Retrospective Analysis of Patients with Systemic Sclerosis Using Bosentan for Digital Ulcer: A Ten-Year Single Center Experience
Abstract
The risk of ischemic digital ulcer (DU) development is high in systemic sclerosis (SS). The use of bosentan, an endothelin receptor antagonist, is recommended in the treatment of DU secondary to SS. In our study, we aimed to raise awareness of clinicians about the side effects that clinicians may encounter as a result of bosentan use and its management by presenting long-term data of patients who used bosentan in the treatment of DU, which is difficult to manage in patients with SS. The most common side effects that develop during bosentan treatment are headache, dizziness, cough, dyspnea, syncope, flushing, elevated liver enzymes and palpitations. In our study, safety data of bosentan were analyzed by evaluating side effects. Of the 25 patients included in the study, 24 (96%) were female, the median age was 54 years and the mean follow-up period was 15.16± 9.01 years. All patients had used at least one vasodilator drug for the treatment of DU. All patients used calcium channel blockers and pentoxifylline, 23 (92%) patients used iloprost and 11 (44%) patients used sildenafil and/or tadalafil. There were five (20%) patients who died during follow-up while on bosentan for reasons not related to drug use. No side effects were observed in these five patients during follow-up. In five patients, the drug was discontinued for different reasons. One of them was discontinued because of pregnancy and the other one was discontinued voluntarily because she said she felt unwell. In three patients, the drug was discontinued because of palpitations in one, headache in one and elevated aminotransferase in the other. The use of bosentan may reduce the development of DU when used alone or in combination with other drugs. The most important point for a clinician in terms of safety while using bosentan is the side effects that may develop and their management. In our study, there was one patient with headache, aminotransferase elevation and palpitations. This study emphasizes that clinicians should be more careful in terms of side effects when using bosentan for digital ulcers that require difficult and laborious treatment management.
References
- 1. Wigley, F. M. (2009). Vascular disease in scleroderma. Clinical reviews in allergy & immunology, 36(2), 150-175.
- 2. Walker, U. A., Tyndall, A., Czirjak, L., Denton, C., Farge-Bancel, D., Kowal-Bielecka, O., et al. (2007). Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Annals of the rheumatic diseases, 66(6), 754-763.
- 3. Mawdsley AH. Patient perception of UK scleroderma services – results of an anonymous questionnaire. Rheumatology (Oxford) 2006;45:1573.
- 4. Ferri, C., Valentini, G., Cozzi, F., Sebastiani, M., Michelassi, C., La Montagna, G., et al. & Systemic Sclerosis Study Group of the Italian Society of Rheumatology (SIR-GSSSc. (2002). Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine, 81(2), 139-153.
- 5. Steen, V., Denton, C. P., Pope, J. E., & Matucci-Cerinic, M. (2006). Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology, 48(suppl_3), iii19-iii24.
- 6. Denton, C. P., Krieg, T., Guillevin, L., Schwierin, B., Rosenberg, D., Silkey, M., et al. (2012). Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry. Annals of the rheumatic diseases, 71(5), 718-721.
- 7. Mihai, C., Landewé, R., Van Der Heijde, D., Walker, U. A., Constantin, P. I., Gherghe, A. M., et al. (2016). Digital ulcers predict a worse disease course in patients with systemic sclerosis. Annals of the rheumatic diseases, 75(4), 681-686.
- 8. Hachulla E, Clerson P, Launay D, Lambert M, Morell-Dubois S, Queyrel V, et al. Natural history of ischemic digital ulcers in systemic sclerosis: single- center retrospective longitudinal study. J Rheumatol. 2007;34:2423–2430.
- 9. Korn, J. H., Mayes, M., Matucci Cerinic, M., Rainisio, M., Pope, J., Hachulla, E., et al. & RAPIDS‐1 Study Group. (2004). Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis & Rheumatism, 50(12), 3985-3993.
- 10.Matucci-Cerinic, M., Denton, C. P., Furst, D. E., Mayes, M. D., Hsu, V. M., Carpentier, P., et al. (2011). Bosentan treatment ofdigital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Annals of the rheumatic diseases, 70(1), 32-38.
- 11.Kowal-Bielecka, O., Fransen, J., Avouac, J., Becker, M., Kulak, A., Allanore, Y., et al. (2017). Update of EULARrecommendations for the treatment of systemic sclerosis. Annals of the rheumatic diseases, 76(8), 1327-1339.
- 12.Rubin, L. J., Badesch, D. B., Barst, R. J., Galiè, N., Black, C. M., Keogh, A., et al. (2002). Bosentan therapy for pulmonary arterial hypertension. New England Journal of Medicine, 346(12), 896-903.
- 13.Castellvi, I., Simeon, C. P., Sarmiento, M., Casademont, J., Corominas, H., & Fonollosa, V. (2020). Effect of bosentan in pulmonary hypertension development in systemic sclerosispatients with digital ulcers. PloS one, 15(12), e0243651.
- 14.Hughes, M., & Herrick, A. L. (2017). Digital ulcers in systemic sclerosis. Rheumatology, 56(1), 14-25.
- 15.Kowal-Bielecka, O., Fransen, J., Avouac, J., Becker, M., Kulak, A., Allanore, Y., et al. (2017). Update of EULARrecommendations for the treatment of systemic sclerosis. Annals of the rheumatic diseases, 76(8), 1327-1339.
- 16.Hamaguchi, Y., Sumida, T., Kawaguchi, Y., Ihn, H., Tanaka, S., Asano, Y., et al. (2017). Safety and tolerability of bosentan for digital ulcers in Japanese patients with systemic sclerosis:Prospective, multicenter, open‐label study. The Journal of Dermatology, 44(1), 13-17.
- 17.Öztaş, M., Özgül, H., & Uğurlu, S. (2020). Dijital ülsernedeniyle bosentan kullanan sistemik sklerozis hastalarında tedavide kalım süresi ve yan etki profilinin değerlendirilmesi: gerçek yaşam deneyimi. RAED Journal/RAED Dergisi, 12(2).
- 18.European Medicines Agency. Tracleer (bosentan) 62.5 mg film-coated tablets: summary of product characteristics [online]. Available from URL: https://www.ema.europa.eu/en/documents/variation-report/tracleer-h-c-401-x-0039-epar-assessment-report-extension_en.pdf [Accessed 2009 Aug 6]
- 19.Humbert, M., Segal, E. S., Kiely, D. G., Carlsen, J., Schwierin, B., & Hoeper, M. M. (2007). Results of European post-marketing surveillance of bosentan in pulmonary hypertension. European Respiratory Journal, 30(2), 338-344.
- 20.Funauchi, M., Kishimoto, K., Shimazu, H., Nagare, Y., Hino, S., Yano, T., & Kinoshita, K. (2009). Effects of bosentan on the skin lesions: an observational study from a single center in Japan. Rheumatology international, 29(7), 769-775.
- 21.Ivorra, J. A. R., Simeon, C. P., Sancho, J. J. A., Egurbide, M. V., Castillo, M. J., Lloria, X., et al. (2011). Bosentan in clinical practice for treating digital and other ischemic ulcers in Spanish patients with systemic sclerosis: IBER-DU cohort study. The Journal of Rheumatology, 38(8), 1631-1635.
Sistemik Sklerozis Tanılı ve Dijital Ülser Nedeniyle Bosentan Kullanan Hastaların Retrospektif İncelenmesi: On Yıllık Tek Merkez Deneyimi
Abstract
Sistemik sklerozis (SS)’te iskemik dijital ülser (DÜ) gelişimi riski yüksektir. SS’a ikincil gelişen DÜ tedavisinde endotelin reseptör antagonisti olan bosentan kullanımı önerilmektedir. Çalışmamızda SS tanılı hastalarda görülen, tedavi yönetimi zor olan DÜ tedavisinde bosentan kullanan hastaların uzun dönem verilerini sunarak, klinisyenlerin bosentan kullanımı sonucu karşılaşabilecekleri yan etkiler ve yönetimiyle ilgili farkındalık oluşturmayı amaçladık. Bosentan tedavisi sırasında gelişen en sık yan etkiler baş ağrısı, baş dönmesi, öksürük, nefes darlığı, senkop, flushing, karaciğer enzim yüksekliği ve çarpıntıdır. Çalışmamızda bosentanın güvenlik verileri yan etkiler üzerinden değerlendirilerek incelendi. Çalışmaya alınan 25 hastanın 24’ü (%96) kadın olup, medyan yaş 54 yıl, hastalık ortalama takip süresi 15.16± 9.01 yıldı. Hastaların tamamı DÜ tedavisi için en az bir vazodilatatör ilaç kullanmıştı. Tüm hastaların kalsiyum kanal blokeri ve pentoxifilin kullanımı, 23 (%92) hastanın iloprost, 11 (%44) hastanın ise sildenafil ve/veya tadalafil kullanımı vardı. Bosentan kullanırken takip süresince ilaç kullanımına bağlı olmayan sebeplerden exitus olan beş (%20) hasta vardı. Bu beş hastanın takipleri süresince yan etki gözlenmedi. Beş hastada ise farklı nedenlerle ilaç kesildi. Biri gebelik nedeniyle, diğeri ise kendini kötü hissettiğini söylediğinden kendi isteğiyle ilaç kesildi. Üç hastanın birinde çarpıntı, birinde baş ağrısı ve diğerinde ise aminotransferaz yüksekliği nedeniyle ilaç kesildi. Bosentan kullanımı DÜ gelişimini tek başına ya da diğer ilaçlarla kombine kullanıldığında azaltabilmektedir. Bosentanı kullanırken bir klinisyen için güvenlik açısından en önemli nokta gelişebilecek yan etkiler ve bunların yönetimidir. Çalışmamızda baş ağrısı, aminotransferaz yüksekliği ve çarpıntı görülen birer hasta vardı. Bu çalışmayla klinisyenlerin zor ve zahmetli bir tedavi yönetimi gerektiren dijital ülserler için bosentan kullanımında yan etkiler açısından daha dikkatli davranmaları gerektiği vurgulanmıştır.
References
- 1. Wigley, F. M. (2009). Vascular disease in scleroderma. Clinical reviews in allergy & immunology, 36(2), 150-175.
- 2. Walker, U. A., Tyndall, A., Czirjak, L., Denton, C., Farge-Bancel, D., Kowal-Bielecka, O., et al. (2007). Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Annals of the rheumatic diseases, 66(6), 754-763.
- 3. Mawdsley AH. Patient perception of UK scleroderma services – results of an anonymous questionnaire. Rheumatology (Oxford) 2006;45:1573.
- 4. Ferri, C., Valentini, G., Cozzi, F., Sebastiani, M., Michelassi, C., La Montagna, G., et al. & Systemic Sclerosis Study Group of the Italian Society of Rheumatology (SIR-GSSSc. (2002). Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine, 81(2), 139-153.
- 5. Steen, V., Denton, C. P., Pope, J. E., & Matucci-Cerinic, M. (2006). Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology, 48(suppl_3), iii19-iii24.
- 6. Denton, C. P., Krieg, T., Guillevin, L., Schwierin, B., Rosenberg, D., Silkey, M., et al. (2012). Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry. Annals of the rheumatic diseases, 71(5), 718-721.
- 7. Mihai, C., Landewé, R., Van Der Heijde, D., Walker, U. A., Constantin, P. I., Gherghe, A. M., et al. (2016). Digital ulcers predict a worse disease course in patients with systemic sclerosis. Annals of the rheumatic diseases, 75(4), 681-686.
- 8. Hachulla E, Clerson P, Launay D, Lambert M, Morell-Dubois S, Queyrel V, et al. Natural history of ischemic digital ulcers in systemic sclerosis: single- center retrospective longitudinal study. J Rheumatol. 2007;34:2423–2430.
- 9. Korn, J. H., Mayes, M., Matucci Cerinic, M., Rainisio, M., Pope, J., Hachulla, E., et al. & RAPIDS‐1 Study Group. (2004). Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis & Rheumatism, 50(12), 3985-3993.
- 10.Matucci-Cerinic, M., Denton, C. P., Furst, D. E., Mayes, M. D., Hsu, V. M., Carpentier, P., et al. (2011). Bosentan treatment ofdigital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Annals of the rheumatic diseases, 70(1), 32-38.
- 11.Kowal-Bielecka, O., Fransen, J., Avouac, J., Becker, M., Kulak, A., Allanore, Y., et al. (2017). Update of EULARrecommendations for the treatment of systemic sclerosis. Annals of the rheumatic diseases, 76(8), 1327-1339.
- 12.Rubin, L. J., Badesch, D. B., Barst, R. J., Galiè, N., Black, C. M., Keogh, A., et al. (2002). Bosentan therapy for pulmonary arterial hypertension. New England Journal of Medicine, 346(12), 896-903.
- 13.Castellvi, I., Simeon, C. P., Sarmiento, M., Casademont, J., Corominas, H., & Fonollosa, V. (2020). Effect of bosentan in pulmonary hypertension development in systemic sclerosispatients with digital ulcers. PloS one, 15(12), e0243651.
- 14.Hughes, M., & Herrick, A. L. (2017). Digital ulcers in systemic sclerosis. Rheumatology, 56(1), 14-25.
- 15.Kowal-Bielecka, O., Fransen, J., Avouac, J., Becker, M., Kulak, A., Allanore, Y., et al. (2017). Update of EULARrecommendations for the treatment of systemic sclerosis. Annals of the rheumatic diseases, 76(8), 1327-1339.
- 16.Hamaguchi, Y., Sumida, T., Kawaguchi, Y., Ihn, H., Tanaka, S., Asano, Y., et al. (2017). Safety and tolerability of bosentan for digital ulcers in Japanese patients with systemic sclerosis:Prospective, multicenter, open‐label study. The Journal of Dermatology, 44(1), 13-17.
- 17.Öztaş, M., Özgül, H., & Uğurlu, S. (2020). Dijital ülsernedeniyle bosentan kullanan sistemik sklerozis hastalarında tedavide kalım süresi ve yan etki profilinin değerlendirilmesi: gerçek yaşam deneyimi. RAED Journal/RAED Dergisi, 12(2).
- 18.European Medicines Agency. Tracleer (bosentan) 62.5 mg film-coated tablets: summary of product characteristics [online]. Available from URL: https://www.ema.europa.eu/en/documents/variation-report/tracleer-h-c-401-x-0039-epar-assessment-report-extension_en.pdf [Accessed 2009 Aug 6]
- 19.Humbert, M., Segal, E. S., Kiely, D. G., Carlsen, J., Schwierin, B., & Hoeper, M. M. (2007). Results of European post-marketing surveillance of bosentan in pulmonary hypertension. European Respiratory Journal, 30(2), 338-344.
- 20.Funauchi, M., Kishimoto, K., Shimazu, H., Nagare, Y., Hino, S., Yano, T., & Kinoshita, K. (2009). Effects of bosentan on the skin lesions: an observational study from a single center in Japan. Rheumatology international, 29(7), 769-775.
- 21.Ivorra, J. A. R., Simeon, C. P., Sancho, J. J. A., Egurbide, M. V., Castillo, M. J., Lloria, X., et al. (2011). Bosentan in clinical practice for treating digital and other ischemic ulcers in Spanish patients with systemic sclerosis: IBER-DU cohort study. The Journal of Rheumatology, 38(8), 1631-1635.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Rheumatology and Arthritis |
| Journal Section | Research Article |
| Authors | |
| Publication Date | June 9, 2023 |
| Acceptance Date | February 22, 2023 |
| Published in Issue | Year 2023 Volume: 49 Issue: 1 |
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