Bosentan for digital ulcers prevention does not worsen cardiopulmonary

exercise test parameters in SSc patients with interstitial lung diseas

Amoroso, Daria

Barbano, Biagio

DI PAOLO, Marcello

Gigante, Antonietta

Palange, Paolo

Romaniello, Antonella

Rosato, Edoardo

Tallerini, Gaia

English

Antonella Romaniello

Antonietta Gigante

Marcello Di Paolo

Gaia Tallerini

Biagio Barbano

Daria Amoroso

Paolo Palange

Edoardo Rosato

Crossref

International Journal of Cardiology

Bosentan for digital ulcers prevention does not worsen cardiopulmonary exercise test parameters in SSc patients with interstitial lung disease

Bosentan for digital ulcers prevention does not worsen cardiopulmonary
exercise test parameters in SSc patients with interstitial lung diseas

GIGANTE, ANTONIETTA

DI PAOLO, MARCELLO

BARBANO, BIAGIO

PALANGE, Paolo

ROSATO, Edoardo

Archivio della ricerca- Università di Roma La Sapienza

International Journal of Cardiology 223 (2016) 113–115Contents lists available at ScienceDirectInternational Journal of Cardiologyj ourna l homepage: www.e lsev ie r .com/ locate / i j ca rdCorrespondenceBosentan for digital ulcers prevention does not worsen cardiopulmonaryexercise test parameters in SSc patients with interstitial lung diseaseAntonella Romaniello a, Antonietta Gigante b,⁎, Marcello Di Paolo c, Gaia Tallerini b, Biagio Barbano b,Daria Amoroso d, Paolo Palange c, Edoardo Rosato ba Sapienza University of Rome, Department of Clinical and Molecular Medicine, Cardiology Unit, Italyb Sapienza University of Rome, Department of Clinical Medicine, Clinical Immunology Unit-Scleroderma Center, Italyc Sapienza University of Rome, Department of Public Health and Infectious Diseases, Italyd Sapienza University of Rome, Department of Emergency Medicine, Italy⁎ Corresponding author at: Sapienza University of RMedicine, Clinical Immunology Unit Scleroderma Center,Rome, Italy.E-mail address: antonietta_gigante@yahoo.it (A. Giganhttp://dx.doi.org/10.1016/j.ijcard.2016.08.0950167-5273/© 2016 Elsevier Ireland Ltd. All rights reserveda r t i c l e i n f oArticle history:Received 1 July 2016Accepted 5 August 2016Available online 6 August 2016Keywords:duration of disease was 4.3 (1–14) years. Four patients had limitedcutaneous SSc and eight had diffuse cutaneous SSc.All SSc patients underwent treatmentwith calcium channel blockers(Nifedipine 30 mg/day). None of the patients were treated with immu-nosuppressive agents. Scleroderma patients with coronary arteryCardiopulmonary exercise testSystemic sclerosisPulmonary arterial hypertensionInterstitial lung diseaseEndothelin receptor antagonistsPulmonary arterial hypertension (PAH) and interstitial lung disease(ILD) are serious pulmonary complications in patients with Systemicsclerosis (SSc) [1] and despite recent advances in the treatment, remainthe major causes of death. Bosentan, a dual endothelin-1 receptorantagonist is an effective approach to therapy for PAH, improvingpulmonary hemodynamics and functional capacity, and it is also ableto reduce the number of new digital ulcers in patients with SSc [2].By contrast, Endothelin-1 receptor antagonist administered in idiopath-ic pulmonary fibrosis was not associatedwith clear benefits increasing riskfor disease progression and respiratory hospitalizations [3].The aim of this study is to evaluate the effects of bosentan adminis-tered as prevention for digital ulcers (DUs), in SSc patients affected byILD, at baseline and post therapy with cardiopulmonary exercise test(CPET) and pulmonary function tests (PFT).Twelve consecutive SSc patients [8 females and 4males;median age45 years (35–60)] in bosentan therapy for DUs prevention wereenrolled in this study. Median duration of disease was 4.5 (1–15)years. Four patients had limited cutaneous SSc and eight had diffusecutaneous SSc.ome, Department of ClinicalViale dell'Università 37, 00185te)..Twelve consecutive SSc patients [9 females and 3males;median age46 years (37–58)] were enrolled in this study as control group. Mediandisease, congestive heart failure, left ventricular dysfunction, pulmo-nary hypertension, valvular abnormalities and arrhythmias were notincluded in the study. Patients with diabetes mellitus, renal failure, he-patic or thyroid dysfunction and anemia were excluded. Patients werenot taking β-blockers, antiarrhythmic drugs, ACE inhibitors orangiotensin receptor antagonists.The subjects'written consentwas obtained according to theDeclara-tion of Helsinki and the study was approved by the Ethics Committee ofthe Sapienza University. All examined patients underwent clinical eval-uation, electrocardiography, transthoracic echocardiogram, baselinePFT and high resolution computed tomography (HRCT) of the chest. Amaximal symptom-limited CPET was performed on an electronicallybraked cycloergometer (Ergoline-800, Mortara, Bologna, Italy) accord-ing to the recommendations on the use of exercise testing in clinicalpractice [4]. The SSc patients with DUs underwent to CPET beforebosentan therapy (T0) and 24 months after bosentan therapy (T1). ASSc group matched for sex and age was enrolled as control group andunderwent to CPET at enrollment (T0) and after 24 months (T1).All data were expressed asmedian and range. TheMann–Whitney Utest or the Kruskal–Wallis was used to test differences between twoindividual study groups. P-values b0.05 were considered significant.In the SSc patients group treatedwith bosentanwe did not observedany significant (p N 0,05) modification of PFTs and CPET parametersafter 24 months of bosentan therapy (Table 1). The median value ofsingle-breath carbon monoxide (CO) diffusing capacity (DLCO) was80,6% (66,6–101,4%) at baseline and 72,5% (63,1–90,2%) post bosentantherapy. Also the relation between minute ventilation (VE) and carbondioxide output (VCO2) (VE/VCO2 slope) did not showed any significantmodification (p N 0,05) post bosentan therapy: 26,4 (18,2–51,2) vs 26,7(21,4–44,4).Also in SSc control group we did not observed any significant modi-fication of PFTs and CPET parameters at T1 (Table 1). The median valueTable 1Pulmonary function tests (PFT) and cardiopulmonary exercise test parameters in SSc patients in bosentan therapy and in SSc control group. All PFTs parameters are expressed as percent-age of predicted.SSc patients in bosentan therapy SSc control groupPre Post Pre PostFVC (%) 87,3 (62,6–108,8) 79,8 (56,8–102,9) 112,3 (61,5–120) 113,3 (71,9–121,5)FEV1 (%) 87,3 (65,2–104,8) 85,8 (59–106,2) 108,9 (50,8–134) 107,5 (68,3–131,8)DLCO (%) 80,6 (66,6–101,4) 72,5 (63,1–90,2) 78,9 (64,5–110) 78,8 (56–102,5)VO2 max (L/min) 1335 (938–2048) 1293 (902–1867) 1328 (883–2521) 1259 (842–2095)VE/VCO2 slope 26,4 (18,2–51,2) 26,7 (21,4–44,4) 29,5 (21,2–38,4) 25,8 (20,3–32,9)PAPs (mm Hg) 26,5 (18–36) 27 (23−33) 30 (25–37) 29 (25–35)FVC: Forced vital capacity, FEV1: forced expiratory volume in the 1st second,DLCO: single-breath carbonmonoxide (CO)diffusing capacity, VO2max:maximal oxygen consumption, PAPs:pulmonary artery systolic pressure, VE/VCO2 slope: VE/VCO2 slope: relation between minute ventilation (VE) and carbon dioxide output (VCO2).114 Correspondenceof DLCO was 78,9% (64,5–110,4%) at baseline and 78,8% (56–102,5%) atT1. Also The VE/VCO2 slope did not show any significant modification aT1: 29,5 (21,2–38,4) vs 25,8 (20,3–32,9) (Fig. 1).In our study bosentan was safe in SSc patients with ILD not causingimbalance ventilation perfusion as shownby parameters VE/VECO2 slope.It is well known that in SSc patients endothelin 1 (ET-1) is able toinduce fibroblast chemotaxis and proliferation [5]. Although bosentanhas not shown antifibrotic effects, it is safe in the treatment of vascularcomplications of SSc patients with ILD [6].However, these vasodilators can worsen pulmonary hemodynamic,producing an imbalance ventilation/perfusion due to inhibition ofhypoxic pulmonary vasoconstriction [7].Rosato et al. have demonstrated that VE/VCO2 slope correlates withdisease severity and activity, thus suggesting a relationship betweenFig. 1. DLCO and VE/VECO2 slope in SSc patients in bosthis marker of ventilation-perfusion mismatch and SSc severity [8].Moreover CPET was able to detect the early renal and cardiopulmonarydamage in asymptomatic SSc patients [9].Thus, CPET is useful to assess ventilation/perfusion in ILD SScpatients to evaluate any vasodilators side effects.In conclusionwe can assume that bosentan, administered to preven-tion digital ulcers in SSc patients affected by ILD without PAH, do notcause a worsening CPET parameters and gas exchange.Conflict of interestThe authors report no relationships that could be construed as a con-flict of interest.entan therapy (T0–T1) and control group (T0–T1).115CorrespondenceReferences[1] V.D. Steen, T.A. Medsger Jr., Changes in causes of death in sistemic sclerosis,1972–2002, Ann. Rheum. Dis. 66 (2007) 940–944.[2] M. Matucci-Cerinic, C.P. Denton, D.E. Furst, et al., Bosentan treatment of digital ulcersrelated to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind,placebo-controlled trial, Ann. Rheum. Dis. 70 (1) (2011) 32–38.[3] G. Raghu, J. Behr, K.K. Brown, et al., Treatment of idiopathic pulmonary fibrosis withambrisentan: a parallel, randomized trial, Ann. Intern. Med. 158 (9) (2013) 641–649.[4] ERS Task Force, P. Palange, S.A. Ward, et al., Recommendations on the use of exercisetesting in clinical practice, Eur. Respir. J. 29 (2007) 185–209.[5] A.J. Peacock, K.E. Dawes, A. Shock, et al., Endothelin-1 and endothelin-3 inducechemotaxis and replication of pulmonary artery fibroblasts, Am. J. Respir. Cell Mol.Biol. 7 (1992) 492–499.[6] J.R. Seibold, C.P. Denton, D.E. Furst, et al., Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis,Arthritis Rheum. 62 (7) (2010) 2101–2108.[7] J. Le Pavec, R.E. Girgis, N. Lechtzin, et al., Systemic sclerosis-related pulmonaryhypertension associated with interstitial lung disease: impact of pulmonary arterialhypertension therapies, Arthritis Rheum. 63 (8) (2011) 2456–2464.[8] E. Rosato, A. Romaniello, D. Magrì, et al., Exercise tolerance in systemic sclerosispatients without pulmonary impairment: correlation with clinical variables, Clin.Exp. Rheumatol. 32 (6 Suppl. 86) (2014) 103–108.[9] A. Gigante, A. Romaniello, D. Magrì, et al., Correlation between intrarenal arterialstiffness and exercise tolerance in systemic sclerosis patients without renal andcardiopulmonary impairment: the role of the microvascular damage, Int. J. Cardiol.15 (185) (2015) 122–124.

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Bosentan for digital ulcers prevention does not worsen cardiopulmonary exercise test parameters in SSc patients with interstitial lung disease

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