A Narrative Review of Pathogenetic and Histopathologic Aspects, Epidemiology, Classification Systems, and Disease Outcome Measures in Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is a rare systemic autoimmune disease, characterized by the presence of three main actors: vasculopathy, immune activation, and fibrosis. This pathologic process is then translated in a clinical picture with great variability among different patients in terms of type of organ involvement, disease severity and prognosis. This heterogeneity is a main feature of SSc, which, in addition to the presence of early phases of the disease characterized by mild symptoms, can explain the high difficulty in establishing classification criteria, and in defining patients' subsets and disease outcomes. The definition of disease outcomes is particularly relevant in the setting of clinical trials, where the aim is to provide reliable endpoints, able to measure the magnitude of the efficacy of a certain drug or intervention. For this reason, in the last years, increasing efforts have been done to design measures of disease activity, damage, severity, and response to treatment, often in the context of composite indexes. When considering disease outcomes, the experience of the patient represents a relevant and complementary aspect. The tools able to capture this experience, the patient-reported outcomes, have been increasingly used in the last years in clinical practice and in clinical trials, both as primary and secondary endpoints. This comprehensive narrative review on SSc will therefore cover pathogenetic and histopathologic aspects, epidemiology, classification systems, and disease outcome measures, in order to focus on issues that are relevant for clinical research and design of clinical trials.

Keywords: Classification; Disease outcomes; Epidemiology; Patient-reported outcomes; Systemic sclerosis; Vasculopathy.

Fig. 1

Overview on the pathogenesis of systemic sclerosis. Anti RNA-Pol-III, antibodies against RNA polymerase-III; Anti Scl-70, antibodies against scleroderma-associated autoantigen of 70-kDa; NOS, nitric oxide synthase; O2, oxygen; VEGF, vascular endothelial growth factor; EMT, endothelial-to-mesenchymal transition; TGFβ, tissue growth factor β; IL-6, interleukin 6; MO, macrophage; Th17, lymphocyte T helper-17; Th2, lymphocyte T helper-2. Created with BioRender. Academic license