we design better trials?Strides have been made in the treatment of pulmonary arterial hypertension and interstitial lung disease in patients with systemic sclerosis, with successful trials of combination therapies in pulmonary arterial hypertension and of new drugs that slow the decline of lung function in interstitial lung disease. However, many trials in patients with early diffuse cutaneous systemic sclerosis have been negative, including trials of tocilizumab, abatacept, and riociguat, despite improvements in skin scores and other endpoints that approached statistical significance. Full-Text PDF Systemic sclerosis-associated interstitial lung diseaseSystemic sclerosis is an autoimmune connective tissue disease, which is characterised by immune dysregulation and progressive fibrosis that typically affects the skin, with variable internal organ involvement. It is a rare condition that affects mostly young and middle-aged women, resulting in disproportionate morbidity and mortality. Currently, interstitial lung disease is the most common cause of death among patients with systemic sclerosis, with a prevalence of up to 30% and a 10-year mortality of up to 40%. Full-Text PDF The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statementsThrough a robust modified Delphi process developed by a diverse panel of experts, the first evidence-based consensus statements were established on guidance for the identification and medical management of systemic sclerosis-associated ILD. Full-Text PDF How can fatigue be addressed in individuals with systemic sclerosis?Fatigue is consistently reported to be one of the most problematic symptoms in systemic sclerosis (SSc),1,2 with cross-cutting effects that restrict patients' ability to participate in social roles, parenting, and work.3 Although fatigue in SSc is severe and stable over time,4 it is perceived by patients to be insufficiently addressed in clinical care.5 Treating fatigue might not only better serve patients with SSc who need to manage a rare and complex chronic condition themselves, but would also support the movement towards value-based health care, in which patient-reported outcomes and treatment satisfaction are part of quality metrics. Full-Text PDF Choosing a treatment: how can patients be guided through the labyrinth?Diffuse cutaneous systemic sclerosis (SSc) is a subtype of SSc, a rare autoimmune connective tissue disease characterised by inflammation, fibrosis, and vasculopathy, resulting in generalised skin thickening and organ damage.1 The disease can be rapidly progressive leading to severe morbidity and premature death. Although diffuse cutaneous SSc is incurable, disease progression can be suppressed if treatment is started early.2,3 The following treatment options are generally considered in progressive stages of the disease: methotrexate, mycophenolate mofetil, cyclophosphamide, or autologous hematopoietic stem cell transplantation (AHSCT),4 all differing in tolerability, risk–benefit, and costs. Full-Text PDF