Immunology-based recommendations for available and upcoming biologics in aspirin-exacerbated respiratory disease

Abstract

Aspirin-exacerbated respiratory disease (AERD) is characterized by severe chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic asthma. The upper and lower respiratory tract symptoms are notoriously difficult to treat, with many patients failing first-line therapies.1White A.A. Stevenson D.D. Aspirin-exacerbated respiratory disease.N Engl J Med. 2018; 379: 1060-1070Crossref PubMed Scopus (102) Google Scholar The advent of targeted respiratory biologic medications offers promise for patients with AERD who have had inadequate response to prior standard-of-care approaches. However, there are limited data to guide selection of the proper respiratory biologic for patients with AERD. Herein we discuss our understanding of the immunopathology of respiratory tract inflammation in AERD and how that may help guide biologic selection in this patient population. AERD is predominantly a type 2 inflammatory disease characterized by marked tissue eosinophilia, activated mast cells, and dysregulated production of cysteinyl leukotrienes and prostaglandins.1White A.A. Stevenson D.D. Aspirin-exacerbated respiratory disease.N Engl J Med. 2018; 379: 1060-1070Crossref PubMed Scopus (102) Google Scholar More recently, a subendotype of AERD defined by type 1 and type 3 cytokines has also been identified.2Scott W.C. Cahill K.N. Milne G.L. Li P. Sheng Q. Huang L.C. et al.Inflammatory heterogeneity in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2021; 147: 1318-1328.e5Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar We now know that the respiratory tract epithelium in nasal polyp tissue is also severely dysregulated, with basal cell hyperplasia and glandular cell reductions.3Ordovas-Montanes J. Dwyer D.F. Nyquist S.K. Buchheit K.M. Vukovic M. Deb C. et al.Allergic inflammatory memory in human respiratory epithelial progenitor cells.Nature. 2018; 560: 649-654Crossref PubMed Scopus (145) Google Scholar Both intrinsic and extrinsic factors likely drive the epithelial dysregulation and overproduction of the innate epithelial cell–derived type 2 cytokines IL-33 and thymic stromal lymphopoietin (TSLP). Levels of both IL-33 and TSLP are elevated in the respiratory tissue of patients with AERD and play a role in promoting eosinophilic inflammation and mast cell activation, with consequent overproduction of prostaglandin D2 and leukotrienes.1White A.A. Stevenson D.D. Aspirin-exacerbated respiratory disease.N Engl J Med. 2018; 379: 1060-1070Crossref PubMed Scopus (102) Google Scholar Group 2 innate lymphoid cells (ILC2s) and TH2 cells are abundant in polyp tissue, and along with mast cells, they produce type 2 cytokines such as IL-4, IL-5, and IL-13 (Fig 1). IL-4 and IL-13 signal through the common IL-4Rα subunit to promote a number of effects, including tissue fibrosis and remodeling, goblet cell hyperplasia and mucus production, mast cell activation and survival, and local IgE class switching.1White A.A. Stevenson D.D. Aspirin-exacerbated respiratory disease.N Engl J Med. 2018; 379: 1060-1070Crossref PubMed Scopus (102) Google Scholar Although AERD is not typically considered an atopic disease, a recent study identified a relationship between nasal polyp tissue IgE and rapidity of nasal polyp regrowth in patients with AERD, suggesting IgE as a marker of severe disease and perhaps as a driver of ongoing mast cell activation and respiratory tissue inflammation (Fig 1).4Buchheit K.M. Dwyer D.F. Ordovas-Montanes J. Katz H.R. Lewis E. Vukovic M. et al.IL-5Ralpha marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2020; 145: 1574-1584Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar IL-5 is required for eosinophil survival and activation, but other cell types also express a functional IL-5Rα, and recently a possible role for IL-5/IL-5Rα signaling on nasal polyp plasma cells in patients with AERD has been identified.4Buchheit K.M. Dwyer D.F. Ordovas-Montanes J. Katz H.R. Lewis E. Vukovic M. et al.IL-5Ralpha marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2020; 145: 1574-1584Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Although much attention has been focused on the nasal polyp tissue eosinophilia that is prominent in AERD, complete depletion of eosinophils from the respiratory tissue with the small molecule dexpramipexole did not lead to symptomatic improvement or reduction in nasal polyposis, suggesting that eosinophils may not be the main effector cell that drives the chronic inflammation.5Laidlaw T.M. Prussin C. Panettieri R.A. Lee S. Ferguson B.J. Adappa N.D. et al.Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size.Laryngoscope. 2019; 129: E61-E66Crossref PubMed Scopus (34) Google Scholar Increased understanding of the immunobiology of CRSwNP and asthma in AERD has resulted in the identification of several type 2 cytokines and cytokine receptors that may be targeted by available and upcoming biologics. Among these, dupilumab (anti–IL-4Rα) and omalizumab (anti-IgE) have been specifically studied in patients with AERD, and both have received US Food and Drug Administration approval for the treatment of moderate-to-severe asthma and as add-on therapy for inadequately controlled CRSwNP. Dupilumab inhibits signaling of both IL-4 and IL-13, which are 2 pivotal drivers of type 2 inflammation (Fig 1). A nested analysis of 19 patients with AERD who were receiving either dupilumab or placebo in a phase 2a, randomized controlled trial (NCT01920893) demonstrated improved upper and lower airway symptom control among those with AERD versus among patients with CRSwNP without nonsteroidal anti-inflammatory drug (NSAID) sensitivity.6Laidlaw T.M. Mullol J. Fan C. Zhang D. Amin N. Khan A. et al.Dupilumab improves nasal polyp burden and asthma control in patients with CRSwNP and AERD.J Allergy Clin Immunol Pract. 2019; 7: 2462-2465.e1Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Specific improvement was seen in the objective nasal polyp score (least squares mean differences of –2.51 versus placebo and –0.72 versus CRSwNP without NSAID sensitivity), as well as objective measures of mucosal inflammation and olfaction. Additionally, subjective improvements in asthma control, sinonasal symptoms, and sense of smell and/or taste were found in patients with CRSwNP with or without comorbid NSAID sensitivity. Elevated IgE level is found in nasal polyp tissues and is associated with increasing airway inflammation in AERD.4Buchheit K.M. Dwyer D.F. Ordovas-Montanes J. Katz H.R. Lewis E. Vukovic M. et al.IL-5Ralpha marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2020; 145: 1574-1584Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Omalizumab is an anti-IgE biologic that may improve airway inflammation in AERD via direct reductions in eosinophil, basophil, and mast cell activation (Fig 1). In a study of 21 patients with AERD with comorbid aeroallergen sensitivity treated with omalizumab, Hayashi et al7Hiroaki Hayashi CMENYFKKKWKSTTKAYHMT Omalizumab reduces cysteinyl leukotriene and 9α,11β-prostaglandin F2 overproduction in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2016; 137: 1585-1587.e4Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar demonstrated decreased levels of biomarkers of mast cell activation (leukotriene E4 and a prostaglandin D2 metabolite) following 12 months of therapy. Patient symptoms also improved, with reductions in lower airway exacerbations, corticosteroid utilization, hospitalization, and CRSwNP and/or asthma symptom scores. Anti–IL-5/IL-5Rα biologics, which reduce local respiratory tissue eosinophilia in patients with CRSwNP and asthma, have shown promise in the treatment of severe asthma, and they can be efficacious for upper respiratory symptoms in AERD.8Bavaro N, Gakpo D, Mittal A, Bensko J, Laidlaw TM, Buchheit KM. Efficacy of dupilumab in patients with aspirin-exacerbated respiratory disease and previous inadequate response to anti-IL-5 or anti-IL-5Ralpha in a real-world setting [e-pub ahead of print]. J Allergy Clin Immunol Pract https://doi.org/10.1016/j.jaip.2021.02.020. Accessed March 10, 2021.Google Scholar However, as isolated depletion of eosinophils does not provide symptomatic improvement or the reduction of obstructive nasal polyps,5Laidlaw T.M. Prussin C. Panettieri R.A. Lee S. Ferguson B.J. Adappa N.D. et al.Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size.Laryngoscope. 2019; 129: E61-E66Crossref PubMed Scopus (34) Google Scholar the mechanism of anti–IL-5 biologics in patients with AERD may not be limited to its effects on eosinophils. Additional cellular mechanisms by which IL-5 blockade may provide benefit include decreased mast cell leukotriene E4 production and improved function of the respiratory epithelial barrier (Fig 1), as shown in a recent case-control study9Buchheit KM, Lewis E, Gakpo D, Hacker J, Sohail A, Taliaferro F, et al. Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease [e-pub ahead of print]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2021.05.043. Accessed June 15, 2021.Google Scholar of patients with AERD treated with mepolizumab. Benralizumab (anti–IL-5Rα) and mepolizumab (anti–IL-5) are currently being evaluated for the treatment of CRSwNP. In a recently completed phase 3 study of mepolizumab for treatment of CRSwNP, a subgroup analysis of the subjects with comorbid AERD showed greater improvement in the coprimary end points nasal obstruction and nasal polyp size in the mepolizumab-treated AERD subjects than in those who received placebo.10Han JK, Bachert C, Fokkens W, Desrosiers M, Wagenmann M, Lee SE, et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial [e-pub ahead of print]. Lancet Respir Med https://doi.org/10.1016/S2213-2600(21)00097-7. Accessed June 5, 2021.Google Scholar Benralizumab has a current indication for severe eosinophilic asthma, and its use for CRSwNP is supported by a subgroup analysis of a phase 3b clinical trial that demonstrated improved 22-Item Sinonasal Outcome Test (SNOT-22) scores among 153 subjects with comorbid CRSwNP (NCT03170271). Although this field continues to emerge, early findings suggest that only a subset of patients with AERD have satisfactory clinical response to biologics targeting IL-5/IL-5Rα and that dupilumab may improve respiratory symptoms in AERD patients who have had an inadequate response to anti–IL-5/IL-5Rα biologics.8Bavaro N, Gakpo D, Mittal A, Bensko J, Laidlaw TM, Buchheit KM. Efficacy of dupilumab in patients with aspirin-exacerbated respiratory disease and previous inadequate response to anti-IL-5 or anti-IL-5Ralpha in a real-world setting [e-pub ahead of print]. J Allergy Clin Immunol Pract https://doi.org/10.1016/j.jaip.2021.02.020. Accessed March 10, 2021.Google Scholar mAbs targeting IL-33 and TSLP are currently under investigation for treatment of asthma and/or CRSwNP (NCT03469934, NCT03112577, NCT03614923, and NCT03706079). We look forward to studies of these biologics in patients with AERD, as the levels of both cytokines are significantly elevated in tissue from patients with AERD and likely have an important role in driving mast cell–mediated inflammation. Targeted respiratory biologics represent a clinically significant advancement in our ability to improve treatment outcomes for recalcitrant type 2 inflammatory diseases such as AERD. However, these immunomodulatory medications are very costly; in addition, many of them do not yet have long-term safety or outcome data available and therefore are neither required by nor appropriate for all patients with AERD. We therefore use the treatment pathway shown in Fig 2 to aid in decision making and typically offer biologics only following comprehensive sinus surgery and a trial of aspirin desensitization. Future head-to-head studies and real-world evidence is needed to support personalized treatment strategies and identification of the most efficacious biologic for a given patient.