Modern Rheumatology

ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20

Effect of ambrisentan on peripheral circulation in patients with systemic sclerosis Hayakazu Sumida, Yoshihide Asano, Masaru Hatano, Naohiko Aozasa, Tetsuo Toyama, Kaname Akamata, Miki Miyazaki, Takashi Taniguchi, Takehiro Takahashi, Yohei Ichimura, Shinji Noda, Yoshihiro Kuwano, Koichi Yanaba & Shinichi Sato To cite this article: Hayakazu Sumida, Yoshihide Asano, Masaru Hatano, Naohiko Aozasa, Tetsuo Toyama, Kaname Akamata, Miki Miyazaki, Takashi Taniguchi, Takehiro Takahashi, Yohei Ichimura, Shinji Noda, Yoshihiro Kuwano, Koichi Yanaba & Shinichi Sato (2014): Effect of ambrisentan on peripheral circulation in patients with systemic sclerosis, Modern Rheumatology To link to this article: http://dx.doi.org/10.3109/14397595.2014.885377

Published online: 04 Mar 2014.

Submit your article to this journal

Article views: 62

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=imor20 Download by: [University of Birmingham]

Date: 12 November 2015, At: 23:17

http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; Early Online: 1–4 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2014.885377

CASE REPORT

Effect of ambrisentan on peripheral circulation in patients with systemic sclerosis

Downloaded by [University of Birmingham] at 23:17 12 November 2015

Hayakazu Sumida1, Yoshihide Asano1, Masaru Hatano2, Naohiko Aozasa1, Tetsuo Toyama1, Kaname Akamata1, Miki Miyazaki1, Takashi Taniguchi1, Takehiro Takahashi1, Yohei Ichimura1, Shinji Noda1, Yoshihiro Kuwano1, Koichi Yanaba1 , and Shinichi Sato1 1Department of Dermatology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan and 2Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Abstract

Keywords

Systemic sclerosis (SSc) is characterized by disturbed blood circulation. The effect of ambrisentan, an endothelin-A receptor-selective antagonist, on impaired peripheral circulation in SSc remains largely elusive. Here we show SSc patients, whose clinical symptoms such as cyanosis and Raynaud’s phenomenon, were ameliorated by the treatment with ambrisentan. Additionally, objective evaluations with thermography showed improvement of hand coldness in steady-state and cold challenge tests. Ambrisentan might have a potential to improve peripheral circulation in SSc.

Ambrisentan, Cyanosis, Raynaud’s phenomenon, Systemic sclerosis, Thermography

Introduction Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by initial vascular injuries and resultant fibrosis of the skin and certain internal organs. In particular, vascular damages link to impaired peripheral circulation including cyanosis of the fingers, Raynaud’s phenomenon (RP), and digital ulcers (DUs) [1]. In the pathology of SSc, vascular changes are classified into two subgroups: destructive vasculopathy and proliferative obliterative vasculopathy [2]. Destructive vasculopathy contributes to progressive loss of capillaries and impaired angiogenesis; whereas, proliferative obliterative vasculopathy is characterized by the proliferation of vascular smooth muscle cells and resultant intravascular stenosis in arterioles and arteries [3]. Increased serum levels of endothelin-1 (ET-1) were reported to be well correlated with the extent of vascular damage in SSc [4]. In addition, ET-1 exerts its major vascular effects of vasoconstriction and cell proliferation through ETA and ETB receptors on vascular smooth muscle cells [5]. Therefore, endothelin receptor antagonists (ETRAs) have been thought to be effective for SSc-related proliferative obliterative vasculopathy including SSc-associated pulmonary arterial hypertension (SSc-PAH). In addition to prostanoids and phosphodiesterase type 5 (PDE-5) inhibitors, ETRAs have also been shown to improve not only idiopathic PAH but also SSc-PAH [1]. Two randomized controlled trials demonstrated that bosentan, a dual ETA/ETB receptor antagonist, reduced the appearance of new DUs in SSc patients [6,7]. Probably, these successes of bosentan might be due to not only its vasodilatory effects but also its reverse remodeling effects, which are not shared by prostanoids or PDE-5 inhibitors. To further complicate matters, endothelial ETB receptor Correspondence to: Yoshihide Asano, MD, PhD, Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan. Tel: ⫹ 81 3 5800 8661. Fax: ⫹ 81 3 3814 1503. E-mail: [email protected]

History Received 17 December 2013 Accepted 16 January 2014 Published online 24 February 2014

alone has an opposing role in vasodilation [5]. Therefore, selective ETA receptor antagonists have been expected to exert beneficial effects especially on vasodilatation. Ambrisentan, an ETA selective antagonist, has recently proven effective in SSc-PAH [8]. Given few data on the use of ambrisentan for SSc patients [8,9], it remains largely unknown whether ambrisentan would show efficacy as well as bosentan in the SSc-related impaired peripheral circulation.

Patients and methods Patients Among eight patients starting ambrisentan for PAH between October 2011 and March 2013, three SSc patients with severe cyanosis and RP in the distal extremities were selected. PAH was diagnosed using ultrasound cardiography and/or right ventricular catheterization. Patients were treated with ambrisentan 5 mg daily. Concomitant medications were not substantially modified during the follow-up period. Thermographic examination Thermographic examination was performed using thermotracer (TH5100, NEC, Japan). In steady-state tests, the finger temperature was measured in an air conditioned room at 25°C and 60% relative humidity. After 15 minutes of habituation, the thermographic images of the dorsal and ventral sides of hands were taken. In cold challenge tests, hands were immersed in water at 10°C for 60 s after the equilibration phase of 25°C for 15 min. Immediately after the hands were taken out of the water, thermographic images were recorded at 5-min intervals over 20 min.

Results Clinical features and information of all three patients are summarized in Table 1. Efficacy of ambrisentan for impaired peripheral

2

H. Sumida et al.

Mod Rheumatol, 2014; Early Online: 1–4

Table 1. Clinical features and information of the patients treated with ambrisentan. Patient Age (years)/Gender Disease duration (years) Type of SSc Specific antibodies Cyanosis of the distal extremities Raynaud’s phenomenon Digital pitting scars and/or ulcers Efficacy of ambrisentan for impaired peripheral circulation Concomitant drugs aimed at improving peripheral circulation

Patient 1 75/F 6 Diffuse ssDNA, Ro/SS-A ⫹ ⫹ ⫹ ⫹

Patient 2 61/F 15 Diffuse Topo-I ⫹ ⫹ ⫹ ⫹

Patient 3 68/F 3 Diffuse Topo-I, ssDNA ⫹ ⫹ ⫹ ⫹

Beraprost sodium, Sarpogrelate hydrochloride, Tocopherol nicotinate, Ethyl icosapentate

Beraprost sodium, Sarpogrelate hydrochloride, Limaprost alfadex, Tocopherol nicotinate

Sarpogrelate hydrochloride, Tocopherol nicotinate

Downloaded by [University of Birmingham] at 23:17 12 November 2015

F, Female; SSc, systemic sclerosis; ssDNA, anti-single-stranded DNA antibody; Topo-I, anti-topoisomerase I antibody.

circulation was observed in all patients, as described in detail below. Although all patients had interstitial lung disease (ILD), deterioration of respiratory manifestation and ILD parameters were not found during observation periods. Ambrisentan did not affect the serum levels of C-reactive protein, immunoglobulin G, and anti-topoisomerase I antibodies.

tool for cyanosis or RP in the distal extremities [10]. The steadystate tests showed the increase in finger temperature after starting the therapy with ambrisentan (Figure 1c, d). Furthermore, cold challenge tests showed that ambrisentan treatment markedly reduced recovery time of finger temperature (Figure 1e, f). Patient 2

Patient 1 A 75-year-old woman with a 6-year history of SSc had suffered from RP with triphasic color changes and small pitting scars on her fingers from 74 years. High levels of antibodies to single-stranded DNA and Ro/SS-A were detected in her laboratory examinations. Within one week after the start of treatment with ambrisentan, her cyanosis of the fingers was promptly improved (Figure 1a, b). To provide objective evaluations, we conducted thermographic examination, since thermography shows promise as a diagnostic

A 61-year-old woman with a 15-year history of SSc had suffered from severe RP with biphasic color changes and recurrent DUs for 15 years. Antibodies to topoisomerase I was detected in her laboratory examinations. Within two weeks after the treatment with ambrisentan, the degree of cyanosis of the fingers was improved (Figure 1g, h). Moreover, DUs also showed healing tendency. She showed slight and controllable edema on the lower leg, which is known to be a frequent side effect of ambrisentan [11].

Figure 1. Clinical course of peripheral vascular involvement in SSc patients treated with ambrisentan. (a and b; Patient 1) Raynaud’s phenomenon (RP) in the left hands before (a) and after (b) the administration of ambrisentan. (c and d; Patient 1) Thermographic images of the dorsal sides of both hands before (c) and after (d) starting the therapy with ambrisentan at room temperature condition (25°C and 60% relative humidity for 15 min). Median temperature, 27.6°C. Thermal sensitivity (temperature resolution), 1.0°C. (e; Patient 1 before the treatment with ambrisentan) Thermographic images of the dorsal sides of both hands just after the immersion in water at 10°C for 60 s (left image) and after the following 20-min exposure to an room temperature condition (right image). Median temperature, 27.2°C. Thermal sensitivity (temperature resolution), 1.0°C. (f; Patient 1 after the treatment with ambrisentan) Thermographic images as is the case before the treatment. Median temperature, 29.0°C. Thermal sensitivity (temperature resolution), 1.5°C. (g and h; Patient 2) RP in the right toes before (g) and after (h) the administration of ambrisentan. (i and j; Patient 3) RP in the right heels before (i) and after (j) the administration of ambrisentan.

DOI 10.3109/14397595.2014.885377

Patient 3 A 68-year-old woman with a 3-year history of SSc had severe cyanosis and RP in the distal extremities. Antibodies to topoisomerase I and single-stranded DNA were detected in her laboratory data. Within two or three weeks after starting treatment with ambrisentan, the degree of cyanosis was obviously improved (Figure 1i, j). Furthermore, the pain of lower legs probably due to the blood flow disturbance was also attenuated.

Downloaded by [University of Birmingham] at 23:17 12 November 2015

Discussion The current study demonstrated that an ETA-selective antagonist was useful for the improvement of peripheral circulation in SSc patients. Specifically, peripheral vascular involvement manifesting as peripheral cyanosis or RP was attenuated after the administration of ambrisentan. ETRAs have short-term vasodilator and long-term reverse vascular remodeling effects [12]. In PAH animal model, positive vasodilatory effects have been observed in both selective ETA-receptor and nonselective antagonism [13]. Furthermore, several studies in animal models revealed that both nonselective and ETA-selective blockade attenuated vascular remodeling [14,15]. Considering these evidences and the fact that peripheral vasculopathy is attributed to constriction and vascular remodeling in SSc patients, the vasodilator and reverse vascular remodeling effects of ETRAs might have a great influence on our observations. In particular, our patients showed the amelioration of cyanosis of the fingers soon after starting the treatment with ambrisentan. Therefore, the short-term vasodilator mechanism must be greatly involved in the improvement of impaired vascular perfusion in our patients. Furthermore, thermographic images from Patient 1 showed improved peripheral vascular perfusion by ambrisentan both in steady-state and under cold challenge tests. Steady-state and cold challenge tests are suitable for the evaluation of cyanosis of the distal extremities without attack and RP with attack, respectively. RP is mainly induced by vasoconstriction; whereas, cyanosis is closely related to vascular remodeling in addition to vasoconstriction. Therefore, the results of this study suggest that ambrisentan has both reverse remodeling and vasodilator effects. Clinical efficacy of ambrisentan has been reported for the symptoms such as PAH and DUs in SSc [8,9]. In addition to these symptoms, this report suggests the effects of ambrisentan on cyanosis and RP. These all clinical symptoms were considered to be caused by proliferative obliterative vasculopathy. Moreover, reverse vascular remodeling effects of ETRAs are exerted by restoring proliferative vascular changes [5]. Therefore, ETRAs including ambrisentan may achieve those clinical utilities via reverse vascular remodeling effects. In terms of safety of ambrisentan, systemic vasodilators have been shown to interfere with ventilation/perfusion matching in fibrotic lung disease [16]. Therefore, there is a concern that ETRAs may have similar disadvantageous effects on gas exchange. Recently, a study of patients with PAH and ILD has reported very small incidence of worsening ventilation/perfusion mismatch [17]. Similarly, deterioration of respiratory manifestation and ILD parameters were not found in our all three patients with SScrelated ILD. Meanwhile, a recent double-blind study of ambrisentan for idiopathic pulmonary fibrosis, not SSc-related ILD, showed the possibility that ambrisentan might increase the risk for disease progression [18]. Therefore, it must be still important to keep in mind the possibility of ILD exacerbation in the use of ETRAs for SSc patients. For more discussion about side effects, compared with bosentan, ambrisentan appears to have a better safety profile with regards to hepatic dysfunction and drug–drug interactions [19]. Therefore, ambrisentan is a viable option for SSc patients, who have liver damage resulting from bosentan or other reasons.

Ambrisentan on peripheral circulation in patients with SSc 3 However, ambrisentan shows a higher rate of other adverse events, such as peripheral edema [11]. It is consistent that one of our patients (Patient 2) showed edema on the legs. Therefore, the use of ambrisentan for SSc patients requires special care for the presence of edema. We herein reported three SSc patients with severely impaired vascular perfusion, which was attenuated by ambrisentan probably due to its vasodilator and reverse remodeling effect. The current observation strongly supports the possibility that ambrisentan might be useful for the treatment of impaired peripheral circulation leading to RP or DUs in SSc patients.

Acknowledgments None.

Conflicts of interest None.

References 1. Asano Y. Future treatments in systemic sclerosis. J Dermatol. 2010;37(1):54–70. 2. Horn A, Distler JH. Vascular alterations upon activation of TGFbeta signaling in fibroblasts–implications for systemic sclerosis. Arthritis Res Ther. 2010;12(3):125. 3. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360(19):1989–2003. 4. Vancheeswaran R, Magoulas T, Efrat G, Wheeler-Jones C, Olsen I, Penny R, Black CM. Circulating endothelin-1 levels in systemic sclerosis subsets–a marker of fibrosis or vascular dysfunction? J Rheumatol. 1994;21(10):1838–44. 5. Spieker LE, Noll G, Ruschitzka FT, Luscher TF. Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J Am Coll Cardiol. 2001;37(6):1493–505. 6. Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, Pope J, Hachulla E, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004;50(12):3985–93. 7. Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, doubleblind, placebo-controlled trial. Ann Rheum Dis. 2011;70(1):32–8. 8. Saggar R, Khanna D, Shapiro S, Furst DE, Maranian P, Clements P, et al. Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single-center, open-label pilot study. Arthritis Rheum. 2012;64(12):4072–7. 9. Parisi S, Peroni CL, Lagana A, Scarati M, Ambrogio F, Bruzzone M, Fusaro E. Efficacy of ambrisentan in the treatment of digital ulcers in patients with systemic sclerosis: a preliminary study. Rheumatology (Oxford). 2013;52(6):1142–4. 10. O’Reilly D, Taylor L, el-Hadidy K, Jayson MI. Measurement of cold challenge responses in primary Raynaud’s phenomenon and Raynaud’s phenomenon associated with systemic sclerosis. Ann Rheum Dis. 1992;51(11):1193–6. 11. Shapiro S, Pollock DM, Gillies H, Henig N, Allard M, Blair C, et al. Frequency of edema in patients with pulmonary arterial hypertension receiving ambrisentan. Am J Cardiol. 2012;110(9):1373–7. 12. Opitz CF, Ewert R, Kirch W, Pittrow D. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J. 2008;29(16):1936–48. 13. Opitz CF, Ewert R. Dual ET(A)/ET(B) vs. selective ET(A) endothelin receptor antagonism in patients with pulmonary hypertension. Eur J Clin Invest. 2006;36 Suppl 3:1–9. 14. Chen SJ, Chen YF, Meng QC, Durand J, Dicarlo VS, Oparil S. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol. 1995;79(6):2122–31. 15. Tilton RG, Munsch CL, Sherwood SJ, Chen SJ, Chen YF, Wu C, et al. Attenuation of pulmonary vascular hypertension and cardiac hypertrophy with sitaxsentan sodium, an orally active ET(A) receptor antagonist. Pulm Pharmacol Ther. 2000;13(2):87–97.

4

H. Sumida et al.

Downloaded by [University of Birmingham] at 23:17 12 November 2015

16. Olschewski H, Ghofrani HA, Walmrath D, Schermuly R, Temmesfeld-Wollbruck B, Grimminger F, Seeger W. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med. 1999;160(2):600–7. 17. Gunther A, Enke B, Markart P, Hammerl P, Morr H, Behr J, et al. Safety and tolerability of bosentan in idiopathic pulmonary fibrosis: an open label study. Eur Respir J. 2007;29(4):713–9.

Mod Rheumatol, 2014; Early Online: 1–4

18. Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158(9):641–9. 19. Vizza CD, Fedele F, Pezzuto B, Rubin LJ. Safety and efficacy evaluation of ambrisentan in pulmonary hypertension. Expert Opin Drug Saf. 2012;11(6):1003–11.