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Efficacy of Bosentan in Digital Ischemic Ulcers
Case Report Abstracts Efficacy of Bosentan in Digital Ischemic Ulcers Jose A. Todoli Parra,1 Manuel Miralles Hern andez,2 and Manuel A. Arrebola L opez,3 Valencia, Spain
Thromboangiitis obliterans (also known as Buerger’s disease) is an inflammatory vascular disorder that affects small and medium-sized arteries and veins in the extremities. There is no specific treatment and the only effective intervention is absolute cessation of tobacco use. Endothelial dysfunction appears to be of relevance to this condition and a report has even found that high serum levels of endothelin correlate with the presence of necrosis. We report two cases of digital necrosis showing a very satisfactory response to treatment with bosentan, a dual endothelin receptor antagonist.
Thromboangiitis obliterans is an inflammatory segmental vascular disorder that affects arteries and veins in the distal extremities, specifically the small and medium-sized vessels. It is most common in young men and in individuals from Asia and Eastern Europe. However, in the last years, there has been a trend of the disease affecting patients of older age. Olin reports that 7 % of the cases were aged >60 years. Despite the associated mortality rate being low, the incidence of amputations is much higher than that for arteriosclerotic ischemia.1,2 Although of unknown etiology, Buerger’s disease is directly associated with tobacco use, an absolute requirement for both the onset and progression of this condition. Regarding the pathogenic mechanism, Adar et al. found cellular hypersensitivity to types I and III 1 Internal Medicine Department, Hospital Universitario La Fe, Valencia, Spain. 2 Angiology and Vascular Surgery Department, Hospital Universitario La Fe, Valencia, Spain. 3 Angiology and Vascular Surgery Department, Hospital Universitario La Fe, Valencia, Spain. Correspondence to: Jose A. Todoli-Parra, Internal Medicine Department, Hospital Universitario La Fe, Avenida de Campanar 21, 46009 Valencia, Spain, E-mail: [email protected]
Ann Vasc Surg 2010; 24: 690.e1-690.e4 DOI: 10.1016/j.avsg.2010.03.011 Ó Annals of Vascular Surgery Inc.
collagens.3 There have also been reports of higher levels of anti-endothelial cell antibodies in patients with active disease compared with remitting patients and controls.4 The pathological evaluation of the vessels involved shows inflammation and thrombosis of arteries and veins which cause vascular fibrosis and chronic vascular obliteration. Patients present Raynaud’s phenomenon, distal claudication, thrombophlebitis migrans, and ischemic ulcerations on toes, feet, or fingers. In the initial stages, they can present with arthralgia or arthritis. Shionoya5 suggested the following diagnostic criteria in 1998: history of tobacco use, presentation under the age of 50, artery occlusion in the infrapopliteal region, compromise of the upper extremity or migratory phlebitis in the absence of other risk factors for atherosclerotic disease. Generally, there are no significant inflammatory parameters or serologic findings common to other autoimmune disorders. Rheumatoid factor, antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, complement levels, and cryoglobulins are negative or within normal limits.1,6 Frequently, the disease runs a course with exacerbations of devastating effects, which require several surgical amputations. This silent progression usually has negative psychological consequences, which are made even worse by the knowledge that no treatment has proven efficacy. 690.e1
690.e2 Case reports
Annals of Vascular Surgery
Clinical trials with vasodilators have shown little efficacy, except for intravenous, or even intraarterial, infusion of alprostadil (PGE1);7,8 a major shortcoming being that the effects fade on finishing the treatment (4-5 weeks). More recently, bosentan, an endothelin receptor antagonist, currently indicated in the treatment of pulmonary arterial hypertension and the prevention of digit ulceration in systemic sclerosis, has been introduced, bringing in a new alternative for prolonged, oral treatment.9 We report two patients with Buerger’s disease whose outcome was greatly improved by treatment with bosentan, a dual endothelin receptor antagonist.
CASE 1 A 51-year-old man presented with distal necrosis in his right second and third fingers (considering thumb as first), after restarting tobacco use. The patient had a 15-year long history of Buerger’s disease and stabilized disabling intermittent claudication. Intravenous alprostadil was prescribed, which was stopped after 2 weeks. Twenty days later, without any improvement of the ischemic lesions, approval for compassionate use was granted and oral treatment with bosentan was initiated at the current dose (62.5 mg twice daily for a month, and then increased to 125 mg twice daily). The ischemic lesions were seen to ameliorate gradually and healed completely 10 months later. The treatment was then terminated, with no relevant adverse effects been observed. The patient stopped tobacco use at the onset of the episode, and did not smoke again during the 48-month follow-up period. Follow-up assessments by nailfold capillaroscopy revealed neoangiogenesis with a gradual increase in the number of nutritional capillaries. The magnetic resonance angiography of the patient’s right hand is seen in Fig. 1 and the capillaroscopy image of the patient’s nailfold before and after treatment with bosentan is seen in Fig. 2.
CASE 2 A 72-year-old man with a 5-year history of Buerger’s disease presented with a 2-month history of ischemic ulcers in his left second finger and his right fourth finger (considering thumb as first) after restarting tobacco use. Nailfold capillaroscopy findings revealed widespread capillary loss and thrombosis in the fingers involved, and a shortened loop pattern in the other fingers. The patient gave up smoking; treatment with bosentan was prescribed
Fig. 1. Case 1: Magnetic resonance angiography image of the right hand showing distal involvement and presence of digital arteries with ‘‘corkscrew-like’’ or coiled appearance.
at the standard initial dose of 62.5 mg twice daily for a month, and then 125 mg twice daily. Three months later, all digital lesions had resolved and laboratory findings revealed elevated serum transaminases over previous normal levels (AST/GOT: 90 U/L; ALT/GPT: 250 U/L). Hence, bosentan termination was decided and, subsequently, all analytical parameters returned to normal. Three months after finishing the treatment, the nailfold capillaroscopy imaging demonstrated that the number of capillaries had increased and that the avascular areas had been reduced. The digital plethysmograph of the patient’s left forefinger before and after treatment is shown in Fig. 3.
DISCUSSION Buerger’s disease has no etiologic treatment, absolute cessation of tobacco use being the only effective intervention. A randomized double-blind study showed an improved outcome with iloprost IV versus aspirin
Vol. 24, No. 5, July 2010
Case reports 690.e3
Fig. 2. Case 1: Nailfold capillaroscopy. A Before treatment with bosentan: absence of capillaries; and B 6 months after treatment with bosentan, the capillary pattern shows neoangiogenesis with new tortuous capillary branching.
Fig. 3. Case 2: Digital plethysmograph of the forefinger of the left hand. A Before treatment with bosentan: a decrease in the amplitude of the pulse wave. B Two months after finishing treatment, digital perfusion is shown to have improved.
after 28 days and also after 6 months (85% responders in the iloprost arm vs. 21% in the aspirin arm after 6 months, with an incidence of amputation of 6 and 18%, respectively).10 Other experimental treatments are therapeutic angiogenesis with intramuscular administration of ‘‘vascular endothelial growth factor’’11 or the thrombolytic therapy.12 Surgical revascularization is generally not possible because of the frequent distal and segmental involvement. Endothelial dysfunction seems to be a relevant factor for this condition since some preliminary studies have shown impaired endothelium-dependent
vasodilation, whereas endothelium-independent vasodilation mechanisms remain unaltered.13,14 Czarnacki et al.15 have correlated the endothelin levels and clinical activity in a cohort of patients and found elevated levels of endothelin in patients with necrotic lesions compared with patients with no clinically active disease and controls. This study also found a significant correlation between high pretreatment endothelin levels and anti-elastase antibodies. These authors suggest that the serum levels of endothelin increase as a consequence of the endothelial dysfunction caused by the immunologic reaction activated by nicotine. A very
690.e4 Case reports
interesting finding of this study was that the serum levels of endothelin remained unmodified after treatment with alprostadil, whereas those of selectin L were reduced. Two of our patients showed a very satisfactory clinical response to bosentan, a dual endothelin receptor antagonist indicated for prevention of new digital ulcers in systemic sclerosis.16 Although these findings reflect just two isolated clinical observations, they highlight the need for studying the effect of bosentan in vascular lesions associated with Buerger’s disease. REFERENCES 1. Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med 2000;343:864-869. 2. Olin JW, Young JR, Graor RA, Ruschhaupt WF, Bartholomew JR. The changing clinical spectrum of thromboangiitis obliterans (Buerger’s disease). Circulation 1990; 82(Suppl 5):IV3-IV8. 3. Adar R, Papa MZ, Halpern Z, et al. Cellular sensitivity to collagen in thromboangiitis obliterans. N Engl J Med 1983;308:1113-1116. 4. Eichhorn J, Sima D, Lindschau C, et al. Antiendothelial cell antibodies in thromboangiitis obliterans. Am J Med Sci 1998;315:17-23. 5. Shionoya S. Diagnostic criteria of Buerger’s disease. Int J Cardiol 1998;66(Suppl 1):S243-S245. 6. Kobayashi M, Nishikimi N, Komori K. Current pathological and clinical aspects of Buerger’s disease in Japan. Ann Vasc Surg 2006;20:148-156.
Annals of Vascular Surgery
7. Zdrojowy K, Adamiec R, Czarnacki M. New aspects of prostaglandin E1 therapeutic influence in thrombo-angiitis obliterans. Pol Arch Med Wewn 2002;108:1071-1077. 8. Olin JW, Shih A. Thromboangiitis obliterans (Buerger’s disease). Curr Opin Rheumatol 2006;18:18-24. 9. De Haro J, Florez A, Fernandez JL, Acin F. Treatment of Buerger disease (thromboangiitis obliterans) with bosentan: a case report. BMJ Case Reports 2009. doi:10.1136/bcr. 08.2008.0691. Copyright Ó 2009 by the BMJ Publishing Group Ltd. 10. Fiessinger JN, Scha¨fer M. Trial of iloprost versus aspirin treatment for critical limb ischaemia of thromboangiitis obliterans. The TAO Study. Lancet 1990;335:555-557. 11. Isner JM, Baumgartner I, Rauh G, et al. Treatment of thromboangiitis obliterans (Buerger’s disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J Vasc Surg 1998;28:964-973. discussion 73-75. 12. Hussein EA, el Dorri A. Intra-arterial streptokinase as adjuvant therapy for complicated Buerger’s disease: early trials. Int Surg 1993;78:54-58. 13. Makita S, Nakamura M, Murakami H, et al. Impaired endothelium-dependent vasorelaxation in peripheral vasculature of patients with thromboangiitis obliterans (Buerger’s disease). Circulation 1996;94:211-215. 14. Kenji N, Yukihito H, Takashi U, et al. Vascular function and endothelial progenitor cells in thromboangiitis obliterans (Buerger’s Disease). Circulation 2008;118:Se635. 15. Czarnacki M, Gacka M, Adamiec R. A role of endothelin 1 in the pathogenesis of thromboangiitis obliterans (initial news). Przegl Lek 2004;61:1346-1350. 16. 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.
Thromboangiitis obliterans (also known as Buerger’s disease) is an inflammatory vascular disorder that affects small and medium-sized arteries and veins in the extremities. There is no specific treatment and the only effective intervention is absolute cessation of tobacco use. Endothelial dysfunction appears to be of relevance to this condition and a report has even found that high serum levels of endothelin correlate with the presence of necrosis. We report two cases of digital necrosis showing a very satisfactory response to treatment with bosentan, a dual endothelin receptor antagonist.
Thromboangiitis obliterans is an inflammatory segmental vascular disorder that affects arteries and veins in the distal extremities, specifically the small and medium-sized vessels. It is most common in young men and in individuals from Asia and Eastern Europe. However, in the last years, there has been a trend of the disease affecting patients of older age. Olin reports that 7 % of the cases were aged >60 years. Despite the associated mortality rate being low, the incidence of amputations is much higher than that for arteriosclerotic ischemia.1,2 Although of unknown etiology, Buerger’s disease is directly associated with tobacco use, an absolute requirement for both the onset and progression of this condition. Regarding the pathogenic mechanism, Adar et al. found cellular hypersensitivity to types I and III 1 Internal Medicine Department, Hospital Universitario La Fe, Valencia, Spain. 2 Angiology and Vascular Surgery Department, Hospital Universitario La Fe, Valencia, Spain. 3 Angiology and Vascular Surgery Department, Hospital Universitario La Fe, Valencia, Spain. Correspondence to: Jose A. Todoli-Parra, Internal Medicine Department, Hospital Universitario La Fe, Avenida de Campanar 21, 46009 Valencia, Spain, E-mail: [email protected]
Ann Vasc Surg 2010; 24: 690.e1-690.e4 DOI: 10.1016/j.avsg.2010.03.011 Ó Annals of Vascular Surgery Inc.
collagens.3 There have also been reports of higher levels of anti-endothelial cell antibodies in patients with active disease compared with remitting patients and controls.4 The pathological evaluation of the vessels involved shows inflammation and thrombosis of arteries and veins which cause vascular fibrosis and chronic vascular obliteration. Patients present Raynaud’s phenomenon, distal claudication, thrombophlebitis migrans, and ischemic ulcerations on toes, feet, or fingers. In the initial stages, they can present with arthralgia or arthritis. Shionoya5 suggested the following diagnostic criteria in 1998: history of tobacco use, presentation under the age of 50, artery occlusion in the infrapopliteal region, compromise of the upper extremity or migratory phlebitis in the absence of other risk factors for atherosclerotic disease. Generally, there are no significant inflammatory parameters or serologic findings common to other autoimmune disorders. Rheumatoid factor, antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, complement levels, and cryoglobulins are negative or within normal limits.1,6 Frequently, the disease runs a course with exacerbations of devastating effects, which require several surgical amputations. This silent progression usually has negative psychological consequences, which are made even worse by the knowledge that no treatment has proven efficacy. 690.e1
690.e2 Case reports
Annals of Vascular Surgery
Clinical trials with vasodilators have shown little efficacy, except for intravenous, or even intraarterial, infusion of alprostadil (PGE1);7,8 a major shortcoming being that the effects fade on finishing the treatment (4-5 weeks). More recently, bosentan, an endothelin receptor antagonist, currently indicated in the treatment of pulmonary arterial hypertension and the prevention of digit ulceration in systemic sclerosis, has been introduced, bringing in a new alternative for prolonged, oral treatment.9 We report two patients with Buerger’s disease whose outcome was greatly improved by treatment with bosentan, a dual endothelin receptor antagonist.
CASE 1 A 51-year-old man presented with distal necrosis in his right second and third fingers (considering thumb as first), after restarting tobacco use. The patient had a 15-year long history of Buerger’s disease and stabilized disabling intermittent claudication. Intravenous alprostadil was prescribed, which was stopped after 2 weeks. Twenty days later, without any improvement of the ischemic lesions, approval for compassionate use was granted and oral treatment with bosentan was initiated at the current dose (62.5 mg twice daily for a month, and then increased to 125 mg twice daily). The ischemic lesions were seen to ameliorate gradually and healed completely 10 months later. The treatment was then terminated, with no relevant adverse effects been observed. The patient stopped tobacco use at the onset of the episode, and did not smoke again during the 48-month follow-up period. Follow-up assessments by nailfold capillaroscopy revealed neoangiogenesis with a gradual increase in the number of nutritional capillaries. The magnetic resonance angiography of the patient’s right hand is seen in Fig. 1 and the capillaroscopy image of the patient’s nailfold before and after treatment with bosentan is seen in Fig. 2.
CASE 2 A 72-year-old man with a 5-year history of Buerger’s disease presented with a 2-month history of ischemic ulcers in his left second finger and his right fourth finger (considering thumb as first) after restarting tobacco use. Nailfold capillaroscopy findings revealed widespread capillary loss and thrombosis in the fingers involved, and a shortened loop pattern in the other fingers. The patient gave up smoking; treatment with bosentan was prescribed
Fig. 1. Case 1: Magnetic resonance angiography image of the right hand showing distal involvement and presence of digital arteries with ‘‘corkscrew-like’’ or coiled appearance.
at the standard initial dose of 62.5 mg twice daily for a month, and then 125 mg twice daily. Three months later, all digital lesions had resolved and laboratory findings revealed elevated serum transaminases over previous normal levels (AST/GOT: 90 U/L; ALT/GPT: 250 U/L). Hence, bosentan termination was decided and, subsequently, all analytical parameters returned to normal. Three months after finishing the treatment, the nailfold capillaroscopy imaging demonstrated that the number of capillaries had increased and that the avascular areas had been reduced. The digital plethysmograph of the patient’s left forefinger before and after treatment is shown in Fig. 3.
DISCUSSION Buerger’s disease has no etiologic treatment, absolute cessation of tobacco use being the only effective intervention. A randomized double-blind study showed an improved outcome with iloprost IV versus aspirin
Vol. 24, No. 5, July 2010
Case reports 690.e3
Fig. 2. Case 1: Nailfold capillaroscopy. A Before treatment with bosentan: absence of capillaries; and B 6 months after treatment with bosentan, the capillary pattern shows neoangiogenesis with new tortuous capillary branching.
Fig. 3. Case 2: Digital plethysmograph of the forefinger of the left hand. A Before treatment with bosentan: a decrease in the amplitude of the pulse wave. B Two months after finishing treatment, digital perfusion is shown to have improved.
after 28 days and also after 6 months (85% responders in the iloprost arm vs. 21% in the aspirin arm after 6 months, with an incidence of amputation of 6 and 18%, respectively).10 Other experimental treatments are therapeutic angiogenesis with intramuscular administration of ‘‘vascular endothelial growth factor’’11 or the thrombolytic therapy.12 Surgical revascularization is generally not possible because of the frequent distal and segmental involvement. Endothelial dysfunction seems to be a relevant factor for this condition since some preliminary studies have shown impaired endothelium-dependent
vasodilation, whereas endothelium-independent vasodilation mechanisms remain unaltered.13,14 Czarnacki et al.15 have correlated the endothelin levels and clinical activity in a cohort of patients and found elevated levels of endothelin in patients with necrotic lesions compared with patients with no clinically active disease and controls. This study also found a significant correlation between high pretreatment endothelin levels and anti-elastase antibodies. These authors suggest that the serum levels of endothelin increase as a consequence of the endothelial dysfunction caused by the immunologic reaction activated by nicotine. A very
690.e4 Case reports
interesting finding of this study was that the serum levels of endothelin remained unmodified after treatment with alprostadil, whereas those of selectin L were reduced. Two of our patients showed a very satisfactory clinical response to bosentan, a dual endothelin receptor antagonist indicated for prevention of new digital ulcers in systemic sclerosis.16 Although these findings reflect just two isolated clinical observations, they highlight the need for studying the effect of bosentan in vascular lesions associated with Buerger’s disease. REFERENCES 1. Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med 2000;343:864-869. 2. Olin JW, Young JR, Graor RA, Ruschhaupt WF, Bartholomew JR. The changing clinical spectrum of thromboangiitis obliterans (Buerger’s disease). Circulation 1990; 82(Suppl 5):IV3-IV8. 3. Adar R, Papa MZ, Halpern Z, et al. Cellular sensitivity to collagen in thromboangiitis obliterans. N Engl J Med 1983;308:1113-1116. 4. Eichhorn J, Sima D, Lindschau C, et al. Antiendothelial cell antibodies in thromboangiitis obliterans. Am J Med Sci 1998;315:17-23. 5. Shionoya S. Diagnostic criteria of Buerger’s disease. Int J Cardiol 1998;66(Suppl 1):S243-S245. 6. Kobayashi M, Nishikimi N, Komori K. Current pathological and clinical aspects of Buerger’s disease in Japan. Ann Vasc Surg 2006;20:148-156.
Annals of Vascular Surgery
7. Zdrojowy K, Adamiec R, Czarnacki M. New aspects of prostaglandin E1 therapeutic influence in thrombo-angiitis obliterans. Pol Arch Med Wewn 2002;108:1071-1077. 8. Olin JW, Shih A. Thromboangiitis obliterans (Buerger’s disease). Curr Opin Rheumatol 2006;18:18-24. 9. De Haro J, Florez A, Fernandez JL, Acin F. Treatment of Buerger disease (thromboangiitis obliterans) with bosentan: a case report. BMJ Case Reports 2009. doi:10.1136/bcr. 08.2008.0691. Copyright Ó 2009 by the BMJ Publishing Group Ltd. 10. Fiessinger JN, Scha¨fer M. Trial of iloprost versus aspirin treatment for critical limb ischaemia of thromboangiitis obliterans. The TAO Study. Lancet 1990;335:555-557. 11. Isner JM, Baumgartner I, Rauh G, et al. Treatment of thromboangiitis obliterans (Buerger’s disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J Vasc Surg 1998;28:964-973. discussion 73-75. 12. Hussein EA, el Dorri A. Intra-arterial streptokinase as adjuvant therapy for complicated Buerger’s disease: early trials. Int Surg 1993;78:54-58. 13. Makita S, Nakamura M, Murakami H, et al. Impaired endothelium-dependent vasorelaxation in peripheral vasculature of patients with thromboangiitis obliterans (Buerger’s disease). Circulation 1996;94:211-215. 14. Kenji N, Yukihito H, Takashi U, et al. Vascular function and endothelial progenitor cells in thromboangiitis obliterans (Buerger’s Disease). Circulation 2008;118:Se635. 15. Czarnacki M, Gacka M, Adamiec R. A role of endothelin 1 in the pathogenesis of thromboangiitis obliterans (initial news). Przegl Lek 2004;61:1346-1350. 16. 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.