Inhaled budesonide and pulmonary sarcoidosis revisited

Main Article Content

Olof Selroos
Ralph Brattsand

Keywords

Pulmonary sarcoidosis, Inhaled corticosteroids, Budesonide, Pharmacokinetics

Abstract

Results of a few controlled clinical studies have been reported with inhaled corticosteroids (ICS) in patients with pulmonary sarcoidosis. Some evidence of efficacy has been observed, but mainly with the ICS budesonide (BUD). These clinically important and statistically significant results are restricted to maintenance therapy with BUD after induction of treatment with systemic corticosteroids for a few weeks or months.  Positive results have also been described in patients with relapses after earlier treatment with oral corticosteroids. A possible explanation for BUD’s efficacy in patients with parenchymal lesions could be that inhaled BUD is rapidly absorbed into systemic circulation, creating plasma peaks which result in systemic anti-inflammatory activity in both peripheral airways and lung tissue.  At airway level this steroid activity is furthermore prolonged because a BUD fraction is intracellularly, reversibly transformed into lipophilic BUD-oleate. These mechanisms have been proposed to explain the theoretically unexpected similar efficacy of BUD compared with more lipophilic ICSs in patients with asthma and COPD. In this review we summarize the results of clinical studies with ICSs in patients with pulmonary sarcoidosis. It is obvious that current ICSs, including BUD, cannot generally be recommended as such for treatment of sarcoidosis. However, using BUD as a model substance further pharmacologic and kinetic studies could possibly define a kinetic profile giving optimal partitioning between airway and systemic activity with less adverse systemic risks. Such a substance could replace or reduce oral corticosteroids in the treatment of airway and pulmonary parenchymal diseases. 

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References

1. Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG Statement on sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16:149-173.
2. Wells A, Singh S, Spiro S, Mitchell D. Treatment of sarcoidosis. In: Sarcoidosis. Mitchell D, Wells A, Spiro S, Moller D., eds Hodder Arnold 2012, pp 415-28.
3. Paramothayan NS, Lasserson TJ, Jones PW. Corticosteroids for pulmonary sarcoidosis. Cochrane Database Systematic Review, 2005, CD001114.pub2.
4. Baughman RP, Selroos O. Evidence-based approach to treatment of sarcoidosis. In: Evidence-based respiratory medicine. P.G.Gibson, ed. BMJ Books and Blackwell Publ., London 2005;491-508.
5. Caliskan C, Prasse A. Treating sarcoidosis and potential new drugs. In: Bonella T, Culver DA, Israël-Biet G, eds. Sarcoidosis (ERS monograph) Sheffield, ERS 2022, pp 328-36.
6. Milman N. Oral and inhaled corticosteroids in the treatment of pulmonary sarcoidosis – a critical reappraisal. Sarcoidosis Vasc Diffuse Lung Dis 1998;15:150-7.
7. Kirsten D. Inhaled steroids for sarcoidosis? Eur Respir J 1995;8:679-81.
8. Newman SP. Drug delivery to the lungs: challenges and opportunities. Ther Deliv 2017;8:647-61.
9. Selroos OB. Relapsing pulmonary stage II-III sarcoidosis can be treated with inhaled budesonide Am Rev Respir Dis 1987;135:A349.
10. Selroos O. Use of budesonide in the treatment of pulmonary sarcoidosis. In: Advance in the use of inhaled corticosteroids. (Eds. R. Ellul-Micallef, W.K. Lam, J.H. Toogood) Hong Kong, Excerpta Medica Asia Pacific Congress Series no 58, 1987,188-97.
11. Pietinalho A, Haahtela T, Tukiainen P, Persson T, Selroos O. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis. A double-blind, placebo-controlled, multicenter study. Chest 1999;116:424-31.
12. Miller-Larsson A, Mattsson H, Hjertberg E, Dahlbäck M, Tunek A, Brattsand R. Reversible fatty acid conjugation of budesonide. Novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998;26:623-30.
13. Dalby C, Polanowski T, Larsson T, Borgström L, Edsbäcker S, Harrison T. The bioavailability and airway clearance of the steroid component of budesonide/formoterol and salmeterol/fluticasone after inhaled administration in patients with COPD and healthy subjects: a randomized controlled study. Respir Res. 2009;10(1):104. doi: 10.1186/1465-9921-10-104. PMID: 19878590; PMCID: PMC2780403.
14. Brattsand R, Selroos O. May a different kinetic mode explain the high efficacy/safety profile of inhaled budesonide? Pulm Pharmacol Ther 2022;77:102167.
15. Selroos OB. Use of budesonide in the treatment of pulmonary sarcoidosis. Ann N Y Acad Sci 1986;465:713-21.
16. Selroos O. Use of budesonide in the treatment of pulmonary sarcoidosis. In: Advances in the use of inhaled corticosteroids. Ellul-Micallef R, Lam WK, Toogood JH, eds. Excerpta Medica Asia Pacific Congress series no, 58, HongKong 1987:188-97.
17. Morgan AD, Johnson MA, Kerr I, Turner-Warwick M. The action of an inhaled corticosteroid as a steroid sparing agent in chronic pulmonary sarcoidosis. Am Rev Respir Dis 1987;135:A349.
18. Selroos O. Further experiences with inhaled budesonide in the treat¬ment of pulmonary sarcoidosis. In: Sarcoidosis and other granulomatous disorders. C Grassi, G Rizzato, E Pozzi, eds. Elsevier Science Publ. BV, Amsterdam 1988,637-40.
19. Bjermer L, Nilsson K, Karlström R. Maintenance therapy with inhaled budesonide 1600 µg once daily vs oral prednisone 20 mg every other day in patients with progressive sarcoidosis. Sarcoidosis 1992;9:153.
20. Zych D, Pawlicka L, Zielinski J. Inhaled budesonide vs prednisone in the maintenance treatment of pulmonary sarcoidosis. Sarcoidosis 1993;10:56-61.
21. Selroos O, Löfroos A-B, Pietinalho A, Niemistö M, Riska H. Inhaled budesonide for maintenance treatment of pulmonary sarcoidosis. Sarcoidosis 1994;11:126-31.
22. Tolokh O, Ilnitsky I, Hobzey M. Comparison of prednisone and budesonide in the treatment of pulmonary sarcoidosis. Tubercle Lung Dis 1994;75, suppl 1:101.
23. Milman N, Graudal N, Grode G, Munch E. No effect of high-dose inhaled steroids in pulmonary sarcoidosis: a double-blind, placebo-controlled study. J Int Med 1994;236:285-90.
24. Alberts C, van der Mark ThW, Jansen HM, and the Dutch study group on pulmonary sarcoidosis. Eur Respir J 1995;5:682-8.
25. Pietinalho A, Tukiainen P, Haahtela T, Persson T, Selroos O. Early treatment of stage II sarcoidosis improves 5-year pulmonary function. Chest 2002;121:24-31.
26. Ohno S, Nakazawa S, Kobayashi A, Yamasawa H, Bando M, Sugiyama Y. Inhaled corticosteroid rapidly improved pulmonary sarcoidosis. Intern Med 2005;44:1276-9.
27. Morimatsu Y, Okamoto M, Kawayama T, et al. Remarkable improvement in clinical course and serum KL-6 levels after initiation of high-dose budesonide in pulmonary sarcoidosis. Kurume Med J 2019;66:71-5.
28. Yamaguchi T. Treatment of sarcoidosis: A case-based approach. Jpn J Sarcoidosis and other Granulomatous disorders (in Japanese) 2014; 34:7-10.
29. Gupta SK. Treatment of sarcoidosis patients by steroid aerosol: a ten-year prospective study from Eastern India. Sarcoidosis 1989;6:51-4.
30. Tolokh O. Efficiency of inhaled steroids in the treatment of pulmonary sarcoidosis. Eur, Respir J 1996;9, suppl 23:406s.
31. Niven AS, Poropatich RK, Phillips YY, Parker JM, Torrington KG. High dose triamcinolone acetonide (TA) as induction therapy for pulmonary sarcoidosis. Am J Respir Crit Care Med 1997; 155 (No 4 Pt2):944.
32. Du Bois RM, Greenhalgh PM, Southcott AM, Johnson NM, Harris TA. Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study. Eur Respir J 1999;13:1345-50.
33. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19:198-204.
34. Ludwig-Sengpiel A, Jaksztat E, Welker L, et al. Effect of beclomethasone dipropionate (BDP) as extrafine aerosol on bronchoalveolar lavage (BAL) lymphocytes in chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005;22:214-21.
35. Milman N, Mortensen J, Sloth C. Fluorodeoxyglucose PET scan in pulmonary sarcoidosis during treatment with inhaled and oral corticosteroids. Respiration 2003;70:408-13.
36. Erkkilä S, Fröseth B, Hellström P-E, et al. Inhaled budesonide influences cellular and biochemical abnormalities in pulmonary sarcoidosis. Sarcoidosis 1988; 5:106-10.
37. Petermann W, Entzian P, Barth J. BAL and lung function tests in steropid-treated patients with sarcoidosis – comparison between oral and inhalative administration of steroids. Eur Respir J 1988;1, suppl 2:259.
38. Spiteri MA, Newman SP, Clarke SW, Poulter LW. Inhaled corticosteroids can modulate the immunopathogenesis of pulmonary sarcoidosis. Eur Respir J 1989;2:218-24.
39. Alberts C, Jansen HM, Roos CM, Out TA. Effects of inhaled budesonide in patients with pulmonary sarcoidosis. Eur Respir J 1991;4, suppl 14:253s.
40. Baughman RP, Judson MA. Relapses of sarcoidosis: what are they and can we predict who will get them? Eur Respir J 2014;43:337-9.
41. Gottlieb JE, Israel HL, Steiner RM, Triolo J, Patrick H. Outcome of sarcoidosis. The relationship of relapse to corticosteroid therapy. Chest 1997;111:623-31.
42. Scadding JG. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’s observation. Brit med J 1961;2:1165-72.
43. Dahlberg E, Thalén A, Brattsand R, et al. Correlation between chemical structure, receptor binding and biological activity of some novel, highly active 16α,17α-substituted glucocorticoids. Mol Pharmacol 1984;25:70-6.
44. Brattsand R, Axelsson B. Basis of airway selectivity of inhaled glucocorticoids. In “Inhaled Glucocorticoids in Asthma” (eds. Schleimer RP, Busse WW, O´Byrne PM), Marcel Dekker, Inc; New York 1997, pp: 351-79.
45. Miller-Larsson A, Brattsand R. Topical anti-inflammatory activity of the glucocorticoid budesonide on airway mucosa. Evidence for a “hit and run” type of activity. Agents and Actions 1990;29:1/2.
46. Ryrfeldt Å, Persson G, Nilsson E. Pulmonary disposition of the potent glucocorticosteroid budesonide in an isolated perfused rat lung model. Biochem Pharmacol 1989;38:17-22.
47. van den Bosch JMM, Westermann CJJ, Aumann J, Edsbäcker S, Tönnesson M, Selroos O. Relationship between lung tissue and blood plasma concentrations of inhaled budesonide. Biopharm Drug Dispos 1993;14:455-9.
48. Maassen van den Brink KI, Boorsma M, Staal-van den Brekel AJ, Edsbäcker S, Wouters EF, Thorsson L. Evidence of the in vivo esterification of budesonide in human airways. Brit J Clin Pharmacol 2008;66:27-35.
49. McGrath DS, Wells AV, Desai SR, et al. Efficacy, safety and tolerability of 3M HFA-134A beclomethasone dipropionate in pulmonary sarcoidosis. Am J Respir Crit Care Med 2002;165, suppl 8:A495.