Systemic sclerosis is a rare, complex, and chronic multisystem disease. Scleroderma means hard and thick skin. It is derived from the ancient Greek words "skleros," which means (hard) and "derma," which means (skin). Skin involvement is one of the features of systemic sclerosis (SSc). The hallmark features of systemic sclerosis include immune dysregulation with inflammation, vascular injury with an anatomic and functional abnormality, and systemic interstitial fibrosis of organs and skin, leading to multisystem organ damage. Cardiac involvement is well recognized in systemic sclerosis, which can affect the pericardium, the myocardium, and the conduction system. Primary cardiac disease is reported in both diffuse and limited systemic sclerosis. However, it was found to be more prevalent and more severe in diffuse systemic sclerosis.
The etiology of systemic sclerosis and the exact contributing genetic susceptibility is not fully understood. However, several factors are thought to play a role, and environmental exposure in genetically susceptible individuals is thought to be plausible. Some studies showed that the risk of systemic sclerosis is increased in first-degree relatives; on the other hand, in a twin study, the concordance for systemic sclerosis was found to be relatively low. As with other autoimmune diseases, the major histocompatibility complex (MHC) has been implicated in systemic sclerosis development. Multiple and unique human leukocyte antigens (HLA) class II alleles are associated with systemic sclerosis and specific antibodies profile. For example, HLA DQB1*0301, DRB1*1104, and DQA1*0501 haplotypes were found to be strongly associated with systemic sclerosis. Also, multiple non-MHC loci have been identified to be associated with systemic sclerosis. These, for example, include IRF5, STAT4, TNIP1, CD247, and PTPN22.
Some of these non-MHC loci have also been implicated in other autoimmune diseases, such as systemic lupus erythematosus, suggesting that immune dysregulation is a very important factor in systemic sclerosis development. Epigenetic factors, most notably involving post-translational modification processes, have been described in systemic sclerosis. These are thought to be triggered by environmental factors and commonly involve histone modification, DNA methylation, and changes in non-coding RNAs. The result is thought to be the promotion of profibrotic genes, suppression of antifibrotic molecules, and alteration of fibroblasts function. These changes were also found in some studies to be associated with vasculopathy, fibrosis, B-cell activation, and antibody production.
Infectious agents, specifically viruses, have been studied and thought to be a factor in SSc development. These include cytomegalovirus (CMV), parvovirus B19, and Epstein-Barr virus (EBV). Several findings and theories have been studied in this regard. These include possible molecular mimicry as some of these viruses contain antigens that were found to share immunogenicity with endothelial peptides. Profibrotic molecules were found to be stimulated by CMV in certain tissues. Also, CMV has been implicated in the allograft vasculopathy, inducing similar vascular pathologic changes as SSc. Other environmental factors that are studied in SSc development include exposure to silica dust, occupational organic solvents, polyvinyl chloride, toluene, xylene, trichloroethylene, rapeseed oil, and L-tryptophan. The latter two were associated with SSc-like syndromes, toxic-oil syndrome, and eosinophilia-myalgia syndrome, respectively.
Certain drugs have been implicated in SSc such as bleomycin, taxol, pentazocine, and cocaine. Another potentially plausible finding in some SSc patients is the so-called microchimerism, where persistent fetal cells in the maternal serum are thought to produce immune reaction resulting in SSc. However, not all patients with SSc were found to have increased microchimerism. Moreover, microchimerism is thought to have a genetic background where individuals with positive HLA-DQA1*0501 were found to have increased microchimerism regardless of SSc development. These findings make microchimerism questionable in SSc pathogenesis.
The incidence and prevalence of SSc vary among different studies. The overall worldwide incidence of SSc is reported to be between 8 to 56 new cases/million/year. Whereas, the overall prevalence is between 38 to 341 cases/million/year. SSc is more common in women (3 to 7: 1 female to male ratio), with an average age of disease onset being 35 to 50. There are several differences in disease presentation between males and females. For instance, females are found to have disease onset at a younger age with longer disease duration. Females are also found to have more limited SSc than men, more frequent but less severe peripheral vascular involvement, and increased frequency of anti-centromere antibodies with pulmonary hypertension being the most frequent cause of mortality.
Primary cardiac disease is reported in both diffuse and limited systemic sclerosis; however, it is more prevalent and more severe in diffuse systemic sclerosis. Several risk factors for cardiac disease in systemic sclerosis have been reported. These include the presence of specific serologies like the anti-U3-RNP antibodies, rapid skin thickness progression, and skeletal muscle involvement. With the advent of more sensitive cardiac studies, the prevalence of cardiac involvement in SSc is found to be up to 70%, with the majority of cases being subclinical. Clinically overt cardiac involvement is estimated to be around 30%.
The pathophysiology of cardiac disease in SSc involves repeated abnormal vasoreactivity with coronary microvascular ischemia, reperfusion injury, and myocardial inflammation. Microvascular changes are often seen in the endocardium, whereas lesions suggestive of macrovascular coronary artery disease and atherosclerosis do not appear to be increased in SSc. It appears that microcirculation changes similar to Raynaud changes in peripheral circulation occur in the myocardium. These Recurrent episodes of ischemia and reperfusion often result in contraction band necrosis and replacement fibrosis. The result is an increased myocardial stiffness with reduced compliance. This is thought to be the cause of diastolic dysfunction in SSc, which is known to be associated with increase mortality. The changes in coronary microcirculation are thought to be reversible in early disease, with irreversible structural changes occurring late with disease progression. Acute myocarditis can also occur in SSc and is often reported to be associated with skeletal myositis. Several extracellular factors and signaling molecules appear to play a role in myocardial injury and fibrosis. These include transforming growth factor-beta, endothelin-1, and oxidative stress via reactive oxygen species. Systolic dysfunction is reported in SSc but less frequently. It is likely attributable to myocardial inflammation with acute myocarditis being an important risk factor and often associated with skeletal myositis.
The hallmark pathologic features of SSc include proliferative and/or obliterative vasculopathy with minimal inflammation affecting mainly small vessels with capillary loss and fibrosis. Myocardial fibrosis in SSc was first described in 1943 by Weiss et al. They reported findings of myocardial scarring not associated with coronary artery disease and recognizing these findings to be unique and specific to SSc. Other frequently reported pathologic findings in the myocardium, including foci of fibrosis distributed throughout the heart. These fibrotic changes are distinct from those related to myocardial infarction in that they tend to involve both ventricles somewhat equally with no correlation to extramural coronary artery distribution. Moreover, these fibrotic changes tend to extend to the endocardium without sparing subendocardial myocardium, as seen in myocardial infarction. Another consistently reported pathologic findings is the presence of contraction band necrosis with cellular inflammatory response followed by replacement fibrosis.
Microvascular coronary artery disease is usually the underlying pathology, with many patients being asymptomatic years before presentation. Some patients may present with anginal chest pain similar to patients with obstructive macrovascular coronary artery disease. Similarly, many patients with myocardial involvement are found to be asymptomatic, with pathological findings seen on cardiac screening imaging. Those who are symptomatic usually present with heart failure symptoms of fatigue, dyspnea, and signs of volume overload. Acute myocarditis is also reported in SSc and is usually associated with skeletal myositis and overlap syndrome. This usually presents with acute heart failure symptoms with or without skeletal myopathy symptoms of symmetric proximal muscle weakness and possibly dysphagia. Heart failure symptoms and signs include dyspnea on exertion or at rest, orthopnea, paroxysmal nocturnal dyspnea, fatigue, weight gain with signs of volume overload including lower extremity edema, positive third heart sound on cardiac auscultation, elevated jugular venous pressure, and hepatojugular reflux. Arrhythmias can also occur with myocardial involvement and usually present with palpitation, presyncope, or syncope.
Evaluation for myocardial disease in scleroderma is very important, given that the majority of patients have no cardiac symptoms early in the course of the disease. Therefore, cardiac screening for asymptomatic patients with SSc has been proposed. This includes obtaining a baseline cardiac clinical evaluation with history and exam, transthoracic echocardiogram, electrocardiogram, lab testing with troponin, and plasma brain natriuretic peptide. Additional testing is indicated in symptomatic patients include cardiac magnetic resonance imaging, stress testing, and/or cardiac catheterization. Referral to a cardiologist is warranted based on the findings of these studies. An interprofessional approach is recommended with the involvement of rheumatologists and cardiologists to provide comprehensive care and recommendations.
Generally, the management of SSc mostly involves target organ management. Treatment of microvascular coronary artery disease is similar to the general population with optimization of anti-anginal therapy, including antiplatelets, lipid-lowering therapy, nitrates, and calcium channel blockers. Heart failure is generally similar to the general population. Non-selective beta-blockers should generally be considered due to the lower risk of worsening vasoreactivity. Limited data showed some benefits on myocardial function and perfusion with the use of vasodilators such as calcium channel blockers or angiotensin-converting enzyme inhibitors. One study of 601 patients on the use of vasodilators or low dose aspirin suggested potential myocardial preventive benefits in SSc.
Management of heart failure is not different than the general population. This generally varies based on the type of heart failure, whether diastolic, which is more common with SSc or systolic heart failure. The treatment of diastolic heart failure is mainly with diuretics and blood pressure control. The treatment of systolic heart failure is mainly with beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), diuresis, and the use of inotropes and device therapy in select cases if indicated. Care should be taken to address any underlying medical condition that may predispose to or worsen heart failure or coronary artery diseases such as hypertension, diabetes, and hyperlipidemia. Myocardial inflammation in SSc, whether myocarditis or myopericarditis, was shown to respond to immunosuppression in some studies. However, these data are limited and mostly observational. Several treatments were suggested with reported success, including systemic steroids, cyclophosphamide, mycophenolate, and intravenous immunoglobulin. Normalization of cardiac enzymes with clinical improvement was reported with the use of systemic steroids and cyclophosphamide.
Several conditions can mimic SSc. These include scleredema, which is characterized by excess mucin deposition presenting with skin thickening and woody induration involving the upper back and posterior portion of the neck. Scleredema is associated with diabetes mellitus, viral infections, and monoclonal gammopathies. Scleromyxedema is another potential mimic of SSc and usually presents with diffuse papular and scleroderma eruptions, mucin deposition, and association with monoclonal gammopathy with the absence of thyroid disease. Eosinophilic fasciitis can also mimic SSc with the collagenous thickening of the subcutaneous fascia. Finally, morphea is a relatively benign inflammatory disorder that causes skin thickening and sclerosis mimicking SSc and should be considered in the differential diagnosis. The myocardial disease appears to be prevalent in patients with SSc even in the absence of symptoms; nonetheless, other causes of myocardial disease should be considered in patients with atypical findings or findings that suggest alternative etiology.
Myocardial involvement in SSc carries a poor prognosis. Several studies have shown that a significant number of SSc mortality was related to the presence of cardiac disease, including heart failure and arrhythmias. Cardiac disease was found to be the third leading cause of death in SSc after interstitial lung disease and pulmonary arterial hypertension. In a metanalysis, the hazard ratio of increased mortality was 2.8 (HR = 2.8; 95% CI: 2.1 to 3.8) in patients with cardiac disease. These findings highlight the importance of early diagnosis and management of myocardial disease in SSc.
Cardiac involvement in SSc is associated with increased mortality. Several complications can occur with myocardial disease, including heart failure, conduction defects, and tachyarrhythmias.
Patients should be educated on living with scleroderma and educated about signs of cardiac involvement such as new-onset chest pain, shortness of breath, palpitations, weight gain, and fatigue. Patients with heart failure should be warned about symptoms and signs of volume overload.
Scleroderma is a multisystem disease and involves multiple organs. It affects the lives of our patients and their families. The timely diagnosis of this disease and its complications are very important. This population will benefit from an interprofessional team and a care coordinator who can manage their follow-ups.
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