[Esthiningrum Dewi Agustin_JR_290125].pptx

[Esthiningrum Dewi Agustin_JR_290125].pptx

1. Primary heart INVOLVEMENT IN SYSTEMIC SCLEROSIS JOURNAL READING Dr. dr. Lita Diah Rahmawati, Sp.PD , K-R dr. Esthiningrum Dewi Agustin

2. Sources Nadel A, Nadel M, Taborska N, Stepien B, Gajdecki J, Brzezinska O, et al. Heart involvement in patients with systemic sclerosis-what have we learned about it in the last 5 years. Rheumatol Int. 2024;44(10):1823-36. Batani V, Dagna L, De Luca G. Therapeutic strategies for primary heart involvement in systemic sclerosis. Rheumatol Immunol Res. 2024;5(2):72-82. Denton CP, De Lorenzis E, Roblin E, Goldman N, Alcacer-Pitarch B, Blamont E, et al. The 2024 British Society for Rheumatology guideline for management of systemic sclerosis. Rheumatology (Oxford). 2024;63(11):2956-75.

3. OUTLINE Introduction Pathophysiology of Cardiac Complications in Systemic Sclerosis Risk Factors of Systemic Sclerosis Heart Involvements ( SSc -HI) Arrythmia Heart Failure Pericardial Diseases Valvular Heart Diseases Diagnostic Approach of SSc -HI Treatment What the Guideline Says

4. INTRODUCTION Systemic sclerosis ( SSc ) is a connective tissue disease (CTD) with pooled global prevalence of 17.6 per 100,000 individuals . The clinical hallmarks: fibrosis of the skin and internal organs with concomitant vasculopathy . SSc -associated heart involvement ( SSc -HI) is one of the most frequent complications causing death. A n extensive review uncovered a broad spectrum of estimated clinical prevalence rates for heart involvement in SSc , ranging from 7% to over 39%  the necessity to evaluate the heterogeneity in defining heart involvement across studies.

5. Primary heart involvements in SSc

6. Pathophysiology of cardiac complications Cardiac complication in SSc is cause by the complex nature of the disease , such as vessel damage , vasoconstriction , chronic-ischemia-reperfusion injury , cardiac inflammation and fibrosis --> damaging the heart structure. Vascular hypothesis: intermittent vascular spasm, ischemic necrosis, and reperfusion injury  the most well known mechanism leading to fibrogenesis. IL-1, IL-6 are crucial for cardiac inflammation and subsequent fibrosis.

7. RISK FACTORS of SSc -Hi Male gender Age of onset >= 65 Diffuse cutaneous SSc Presence of anti-topoisomerase antibodies with rapid progression of skin thickness Presence of tendon friction rubs, digital ulcers, lung involvement, and myositis Patients with anti-Th/To Presence of other antibodies : anti-Ku, anti-Histone, anti-RNA polymerase, and anti-U3-RNP antibodies

8. Primary heart involvement in systemic sclerosis Arrythmia Heart Failure Myocarditis Pericardial disease Valvular disease

9. Arrythmia Patients with SSc have an increased risk of conduction and rhythm disorders both at disease onset and over time, compared to individuals without SSc . Accounts for 6% of deaths among patients with SSc . Arrythmia occurs due to microvascular injury, subsequent fibrosis development, and autonomic dysfunction. The most frequent rhythm disorder: PVCs Patients with SSC have a two fold higher risk of AF.

10. Heart failure In SSC, left and right ventricles might be affected due the vessel obliteration and arteriolar endothelial injury resulting in myocardial fibrosis. Among patients hospitalized due to HF, those with SSc had a higher likelihood of in-hospital mortality compared to those without SSc . LVEF was reduced in SSc patients compared with control individuals. Risk factors of LVSD in SSc : high mRSS , steroid use, elevated creatinine kinase The administration of MMF could help prevent the progression of LVSD LVSD, left ventricular systolic dysfunction

11. Pericardial disease Can manifest as either acute or chronic. Cardiac tamponade was less common, occurring in 0.2% of patients with pericardial effusion, with a higher incidence among those with a history of atrial fibrillation. Patients with pericardial effusion often present with pulmonary circulatory diseases, PAH, congestive heart failure, and end-stage renal disease. Persistent pericardial effusion in SSc -PAH patients is linked to poorer survival outcomes Echocardiography: the initial approach to assess pericardial involvement PAH, pulmonary arterial hypertension

12. Valvular diseases The prevalence is often underestimated Primarily linked with tricuspid regurgitation secondary to pulmonary artery hypertension. Danish nationwide cohort study explained that aortic stenosis, aortic regurgitation, and mitral regurgitation are three, four, and five times higher in SSc patients compared to general population, consecutively. Systematic echocardiography screening is recommended to achieve early VHD detection.

13. Diagnostic approach of SSc -HI Echocardiography Cardiac magnetic resonance Positron emission tonography Lab biomarkers.

14. Echocardiography Wide availability, low cost, fine safety. Done during initial patient evaluation Recommended technique: STE  estimating myocardial deformation by measuring myocardial strain, usually used in monitoring cardiotoxic drug therapy or defining the etiology of certain cardiomyopathies. GLS: represents impairment of left and right ventricular function, as well as damage of the basal and mid segments of the anterior, lateral, and infero -basal walls. GLS tends to decrease during several years of evaluation rather than LVEF. Deformation parameters : left ventricular global longitudinal strain, left ventricular global circumferential strain, left ventricular global radial strain, right ventricular global wall strain, both left and right atrial conduit strain  all indicate impaired myocardium involving both the ventricle and the atrium. STE, speckle tracking echocardiography ; GLS, global longitudinal strain

15. Cardiac magnetic resonance (CMR) A complementary method to echocardiography Able to detect both left and right ventricular diastolic dysfunction, myocardial strain, and perfusion among newly diagnosed patients, even in those without significant abnormalities in echocardiography LGE: reliable mark of myocardial fibrosis , detectable in CMR. Focal LGE fibrosis  significantly higher Rodnan skin Parametric mapping: allows the visualization of tissue properties (T1 and T2 relaxation)  the presence and extent of diffuse myocardial fibrosis and the presence of inflammation LGE, late gadolinium enhancement

16. POSITRON EMISSION Tomography Finding: Reduced myocardial flow reserve , pathological fluorodeoxyglucose (FDG) uptake suggesting myocardial inflammation in 50% of asymptomatic SSc patients The most recent discovery: PET tracer for assessment of fibroblast activation to detect myocardial fibrosis.

17. Biomarkers Recommended typical biomarkers: NT- proBNP , high sensitive troponin  detect subclinical cardiac involvement. Troponin I: specific to myocardial tissue; Troponin T: observed in regenerating skeletal muscle tissue Ongoing research : AHA and AIDA --> more prevalent in SSC patients than in control. Angiopoeitin 2, osteopontin , and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are associated with left and right ventricular dysfunction in SSc Non-typical biomarkers: ESR, CRP, CK. AHA, anti-heart antibodies; AIDA, anti-intercalated disk autoantibodies,; ESR, erythrocyte sedimentation rate, CRP, C-reactive protein, CK, creatinine kinase

18. SSc -HI monitoring and EVALUATION

19. Treatment (DMARDs) such as azathioprine (AZA), MMF, methotrexate (MTX), and cyclophosphamide (CYC), either alone or in combination with glucocorticosteroids (GCs), have exhibited positive outcomes in SSc myocarditis. Possible beneficial agents: anti IL-1 and anti IL-6

20. Treatment (2) Targeting myocardial inflammation Targeting myocardial fibrosis Corticosteroid DMARD Biologic agents Hematopoietic Stem Cell Transplantation Nintedanib Targeting vasculopathy Vasodilators and antiplatelet agents

21. Corticosteroid an open-label pilot study: 12 patients were treated with a dose equivalent to prednisolone 0.5 mg/kg/d for 2-weeks , then tapered off 10 mg every 2 weeks until 10 mg/d at week 4, then slowly tapered off completely by 24-weeks. At the end of treatment, 8 out of the 12 patients experienced a clinical improvement of myocarditis. Carrete et al declared resolution of myocardial edema after treatment with pulse methylprednisolone (1 g/ m2 i.v. for 3 consecutive days, followed by 20 mg i.m. for 30 days, then maintained at 4 mg/day) Glucocorticoids should be prescribed judiciously due to an elevated risk of precipitating scleroderma renal crisis

22. Dmard Stack et al . firstly described a case of myocarditis in a rapidly progressive diffuse cutaneous SSc successfully treated with a total of 12 pulsed intravenous (IV) cyclophosphamide (10 mg/kg monthly) and methylprednisolone (0.5 mg/kg given for 3 days each month with a maintenance dose of prednisolone 70 mg once daily between cycles), before receiving mycophenolate mofetil (MMF) and prednisolone 20 mg once daily as maintenance therapy. prednisone (1 mg/kg/day) plus azathioprine (2 mg/kg/ day ) improve patients’ outcome  azathioprine has been used in recent years as first-line therapy to curb myocardial inflammation in cardiomyopathies. MMF has been used in SSc-pHI both as first-line agent , or as maintenance therapy after cyclophosphamide , or as second-line therapy in patients intolerant or resistant to azathioprine , and regardless of steroid dosage

23. Biologic therapies Preceding studies have disclosed the use of rituximab, intravenous immunoglobulin in patients with diffuse Ssc and severe cardiac involvements resulting in progressive improvement of respiratory effort and ejection fraction . Anakinra (anti-IL1) has never been reported before. The administration of tocilizumab may overcome SSC-related myocarditis.

24. Hematopoietic Stem Cell Transplantation has been shown to be superior to treatment with intravenous cyclophosphamide

25. NINTEDANIB A selective inhibitor of certain tyrosine kinases rece ptor , including vascular-endothelial growth factor receptor (VEGFR)-1–2–3, platelet-derived growth factor receptor (PDGFR)- α and β , and fibroblasts growth factor receptor (FGFR)-1–2–3 Nintedanib attenuates macrophage activation and mitigates both vascular and fibrotic presentations in the Fra2 transfenic mouse model of SSc In the SSc patients, M2 macrophage in peripheral blood is upregulated  myocardial remodelling Nintedanib has an antifibrotic activity correlating with impairment in M2 monocyte polarization and M2 macrophage population decrement.

26. Vasodilators and antiplatelet agents The use of vasodilators was associated with lower incidence of ventricular arrhythmias L ow-dose aspirin was associated with lower incidence of Q waves, conduction blocks and/or pacemaker implantation

27. What the guidelines say:

28. SCREENING and Diagnosis of SSC- pHI A multi-speciality team should inform the management and treatment of possible SSc-pHI and other cardiovascular pathology should be excluded ( 1C , 100%). Screening for pHI (in asymptomatic individuals ) should be undertaken in all people with SSc on an annual basis . This would typically comprise ECG, ECHO and serum troponin (ideally, I or T) and NTpro BNP (or BNP in renal disease) ( 2C , 96%). Where pHI is suspected, diagnostic work up should include CMR . Endomyocardial biopsy should only be considered in selected cases, after exclusion of coronary artery disease. Holter monitor should be performed to detect arrhythmic burden ( 2C , 96%). Screening with CMR (or other sensitive cardiovascular imaging) may be considered in high-risk individuals ( male gender, diffuse cutaneous skin subset, anti- topoisomerase I, early disease, presence of interstitial lung disease, peripheral myositis, and other inflammatory manifestations ) ( 2C , 95%). In jSSC with suspected pHI , a formal assessment by a paediatric cardiologist is recommended ( 1C , 100%).

29. SSC-PHI and HEART FAILURE WITH reduced ejection fraction ( hfref ) First exclude other aetiologies for HFrEF including coronary artery disease and perform CMR to confirm diagnosis attributable to SSc ( 1C , 95%). Having excluded other aetiologies, consider immunosuppression as detailed above with observed reduction in EF ( 2C , 91%). Medical therapy should be undertaken collaboratively with a heart failure team and the following treatments considered: (a ) Loop diuretics (for fluid retention); (b) the ‘four pillars of heart failure’, namely: ( i ) beta block- ers ; (ii) angiotensin converting enzyme inhibitors ( ACEi )/ angiotensin II receptor blockers (ARB)/angiotensin II receptor- neprilysin inhibitor (ARNI ); (iii) mineralocorticoid receptor antagonists (MRA); (iv) sodium glucose co-transporter-2 inhibitors (SGLT2i, such as dapagliflozin, empagliflozin) . Consider increased risk of urinary tract infection with SGLT2 inhibitors and worsening of digital vasculopathy with beta blockers ( 1C , 98%). Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure should be considered as per NICE Technology Appraisal Guidance [TA314] and ESC guidelines; those not fulfilling criteria may warrant discussion with the multi-disciplinary team ( 2C , 95%). Calcium channel blockers may reduce the frequency of systolic heart failure in SSc with evidence of vasodilator therapy and low-dose aspirin reducing manifestations of pHI in individuals with LVEF<55% ( 2C , 85%).

30. Ssc -phi and heart failure with preserved ejection fraction ( hfpef ) First exclude other aetiologies for HFpEF and apply CMR to confirm diagnosis secondary to SSc ( 1C , 99%). Medical therapy should be undertaken with a heart failure team and using standard treatments including diuretics for management of fluid overload (e.g. furosemide and spironolactone). SGLT2 inhibitors (dapagliflozin, empagliflozin) may improve outcome and are recommended. Increased risk of urinary tract infection with SGLT2 inhibitors should be considered in the context of immunosuppression, with appropriate counselling ( 1C , 95%).

31. RECOMMENDATIONS ON THE USE OF IMMUNOSUPPRESIVE AGENTS OF SSC-phi Immunosuppression with MMF should be considered in SSc-pHI when investigation suggests myocardial inflam-mation . Glucocorticoids may also be added to MMF (although risk of SRC in adults should warrant caution) ( 2C , 95%). Other bDMARDs (rituximab, tocilizumab,) may be added to MMF therapy if appropriate and/or cyclophosphamide ( 2C , 89%). Immunosuppression with MMF may be considered for SSc-pHI with evidence of myocardial fibrosis although robust studies are lacking. Evidence of myocardial fibro- sis may support additional treatment as indicated in (ii) ( 2C , 92%).

32. Thank you.