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Annual Review of Medicine

Volume 76, 2025

Biologic Medications for Severe Asthma: Implications for Understanding Pathogenic Heterogeneity and Endotypes

Abstract

Asthma is a chronic inflammatory disease of the airways long known for phenotypic heterogeneity. Phenotyping studies in asthma have led to a better characterization of disease pathogenesis, yet further work is needed to pair available treatments with disease endotypes. In this review, the biology of targeted pathways is discussed along with the efficacy of biologic therapies targeting those pathways. Results of asthma clinical trials are included, as well as results of trials in related diseases. This review then analyzes how biologics help to inform the complex immunobiology of asthma and further guide their use while identifying areas for future research.

Keyword(s): biologic therapy, cytokines, endotypes, eosinophils, molecular phenotypes, severe asthma

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An erratum has been published for this article:
Erratum: Biologic Medications for Severe Asthma: Implications for Understanding Pathogenic Heterogeneity and Endotypes
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/content/journals/10.1146/annurev-med-070323-103158
2025-01-27
2025-04-26
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Literature Cited

  1. 1.
    Glob. Initiat. Asthma. 2023.. Global Strategy for Asthma Management and Prevention (2023 Update). Rep. Fontana, WI:: Glob. Initiat. Asthma. https://ginasthma.org/2023-gina-main-report/
    [Google Scholar]
  2. 2.
    Wenzel S. 2012.. Severe asthma: from characteristics to phenotypes to endotypes. . Clin. Exp. Allergy 42:(5):650–58
     [Crossref] [Google Scholar]
  3. 3.
    Wenzel SE. 2021.. Severe adult asthmas: integrating clinical features, biology, and therapeutics to improve outcomes. . Am. J. Respir. Crit. Care Med. 203:(7):809–21
     [Crossref] [Google Scholar]
  4. 4.
    Brusselle GG, Koppelman GH. 2022.. Biologic therapies for severe asthma. . N. Engl. J. Med. 386:(2):157–71
     [Crossref] [Google Scholar]
  5. 5.
    Buhl R, Bel E, Bourdin A, et al. 2022.. Effective management of severe asthma with biologic medications in adult patients: a literature review and international expert opinion. . J. Allergy Clin. Immunol. Pract. 10:(2):422–32
     [Crossref] [Google Scholar]
  6. 6.
    Wenzel SE. 2012.. Asthma phenotypes: the evolution from clinical to molecular approaches. . Nat. Med. 18:(5):716–25
     [Crossref] [Google Scholar]
  7. 7.
    Ray A, Das J, Wenzel SE. 2022.. Determining asthma endotypes and outcomes: complementing existing clinical practice with modern machine learning. . Cell Rep. Med. 3:(12):100857
     [Crossref] [Google Scholar]
  8. 8.
    Anderson GP. 2008.. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. . Lancet 372:(9643):1107–19
     [Crossref] [Google Scholar]
  9. 9.
    Gauthier M, Ray A, Wenzel SE. 2015.. Evolving concepts of asthma. . Am. J. Respir. Crit. Care Med. 192:(6):660–68
     [Crossref] [Google Scholar]
  10. 10.
    Rackemann FM. 1947.. A working classification of asthma. . Am. J. Med. 3:(5):601–6
     [Crossref] [Google Scholar]
  11. 11.
    Huang SK, Xiao HQ, Kleine-Tebbe J, et al. 1995.. IL-13 expression at the sites of allergen challenge in patients with asthma. . J. Immunol. 155:(5):2688–94
     [Crossref] [Google Scholar]
  12. 12.
    Humbert M, Durham SR, Ying S, et al. 1996.. IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity. . Am. J. Respir. Crit. Care Med. 154:(5):1497–504
     [Crossref] [Google Scholar]
  13. 13.
    Humbert M, Grant JA, Taborda-Barata L, et al. 1996.. High-affinity IgE receptor (FcepsilonRI)-bearing cells in bronchial biopsies from atopic and nonatopic asthma. . Am. J. Respir. Crit. Care Med. 153:(6 Part 1):1931–37
     [Crossref] [Google Scholar]
  14. 14.
    Mosmann TR, Cherwinski H, Bond MW, et al. 1986.. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. . J. Immunol. 136:(7):2348–57
     [Crossref] [Google Scholar]
  15. 15.
    Robinson D, Hamid Q, Bentley A, et al. 1993.. Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. . J. Allergy Clin. Immunol. 92:(2):313–24
     [Crossref] [Google Scholar]
  16. 16.
    Brown HM. 1958.. Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. . Lancet 2:(7059):1245–47
     [Crossref] [Google Scholar]
  17. 17.
    Berry M, Morgan A, Shaw DE, et al. 2007.. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. . Thorax 62:(12):1043–49
     [Crossref] [Google Scholar]
  18. 18.
    Wenzel SE, Schwartz LB, Langmack EL, et al. 1999.. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. . Am. J. Respir. Crit. Care Med. 160:(3):1001–8
     [Crossref] [Google Scholar]
  19. 19.
    Gibson PG, Simpson JL, Chalmers AC, et al. 2001.. Airway eosinophilia is associated with wheeze but is uncommon in children with persistent cough and frequent chest colds. . Am. J. Respir. Crit. Care Med. 164:(6):977–81
     [Crossref] [Google Scholar]
  20. 20.
    Gibson PG, Saltos N, Borgas T. 2000.. Airway mast cells and eosinophils correlate with clinical severity and airway hyperresponsiveness in corticosteroid-treated asthma. . J. Allergy Clin. Immunol. 105:(4):752–59
     [Crossref] [Google Scholar]
  21. 21.
    Brightling CE, Symon FA, Birring SS, et al. 2003.. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. . Thorax 58:(6):528–32
     [Crossref] [Google Scholar]
  22. 22.
    Moore WC, Bleecker ER, Curran-Everett D, et al. 2007.. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. . J. Allergy Clin. Immunol. 119:(2):405–13
     [Crossref] [Google Scholar]
  23. 23.
    Wu W, Bleecker E, Moore W, et al. 2014.. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. . J. Allergy Clin. Immunol. 133:(5):1280–88
     [Crossref] [Google Scholar]
  24. 24.
    Shaw DE, Sousa AR, Fowler SJ, et al. 2015.. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. . Eur. Respir. J. 46:(5):1308–21
     [Crossref] [Google Scholar]
  25. 25.
    Lefaudeux D, De Meulder B, Loza MJ, et al. 2017.. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. . J. Allergy Clin. Immunol. 139:(6):1797–807
     [Crossref] [Google Scholar]
  26. 26.
    Konno S, Taniguchi N, Makita H, et al. 2018.. Distinct phenotypes of smokers with fixed airflow limitation identified by cluster analysis of severe asthma. . Ann. Am. Thor. Soc. 15:(1):33–41
     [Crossref] [Google Scholar]
  27. 27.
    Ray A, Oriss TB, Wenzel SE. 2015.. Emerging molecular phenotypes of asthma. . Am. J. Physiol. Lung Cell Mol. Physiol. 308:(2):L130–40
     [Crossref] [Google Scholar]
  28. 28.
    Byrwa-Hill BM, Morphew TL, Presto AA, et al. 2023.. Living in environmental justice areas worsens asthma severity and control: differential interactions with disease duration, age at onset, and pollution. . J. Allergy Clin. Immunol. 152:(5):1321–29.e5
     [Crossref] [Google Scholar]
  29. 29.
    Morgenstern V, Zutavern A, Cyrys J, et al. 2008.. Atopic diseases, allergic sensitization, and exposure to traffic-related air pollution in children. . Am. J. Respir. Crit. Care Med. 177:(12):1331–37
     [Crossref] [Google Scholar]
  30. 30.
    Gould HJ, Sutton BJ. 2008.. IgE in allergy and asthma today. . Nat. Rev. Immunol. 8:(3):205–17
     [Crossref] [Google Scholar]
  31. 31.
    Boulet LP, Chapman KR, Cote J, et al. 1997.. Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. . Am. J. Respir. Crit. Care Med. 155:(6):1835–40
     [Crossref] [Google Scholar]
  32. 32.
    Fahy JV, Fleming HE, Wong HH, et al. 1997.. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. . Am. J. Respir. Crit. Care Med. 155:(6):1828–34
     [Crossref] [Google Scholar]
  33. 33.
    Busse W, Corren J, Lanier BQ, et al. 2001.. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. . J. Allergy Clin. Immunol. 108:(2):184–90
     [Crossref] [Google Scholar]
  34. 34.
    Bousquet J, Rabe K, Humbert M, et al. 2007.. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. . Respir. Med. 101:(7):1483–92
     [Crossref] [Google Scholar]
  35. 35.
    Chung KF, Wenzel SE, Brozek JL, et al. 2014.. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. . Eur. Respir. J. 43:(2):343–73
     [Crossref] [Google Scholar]
  36. 36.
    Hanania NA, Alpan O, Hamilos DL, et al. 2011.. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. . Ann. Intern. Med. 154:(9):573–82
     [Crossref] [Google Scholar]
  37. 37.
    Lanier B, Bridges T, Kulus M, et al. 2009.. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. . J. Allergy Clin. Immunol. 124:(6):1210–16
     [Crossref] [Google Scholar]
  38. 38.
    Busse WW, Morgan WJ, Gergen PJ, et al. 2011.. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. . N. Engl. J. Med. 364:(11):1005–15
     [Crossref] [Google Scholar]
  39. 39.
    Gevaert P, Omachi TA, Corren J, et al. 2020.. Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials. . J. Allergy Clin. Immunol. 146:(3):595–605
     [Crossref] [Google Scholar]
  40. 40.
    Chan S, Cornelius V, Cro S, et al. 2020.. Treatment effect of omalizumab on severe pediatric atopic dermatitis: the ADAPT randomized clinical trial. . JAMA Pediatr. 174:(1):29–37
     [Crossref] [Google Scholar]
  41. 41.
    Casale TB, Condemi J, LaForce C, et al. 2001.. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial. . JAMA 286:(23):2956–67
     [Crossref] [Google Scholar]
  42. 42.
    Ray A, Camiolo M, Fitzpatrick A, et al. 2020.. Are we meeting the promise of endotypes and precision medicine in asthma?. Physiol. Rev. 100:(3):983–1017
     [Crossref] [Google Scholar]
  43. 43.
    Hanania NA, Wenzel S, Rosen K, et al. 2013.. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. . Am. J. Respir. Crit. Care Med. 187:(8):804–11
     [Crossref] [Google Scholar]
  44. 44.
    Rothenberg ME. 1998.. Eosinophilia. . N. Engl. J. Med. 338:(22):1592–600
     [Crossref] [Google Scholar]
  45. 45.
    Laviolette M, Gossage DL, Gauvreau G, et al. 2013.. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. . J. Allergy Clin. Immunol. 132:(5):1086–96.e5
     [Crossref] [Google Scholar]
  46. 46.
    Price D, Wilson AM, Chisholm A, et al. 2016.. Predicting frequent asthma exacerbations using blood eosinophil count and other patient data routinely available in clinical practice. . J. Asthma Allergy 9::1–12
     [Crossref] [Google Scholar]
  47. 47.
    Zeiger RS, Schatz M, Dalal AA, et al. 2017.. Blood eosinophil count and outcomes in severe uncontrolled asthma: a prospective study. . J. Allergy Clin. Immunol. Pract. 5:(1):144–53.e8
     [Crossref] [Google Scholar]
  48. 48.
    Carr TF, Berdnikovs S, Simon HU, et al. 2016.. Eosinophilic bioactivities in severe asthma. . World Allergy Organ. J. 9::21
     [Crossref] [Google Scholar]
  49. 49.
    Canas JA, Sastre B, Rodrigo-Munoz JM, et al. 2018.. Eosinophil-derived exosomes contribute to asthma remodelling by activating structural lung cells. . Clin. Exp. Allergy 48:(9):1173–85
     [Crossref] [Google Scholar]
  50. 50.
    Hammad H, Lambrecht BN. 2021.. The basic immunology of asthma. . Cell 184:(6):1469–85
     [Crossref] [Google Scholar]
  51. 51.
    Lambrecht BN, Hammad H. 2015.. The immunology of asthma. . Nat. Immunol. 16:(1):45–56
     [Crossref] [Google Scholar]
  52. 52.
    Kolbeck R, Kozhich A, Koike M, et al. 2010.. MEDI-563, a humanized anti-IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. . J. Allergy Clin. Immunol. 125:(6):1344–53.e2
     [Crossref] [Google Scholar]
  53. 53.
    Leckie MJ, ten Brinke A, Khan J, et al. 2000.. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. . Lancet 356:(9248):2144–48
     [Crossref] [Google Scholar]
  54. 54.
    Flood-Page P, Swenson C, Faiferman I, et al. 2007.. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. . Am. J. Respir. Crit. Care Med. 176:(11):1062–71
     [Crossref] [Google Scholar]
  55. 55.
    Haldar P, Brightling CE, Hargadon B, et al. 2009.. Mepolizumab and exacerbations of refractory eosinophilic asthma. . N. Engl. J. Med. 360:(10):973–84
     [Crossref] [Google Scholar]
  56. 56.
    Pavord ID, Korn S, Howarth P, et al. 2012.. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. . Lancet 380:(9842):651–59
     [Crossref] [Google Scholar]
  57. 57.
    Ortega HG, Liu MC, Pavord ID, et al. 2014.. Mepolizumab treatment in patients with severe eosinophilic asthma. . N. Engl. J. Med. 371:(13):1198–207
     [Crossref] [Google Scholar]
  58. 58.
    Bel EH, Wenzel SE, Thompson PJ, et al. 2014.. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. . N. Engl. J. Med. 371:(13):1189–97
     [Crossref] [Google Scholar]
  59. 59.
    Chupp GL, Bradford ES, Albers FC, et al. 2017.. 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. 5:(5):390–400
     [Crossref] [Google Scholar]
  60. 60.
    Castro M, Zangrilli J, Wechsler ME, et al. 2015.. 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. 3:(5):355–66
     [Crossref] [Google Scholar]
  61. 61.
    Bjermer L, Lemiere C, Maspero J, et al. 2016.. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. . Chest 150:(4):789–98
     [Crossref] [Google Scholar]
  62. 62.
    FitzGerald JM, Bleecker ER, Nair P, et al. 2016.. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. . Lancet 388:(10056):2128–41
     [Crossref] [Google Scholar]
  63. 63.
    Bleecker ER, FitzGerald JM, Chanez P, et al. 2016.. 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 388:(10056):2115–27
     [Crossref] [Google Scholar]
  64. 64.
    Liu LY, Sedgwick JB, Bates ME, et al. 2002.. Decreased expression of membrane IL-5 receptor α on human eosinophils: II. IL-5 down-modulates its receptor via a proteinase-mediated process. . J. Immunol. 169:(11):6459–66
     [Crossref] [Google Scholar]
  65. 65.
    Ferguson GT, FitzGerald JM, Bleecker ER, et al. 2017.. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. . Lancet Respir. Med. 5:(7):568–76
     [Crossref] [Google Scholar]
  66. 66.
    Gauvreau GM, Sehmi R, FitzGerald JM, et al. 2024.. Benralizumab for allergic asthma: a randomised, double-blind, placebo-controlled, trial. . Eur. Respir. J. 64:(3):2400512
     [Crossref] [Google Scholar]
  67. 67.
    Jackson DJ, Bacharier LB, Gergen PJ, et al. 2022.. Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial. . Lancet 400:(10351):502–11
     [Crossref] [Google Scholar]
  68. 68.
    Nair P, Wenzel S, Rabe KF, et al. 2017.. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. . N. Engl. J. Med. 376:(25):2448–58
     [Crossref] [Google Scholar]
  69. 69.
    Han JK, Bachert C, Fokkens W, et al. 2021.. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. . Lancet Respir. Med. 9:(10):1141–53
     [Crossref] [Google Scholar]
  70. 70.
    Bachert C, Han JK, Desrosiers MY, et al. 2022.. Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: a randomized, placebo-controlled trial. . J. Allergy Clin. Immunol. 149:(4):1309–17.e12
     [Crossref] [Google Scholar]
  71. 71.
    Grayson PC, Ponte C, Suppiah R, et al. 2022.. American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for eosinophilic granulomatosis with polyangiitis. . Ann. Rheum. Dis. 81:(3):309–14
     [Crossref] [Google Scholar]
  72. 72.
    Wechsler ME, Akuthota P, Jayne D, et al. 2017.. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. . N. Engl. J. Med. 376:(20):1921–32
     [Crossref] [Google Scholar]
  73. 73.
    Wechsler ME, Nair P, Terrier B, et al. 2024.. Benralizumab versus mepolizumab for eosinophilic granulomatosis with polyangiitis. . N. Engl. J. Med. 390:(10):911–21
     [Crossref] [Google Scholar]
  74. 74.
    Gauvreau GM, El-Gammal AI, O'Byrne PM. 2015.. Allergen-induced airway responses. . Eur. Respir. J. 46:(3):819–31
     [Crossref] [Google Scholar]
  75. 75.
    Bleecker ER, Wechsler ME, FitzGerald JM, et al. 2018.. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. . Eur. Respir. J. 52:(4):1800936
     [Crossref] [Google Scholar]
  76. 76.
    Li X, Newbold P, Katial R, et al. 2024.. Multivariate cluster analyses to characterize asthma heterogeneity and benralizumab responsiveness. . J. Allergy Clin. Immunol. Pract. 12:(10):273243
     [Crossref] [Google Scholar]
  77. 77.
    Robinson DS, Hamid Q, Ying S, et al. 1992.. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. . N. Engl. J. Med. 326:(5):298–304
     [Crossref] [Google Scholar]
  78. 78.
    Wills-Karp M. 2004.. Interleukin-13 in asthma pathogenesis. . Immunol. Rev. 202:(1):175–90
     [Crossref] [Google Scholar]
  79. 79.
    O'Garra A. 1998.. Cytokines induce the development of functionally heterogeneous T helper cell subsets. . Immunity 8:(3):275–83
     [Crossref] [Google Scholar]
  80. 80.
    Kashiwada M, Levy DM, McKeag L, et al. 2010.. IL-4-induced transcription factor NFIL3/E4BP4 controls IgE class switching. . PNAS 107:(2):821–26
     [Crossref] [Google Scholar]
  81. 81.
    Bradding P, Walls AF, Holgate ST. 2006.. The role of the mast cell in the pathophysiology of asthma. . J. Allergy Clin. Immunol. 117:(6):1277–84
     [Crossref] [Google Scholar]
  82. 82.
    Rodriguez-Rodriguez N, Gogoi M, McKenzie ANJ. 2021.. Group 2 innate lymphoid cells: team players in regulating asthma. . Annu. Rev. Immunol. 39::167–98
     [Crossref] [Google Scholar]
  83. 83.
    Schmid-Grendelmeier P, Altznauer F, Fischer B, et al. 2002.. Eosinophils express functional IL-13 in eosinophilic inflammatory diseases. . J. Immunol. 169:(2):1021–27
     [Crossref] [Google Scholar]
  84. 84.
    Grunstein MM, Hakonarson H, Leiter J, et al. 2002.. IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle. . Am. J. Physiol. Lung Cell. Mol. Physiol. 282:(3):L520–28
     [Crossref] [Google Scholar]
  85. 85.
    Barnes PJ. 2008.. The cytokine network in asthma and chronic obstructive pulmonary disease. . J. Clin. Investig. 118:(11):3546–56
     [Crossref] [Google Scholar]
  86. 86.
    Andrews A-L, Holloway JW, Holgate ST, Davies DE. 2006.. IL-4 receptor α is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets. . J. Immunol. 176:(12):7456–61
     [Crossref] [Google Scholar]
  87. 87.
    Wenzel S, Ford L, Pearlman D, et al. 2013.. Dupilumab in persistent asthma with elevated eosinophil levels. . N. Engl. J. Med. 368:(26):2455–66
     [Crossref] [Google Scholar]
  88. 88.
    Wenzel S, Castro M, Corren J, et al. 2016.. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. . Lancet 388:(10039):31–44
     [Crossref] [Google Scholar]
  89. 89.
    Castro M, Corren J, Pavord ID, et al. 2018.. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. . N. Engl. J. Med. 378:(26):2486–96
     [Crossref] [Google Scholar]
  90. 90.
    Bacharier LB, Maspero JF, Katelaris CH, et al. 2021.. Dupilumab in children with uncontrolled moderate-to-severe asthma. . N. Engl. J. Med. 385:(24):2230–40
     [Crossref] [Google Scholar]
  91. 91.
    Wenzel S, Wilbraham D, Fuller R, et al. 2007.. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. . Lancet 370:(9596):1422–31
     [Crossref] [Google Scholar]
  92. 92.
    Rabe KF, Nair P, Brusselle G, et al. 2018.. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. . N. Engl. J. Med. 378:(26):2475–85
     [Crossref] [Google Scholar]
  93. 93.
    Pavord ID, Casale TB, Corren J, et al. 2024.. Dupilumab reduces exacerbations independent of changes in biomarkers in moderate-to-severe asthma. . J. Allergy Clin. Immunol. Pract. 12:(7):1763–72
     [Crossref] [Google Scholar]
  94. 94.
    Willsmore ZN, Woolf RT, Hughes C, et al. 2019.. Development of inflammatory arthritis and enthesitis in patients on dupilumab: a case series. . Br. J. Dermatol. 181:(5):1068–70
     [Crossref] [Google Scholar]
  95. 95.
    Brumfiel CM, Patel MH, Zirwas MJ. 2022.. Development of psoriasis during treatment with dupilumab: a systematic review. . J. Am. Acad. Dermatol. 86:(3):708–9
     [Crossref] [Google Scholar]
  96. 96.
    Bridgewood C, Wittmann M, Macleod T, et al. 2022.. T helper 2 IL-4/IL-13 dual blockade with dupilumab is linked to some emergent T helper 17–type diseases, including seronegative arthritis and enthesitis/enthesopathy, but not to humoral autoimmune diseases. . J. Invest. Dermatol. 142:(10):2660–67
     [Crossref] [Google Scholar]
  97. 97.
    Guttman-Yassky E, Renert-Yuval Y, Bares J, et al. 2022.. Phase 2a randomized clinical trial of dupilumab (anti-IL-4Rα) for alopecia areata patients. . Allergy 77:(3):897–906
     [Crossref] [Google Scholar]
  98. 98.
    Fukuyama M, Kinoshita-Ise M, Mizukawa Y, Ohyama M. 2023.. Two-sided influence of dupilumab on alopecia areata co-existing with severe atopic dermatitis: a case series and literature review. . J. Cutaneous Immunol. Allergy 6:(1):13–17
     [Crossref] [Google Scholar]
  99. 99.
    Thaçi D, Simpson EL, Deleuran M, et al. 2019.. Efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe atopic dermatitis: a pooled analysis of two phase 3 randomized trials (LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2). . J. Dermatol. Sci. 94:(2):266–75
     [Crossref] [Google Scholar]
  100. 100.
    Lee SE, Hopkins C, Mullol J, et al. 2022.. Dupilumab improves health related quality of life: results from the phase 3 SINUS studies. . Allergy 77:(7):2211–21
     [Crossref] [Google Scholar]
  101. 101.
    Bachert C, Han JK, Desrosiers M, et al. 2019.. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. . Lancet 394:(10209):1638–50
     [Crossref] [Google Scholar]
  102. 102.
    Simpson EL, Bieber T, Guttman-Yassky E, et al. 2016.. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. . N. Engl. J. Med. 375:(24):2335–48
     [Crossref] [Google Scholar]
  103. 103.
    Hanania NA, Korenblat P, Chapman RK, et al. 2016.. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOTLA I and LAVOLTA II): replicate, phase 3, randomized, double-blind, placebo-controlled trials. . Lancet Respir. Med. 4:(10):781–96
     [Crossref] [Google Scholar]
  104. 104.
    Brightling CE, Chanez P, Leigh R, et al. 2015.. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. . Lancet Respir. Med. 3:(9):692–701
     [Crossref] [Google Scholar]
  105. 105.
    Weathington N, O'Brien ME, Radder J, et al. 2019.. BAL cell gene expression in severe asthma reveals mechanisms of severe disease and influences of medications. . Am. J. Respir. Crit. Care Med. 200:(7):837–56
     [Crossref] [Google Scholar]
  106. 106.
    Hastie AT, Mauger DT, Denlinger LC, et al. 2020.. Baseline sputum eosinophil + neutrophil subgroups’ clinical characteristics and longitudinal trajectories for NHLBI Severe Asthma Research Program (SARP 3) cohort. . J. Allergy Clin. Immunol. 146:(1):222–26
     [Crossref] [Google Scholar]
  107. 107.
    Hong H, Liao S, Chen F, et al. 2020.. Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation. . Allergy 75:(11):2794–804
     [Crossref] [Google Scholar]
  108. 108.
    Schmitz J, Owyang A, Oldham E, et al. 2005.. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. . Immunity 23:(5):479–90
     [Crossref] [Google Scholar]
  109. 109.
    Kaur D, Gomez E, Doe C, et al. 2015.. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk. . Allergy 70:(5):556–67
     [Crossref] [Google Scholar]
  110. 110.
    Wu YH, Lai ACY, Chi PY, et al. 2020.. Pulmonary IL-33 orchestrates innate immune cells to mediate respiratory syncytial virus-evoked airway hyperreactivity and eosinophilia. . Allergy 75:(4):818–30
     [Crossref] [Google Scholar]
  111. 111.
    Takai T. 2012.. TSLP expression: cellular sources, triggers, and regulatory mechanisms. . Allergol. Int. 61:(1):3–17
     [Crossref] [Google Scholar]
  112. 112.
    Verstraete K, Peelman F, Braun H, et al. 2017.. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. . Nat. Commun. 8:(1):14937
     [Crossref] [Google Scholar]
  113. 113.
    Corren J, Parnes JR, Wang L, et al. 2017.. Tezepelumab in adults with uncontrolled asthma. . N. Engl. J. Med. 377:(10):936–46
     [Crossref] [Google Scholar]
  114. 114.
    Menzies-Gow A, Corren J, Bourdin A, et al. 2021.. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. . N. Engl. J. Med. 384:(19):1800–9
     [Crossref] [Google Scholar]
  115. 115.
    Wechsler ME, Menzies-Gow A, Brightling CE, et al. 2022.. Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study. . Lancet Respir. Med. 10:(7):650–60
     [Crossref] [Google Scholar]
  116. 116.
    Simpson EL, Parnes JR, She D, et al. 2019.. Tezepelumab, an anti–thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial. . J. Am. Acad. Dermatol. 80:(4):1013–21
     [Crossref] [Google Scholar]
  117. 117.
    Diver S, Khalfaoui L, Emson C, et al. 2021.. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial. . Lancet Respir. Med. 9:(11):1299–312
     [Crossref] [Google Scholar]
  118. 118.
    Gauvreau GM, O'Byrne PM, Boulet L-P, et al. 2014.. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. . N. Engl. J. Med. 370:(22):2102–10
     [Crossref] [Google Scholar]
  119. 119.
    Wechsler ME, Ruddy MK, Pavord ID, et al. 2021.. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma. . N. Engl. J. Med. 385:(18):1656–68
     [Crossref] [Google Scholar]
  120. 120.
    Upham JW, Le Lievre C, Jackson DJ, et al. 2021.. Defining a severe asthma super-responder: findings from a Delphi process. . J. Allergy Clin. Immunol. Pract. 9:(11):3997–4004
     [Crossref] [Google Scholar]
  121. 121.
    Portacci A, Dragonieri S, Carpagnano GE. 2023.. Super-responders to biologic treatment in Type 2-high severe asthma: passing fad or a meaningful phenotype?. J. Allergy Clin. Immunol. Pract. 11:(5):1417–20
     [Crossref] [Google Scholar]
  122. 122.
    Solèr M, Matz J, Townley R, et al. 2001.. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. . Eur. Respir. J. 18:(2):254–61
     [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-med-070323-103158
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Biologic Medications for Severe Asthma: Implications for Understanding Pathogenic Heterogeneity and Endotypes
Annual Review of Medicine 76, 339 (2025); https://doi.org/10.1146/annurev-med-070323-103158
/content/journals/10.1146/annurev-med-070323-103158
/content/journals/10.1146/annurev-med-070323-103158
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