Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by widespread microvascular damage, dysregulation of fibroblasts with collagen overproduction and excessive fibrosis of the skin and internal organs, as well as complex immune system abnormalitie\u2026

Boriani, Giuseppe

Colaci, Michele

Coppi, Francesca

Farinetti, Alberto

Ferri, Clodoveo

Giuggioli, Dilia

Lumetti, Federica

Mattioli, Anna Vittoria

Migaldi, Mario

Rossi, Rosario

Spinella, Amelia

English

Francesca Coppi

Dilia Giuggioli

Amelia Spinella

Michele Colaci

Federica Lumetti

Alberto Farinetti

Mario Migaldi

Rosario Rossi

Clodoveo Ferri

Giuseppe Boriani

Anna Vittoria Mattioli

Crossref

Journal of Cardiovascular Medicine

Cardiac involvement in systemic sclerosis

Systemic sclerosis is a chronic connective tissue disease characterized by widespread microvascular damage, dysregulation of fibroblasts with collagen overproduction and excessive fibrosis of the skin and internal organs, as well as complex immune system abnormalitie

Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

Cardiac involvement in systemic sclerosis: identification of high-risk patient profiles in different patterns of clinical presentation

Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by widespread microvascular damage, dysregulation of fibroblasts with collagen overproduction and excessive fibrosis of the skin and internal organs, as well as complex immune system abnormalitie...

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

Research letterCardiac involvement in systemic sclerosis: identificationof high-risk patient profiles in different patterns ofclinical presentationFrancesca Coppia,, Dilia Giuggiolib,, Amelia Spinellab,, Michele Colacib,,Federica Lumettib,, Alberto Farinettic,, Mario Migaldic,, Rosario Rossic,,Clodoveo Ferrib,, Giuseppe Borianid, and Anna Vittoria Mattiolic,J Cardiovasc Med 2018, 19:393–395aCardiology Division, Azienda Ospedaliera Modena, bDepartment of Medical andSurgical Sciences, cDepartment of Surgical, Medical and Dental Department ofMorphological Sciences related to Transplant, Oncology and RegenerativeMedicine, University of Modena and Reggio Emilia and dCardiology Division,Department of Diagnostics, Clinical and Public Health Medicine University ofModena and Reggio Emilia, Policlinico di Modena, Modena, ItalyCorrespondence to Anna Vittoria Mattioli, Department of Surgical, Medical andDental Department of Morphological Sciences related to Transplant, Oncologyand Regenerative Medicine, University of Modena and Reggio Emilia, Via delpozzo, 71 41100 Modena, ItalyTel: +39 59 4224043; fax: +39 59 4224323;e-mail: annavittoria.mattioli@unimore.itReceived 12 October 2017 Revised 15 December 2017Accepted 30 April 2018Letter to the editorSystemic sclerosis (SSc) is a chronic connective tissuedisease characterized by widespread microvascular dam-age, dysregulation of fibroblasts with collagen overproduc-tion and excessive fibrosis of the skin and internal organs,as well as complex immune system abnormalities.1–3Patients are classified into the diffuse cutaneous form ofSSc (dcSSc) when skin thickening extends to the trunkand the proximal part of the limbs, and into the limitedcutaneous form (lcSSc) when skin induration is limited toface, hands and feet.4The heart is the major organ involved in SSc, being a poorprognostic factor and the leading cause of mortality.5,6Cardiac involvement is reported in 15–20% of patientsand when sensitive tools are used, it has been estimatedto occur in up to 100% of SSc patients.1,4The aim of the present study was to investigate cardiacinvolvement in different patterns of SSc in order toidentify patients at high risk of cardiopulmonaryimpairment.MethodsWe retrospectively analyzed data from 241 consecutiveSSc patients referred to our University-based Rheuma-tology Centre from January 1999 to January 2014 (F/MFrancesca Coppi, Dilia Giuggioli and Amelia Spinella equally contributed to thewriting of this article.1558-2027  2018 Italian Federation of Cardiology. All rights reserved.205/36; mean age 50.8 14.7 years; mean disease dura-tion 10.9 7.0). In all cases, the diagnosis of SSc was doneby an expert rheumatologist on the basis of a wider panelof clinical, serological and capillaroscopic parameters;moreover, they satisfied the new ACR/EULAR classifi-cation criteria.7 Patients were classified on the extent ofskin sclerosis as limited cutaneous scleroderma (lcSSc)and diffuse cutaneous scleroderma (dcSSc).4 All patientsunderwent baseline and periodically clinical evaluation,including demographic, serological and laboratory, pul-monary and cardiological evaluation.The protocol was approved by Local Ethical Committee(pr # 10693 25/05/2016). All patients signed an informedconsensus document.Serum autoantibodiesThe presence of serum autoantibodies was investigatedby means of standard techniques: antinuclear (ANA),anticentromere (ACA) and antinucleolar antibodies byindirect immunofluorescence on Hep-2 cell lines; anti-extractable nuclear antigen antibodies, including anti-Scl70, anti-Sm, anti-RNP, anti-SSA/SSB; antiphospholi-pid antibodies; liver autoimmune profile; rheumatoidfactor and antibodies to cyclic citrullinated peptide.Cardiac assessmentCardiac assessment was performed every 6 months andincluded clinical evaluation, ECG and Doppler echocar-diography.8–12 Cardiac risk stratification was performedaccording to Framingham Score.7 The right heart cathe-terization, when indicated, was performed according tocurrent methodologies.12,13Statistical analysisStatistical analysis was performed using SPSS (IBM soft-ware, New York, version 22.0). We performed a logisticregression analysis to investigate the possible correlationoutcome and cardiopulmonary involvement.Comparison of data between groups was performed byANOVA. The t-test was used to compare data withingroups. P< 0.05 was considered statistically significant.DOI:10.2459/JCM.0000000000000676394 Journal of Cardiovascular Medicine 2018, Vol 19 No 7Table 1 Clinical features, antibodies panel and biomarkersParameter lcSSc dcSSc PSex, F/M 180/29 25/7Age (years) 51.8414.55 43.7814.14 0.0039Follow-up duration (months) 67.1441.86 65.2536.191 nsDisease duration (years) 117.12 10.566.42 nsDeath (%) 32 (15.30) 6 (18.75) nsRaynaud (%) 208 (99.50) 31 (96.80) nsDigital ulcers (%) 104 (49.76) 25 (69.70) 0.02Myositis 9 (4.30) 7 (18.75) 0.007Arthitis 32 (15.30) 7 (18.75) nsSCl 70 antibodies 61 (29.00) 27 (75.00) 0.0025ACA antibodies 88 (42.00) 3 (9.3) 0.0081ANOA antibodies 35 (16.7) 5 (12.50) nsESR 51 (24.4) 18 (50) 0.05CRP 34 (16.2) 15 (40) 0.025Uric acid 10 (4.78) 3 (6.25) nsCreatinine 13 (6.2) 7 (18.75) 0.04ACA, anticentromere; ANOA, antinucleolar antibodies; CRP, C-reactive protein;dcSSc, diffuse cutaneous form of SSc; ESR, erythrocyte sedimentation rate;lcSSc, limited cutaneous form.ResultsThirty-two patients had dcSSc (13.27%) whereas 209patients had lcSSc (86.73%). We did not report differ-ences in sex and duration of disease, whereas dcSScpatients were younger than lcSSc (43.78þ 14.14 yearsvs. 51.84þ 14.55 years; P< 0.01; Table 1). The follow-upduration was similar in the two groups of patients andlasted 65.25 months in dcSSc and 67.14 in lcSSc (P¼ns).Autoimmune and biomarkers patternSCl 70 was positive in a greater number of patients withdcSSc compared with lcSSc (P¼ 0.0025); on the contraryFig. 110.950.90.850.80.75Cum. Survival0.70.650.610 20 30 40MonthsSurvival functionsSurvival curves of patients with and without skin ulcers.a greater number of patients with lcSSc developed ACAantibodies (P¼ 0.0081).Patients with dcSSc showed a higher inflammatory statuswith increased erythrocyte sedimentation rate and CPRvalue (Table 1).Cardiac involvementCardiovascular involvement at baseline was present in107 (51.2%) patients with lcSSc and in 13 patients(40.6%) with dcSSc. According to baseline data, we didnot find differences between the limited and the diffusepresentation of SSc. However, the presence of skin ulcerswas predictive of cardiac involvement [odds ratio (OR)1.2; 95% CI 1.01–1.91; P< 0.05]. Then we categorizedpatients according to the presence of skin ulcers.14 Skinulcers were more frequent in dlSSc patients (7.9 vs. 18.1;P¼ 0.05).Moreover, patients with ulcers showed a greater cardiacinvolvement. Specifically, they had more ECG alterationand ischemia (36 vs. 64%; P< 0.05). Left ventricularejection fraction was also reduced in patients with ulcers(60 4 vs. 58 5; P< 0.01) and diastolic dysfunctionshowed deterioration during follow-up. Patients with skinulcers had a greater cardiac mortality with a trend tosignificance (11.4 vs. 19.7%; P¼ 0.08; Fig. 1).CommentThe present article evaluated the cardiac involvement inpatients affected by SSc, in order to identify high-riskpatients. Cardiac involvement is frequent in SSc and is50 60Patients with skin ulcerPatients without skin ulcerResearch letter Coppi et al. 395the most frequent cause of death.4,15,16 The detection ofcardiac manifestation in the early stage of the disease aswell as their careful monitoring and follow-up are recom-mended to counteract their impact on the overall diseaseoutcome. However, little information is available aboutthe timing of cardiac involvement.17We found that dcSSc patients had a greater inflammatoryactivation. A different immune pattern with a higherprevalence of SCl 70 antibodies in patients having dcSScand a higher prevalence of ACA antibodies in patientswith lcSSc was reported. Patients with ACA antibodiesshowed a greater cardiopulmonary involvement suggest-ing a worse prognosis. However, because of the lownumber of patients, we need more data to clarify theprognostic role of antibodies.18,19The most significant parameter in prediction of outcomewas the presence of skin ulcers.14 We identify patientswith skin ulcers as high-risk patients for cardiac disease.This confirms the analysis from the EUSTAR database.20These patients showed an increase in the number ofarrhythmias during the follow-up; they mainly developedatrial fibrillation and supraventricular arrhythmias.Arrhythmias are associated with poor outcome and rep-resent 6% of the overall causes of death in the largeEULAR Scleroderma Trials and Research database.21,22In addition, our population of patients with skin ulcersshowed a greater cardiac dysfunction involving both leftand right sides of the heart and a greater deterioration ofcardiac function over the follow-up.In conclusion, cardiac involvement occurs frequently inSSc, can manifest in various ways and it is associated witha poor prognosis. There is little evidence on how best todetect and manage this fearful complication in SSc.According to our results, patients with skin ulcers arepatients with high-risk profile of cardiovascular eventsand need a tight follow-up. A multidisciplinary cardior-heumatologic team is necessary to identify these high-risk patients.Additional research by large population-based studies isneeded in order to identify possible subsets of SSc patientsat increased risk of cardiopulmonary complications.AcknowledgementsWewould like to thankMrs Jane Ann Carter for languageediting and Dr Matteo Ballerini Puviani for his help ingraphical editing.Conflicts of interestThere are no conflicts of interest.References1 Ferri C, Sebastiani M, Lo Monaco A, et al. Systemic sclerosis evolution ofdisease pathomorphosis and survival: our experience on Italian patients’population and review of the literature. Autoimmun Rev 2014; 13:1026–1034.2 Medsger TA Jr, Steen VD. Classification and prognosis. In: Clements PJ,Furst DE, editors. Systemic sclerosis. Philadelphia: Williams & Wilkins;2004. pp. 51–64.3 Denton CP. Systemic sclerosis: from pathogenesis to target therapy. ClinExp Rheumatol 2015; 33 (4 Suppl 92):S3–S7.4 Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic,clinical, and serologic features and survival in 1,012 Italian patients.Medicine 2002; 81:139–153.5 Champion HC. The heart in scleroderma. Rheum Dis Clin North Am 2008;34:181–190.6 Meune C, Vignaux O, Kahan A, Allanore Y. Heart involvement in systemicsclerosis: evolving concept and diagnostic methodologies. ArchCardiovasc Dis 2010; 103:46–52.7 Kannel WB, D’Agostino RB, Sullivan L, Wilson PWF. Concept andusefulness of cardiovascular risk profiles. Am Heart J 2004; 148:16–26.8 Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiacchamber quantification by echocardiography in adults: an update from theAmerican Society of Echocardiography and the European Association ofCardiovascular Imaging. J Am Soc Echocardiogr 2015; 28:1.e14–39.e14.9 Ciccone MM, Bilianou E, Balbarini A, et al. Task force on: ’Early markers ofatherosclerosis: influence of age and sex’. JCardiovascMed (Hagerstown)2013; 14:757–766.10 Mattioli AV, Sansoni S, Lucchi GR. Serial evaluation of left atrial dimensionafter cardioversion for atrial fibrillation and rekation to atrial function. Am JCardiol 2000; 85:832–836.11 Piccinino C, Giubertoni A, Zanaboni J, et al. Incremental value of right atrialstrain for early diagnosis of hemodynamic deterioration in pulmonaryhypertension: a new noninvasive tool for a more comprehensive diagnosticparadigm. J Cardiovasc Med 2017; 18:866–874.12 Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterialhypertension in systemic sclerosis: a French Nationwide ProspectiveMulticenter Study. Arthritis Rheum 2005; 52:3792–3800.13 Galie` N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for thediagnosis and treatment of pulmonary hypertension. The Joint Task Forcefor the Diagnosis and Treatment of Pulmonary Hypertension of theEuropean Society of Cardiology (ESC) and the European RespiratorySociety (ERS). Eur Respir J 2015; 46:903–975.14 Giuggioli D, Manfredi A, Lumetti F, et al. Scleroderma skin ulcers definition,classification and treatment strategies our experience and review of theliterature. Autoimmun Rev 2018; 17:155–164.15 Sarzi-Puttini P, Atzeni F, Gerli R, et al. Cardiac involvement in systemicrheumatic diseases: an update. Autoimmun Rev 2010; 9:849–852.16 Allanore Y, Meune C. Primary myocardial involvement in systemic sclerosis:evidence for a microvascular origin. Clin Exp Rheumatol 2010; 28 (5Suppl 62):S48–S53.17 Lambova S. Cardiac manifestations in systemic sclerosis. World J Cardiol2014; 6:993–1005.18 Bartoloni E, Shoenfeld Y, Gerli R. Inflammatory and autoimmunemechanisms in the induction of atherosclerotic damage in systemicrheumatic diseases: two faces of the same coin. Arthritis Care Res(Hoboken) 2011; 63:178–183.19 Cannarile F, Valentini V, Mirabelli G, et al. Cardiovascular disease insystemic sclerosis. Ann Transl Med 2015; 3:8.20 Wirz EG, Jaeger VK, Allanore Y, EUSTAR coauthors. Incidence andpredictors of cutaneous manifestations during the early course of systemicsclerosis: a 10-year longitudinal study from the EUSTAR database. AnnRheum Dis 2016; 75:1285–1292.21 Roberts N, Cabeen W, Moss J, et al. The prevalence of conduction defectsand cardiac arrhythmias in systemic sclerosis. Ann Intern Med 1981;94:38–40.22 Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death insystemic sclerosis: a study from the EULAR Scleroderma Trials andResearch (EUSTAR) database. 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Cardiac involvement in systemic sclerosis: identification of high-risk patient profiles in different patterns of clinical presentation

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Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

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