• Sign Up

Scleroderma And Primary Myocardial Disease


Scleroderma And Primary Myocardial Disease

Article Author:
Mosaab Mohameden
Article Author:
Priyanka Vashisht
Article Editor:
Tariq Sharman
Updated:
10/1/2020 11:28:55 PM
For CME on this topic:
Scleroderma And Primary Myocardial Disease CME
PubMed Link:
Scleroderma And Primary Myocardial Disease

Introduction

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.[1] 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.[2][3] 

Etiology

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.[4][5] 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.[6] Also, multiple non-MHC loci have been identified to be associated with systemic sclerosis. These, for example, include IRF5, STAT4, TNIP1, CD247, and PTPN22.[7][8][9][10][11] 

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.[12] 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.[13][14][15][16][17] 

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.[18][19][20] 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.[21][22] The latter two were associated with SSc-like syndromes, toxic-oil syndrome, and eosinophilia-myalgia syndrome, respectively.[23][24]

Certain drugs have been implicated in SSc such as bleomycin, taxol, pentazocine, and cocaine.[25][26][27] 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.[28][29] 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.[30] These findings make microchimerism questionable in SSc pathogenesis. 

Epidemiology

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.[31]

Primary cardiac disease is reported in both diffuse and limited systemic sclerosis; however, it is more prevalent and more severe in diffuse systemic sclerosis.[2][3] 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.[32][33][34] 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%.[35][36][37][38]

Pathophysiology

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.[35][39][40][41] 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.[42] 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.[43][44]

Histopathology

The hallmark pathologic features of SSc include proliferative and/or obliterative vasculopathy with minimal inflammation affecting mainly small vessels with capillary loss and fibrosis.[45] 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.[46]

History and Physical

Microvascular coronary artery disease is usually the underlying pathology, with many patients being asymptomatic years before presentation.[35][47] Some patients may present with anginal chest pain similar to patients with obstructive macrovascular coronary artery disease.[48] 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.[49] 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.[50] 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.[51] 

Evaluation

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.[52][53]

Treatment / Management

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.[35][54] 

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.[43][52][55][56]

Differential Diagnosis

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.[57] 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.[58] Eosinophilic fasciitis can also mimic SSc with the collagenous thickening of the subcutaneous fascia.[59] Finally, morphea is a relatively benign inflammatory disorder that causes skin thickening and sclerosis mimicking SSc and should be considered in the differential diagnosis.[60] 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.[61]

Prognosis

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.[62][63][64] These findings highlight the importance of early diagnosis and management of myocardial disease in SSc.

Complications

Cardiac involvement in SSc is associated with increased mortality. Several complications can occur with myocardial disease, including heart failure, conduction defects, and tachyarrhythmias.

Deterrence and Patient Education

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.

Enhancing Healthcare Team Outcomes

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.



(Click Image to Enlarge)
Pursed Mouth of Scleroderma
Pursed Mouth of Scleroderma
Contributed by Dr. Shyam Verma, MBBS, DVD, FRCP, FAAD, Vadodara, India

References

[1] Allanore Y,Simms R,Distler O,Trojanowska M,Pope J,Denton CP,Varga J, Systemic sclerosis. Nature reviews. Disease primers. 2015 Apr 23     [PubMed PMID: 27189141]
[2] Steen VD,Powell DL,Medsger TA Jr, Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis and rheumatism. 1988 Feb     [PubMed PMID: 3348823]
[3] Perera A,Fertig N,Lucas M,Rodriguez-Reyna TS,Hu P,Steen VD,Medsger TA Jr, Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody. Arthritis and rheumatism. 2007 Aug     [PubMed PMID: 17665460]
[4] Arnett FC,Howard RF,Tan F,Moulds JM,Bias WB,Durban E,Cameron HD,Paxton G,Hodge TJ,Weathers PE,Reveille JD, Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis and rheumatism. 1996 Aug     [PubMed PMID: 8702445]
[5] Feghali-Bostwick C,Medsger TA Jr,Wright TM, Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis and rheumatism. 2003 Jul     [PubMed PMID: 12847690]
[6] Arnett FC,Gourh P,Shete S,Ahn CW,Honey RE,Agarwal SK,Tan FK,McNearney T,Fischbach M,Fritzler MJ,Mayes MD,Reveille JD, Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Annals of the rheumatic diseases. 2010 May     [PubMed PMID: 19596691]
[7] Gourh P,Tan FK,Assassi S,Ahn CW,McNearney TA,Fischbach M,Arnett FC,Mayes MD, Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis. Arthritis and rheumatism. 2006 Dec     [PubMed PMID: 17133608]
[8] Radstake TR,Gorlova O,Rueda B,Martin JE,Alizadeh BZ,Palomino-Morales R,Coenen MJ,Vonk MC,Voskuyl AE,Schuerwegh AJ,Broen JC,van Riel PL,van 't Slot R,Italiaander A,Ophoff RA,Riemekasten G,Hunzelmann N,Simeon CP,Ortego-Centeno N,González-Gay MA,González-Escribano MF,Airo P,van Laar J,Herrick A,Worthington J,Hesselstrand R,Smith V,de Keyser F,Houssiau F,Chee MM,Madhok R,Shiels P,Westhovens R,Kreuter A,Kiener H,de Baere E,Witte T,Padykov L,Klareskog L,Beretta L,Scorza R,Lie BA,Hoffmann-Vold AM,Carreira P,Varga J,Hinchcliff M,Gregersen PK,Lee AT,Ying J,Han Y,Weng SF,Amos CI,Wigley FM,Hummers L,Nelson JL,Agarwal SK,Assassi S,Gourh P,Tan FK,Koeleman BP,Arnett FC,Martin J,Mayes MD, Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nature genetics. 2010 May     [PubMed PMID: 20383147]
[9] Allanore Y,Saad M,Dieudé P,Avouac J,Distler JH,Amouyel P,Matucci-Cerinic M,Riemekasten G,Airo P,Melchers I,Hachulla E,Cusi D,Wichmann HE,Wipff J,Lambert JC,Hunzelmann N,Tiev K,Caramaschi P,Diot E,Kowal-Bielecka O,Valentini G,Mouthon L,Czirják L,Damjanov N,Salvi E,Conti C,Müller M,Müller-Ladner U,Riccieri V,Ruiz B,Cracowski JL,Letenneur L,Dupuy AM,Meyer O,Kahan A,Munnich A,Boileau C,Martinez M, Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS genetics. 2011 Jul     [PubMed PMID: 21750679]
[10] Bossini-Castillo L,Martin JE,Broen J,Simeon CP,Beretta L,Gorlova OY,Vonk MC,Ortego-Centeno N,Espinosa G,Carreira P,García de la Peña P,Oreiro N,Román-Ivorra JA,Castillo MJ,González-Gay MA,Sáez-Comet L,Castellví I,Schuerwegh AJ,Voskuyl AE,Hoffmann-Vold AM,Hesselstrand R,Nordin A,Lunardi C,Scorza R,van Laar JM,Shiels PG,Herrick A,Worthington J,Fonseca C,Denton C,Tan FK,Arnett FC,Assassi S,Koeleman BP,Mayes MD,Radstake TR,Martin J, Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study. Annals of the rheumatic diseases. 2013 Apr     [PubMed PMID: 22896740]
[11] Martin JE,Assassi S,Diaz-Gallo LM,Broen JC,Simeon CP,Castellvi I,Vicente-Rabaneda E,Fonollosa V,Ortego-Centeno N,González-Gay MA,Espinosa G,Carreira P,Camps M,Sabio JM,D'alfonso S,Vonk MC,Voskuyl AE,Schuerwegh AJ,Kreuter A,Witte T,Riemekasten G,Hunzelmann N,Airo P,Beretta L,Scorza R,Lunardi C,Van Laar J,Chee MM,Worthington J,Herrick A,Denton C,Fonseca C,Tan FK,Arnett F,Zhou X,Reveille JD,Gorlova O,Koeleman BP,Radstake TR,Vyse T,Mayes MD,Alarcón-Riquelme ME,Martin J, A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. Human molecular genetics. 2013 Oct 1     [PubMed PMID: 23740937]
[12] Assassi S,Radstake TR,Mayes MD,Martin J, Genetics of scleroderma: implications for personalized medicine? BMC medicine. 2013 Jan 11     [PubMed PMID: 23311619]
[13] Dees C,Schlottmann I,Funke R,Distler A,Palumbo-Zerr K,Zerr P,Lin NY,Beyer C,Distler O,Schett G,Distler JH, The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Annals of the rheumatic diseases. 2014 Jun     [PubMed PMID: 23698475]
[14] Altorok N,Tsou PS,Coit P,Khanna D,Sawalha AH, Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Annals of the rheumatic diseases. 2015 Aug     [PubMed PMID: 24812288]
[15] Ghosh AK,Bhattacharyya S,Lafyatis R,Farina G,Yu J,Thimmapaya B,Wei J,Varga J, p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-β: epigenetic feed-forward amplification of fibrosis. The Journal of investigative dermatology. 2013 May     [PubMed PMID: 23303459]
[16] Noda S,Asano Y,Nishimura S,Taniguchi T,Fujiu K,Manabe I,Nakamura K,Yamashita T,Saigusa R,Akamata K,Takahashi T,Ichimura Y,Toyama T,Tsuruta D,Trojanowska M,Nagai R,Sato S, Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. Nature communications. 2014 Dec 12     [PubMed PMID: 25504335]
[17] Wang YY,Wang Q,Sun XH,Liu RZ,Shu Y,Kanekura T,Huang JH,Li YP,Wang JC,Zhao M,Lu QJ,Xiao R, DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. The British journal of dermatology. 2014 Jul     [PubMed PMID: 24641670]
[18] Muryoi T,Kasturi KN,Kafina MJ,Cram DS,Harrison LC,Sasaki T,Bona CA, Antitopoisomerase I monoclonal autoantibodies from scleroderma patients and tight skin mouse interact with similar epitopes. The Journal of experimental medicine. 1992 Apr 1     [PubMed PMID: 1372644]
[19] Lunardi C,Bason C,Navone R,Millo E,Damonte G,Corrocher R,Puccetti A, Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nature medicine. 2000 Oct     [PubMed PMID: 11017152]
[20] Markiewicz M,Smith EA,Rubinchik S,Dong JY,Trojanowska M,LeRoy EC, The 72-kilodalton IE-1 protein of human cytomegalovirus (HCMV) is a potent inducer of connective tissue growth factor (CTGF) in human dermal fibroblasts. Clinical and experimental rheumatology. 2004 Jan-Feb     [PubMed PMID: 15344595]
[21] McCormic ZD,Khuder SS,Aryal BK,Ames AL,Khuder SA, Occupational silica exposure as a risk factor for scleroderma: a meta-analysis. International archives of occupational and environmental health. 2010 Oct     [PubMed PMID: 20047060]
[22] Nietert PJ,Sutherland SE,Silver RM,Pandey JP,Knapp RG,Hoel DG,Dosemeci M, Is occupational organic solvent exposure a risk factor for scleroderma? Arthritis and rheumatism. 1998 Jun     [PubMed PMID: 9627022]
[23] Tabuenca JM, Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet (London, England). 1981 Sep 12     [PubMed PMID: 6116011]
[24] Hertzman PA,Blevins WL,Mayer J,Greenfield B,Ting M,Gleich GJ, Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. The New England journal of medicine. 1990 Mar 29     [PubMed PMID: 2314421]
[25] Finch WR,Rodnan GP,Buckingham RB,Prince RK,Winkelstein A, Bleomycin-induced scleroderma. The Journal of rheumatology. 1980 Sep-Oct     [PubMed PMID: 6160247]
[26] Wu M,Varga J, In perspective: murine models of scleroderma. Current rheumatology reports. 2008 Jul     [PubMed PMID: 18638424]
[27] De Angelis R,Bugatti L,Cerioni A,Del Medico P,Filosa G, Diffuse scleroderma occurring after the use of paclitaxel for ovarian cancer. Clinical rheumatology. 2003 Feb     [PubMed PMID: 12605319]
[28] Johnson KL,Nelson JL,Furst DE,McSweeney PA,Roberts DJ,Zhen DK,Bianchi DW, Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis. Arthritis and rheumatism. 2001 Aug     [PubMed PMID: 11508438]
[29] Artlett CM,Welsh KI,Black CM,Jimenez SA, Fetal-maternal HLA compatibility confers susceptibility to systemic sclerosis. Immunogenetics. 1997     [PubMed PMID: 9382916]
[30] Lambert NC,Evans PC,Hashizumi TL,Maloney S,Gooley T,Furst DE,Nelson JL, Cutting edge: persistent fetal microchimerism in T lymphocytes is associated with HLA-DQA1*0501: implications in autoimmunity. Journal of immunology (Baltimore, Md. : 1950). 2000 Jun 1     [PubMed PMID: 10820227]
[31] Peoples C,Medsger TA Jr,Lucas M,Rosario BL,Feghali-Bostwick CA, Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. Journal of scleroderma and related disorders. 2016 May-Aug     [PubMed PMID: 29242839]
[32] Steen VD, Autoantibodies in systemic sclerosis. Seminars in arthritis and rheumatism. 2005 Aug     [PubMed PMID: 16084222]
[33] Nihtyanova SI,Denton CP, Autoantibodies as predictive tools in systemic sclerosis. Nature reviews. Rheumatology. 2010 Feb     [PubMed PMID: 20125179]
[34] Ranque B,Authier FJ,Berezne A,Guillevin L,Mouthon L, Systemic sclerosis-associated myopathy. Annals of the New York Academy of Sciences. 2007 Jun     [PubMed PMID: 17899625]
[35] Kahan A,Allanore Y, Primary myocardial involvement in systemic sclerosis. Rheumatology (Oxford, England). 2006 Oct     [PubMed PMID: 16980717]
[36] Parks JL,Taylor MH,Parks LP,Silver RM, Systemic sclerosis and the heart. Rheumatic diseases clinics of North America. 2014 Feb     [PubMed PMID: 24268011]
[37] Desai CS,Lee DC,Shah SJ, Systemic sclerosis and the heart: current diagnosis and management. Current opinion in rheumatology. 2011 Nov     [PubMed PMID: 21897256]
[38] Tyndall AJ,Bannert B,Vonk M,Airò P,Cozzi F,Carreira PE,Bancel DF,Allanore Y,Müller-Ladner U,Distler O,Iannone F,Pellerito R,Pileckyte M,Miniati I,Ananieva L,Gurman AB,Damjanov N,Mueller A,Valentini G,Riemekasten G,Tikly M,Hummers L,Henriques MJ,Caramaschi P,Scheja A,Rozman B,Ton E,Kumánovics G,Coleiro B,Feierl E,Szucs G,Von Mühlen CA,Riccieri V,Novak S,Chizzolini C,Kotulska A,Denton C,Coelho PC,Kötter I,Simsek I,de la Pena Lefebvre PG,Hachulla E,Seibold JR,Rednic S,Stork J,Morovic-Vergles J,Walker UA, Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Annals of the rheumatic diseases. 2010 Oct     [PubMed PMID: 20551155]
[39] Allanore Y,Meune C, Primary myocardial involvement in systemic sclerosis: evidence for a microvascular origin. Clinical and experimental rheumatology. 2010 Sep-Oct     [PubMed PMID: 21050545]
[40] Hinchcliff M,Desai CS,Varga J,Shah SJ, Prevalence, prognosis, and factors associated with left ventricular diastolic dysfunction in systemic sclerosis. Clinical and experimental rheumatology. 2012 Mar-Apr     [PubMed PMID: 22338601]
[41] Follansbee WP,Zerbe TR,Medsger TA Jr, Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): a high risk association. American heart journal. 1993 Jan     [PubMed PMID: 8417518]
[42] Ayers NB,Sun CM,Chen SY, Transforming growth factor-β signaling in systemic sclerosis. Journal of biomedical research. 2018 Jan 18     [PubMed PMID: 29353817]
[43] Pieroni M,De Santis M,Zizzo G,Bosello S,Smaldone C,Campioni M,De Luca G,Laria A,Meduri A,Bellocci F,Bonomo L,Crea F,Ferraccioli G, Recognizing and treating myocarditis in recent-onset systemic sclerosis heart disease: potential utility of immunosuppressive therapy in cardiac damage progression. Seminars in arthritis and rheumatism. 2014 Feb     [PubMed PMID: 23932313]
[44] West SG,Killian PJ,Lawless OJ, Association of myositis and myocarditis in progressive systemic sclerosis. Arthritis and rheumatism. 1981 May     [PubMed PMID: 7236323]
[45] D'Angelo WA,Fries JF,Masi AT,Shulman LE, Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. The American journal of medicine. 1969 Mar     [PubMed PMID: 5780367]
[46] Bulkley BH,Ridolfi RL,Salyer WR,Hutchins GM, Myocardial lesions of progressive systemic sclerosis. A cause of cardiac dysfunction. Circulation. 1976 Mar     [PubMed PMID: 1248080]
[47] Faccini A,Agricola E,Oppizzi M,Margonato A,Galderisi M,Sabbadini MG,Franchini S,Camici PG, Coronary microvascular dysfunction in asymptomatic patients affected by systemic sclerosis - limited vs. diffuse form. Circulation journal : official journal of the Japanese Circulation Society. 2015     [PubMed PMID: 25740209]
[48] Alexander EL,Firestein GS,Weiss JL,Heuser RR,Leitl G,Wagner HN Jr,Brinker JA,Ciuffo AA,Becker LC, Reversible cold-induced abnormalities in myocardial perfusion and function in systemic sclerosis. Annals of internal medicine. 1986 Nov     [PubMed PMID: 3767147]
[49] Mavrogeni SI,Bratis K,Karabela G,Spiliotis G,Wijk Kv,Hautemann D,Reiber JH,Koutsogeorgopoulou L,Markousis-Mavrogenis G,Kolovou G,Stavropoulos E, Cardiovascular Magnetic Resonance Imaging clarifies cardiac pathophysiology in early, asymptomatic diffuse systemic sclerosis. Inflammation & allergy drug targets. 2015     [PubMed PMID: 26374223]
[50] Paik JJ,Wigley FM,Mejia AF,Hummers LK, Independent Association of Severity of Muscle Weakness With Disability as Measured by the Health Assessment Questionnaire Disability Index in Scleroderma. Arthritis care & research. 2016 Nov     [PubMed PMID: 26881982]
[51] Miller WL, Fluid Volume Overload and Congestion in Heart Failure: Time to Reconsider Pathophysiology and How Volume Is Assessed. Circulation. Heart failure. 2016 Aug     [PubMed PMID: 27436837]
[52] Bissell LA,Anderson M,Burgess M,Chakravarty K,Coghlan G,Dumitru RB,Graham L,Ong V,Pauling JD,Plein S,Schlosshan D,Woolfson P,Buch MH, Consensus best practice pathway of the UK Systemic Sclerosis Study group: management of cardiac disease in systemic sclerosis. Rheumatology (Oxford, England). 2017 Jun 1     [PubMed PMID: 28160468]
[53] Avouac J,Fransen J,Walker UA,Riccieri V,Smith V,Muller C,Miniati I,Tarner IH,Randone SB,Cutolo M,Allanore Y,Distler O,Valentini G,Czirjak L,Müller-Ladner U,Furst DE,Tyndall A,Matucci-Cerinic M, Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Annals of the rheumatic diseases. 2011 Mar     [PubMed PMID: 21081523]
[54] Valentini G,Huscher D,Riccardi A,Fasano S,Irace R,Messiniti V,Matucci-Cerinic M,Guiducci S,Distler O,Maurer B,Avouac J,Tarner IH,Frerix M,Riemekasten G,Siegert E,Czirják L,Lóránd V,Denton CP,Nihtyanova S,Walker UA,Jaeger VK,Del Galdo F,Abignano G,Ananieva LP,Gherghe AM,Mihai C,Henes JC,Schmeiser T,Vacca A,Moiseev S,Foeldvari I,Gabrielli A,Krummel-Lorenz B,Rednic S,Allanore Y,Müeller-Ladner U, Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study. Annals of the rheumatic diseases. 2019 Nov     [PubMed PMID: 31391176]
[55] Winter MP,Sulzgruber P,Koller L,Bartko P,Goliasch G,Niessner A, Immunomodulatory treatment for lymphocytic myocarditis-a systematic review and meta-analysis. Heart failure reviews. 2018 Jul     [PubMed PMID: 29862463]
[56] Stack J,McLaughlin P,Sinnot C,Henry M,MacEneaney P,Eltahir A,Harney S, Successful control of scleroderma myocarditis using a combination of cyclophosphamide and methylprednisolone. Scandinavian journal of rheumatology. 2010 Aug     [PubMed PMID: 20476869]
[57] Beers WH,Ince A,Moore TL, Scleredema adultorum of Buschke: a case report and review of the literature. Seminars in arthritis and rheumatism. 2006 Jun     [PubMed PMID: 16765712]
[58] Rongioletti F,Rebora A, Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. Journal of the American Academy of Dermatology. 2001 Feb     [PubMed PMID: 11174386]
[59] Shulman LE, Diffuse fasciitis with eosinophilia: a new syndrome? Transactions of the Association of American Physicians. 1975     [PubMed PMID: 1224441]
[60] Sehgal VN,Srivastava G,Aggarwal AK,Behl PN,Choudhary M,Bajaj P, Localized scleroderma/morphea. International journal of dermatology. 2002 Aug;     [PubMed PMID: 12207760]
[61] Candell-Riera J,Armadans-Gil L,Simeón CP,Castell-Conesa J,Fonollosa-Pla V,García-del-Castillo H,Vaqué-Rafart J,Vilardell M,Soler-Soler J, Comprehensive noninvasive assessment of cardiac involvement in limited systemic sclerosis. Arthritis and rheumatism. 1996 Jul     [PubMed PMID: 8670322]
[62] Ioannidis JP,Vlachoyiannopoulos PG,Haidich AB,Medsger TA Jr,Lucas M,Michet CJ,Kuwana M,Yasuoka H,van den Hoogen F,Te Boome L,van Laar JM,Verbeet NL,Matucci-Cerinic M,Georgountzos A,Moutsopoulos HM, Mortality in systemic sclerosis: an international meta-analysis of individual patient data. The American journal of medicine. 2005 Jan;     [PubMed PMID: 15639201]
[63] Al-Dhaher FF,Pope JE,Ouimet JM, Determinants of morbidity and mortality of systemic sclerosis in Canada. Seminars in arthritis and rheumatism. 2010 Feb     [PubMed PMID: 18706680]
[64] Czirják L,Kumánovics G,Varjú C,Nagy Z,Pákozdi A,Szekanecz Z,Szucs G, Survival and causes of death in 366 Hungarian patients with systemic sclerosis. Annals of the rheumatic diseases. 2008 Jan     [PubMed PMID: 17519276]