Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement

Abstract

Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and fibrosis of skin and internal organs, including the heart. SSc is associated with high morbidity and mortality. Cardiac involvement is frequent in SSc patients, even though often asymptomatic at early stages, and represents one of the major causes of SSc-related mortality. Heart involvement has a variable clinical presentation, and its pathogenesis is not completely understood. Myocardial fibrosis is traditionally considered the immunopathologic hallmark of heart involvement in SSc. This unique histological feature is paralleled by distinctive clinical and prognostic features. The so-called “vascular hypothesis” represents the most credited hypothesis to explain myocardial fibrosis. More recently, the prominent role of an inflammatory myocardial process has been identified as a cardinal event in the evolution to fibrosis, thus also delineating an “inflammation-driven pathway to fibrosis”. The pro-inflammatory cytokine interleukin (IL)-1 has an apical and cardinal role in the myocardial inflammatory cascade and in cardiac dysfunction. The primary aim of this perspective article is: to present the emerging evidence on the role of IL-1 and inflammasome in both SSc and heart inflammation, to review the complex interplay between cellular metabolism and inflammasome activation, and to discuss the rationale for targeted inhibition of IL-1 for the treatment of SSc-heart involvement, providing preliminary experimental and clinical data to support this hypothesis.

New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

“…Cardiovascular disease is the cause of death in 14–36% of all SSc cases with a wide range of pathologic manifestations including microvascular disease, atherosclerotic coronary artery disease, myocardial fibrosis and pericarditis [ 31 , 32 ]. Microvascular disease manifests with nonocclusive concentric intimal hyperplasia of myocardial arterioles and unique myocardial lesions known as “contraction band necrosis”, which is due to a sort of cardiac Raynaud’s phenomenon, i.e., a sequelae of perfusion and reperfusion injuries (microvascular coronary vasospasm) resulting in ischemic events finally leading to arrhythmias and cardiac dysfunction [ 4 , 7 , 33 , 34 ]. Moreover, different vascular abnormalities such as fibrinoid necrosis, mural fibrosis, intimal proliferation and medial hyperplasia have been detected in in coronary arteries of <1 mm in size [ 24 ].…”

“…Moreover, different vascular abnormalities such as fibrinoid necrosis, mural fibrosis, intimal proliferation and medial hyperplasia have been detected in in coronary arteries of <1 mm in size [ 24 ]. Strikingly, intermittent vascular spasm, reperfusion injury and ischemic necrosis are considered to play a pivotal role in inducing myocardial fibrosis, histologically manifesting as a patchy replacement of cardiac myocytes with acellular collagenous material throughout the myocardium [ 4 , 24 , 33 , 34 ]. As far as macrovascular involvement is concerned, arterial intimal thickening and occlusion by atheromatous plaques characterized by a plenty of foamy macrophages and cholesterol clefts with an overlying fibrous cap have been demonstrated in some SSc patients [ 6 , 35 , 36 , 37 ].…”

The target on B cells in Systemic Sclerosis: a “midsummer dream” to extinguish inflammation and prevent early disease progression to fibrosis

“…Activated B cells overexpress CD19, MHC-II, and costimulatory molecules, secrete inflammatory cytokines as IL-6, and migrate to the site of inflammation, thus contributing to tissue damage and foraging this detrimental pro-inflammatory/pro-fibrotic loop. Currently available therapeutic strategies could target both inflammatory pathways (with anti-CD20 Rituximab and/or mycophenolate mofetil or anti-IL6 tocilizumab), and pro-fibrotic pathways (with nintedanib), to extinguish inflammation and to prevent early disease progression to fibrosis data obtained by the EUSTAR registry [28,29]. The same results have been also obtained with RTX biosimilars [30], and are supported by two meta-analyses [31,32].…”

“…As for many human diseases, a prompt activation of the innate immunity represents the front line in response to various stimuli. Experimental data support the role of innate immunity in SSc, with cellular metabolism imbalance, inflammasome activation, and interleukin (IL)-1β release as main early events [12]. These are followed by a robust inflammatory cascade, involving downstream proinflammatory and pro-fibrotic pathways, promoting SSc progression.…”

“…Given the biologic role of Bcells in SSc, at crossroad between inflammation and fibrosis, the possibility to combine RTX/MMF and nintedanib might looks hazardous today, but in the future, it might represent a fascinating opportunity, which should be carefully investigated. In fact, data from the EUSTAR registry and other studies show that the combination RTX/MMF could be effective on lung fibrosis [29,40]. Thus, the combination of a double anti-inflammation/immunosuppression with an anti-proliferative drug could become a real therapeutic challenge.…”