Dermatologic Therapy, Vol. ••, 2015, ••–•• Printed in the United States · All rights reserved
© 2015 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Treatment of thromboangiitis obliterans (Buerger’s disease) with high-potency vasodilators David Jiménez-Gallo*, Cristina Albarrán-Planelles*, Cintia Arjona-Aguilera*, German Blanco-Sánchez†, María Eugenia Rodríguez-Mateos† & Mario Linares-Barrios* Departments of *Dermatology and †Pharmacy, Hospital Universitario Puerta del Mar, Cadiz, Spain
ABSTRACT: Thromboangiitis obliterans (TAO) or Buerger’s disease is a vascular inflammatory thrombotic occlusive and segmental disease affecting distal small and medium-sized arteries of the limbs. Tobacco is the main trigger factor and avoiding it is the main treatment. Frequently, it is necessary to use high-potency vasodilators, such as iloprost, bosentan, sildenafil, or alprostadil, to relieve symptoms and reduce the risk of amputation. Iloprost is the only one that has been shown to be effective in randomized clinical trials. We report the third case of TAO treated with sildenafil and a new case treated with bosentan. This condition can be diagnosed and treated by a dermatologist. We would like to highlight the excellent clinical response despite the fact that patients continued to smoke. This finding may have important therapeutic implications because early treatment may prevent amputation and can be effective even during the process of giving up smoking. KEYWORDS: bosentan, Buerger’s disease, sildenafil, thromboangiitis obliterans
Introduction Thromboangiitis obliterans (TAO) is a nonatherosclerotic segmental inflammatory disease that mainly affects small and medium-sized arteries and veins at distal level of upper and lower extremities. TAO is also known as Buerger’s disease (1). Exposure to tobacco is responsible for the start and progression of TAO in more than 95% of cases. Its suspension is the only way to prevent recurrence (2). We describe two cases of TAO with good
response to treatment despite continuing to smoke tobacco; one case was resolved successfully with bosentan and the other patient was initially treated with intravenous alprostadil and later with sildenafil for maintenance. In both patients, clinical remission was achieved and avoided the amputation of fingers. In this paper, we note that dermatologists can play a key role in both the diagnosis and the medical treatment of this disease.
Materials and methods Address correspondence and reprint requests to: David Jiménez-Gallo, MD, Dermatologist, Department of Dermatology, Hospital Universitario Puerta del Mar, Ana de Viya Av. 21, Cadiz, Andalusia 11009, Spain, or email: [email protected].
Patient 1 A 49-year-old man with a history of smoking 30 cigarettes a day came to the dermatology department with a 4-month history of intense pain in the
1
Jiménez-Gallo et al.
fingers of both hands. He had previously been treated with acetylsalicylic acid and nifedipine without good symptom control. Physical examination showed necrotic irregular eschars of 1–1.5 cm in diameter on the pads of the first, second, and fourth finger of the left hand and second and third finger of the right hand (Fig. 1A). Peripheral pulses in the upper and lower limbs were preserved bilaterally. The patient was admitted to the dermatology unit to complete his study. All laboratory tests, including blood count, biochemistry, protein count, immunoglobulin count, lactate dehydrogenase, serological tests for human immunodeficiency virus (HIV), hepatitis C virus, and hepatitis B virus, and hypercoagulability study were normal or negative. Laboratory tests for autoimmune disorders, including antinuclear antibodies, extractable nuclear antigen antibodies, cryoglobulins, anti-phospholipid autoantibodies, and lupus anticoagulant antibodies, were also negative. Toxicology screening was negative. The upper limb arteriography showed a significantly altered corkscrew-like vessels and distal stenotic lesions compatible with TAO, which allowed the correct
diagnosis. We told the patient to stop smoking. Meanwhile, we started treatment with bosentan (Tracleer®, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) at a dose of 62.5 mg/12 hour for 1 month with further increase of the dose to 125 mg/12 hour. The patient’s pain rapidly improved and digital necrosis was progressively healed despite admitting he continued smoking. After 3-month treatment, necrotic eschars were completely healed (Fig. 1B). Subsequently, after completing the treatment to give up smoking, we suspended treatment with bosentan without recurrence of TAO during 9-month follow-up. Patient 2 A 36-year-old man with a history of smoking 60 cigarettes a day came to the dermatology department with a 3-month history of severe pain and paresthesias on the first, second, and fifth fingers of the right hand. He also had episodes of purulent suppuration and nail disorder of second finger of the right hand. On physical examination, he presented an ulcerated and hyperkeratotic lesion on the pad of the second finger of the right hand associated with distal onycholysis (Fig. 2A). Peripheral pulses were also preserved. All additional studies carried out and similar to the first case were negative. Angiography also showed data compatible with TAO. We started treatment with alprostadil (Sugiran®, Laboratorios Dr. Esteve, S.A., Barcelona, Spain) 40 μg every 12 hours intravenously during the first days and then 60 μg every 24 hours until reaching 21 days. Severe pain disappeared with the first dose. Later, to prevent recurrence, we prescribed treatment with sildenafil (Revatio®, Pfizer, New York, NY, USA) 20 mg every 8 hours as maintenance therapy. Lesions healed completely at 3 months (Fig. 2B). Pain and paresthesias disappeared even though the patient did not give up smoking. Subsequently, the patient was treated with sildenafil at doses of 20 mg every 12 hours for 6 months to complete the treatment to give up smoking. Later, we suspended sildenafil without recurrence of TAO during 9-month follow-up.
Discussion
FIG. 1. (A) Digital necrosis secondary to thromboangiitis obliterans. (B) Three months after treatment with bosentan.
2
Classic clinical presentation of TAO or Buerger’s disease occurs in men under 50 years old with current or recent history of smoking. TAO manifests as migratory thrombophlebitis or signs of distal arterial insufficiency. The localization is typically infrapopliteal in the lower limbs and distal to
High-potency vasodilators
FIG. 2. (A) Hyperkeratotic and ulcerated lesion with onychopathy of the second finger of the right hand. (B) Three months after the induction regimen with alprostadil and maintenance with sildenafil. The patient continued to smoke while he carried out a program to give up smoking program.
the brachial artery in the upper extremities. These signs of arterial ischemia include intermittent claudication, pain on rest, ischemic ulcers, suppurative and painful onychopathy, Raynaud’s phenomenon, and gangrene (1,3). Physical examination should include palpation of peripheral pulses (3). Traditional diagnosis of TAO is based on meeting the five criteria of Shionoya, which are smoking history, onset before the age of 50 years, infrapopliteal arterial occlusive disease, either upper limb involvement or phlebitis migrans, and absence of atherosclerotic risk factors other than smoking (4). The diagnosis is based on a correlation between the clinical history, physical examination, and vascular abnormalities in the imaging tests. Laboratory studies and imaging tests should exclude systemic autoimmune disease, thrombophilia, diabetes mellitus, as well as source of proxi-
mal embolism (1,3). Arteriography is the main diagnostic test. Segmental occlusive lesions of the small and medium-sized arteries with formation corkscrew collaterals and abrupt occlusion of an otherwise normal artery are typical angiographic findings in TAO. A biopsy is rarely indicated (1,3,5). These patients have a high risk of death and amputation (2). Cooper et al. (6) described a risk of amputation of 11%, 21%, and 23% for evolution of 5, 10, and 20 years, respectively. The main treatment for TAO patients is to give up smoking in any of its forms, avoiding even the use of nicotine gum or patches (5). A problem in the treatment of TAO is that the disease can remain active and progress despite stopping smoking. TAO patients have an alteration of vasorelaxation dependent on endothelium in the peripheral vasculature (1). Another major difficulty lies in the difficulty of these patients to give up smoking (7,8). The therapeutic effect has only been described with high-potency vasodilators, including iloprost, alprostadil, bosentan, and sildenafil. Prostacyclin analog iloprost has shown efficacy in randomized clinical trials. Alprostadil has been described as effective in TAO but may recur after its suspension (9). Oral high-potency vasodilators, such as bosentan or sildenafil, may provide a new therapeutic weapon during the process of giving up tobacco. To our knowledge, there have been three cases of TAO treated with inhibitors of phosphodiesterase-5 (two with sildenafil and one with tadalafil) (9). A clinical pilot study of 12 cases and a recent open-label study of 19 cases on longterm outcomes of bosentan for treating ulcers in TAO have been published as well as several isolated cases (7–9). Larger studies are required with these oral drugs because they are more comfortable and less expensive than intravenous drugs. To the best of our knowledge, there are no randomized controlled trials comparing the effectiveness of highpotency vasodilators in TAO patients. Probably, all high-potency vasodilators described in this paper could be effective to achieve healing of digital necrosis in TAO patients. We summarize on the management of these vasodilators with potential uses in diseases that affect cutaneous microcirculation (Table 1). These vasodilators are being used more and more frequently by the dermatologist. In conclusion, dermatologists must know how to handle these necessary potent vasodilators as TAO can be diagnosed and treated medically. Sildenafil or bosentan may be effective even while the patient continues to smoke during the process of giving up smoking. In the two cases mentioned, all the treatments described rapidly produced a
3
4
Bosentan (Tracleer®)
Sildenafil (Revatio®).
Alprostadil (Prostavasin®) (Sugiran®)
Iloprost (Ilomedin®)
(7–9)
(10–13)
(10,14)
(15,16)
Synthetic analog of prostacyclin
Prostaglandin E1 (PGE1) with vasodilator and antithrombotic action
Phosphodiesterasetype-5 (PDE5) inhibitor
Endothelin-1 (ET-1) receptor antagonist
Action mechanism
Advanced TAO with severe ischemia in the limbs
Severe peripheral arterial occlusive disease
• Pulmonary arterial hypertension • Systemic sclerosis with digital ulcers Pulmonary arterial hypertension
Indications
• Initially 0.5 ng/kg/minute. The administered dose lies between 0.5 and 2.0 ng/kg/minute as an intravenous infusion over 6 hours per day. • The usual duration is 28 days
• Initially 40 μg/12 hours and later 60 μg/24 hours in intravenous infusion of 2–3 hours. Duration of treatment 21 days.
20 mg oral three times a day
62.5 mg oral twice a day for 4 weeks and then increased to the usual dose of 125 mg twice a day
Dose
• Non-arteritic anterior ischemic optic neuropathy • Combination with nitrates and potent CYP3A4 inhibitors • Severe liver disease or severe hypotension or recently stroke or myocardial infarction • Newborn with hyaline membrane disease • Pregnancy and lactation • Heart failure class III–IV of NYHA • Myocardial infarction within last 6 months or unstable angina or atrioventricular block of second and third grade • Hypotension • Glaucoma • Liver disease • Polytrauma or active gastrointestinal ulcer • Chronic respiratory insufficiency • Similar to alprostadil • Similar pharmacodynamic profile
• Liver problems • Pregnant • Interaction with cyclosporin A
Contraindications
• Secondary Raynaud’s syndrome and digital ulcer (therapy duration between 3 and 10 days) • Peripheral occlusive arterial disease • Diabetic foot syndrome • Venous leg ulcer • Postoperative wound healing in plastic-reconstructive surgery
• Used in two patients with TAO • Treatment of lymphatic malformations • Used in digital gangrene secondary to antiphospholipid syndrome • Treatment of digital ulcers due to Raynaud’s phenomenon • Treatment of livedoid vasculopathy • The dosage and the duration of treatment and the interval of infusions have to be adjusted to the patient’s response
• Monthly liver tests: If aminotransferase (ALT/AST) ≤ 3× upper limit of normal; continue to monitor, no change in dosage • Monthly pregnancy tests
Comments
Notes: Summary for the dermatologist to handle these drugs. Alprostadil is a drug not assessed by the EMEA and has not been authorized for this indication by the FDA. Other sources: Food and Drug Administration (FDA); European Medicines Agency (EMEA); Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). NYHA, New York Heart Association Functional Classification; TAO, thromboangiitis obliterans.
Drug
Source
Table 1. Vasodilators used for the treatment of TAO or Buerger’s disease
Jiménez-Gallo et al.
High-potency vasodilators
relief from pain and healing of the digital ulcers, avoiding the amputation of fingers. The paper encourages controlled studies, and combining a preventive as well as a curative treatment would be a valuable approach to treat TAO. A large, doubleblind study is needed to determine the benefit and risk of these agents in TAO. Sildenafil should also be investigated for a potential beneficial role in TAO.
Financial disclosure None reported.
References 1. Vijayakumar A1, Tiwari R, Kumar Prabhuswamy V. Thromboangiitis obliterans (Buerger’s disease) – current practices. Int J Inflam. 2013: 2013: 156905. 2. Ketha SS, Cooper LT. The role of autoimmunity in thromboangiitis obliterans (Buerger’s disease). Ann N Y Acad Sci 2013: 1285: 15–25. 3. Piazza G, Creager MA. Thromboangiitis obliterans. Circulation 2010: 121: 1858–1861. 4. Shionoya S. Diagnostic criteria of Buerger’s disease. Int J Cardiol 1998: 66: S243–S247. 5. Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med 2000: 343: 864–869. 6. Cooper LT, Tse TS, Mikhail MA, McBane RD, Stanson AW, Ballman KV. Long-term survival and amputation risk in thromboangiitis obliterans (Buerger’s disease). J Am Coll Cardiol 2004: 44: 2410–2411.
7. Palomo-Arellano A, Cervigón-González I, Torres-Iglesias LM. Effectiveness of bosentan in the treatment of ischemic lesions in a case of thromboangiitis obliterans (Buerger disease): a case report. Dermatol Online J 2011: 17: 4. 8. De Haro J, Acin F, Bleda S, Varela C, Esparza L. Treatment of thromboangiitis obliterans (Buerger’s disease) with bosentan. BMC Cardiovasc Disord 2012: 12: 5. 9. De Haro J, Bleda S, Acin F. An open-label study on longterm outcomes of bosentan for treating ulcers in thromboangiitis obliterans (Buerger’s disease). Int J Cardiol 2014: 177: 529–531. 10. Abeles AM, Nicolescu M, Pinchover Z, Abeles M. Thromboangiitis obliterans successfully treated with phosphodiesterase type 5 inhibitors. Vascular 2014: 22: 313– 316. 11. Danial C, Tichy AL, Tariq U, et al. An open-label study to evaluate sildenafil for the treatment of lymphatic malformations. J Am Acad Dermatol 2014: 70: 1050–1057. 12. Gonzalez ME, Kahn P, Price HN, Kamino H, Schaffer JV. Retiform purpura and digital gangrene secondary to antiphospholipid syndrome successfully treated with sildenafil. Arch Dermatol 2011: 147: 164–167. 13. Ambach A, Seo W, Bonnekoh B, Gollnick H. Low-dose combination therapy of severe digital ulcers in diffuse progressive systemic sclerosis with the endothelin-1 receptor antagonist bosentan and the phosphodiesterase V inhibitor sildenafil. J Dtsch Dermatol Ges 2009: 7: 888–891. 14. Mofarrah R, Aberer W, Aberer E. Treatment of livedoid vasculopathy with alprostadil (PGE-1): case report and review of published literature. J Eur Acad Dermatol Venereol 2013: 27: e252–e254. 15. Wohlrab J, Schanz S, Ulrich J. Iloprost in dermatology. J Dtsch Dermatol Ges 2011: 9: 56–63. 16. Bozkurt AK, Cengiz K, Arslan C, et al. A stable prostacyclin analogue (iloprost) in the treatment of Buerger’s disease: a prospective analysis of 150 patients. Ann Thorac Cardiovasc Surg 2013: 19: 120–125.
5
© 2015 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Treatment of thromboangiitis obliterans (Buerger’s disease) with high-potency vasodilators David Jiménez-Gallo*, Cristina Albarrán-Planelles*, Cintia Arjona-Aguilera*, German Blanco-Sánchez†, María Eugenia Rodríguez-Mateos† & Mario Linares-Barrios* Departments of *Dermatology and †Pharmacy, Hospital Universitario Puerta del Mar, Cadiz, Spain
ABSTRACT: Thromboangiitis obliterans (TAO) or Buerger’s disease is a vascular inflammatory thrombotic occlusive and segmental disease affecting distal small and medium-sized arteries of the limbs. Tobacco is the main trigger factor and avoiding it is the main treatment. Frequently, it is necessary to use high-potency vasodilators, such as iloprost, bosentan, sildenafil, or alprostadil, to relieve symptoms and reduce the risk of amputation. Iloprost is the only one that has been shown to be effective in randomized clinical trials. We report the third case of TAO treated with sildenafil and a new case treated with bosentan. This condition can be diagnosed and treated by a dermatologist. We would like to highlight the excellent clinical response despite the fact that patients continued to smoke. This finding may have important therapeutic implications because early treatment may prevent amputation and can be effective even during the process of giving up smoking. KEYWORDS: bosentan, Buerger’s disease, sildenafil, thromboangiitis obliterans
Introduction Thromboangiitis obliterans (TAO) is a nonatherosclerotic segmental inflammatory disease that mainly affects small and medium-sized arteries and veins at distal level of upper and lower extremities. TAO is also known as Buerger’s disease (1). Exposure to tobacco is responsible for the start and progression of TAO in more than 95% of cases. Its suspension is the only way to prevent recurrence (2). We describe two cases of TAO with good
response to treatment despite continuing to smoke tobacco; one case was resolved successfully with bosentan and the other patient was initially treated with intravenous alprostadil and later with sildenafil for maintenance. In both patients, clinical remission was achieved and avoided the amputation of fingers. In this paper, we note that dermatologists can play a key role in both the diagnosis and the medical treatment of this disease.
Materials and methods Address correspondence and reprint requests to: David Jiménez-Gallo, MD, Dermatologist, Department of Dermatology, Hospital Universitario Puerta del Mar, Ana de Viya Av. 21, Cadiz, Andalusia 11009, Spain, or email: [email protected].
Patient 1 A 49-year-old man with a history of smoking 30 cigarettes a day came to the dermatology department with a 4-month history of intense pain in the
1
Jiménez-Gallo et al.
fingers of both hands. He had previously been treated with acetylsalicylic acid and nifedipine without good symptom control. Physical examination showed necrotic irregular eschars of 1–1.5 cm in diameter on the pads of the first, second, and fourth finger of the left hand and second and third finger of the right hand (Fig. 1A). Peripheral pulses in the upper and lower limbs were preserved bilaterally. The patient was admitted to the dermatology unit to complete his study. All laboratory tests, including blood count, biochemistry, protein count, immunoglobulin count, lactate dehydrogenase, serological tests for human immunodeficiency virus (HIV), hepatitis C virus, and hepatitis B virus, and hypercoagulability study were normal or negative. Laboratory tests for autoimmune disorders, including antinuclear antibodies, extractable nuclear antigen antibodies, cryoglobulins, anti-phospholipid autoantibodies, and lupus anticoagulant antibodies, were also negative. Toxicology screening was negative. The upper limb arteriography showed a significantly altered corkscrew-like vessels and distal stenotic lesions compatible with TAO, which allowed the correct
diagnosis. We told the patient to stop smoking. Meanwhile, we started treatment with bosentan (Tracleer®, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) at a dose of 62.5 mg/12 hour for 1 month with further increase of the dose to 125 mg/12 hour. The patient’s pain rapidly improved and digital necrosis was progressively healed despite admitting he continued smoking. After 3-month treatment, necrotic eschars were completely healed (Fig. 1B). Subsequently, after completing the treatment to give up smoking, we suspended treatment with bosentan without recurrence of TAO during 9-month follow-up. Patient 2 A 36-year-old man with a history of smoking 60 cigarettes a day came to the dermatology department with a 3-month history of severe pain and paresthesias on the first, second, and fifth fingers of the right hand. He also had episodes of purulent suppuration and nail disorder of second finger of the right hand. On physical examination, he presented an ulcerated and hyperkeratotic lesion on the pad of the second finger of the right hand associated with distal onycholysis (Fig. 2A). Peripheral pulses were also preserved. All additional studies carried out and similar to the first case were negative. Angiography also showed data compatible with TAO. We started treatment with alprostadil (Sugiran®, Laboratorios Dr. Esteve, S.A., Barcelona, Spain) 40 μg every 12 hours intravenously during the first days and then 60 μg every 24 hours until reaching 21 days. Severe pain disappeared with the first dose. Later, to prevent recurrence, we prescribed treatment with sildenafil (Revatio®, Pfizer, New York, NY, USA) 20 mg every 8 hours as maintenance therapy. Lesions healed completely at 3 months (Fig. 2B). Pain and paresthesias disappeared even though the patient did not give up smoking. Subsequently, the patient was treated with sildenafil at doses of 20 mg every 12 hours for 6 months to complete the treatment to give up smoking. Later, we suspended sildenafil without recurrence of TAO during 9-month follow-up.
Discussion
FIG. 1. (A) Digital necrosis secondary to thromboangiitis obliterans. (B) Three months after treatment with bosentan.
2
Classic clinical presentation of TAO or Buerger’s disease occurs in men under 50 years old with current or recent history of smoking. TAO manifests as migratory thrombophlebitis or signs of distal arterial insufficiency. The localization is typically infrapopliteal in the lower limbs and distal to
High-potency vasodilators
FIG. 2. (A) Hyperkeratotic and ulcerated lesion with onychopathy of the second finger of the right hand. (B) Three months after the induction regimen with alprostadil and maintenance with sildenafil. The patient continued to smoke while he carried out a program to give up smoking program.
the brachial artery in the upper extremities. These signs of arterial ischemia include intermittent claudication, pain on rest, ischemic ulcers, suppurative and painful onychopathy, Raynaud’s phenomenon, and gangrene (1,3). Physical examination should include palpation of peripheral pulses (3). Traditional diagnosis of TAO is based on meeting the five criteria of Shionoya, which are smoking history, onset before the age of 50 years, infrapopliteal arterial occlusive disease, either upper limb involvement or phlebitis migrans, and absence of atherosclerotic risk factors other than smoking (4). The diagnosis is based on a correlation between the clinical history, physical examination, and vascular abnormalities in the imaging tests. Laboratory studies and imaging tests should exclude systemic autoimmune disease, thrombophilia, diabetes mellitus, as well as source of proxi-
mal embolism (1,3). Arteriography is the main diagnostic test. Segmental occlusive lesions of the small and medium-sized arteries with formation corkscrew collaterals and abrupt occlusion of an otherwise normal artery are typical angiographic findings in TAO. A biopsy is rarely indicated (1,3,5). These patients have a high risk of death and amputation (2). Cooper et al. (6) described a risk of amputation of 11%, 21%, and 23% for evolution of 5, 10, and 20 years, respectively. The main treatment for TAO patients is to give up smoking in any of its forms, avoiding even the use of nicotine gum or patches (5). A problem in the treatment of TAO is that the disease can remain active and progress despite stopping smoking. TAO patients have an alteration of vasorelaxation dependent on endothelium in the peripheral vasculature (1). Another major difficulty lies in the difficulty of these patients to give up smoking (7,8). The therapeutic effect has only been described with high-potency vasodilators, including iloprost, alprostadil, bosentan, and sildenafil. Prostacyclin analog iloprost has shown efficacy in randomized clinical trials. Alprostadil has been described as effective in TAO but may recur after its suspension (9). Oral high-potency vasodilators, such as bosentan or sildenafil, may provide a new therapeutic weapon during the process of giving up tobacco. To our knowledge, there have been three cases of TAO treated with inhibitors of phosphodiesterase-5 (two with sildenafil and one with tadalafil) (9). A clinical pilot study of 12 cases and a recent open-label study of 19 cases on longterm outcomes of bosentan for treating ulcers in TAO have been published as well as several isolated cases (7–9). Larger studies are required with these oral drugs because they are more comfortable and less expensive than intravenous drugs. To the best of our knowledge, there are no randomized controlled trials comparing the effectiveness of highpotency vasodilators in TAO patients. Probably, all high-potency vasodilators described in this paper could be effective to achieve healing of digital necrosis in TAO patients. We summarize on the management of these vasodilators with potential uses in diseases that affect cutaneous microcirculation (Table 1). These vasodilators are being used more and more frequently by the dermatologist. In conclusion, dermatologists must know how to handle these necessary potent vasodilators as TAO can be diagnosed and treated medically. Sildenafil or bosentan may be effective even while the patient continues to smoke during the process of giving up smoking. In the two cases mentioned, all the treatments described rapidly produced a
3
4
Bosentan (Tracleer®)
Sildenafil (Revatio®).
Alprostadil (Prostavasin®) (Sugiran®)
Iloprost (Ilomedin®)
(7–9)
(10–13)
(10,14)
(15,16)
Synthetic analog of prostacyclin
Prostaglandin E1 (PGE1) with vasodilator and antithrombotic action
Phosphodiesterasetype-5 (PDE5) inhibitor
Endothelin-1 (ET-1) receptor antagonist
Action mechanism
Advanced TAO with severe ischemia in the limbs
Severe peripheral arterial occlusive disease
• Pulmonary arterial hypertension • Systemic sclerosis with digital ulcers Pulmonary arterial hypertension
Indications
• Initially 0.5 ng/kg/minute. The administered dose lies between 0.5 and 2.0 ng/kg/minute as an intravenous infusion over 6 hours per day. • The usual duration is 28 days
• Initially 40 μg/12 hours and later 60 μg/24 hours in intravenous infusion of 2–3 hours. Duration of treatment 21 days.
20 mg oral three times a day
62.5 mg oral twice a day for 4 weeks and then increased to the usual dose of 125 mg twice a day
Dose
• Non-arteritic anterior ischemic optic neuropathy • Combination with nitrates and potent CYP3A4 inhibitors • Severe liver disease or severe hypotension or recently stroke or myocardial infarction • Newborn with hyaline membrane disease • Pregnancy and lactation • Heart failure class III–IV of NYHA • Myocardial infarction within last 6 months or unstable angina or atrioventricular block of second and third grade • Hypotension • Glaucoma • Liver disease • Polytrauma or active gastrointestinal ulcer • Chronic respiratory insufficiency • Similar to alprostadil • Similar pharmacodynamic profile
• Liver problems • Pregnant • Interaction with cyclosporin A
Contraindications
• Secondary Raynaud’s syndrome and digital ulcer (therapy duration between 3 and 10 days) • Peripheral occlusive arterial disease • Diabetic foot syndrome • Venous leg ulcer • Postoperative wound healing in plastic-reconstructive surgery
• Used in two patients with TAO • Treatment of lymphatic malformations • Used in digital gangrene secondary to antiphospholipid syndrome • Treatment of digital ulcers due to Raynaud’s phenomenon • Treatment of livedoid vasculopathy • The dosage and the duration of treatment and the interval of infusions have to be adjusted to the patient’s response
• Monthly liver tests: If aminotransferase (ALT/AST) ≤ 3× upper limit of normal; continue to monitor, no change in dosage • Monthly pregnancy tests
Comments
Notes: Summary for the dermatologist to handle these drugs. Alprostadil is a drug not assessed by the EMEA and has not been authorized for this indication by the FDA. Other sources: Food and Drug Administration (FDA); European Medicines Agency (EMEA); Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). NYHA, New York Heart Association Functional Classification; TAO, thromboangiitis obliterans.
Drug
Source
Table 1. Vasodilators used for the treatment of TAO or Buerger’s disease
Jiménez-Gallo et al.
High-potency vasodilators
relief from pain and healing of the digital ulcers, avoiding the amputation of fingers. The paper encourages controlled studies, and combining a preventive as well as a curative treatment would be a valuable approach to treat TAO. A large, doubleblind study is needed to determine the benefit and risk of these agents in TAO. Sildenafil should also be investigated for a potential beneficial role in TAO.
Financial disclosure None reported.
References 1. Vijayakumar A1, Tiwari R, Kumar Prabhuswamy V. Thromboangiitis obliterans (Buerger’s disease) – current practices. Int J Inflam. 2013: 2013: 156905. 2. Ketha SS, Cooper LT. The role of autoimmunity in thromboangiitis obliterans (Buerger’s disease). Ann N Y Acad Sci 2013: 1285: 15–25. 3. Piazza G, Creager MA. Thromboangiitis obliterans. Circulation 2010: 121: 1858–1861. 4. Shionoya S. Diagnostic criteria of Buerger’s disease. Int J Cardiol 1998: 66: S243–S247. 5. Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med 2000: 343: 864–869. 6. Cooper LT, Tse TS, Mikhail MA, McBane RD, Stanson AW, Ballman KV. Long-term survival and amputation risk in thromboangiitis obliterans (Buerger’s disease). J Am Coll Cardiol 2004: 44: 2410–2411.
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