Asthma: Newer Tx options mean more targeted therapy

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Asthma: Newer Tx options mean more targeted therapy

J Fam Pract. 2020 April;69(3):135-144

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References

1. Centers for Disease Control and Prevention. Most recent national asthma data. Updated May 2019. www.cdc.gov/asthma/most_recent_national_asthma_data.htm. Accessed March 6, 2020.

2. National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): Guidelines for the diagnosis and management of asthma—summary report 2007. J Allergy Clin Immunol. 2007;120(5 suppl):S94-S138.

3. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma [published correction appears in Am J Respir Crit Care Med. 2009;180(8):796]. Am J Respir Crit Care Med. 2009;180:388–395.

4. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15:57–65.

5. Busse WW. Inflammation in asthma: the cornerstone of the disease and target of therapy. J Allergy Clin Immunol. 1998;102(4 pt 2):S17-S22.

6. Lane SJ, Lee TH. Mast cell effector mechanisms. J Allergy Clin Immunol. 1996;98(5 pt 2):S67-S71.

7. Robinson DS, Bentley AM, Hartnell A, et al. Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness. Thorax. 1993;48:26-32.

8. Grigoraş A, Grigoraş CC, Giuşcă SE, et al. Remodeling of basement membrane in patients with asthma. Rom J Morphol Embryol. 2016;57:115-119.

9. Huang SK, Xiao HQ, Kleine-Tebbe J, et al. IL-13 expression at the sites of allergen challenge in patients with asthma. J Immunol. 1995;155:2688-2694.

10. Hansbro PM, Starkey MR, Mattes J, et al. Pulmonary immunity during respiratory infections in early life and the development of severe asthma. Ann Am Thorac Soc. 2014;11 suppl 5:S297-S302.

11. Apter AJ, Reisine ST, Willard A, et al. The effect of inhaled albuterol in moderate to severe asthma. J Allergy Clin Immunol. 1996;98:295-301.

12. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363:1715-1726.

13. Kerstjens HA, O’Byrne PM. Tiotropium for the treatment of asthma: a drug safety evaluation. Expert Opin Drug Saf. 2016;15:1115-1124.

14. Global Initiative for Asthma. Diagnosis of diseases of chronic air flow limitation: asthma, COPD and asthma-COPD overlap syndrome (ACOS) 2014. https://ginasthma.org/wp-content/uploads/2019/11/GINA_GOLD_ACOS_2014-wms.pdf. Accessed March 12, 2020.

15. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2019. https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf. Accessed March 12, 2020.

16. Khanbabaee G, Enayat J, Chavoshzadeh Z, et al. Serum level of specific IgG antibody for aspergillus and its association with severity of asthma in asthmatic children. Acta Microbiol Immunol Hung. 2012;59:43-50.

17. Agbetile J, Bourne M, Fairs A, et al. Effectiveness of voriconazole in the treatment of aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol. 2014;134:33-39.

18. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342:756-762.

19. Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011;163:29-43.

20. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132:1033-1044.

21. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J. 2002;19:182-191.

22. Newton R, Giembycz MA. Understanding how long-acting β2-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma—an update. Br J Pharmacol. 2016;173:3405-3430.

23. Wijesinghe M, Perrin K, Harwood M, et al. The risk of asthma mortality with inhaled long acting beta-agonists. Postgrad Med J. 2008;84:467-472.

24. Cazzola M, Page CP, Rogliani P, et al. β2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013;187:690-696.

25. Bernstein DI, Bateman ED, Woodcock A, et al. Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma. J Asthma. 2015;52:1073-1083.

26. Devillier P, Humbert M, Boye A, et al. Efficacy and safety of once-daily fluticasone furoate/vilanterol (FF/VI) versus twice-daily inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) in patients with uncontrolled asthma: an open-label, randomized, controlled trial. Respir Med. 2018;141:111-120.

27. Beeh KM, LaForce C, Gahlemann M, et al. Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat(R) in patients with moderate to severe persistent asthma. Respir Res. 2015;16:87.

28. LaForce C, Alexander M, Deckelmann R, et al. Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day dose-ranging study. Allergy. 2008;63:103-111.

29. Beasley RW, Donohue JF, Mehta R, et al. Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial. BMJ Open. 2015;5:e006131.

30. Aalbers R, Park HS. Positioning of long-acting muscarinic antagonists in the management of asthma. Allergy Asthma Immunol Res. 2017;9:386-393.

31. Lee LA, Briggs A, Edwards LD, et al. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir Med. 2015;109:63-73.

32. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965-976.

33. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.

34. Hanania NA, Wenzel S, Rosen K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804-811.

35. Slavin RG, Ferioli C, Tannenbaum SJ, et al. Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. J Allergy Clin Immunol. 2009;123:107-113.e3.

36. Ledford D, Busse W, Trzaskoma B, et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. J Allergy Clin Immunol. 2017;140:162-169.e2.

37. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207.

38. Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5:390-400.

39. Lugogo N, Domingo C, Chanez P, et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;38:2058-2070.e1.

40. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197.

41. Castro M, Zangrilli J, Wechsler ME. Corrections. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:e15.

42. Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150:789-798.

43. Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: Effects across a broad range of eosinophil counts. Chest. 2016;150:799-810.

44. Mukherjee M, Aleman Paramo F, Kjarsgaard M, et al. Weight-adjusted intravenous reslizumab in severe asthma with inadequate response to fixed-dose subcutaneous mepolizumab. Am J Respir Crit Care Med. 2018;197:38-46.

45. Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125:1344-1353.e2.

46. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-2127.

47. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388:2128-2141.

48. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356:1327-1337.

49. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176:1185-1191.

50. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181:116-124.

51. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013;132:1295-1302.

52. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: A comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J. 2017;50:1700017.

53. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;(8):CD001186.

54. Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015;(8):CD011293.

55. Mosbech H, Deckelmann R, de Blay F, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134:568575.e7.

56. Virchow JC, Backer V, Kuna P, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma: a randomized clinical trial. JAMA. 2016;315:1715-1725.

57. Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma : the AZALEA randomized clinical trial. JAMA Intern Med. 2016;176:1630-1637.

58. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329.

59. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659-668.

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

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