Skip to main navigation menu Skip to main content Skip to site footer

Original article

Vol. 148 No. 4344 (2018)

Bosentan for patients with steroid-resistant pulmonary sarcoidosis: a randomised controlled trial

  • Katrin E. Hostettler
  • Florent Baty
  • Rebekka Kleiner
  • Lilian Junker
  • Michael Tamm
  • Martin H. Brutsche
DOI
https://doi.org/10.4414/smw.2018.14677
Cite this as:
Swiss Med Wkly. 2018;148:w14677
Published
28.10.2018

Summary

BACKGROUND

Sarcoidosis is a disorder of unknown aetiology. Most patients have steroid-responsive disease, but side effects and steroid resistance may necessitate alternative treatments. Endothelin has in-vitro fibrogenic activity and the endothelin system is activated in sarcoidosis.

OBJECTIVES

We studied the efficacy and safety of the endothelin receptor antagonist bosentan in sarcoidosis patients.

METHODS

In a prospective 12-month, double-blind, 1:1-randomised, placebo-controlled phase II trial, we assessed the effect of bosentan in patients with steroid-resistant sarcoidosis and with impaired exercise capacity and/or resting lung function. Primary endpoints were safety and overall response rate of total lung capacity, diffusion capacity, peak oxygen uptake, 6-minute walking distance and chest computed tomography score. Secondary endpoints included adverse events and quality of life.

MAIN RESULTS

Twenty patients were randomised. Three patients discontinued the study medication prematurely. No serious drug-related adverse events occurred. At 12 months no statistically significant differences were observed in the primary endpoints including total lung capacity, diffusion capacity, 6-minute walking distance, peak oxygen uptake, and computed tomography-score. Sixty-three percent of the patients treated with bosentan showed an increase of 10% in at least one of the primary endpoints, compared with 67% in the placebo group (p = 1).

CONCLUSIONS

There is no evidence to support efficacy of bosentan as an antifibrotic treatment for patients with steroid-resistant pulmonary sarcoidosis. Bosentan was well tolerated and no drug-related adverse effects were observed within the study population.

Trial registration

ISRCTN registry, ISRCTN73579020.

References

  1. Baughman RP. Pulmonary sarcoidosis. Clin Chest Med. 2004;25(3):521–30, vi. doi:.https://doi.org/10.1016/j.ccm.2004.04.006
  2. Hillerdal G, Nöu E, Osterman K, Schmekel B. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis. 1984;130(1):29–32.
  3. Hunninghake GW, Gilbert S, Pueringer R, Dayton C, Floerchinger C, Helmers R, et al. Outcome of the treatment for sarcoidosis. Am J Respir Crit Care Med. 1994;149(4):893–8. doi:.https://doi.org/10.1164/ajrccm.149.4.8143052
  4. Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis. 1999;16(2):149–73.
  5. Baughman RP, Nunes H, Sweiss NJ, Lower EE. Established and experimental medical therapy of pulmonary sarcoidosis. Eur Respir J. 2013;41(6):1424–38. doi:.https://doi.org/10.1183/09031936.00060612
  6. Patterson KC, Chen ES. The Pathogenesis of Pulmonary Sarcoidosis and Implications for Treatment. Chest. 2018;153(6):1432–42.
  7. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5. doi:.https://doi.org/10.1038/332411a0
  8. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA. 1989;86(8):2863–7. doi:.https://doi.org/10.1073/pnas.86.8.2863
  9. Giaid A, Polak JM, Gaitonde V, Hamid QA, Moscoso G, Legon S, et al. Distribution of endothelin-like immunoreactivity and mRNA in the developing and adult human lung. Am J Respir Cell Mol Biol. 1991;4(1):50–8. doi:.https://doi.org/10.1165/ajrcmb/4.1.50
  10. Ehrenreich H, Anderson RW, Fox CH, Rieckmann P, Hoffman GS, Travis WD, et al. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med. 1990;172(6):1741–8. doi:.https://doi.org/10.1084/jem.172.6.1741
  11. Saleh D, Furukawa K, Tsao MS, Maghazachi A, Corrin B, Yanagisawa M, et al. Elevated expression of endothelin-1 and endothelin-converting enzyme-1 in idiopathic pulmonary fibrosis: possible involvement of proinflammatory cytokines. Am J Respir Cell Mol Biol. 1997;16(2):187–93. doi:.https://doi.org/10.1165/ajrcmb.16.2.9032126
  12. Hirata Y, Takagi Y, Fukuda Y, Maruno F. Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis. 1989;78(2-3):225–8. doi:.https://doi.org/10.1016/0021-9150(89)90227-X
  13. Takuwa N, Takuwa Y, Yanagisawa M, Yamashita K, Masaki T. A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts. J Biol Chem. 1989;264(14):7856–61.
  14. Peacock AJ, Dawes KE, Shock A, Gray AJ, Reeves JT, Laurent GJ. Endothelin-1 and endothelin-3 induce chemotaxis and replication of pulmonary artery fibroblasts. Am J Respir Cell Mol Biol. 1992;7(5):492–9. doi:.https://doi.org/10.1165/ajrcmb/7.5.492
  15. Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med. 1997;156(2):600–8. doi:.https://doi.org/10.1164/ajrccm.156.2.9607123
  16. Mutsaers SE, Foster ML, Chambers RC, Laurent GJ, McAnulty RJ. Increased endothelin-1 and its localization during the development of bleomycin-induced pulmonary fibrosis in rats. Am J Respir Cell Mol Biol. 1998;18(5):611–9. doi:.https://doi.org/10.1165/ajrcmb.18.5.2898
  17. Hocher B, Schwarz A, Fagan KA, Thöne-Reineke C, El-Hag K, Kusserow H, et al. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol. 2000;23(1):19–26. doi:.https://doi.org/10.1165/ajrcmb.23.1.4030
  18. Giaid A, Michel RP, Stewart DJ, Sheppard M, Corrin B, Hamid Q. Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet. 1993;341(8860):1550–4. doi:.https://doi.org/10.1016/0140-6736(93)90694-C
  19. Uguccioni M, Pulsatelli L, Grigolo B, Facchini A, Fasano L, Cinti C, et al. Endothelin-1 in idiopathic pulmonary fibrosis. J Clin Pathol. 1995;48(4):330–4. doi:.https://doi.org/10.1136/jcp.48.4.330
  20. Reichenberger F, Schauer J, Kellner K, Sack U, Stiehl P, Winkler J. Different expression of endothelin in the bronchoalveolar lavage in patients with pulmonary diseases. Lung. 2001;179(3):163–74. doi:.https://doi.org/10.1007/s004080000058
  21. Terashita K, Kato S, Sata M, Inoue S, Nakamura H, Tomoike H. Increased endothelin-1 levels of BAL fluid in patients with pulmonary sarcoidosis. Respirology. 2006;11(2):145–51. doi:.https://doi.org/10.1111/j.1440-1843.2006.00826.x
  22. Letizia C, Danese A, Reale MG, Caliumi C, Delfini E, Subioli S, et al. Plasma levels of endothelin-1 increase in patients with sarcoidosis and fall after disease remission. Panminerva Med. 2001;43(4):257–61.
  23. Sakurai T, Yanagisawa M, Takuwat Y, Miyazakit H, Kimura S, Goto K, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990;348(6303):732–5. doi:.https://doi.org/10.1038/348732a0
  24. Clozel M, Breu V, Gray GA, Kalina B, Löffler BM, Burri K, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther. 1994;270(1):228–35.
  25. Paramothayan S, Jones PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. JAMA. 2002;287(10):1301–7. doi:.https://doi.org/10.1001/jama.287.10.1301
  26. Baughman RP, Culver DA, Cordova FC, Padilla M, Gibson KF, Lower EE, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest. 2014;145(4):810–7. doi:.https://doi.org/10.1378/chest.13-1766
  27. Chang JA, Curtis JR, Patrick DL, Raghu G. Assessment of health-related quality of life in patients with interstitial lung disease. Chest. 1999;116(5):1175–82. doi:.https://doi.org/10.1378/chest.116.5.1175
  28. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC ; Official Statement of the European Respiratory Society. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Eur Respir J Suppl. 1993;6(Suppl 16):5–40. doi:.https://doi.org/10.1183/09041950.005s1693
  29. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111–7. doi:.https://doi.org/10.1164/ajrccm.166.1.at1102
  30. American Thoracic Society/American College of Chest Physicians. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003;167(2):211–77. doi:.https://doi.org/10.1164/rccm.167.2.211
  31. Oberstein A, von Zitzewitz H, Schweden F, Müller-Quernheim J. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis. 1997;14(1):65–72.
  32. Drent M, De Vries J, Lenters M, Lamers RJ, Rothkranz-Kos S, Wouters EF, et al. Sarcoidosis: assessment of disease severity using HRCT. Eur Radiol. 2003;13(11):2462–71. doi:.https://doi.org/10.1007/s00330-003-1965-x
  33. Team RCR. A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria URL http://wwwR-projectorg/. 2014.
  34. Morgenthau AS, Iannuzzi MC. Recent advances in sarcoidosis. Chest. 2011;139(1):174–82. doi:.https://doi.org/10.1378/chest.10-0188
  35. King TE, Jr, Brown KK, Raghu G, du Bois RM, Lynch DA, Martinez F, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(1):92–9. doi:.https://doi.org/10.1164/rccm.201011-1874OC
  36. Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, du Bois R, et al.; Sarcoidosis Investigators. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med. 2006;174(7):795–802. doi:.https://doi.org/10.1164/rccm.200603-402OC
  37. Rossman MD, Newman LS, Baughman RP, Teirstein A, Weinberger SE, Miller W, Jr, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23(3):201–8.
  38. Hostettler KE, Studler U, Tamm M, Brutsche MH. Long-term treatment with infliximab in patients with sarcoidosis. Respiration. 2012;83(3):218–24. doi:.https://doi.org/10.1159/000328738
  39. Jamilloux Y, Cohen-Aubart F, Chapelon-Abric C, Maucort-Boulch D, Marquet A, Pérard L, et al.; Groupe Sarcoïdose Francophone. Efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis: A multicenter study of 132 patients. Semin Arthritis Rheum. 2017;47(2):288–94. doi:.https://doi.org/10.1016/j.semarthrit.2017.03.005
  40. Sweiss NJ, Noth I, Mirsaeidi M, Zhang W, Naureckas ET, Hogarth DK, et al. Efficacy Results of a 52-week Trial of Adalimumab in the Treatment of Refractory Sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31(1):46–54.
  41. Fazzi P, Manni E, Cristofani R, Cei G, Piazza S, Calabrese R, et al. Thalidomide for improving cutaneous and pulmonary sarcoidosis in patients resistant or with contraindications to corticosteroids. Biomed Pharmacother. 2012;66(4):300–7. doi:.https://doi.org/10.1016/j.biopha.2012.03.005
  42. Utz JP, Limper AH, Kalra S, Specks U, Scott JP, Vuk-Pavlovic Z, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest. 2003;124(1):177–85. doi:.https://doi.org/10.1378/chest.124.1.177
  43. Sweiss NJ, Lower EE, Mirsaeidi M, Dudek S, Garcia JG, Perkins D, et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J. 2014;43(5):1525–8. doi:.https://doi.org/10.1183/09031936.00224513
  44. Judson MA, Baughman RP, Costabel U, Drent M, Gibson KF, Raghu G, et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J. 2014;44(5):1296–307. doi:.https://doi.org/10.1183/09031936.00000914
  45. Sahoo DH, Bandyopadhyay D, Xu M, Pearson K, Parambil JG, Lazar CA, et al. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis. Eur Respir J. 2011;38(5):1145–50. doi:.https://doi.org/10.1183/09031936.00195010
  46. Marcellis RG, Lenssen AF, de Vries GJ, Baughman RP, van der Grinten CP, Verschakelen JA, et al. Is there an added value of cardiopulmonary exercise testing in sarcoidosis patients? Lung. 2013;191(1):43–52. doi:.https://doi.org/10.1007/s00408-012-9432-6
  47. Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, et al., Irish Thoracic Society. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008;63(Suppl 5):v1–58. doi:.https://doi.org/10.1136/thx.2008.101691
  48. Lopes AJ, Menezes SL, Dias CM, Oliveira JF, Mainenti MR, Guimarães FS. Cardiopulmonary exercise testing variables as predictors of long-term outcome in thoracic sarcoidosis. Braz J Med Biol Res. 2012;45(3):256–63. doi:.https://doi.org/10.1590/S0100-879X2012007500018
  49. Keir G, Wells AU. Assessing pulmonary disease and response to therapy: which test? Semin Respir Crit Care Med. 2010;31(4):409–18. doi:.https://doi.org/10.1055/s-0030-1262209
  50. Baltzan M, Mehta S, Kirkham TH, Cosio MG. Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med. 1999;160(1):192–7. doi:.https://doi.org/10.1164/ajrccm.160.1.9809024

Most read articles by the same author(s)

1 2 > >>