Retrospective analysis of the frequency of centrofacial telangiectasia in systemic sclerosis patients treated with bosentan or ilomedin

European Journal of Medical Research

Bernhard Homey²  Peter Arne Gerber²  Kai Kammers¹  Stephan Meller²  Edwin Bölke²  Holger Schrumpf²  Bettina Alexandra Buhren²  Sonja Hetzer² 

[1] Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA;Department of Dermatology, Medical Faculty, University of Duesseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany

关键词: Systemic sclerosis;    Telangiectasia;    Iloprost;    Bosentan;    Endothelin;   

Others  :  817659
DOI  :  10.1186/2047-783X-19-2

 received in 2013-07-26, accepted in 2013-11-27,  发布年份 2014

【 摘 要 】

Background

Bosentan is a dual endothelin receptor antagonist initially introduced for the treatment of pulmonary arterial hypertension and recently approved for the treatment of digital ulcers in patients with systemic sclerosis (SSc). Our clinical observations indicate that bosentan therapy may be associated with an increased frequency of centrofacial telangiectasia (TAE). Here, we sought to analyze the frequency of TAE in patients with SSc who were treated with either bosentan or the prostacyclin analog iloprost.

Methods

We conducted a retrospective analysis in 27 patients with SSc undergoing therapy with either bosentan (n = 11) or iloprost (n = 16). Standardized photodocumentations of all patients (n = 27) were obtained at a time point ten months after therapy initiation and analyzed. A subgroup of patients (bosentan: n = 6; iloprost: n = 6) was additionally photodocumented prior to therapy initiation, enabling an intraindividual analysis over the course of therapy.

Results

After ten months of therapy patients with SSc receiving bosentan showed a significantly (P = 0.0028) higher frequency of centrofacial TAE (41.6 ± 27.8) as compared to patients with SSc receiving iloprost (14.3 ± 13.1). Detailed subgroup analysis revealed that the frequency of TAE in the bosentan group (n = 6 patients) increased markedly and significantly (P = 0.027) by 44.4 after ten months of therapy (TAE at therapy initiation: 10.8 ± 5.1; TAE after ten months of therapy: 55.2 ± 29.8), whereas an only minor increase of 1.9 was observed in the iloprost group (n = 6 patients; TAE at therapy initiation: 18.3 ± 14.5; TAE after ten months of therapy: 20.2 ± 15.5), yet without reaching statistical significance (P = 0.420).

Conclusions

The use of bosentan may be associated with an increased frequency of TAE in patients with SSc. Patients should be informed about this potential adverse effect prior to therapy. Treatment options may include camouflage or laser therapy.

【 授权许可】

   
2014 Hetzer et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Bhattacharyya S, Wei J, Varga J: Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol 2011, 8(1):42-54.
• [2]Gabrielli A, Avvedimento EV, Krieg T: Scleroderma. N Engl J Med 2009, 360:1989-2003.
• [3]Pope J, Fenlon D, Thompson A, et al.: Iloprost and cisaprost for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2000, 2:CD000953.
• [4]LeRoy EC, Black C, Fleischmajer R, et al.: Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988, 15:202-205.
• [5]Hachulla E, Clerson P, Launay D, et al.: Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J Rheumatol 2007, 34:2423-2430.
• [6]Lambova S, Muller-Ladner U: Connective tissue diseases: treatment of digital ulcers in systemic sclerosis. Nat Rev Rheumatol 2011, 7:5-6.
• [7]Walker UA, Tyndall A, Czirjak L, et al.: Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis 2007, 66:754-763.
• [8]Fleischmajer R, Perlish JS: Capillary alterations in scleroderma. J Am Acad Dermatol 1980, 2:161-170.
• [9]Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P: Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992, 166:255-263.
• [10]Kahaleh MB, LeRoy EC: Autoimmunity and vascular involvement in systemic sclerosis (SSc). Autoimmunity 1999, 31:195-214.
• [11]Sgonc R, Gruschwitz MS, Boeck G, Sepp N, Gruber J, Wick G: Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 2000, 43:2550-2562.
• [12]Kahaleh B, Matucci-Cerinic M: Raynaud’s phenomenon and scleroderma. Dysregulated neuroendothelial control of vascular tone. Arthritis Rheum 1995, 38:1-4.
• [13]Kawaguchi Y, Suzuki K, Hara M, et al.: Increased endothelin-1 production in fibroblasts derived from patients with systemic sclerosis. Ann Rheum Dis 1994, 53:506-510.
• [14]Clozel M: Effects of bosentan on cellular processes involved in pulmonary arterial hypertension: do they explain the long-term benefit? Ann Med 2003, 35:605-613.
• [15]Mayes MD: Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum 2003, 48:1190-1199.
• [16]Abraham D, Dashwood M: Endothelin - role in vascular disease. Rheumatology (Oxford) 2008, 47(Suppl 5):v23-v24.
• [17]Riccardi MT, Chiala A, Lannone F, Grattagliano V, Covelli M, Lapadula G: Treatment of digital ulcers in systemic sclerosis with endothelin-1 receptor antagonist (bosentan). Reumatismo 2007, 59:135-139.
• [18]Caramaschi P, Volpe A, Tinazzi I, Bambara LM, Carletto A, Biasi D: Does cyclically iloprost infusion prevent severe isolated pulmonary hypertension in systemic sclerosis? Preliminary results. Rheumatol Int 2006, 27:203-205.
• [19]Kowal-Bielecka O, Landewe R, Avouac J, et al.: EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2009, 68:620-628.
• [20]Sfikakis PP, Papamichael C, Stamatelopoulos KS, et al.: Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis. Arthritis Rheum 2007, 56:1985-1993.
• [21]Walker KM, Pope J: Expert agreement on EULAR/EUSTAR recommendations for the management of systemic sclerosis. J Rheumatol 2011, 38:1326-1328.
• [22]Matucci-Cerinic M, Del Rosso A, Federico P, et al.: Therapeutic challenges for systemic sclerosis: facts and future targets. Ann N Y Acad Sci 2007, 1110:448-454.
• [23]Scorza R, Caronni M, Mascagni B, et al.: Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud’s phenomenon. A randomized, controlled study. Clin Exp Rheumatol 2001, 19:503-508.
• [24]Balbir-Gurman A, Braun-Moscovici Y, Livshitz V, et al.: Antioxidant status after iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis. Clin Rheumatol 2007, 26:1517-1521.
• [25]Wigley FM, Wise RA, Seibold JR, et al.: Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med 1994, 120:199-206.
• [26]Korn JH, Mayes M, Matucci-Cerinic M, et al.: Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004, 50:3985-3993.
• [27]Matucci-Cerinic M, Denton CP, Furst DE, et al.: Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomized, double-blind, placebo-controlled trial. Ann Rheum Dis 2011, 70:32-38.
• [28]Tingey T, Shu J, Smuczek J, Pope J: Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken) 2013, 65:1460-1471.
• [29]Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980, 23:581-590.
• [30]Bettoni L, Geri A, Airo P, et al.: Systemic sclerosis therapy with iloprost: a prospective observational study of 30 patients treated for a median of three years. Clin Rheumatol 2002, 21:244-250.
• [31]McHugh NJ, Csuka M, Watson H, et al.: Infusion of iloprost, a prostacyclin analog, for treatment of Raynaud’s phenomenon in systemic sclerosis. Ann Rheum Dis 1988, 47:43-47.
• [32]Wigley FM, Seibold JR, Wise RA, McCloskey DA, Dole WP: Intravenous iloprost treatment of Raynaud’s phenomenon and ischemic ulcers secondary to systemic sclerosis. J Rheumatol 1992, 19:1407-1414.
• [33]Paramothayan NS, Lasserson TJ, Wells AU, Walters EH: Prostacyclin for pulmonary hypertension. Cochrane Database Syst Rev 2003, 2:CD002994.
• [34]Dingemanse J, van Giersbergen PL: Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 2004, 43:1089-1115.
• [35]Gallardo F, Toll A, Malvehy J, et al.: Large atypical melanocytic nevi in recessive dystrophic epidermolysis bullosa: clinicopathological, ultrastructural, and dermoscopic study. Pediatr Dermatol 2005, 22:338-343.
• [36]Gasser S, Kuhn M, Speich R: Severe necrotizing leucocytoclastic vasculitis in a patient taking bosentan. BMJ 2004, 329:430.
• [37]Tong PL, Kumarasinghe SP: Bosentan - a previously unrecognized cause of facial telangiectasia. Ann Acad Med Singapore 2010, 39:874-875.
• [38]Mould TL, Roberts-Thomson PJ: Pathogenesis of telangiectasia in scleroderma. Asian Pac J Allergy Immunol 2000, 18:195-200.
• [39]Hachulla E, Launay D: Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol 2011, 40:78-83.
• [40]McDonald J, Bayrak-Toydemir P, Pyeritz RE: Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med 2011, 13:607-616.
• [41]Walshe TE: TGF-beta and microvessel homeostasis. Microvasc Res 2010, 80:166-173.
• [42]van Royen N, Hoefer I, Buschmann I, et al.: Exogenous application of transforming growth factor beta 1 stimulates arteriogenesis in the peripheral circulation. FASEB J 2002, 16:432-434.
• [43]Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M: Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype. J Invest Dermatol 1998, 110:47-51.
• [44]Sato S, Nagaoka T, Hasegawa M, et al.: Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol 2000, 27:149-154.
• [45]Ichimura Y, Asano Y, Hatano M, et al.: Significant attenuation of macrovascular involvement by bosentan in a patient with diffuse cutaneous systemic sclerosis with multiple digital ulcers and gangrene. Mod Rheumatol 2011, 21:548-552.
• [46]Cambrey AD, Harrison NK, Dawes KE, et al.: Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 1994, 11:439-445.
• [47]Yang Z, Krasnici N, Luscher TF: Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Circulation 1999, 100:5-8.