Severe eosinophilic asthma with nasal polyposis: A phenotype for improved sinonasal and asthma outcomes with mepolizumab therapy

Nasal polyposis (NP) is a chronic inflammatory disease of the sinuses that can cause severe nasal symptoms and systemic symptoms that include fatigue, difficulty sleeping, and impairments in social, emotional, and lifestyle well-being.1Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; 23 (preceding table of contents, 1-298): 3PubMed Google Scholar Patients with severe eosinophilic asthma (SEA) frequently have comorbid NP, which may impact asthma severity.1Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; 23 (preceding table of contents, 1-298): 3PubMed Google Scholar The anti–IL-5 mAb mepolizumab improves health-related quality of life (HRQOL) and exacerbation rates in patients with SEA2Chupp G.L. Bradford E.S. Albers F.C. Bratton D.J. Wang-Jairaj J. Nelsen L.M. 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: 390-400Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar,3Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. et al.Mepolizumab treatment in patients with severe eosinophilic asthma.N Engl J Med. 2014; 371: 1198-1207Crossref PubMed Scopus (1514) Google Scholar; however, its effect on HRQOL based on the presence of NP has not been examined. This letter describes results from a post hoc analysis of the MUSCA study2Chupp G.L. Bradford E.S. Albers F.C. Bratton D.J. Wang-Jairaj J. Nelsen L.M. 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: 390-400Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar (n = 551; GlaxoSmithKline ID: 200862/NCT02281318) and a meta-analysis (GlaxoSmithKline ID: 208115) of MUSCA and MENSA3Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. et al.Mepolizumab treatment in patients with severe eosinophilic asthma.N Engl J Med. 2014; 371: 1198-1207Crossref PubMed Scopus (1514) Google Scholar (n = 576; GSK ID: 115588/NCT01691521); their combined objective was to determine the change in HRQOL in mepolizumab-treated patients with SEA either with or without NP. MENSA and MUSCA were phase III, placebo-controlled, randomized, double-blind, parallel-group, multicenter studies. Full study details have been published.2Chupp G.L. Bradford E.S. Albers F.C. Bratton D.J. Wang-Jairaj J. Nelsen L.M. 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: 390-400Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar,3Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. et al.Mepolizumab treatment in patients with severe eosinophilic asthma.N Engl J Med. 2014; 371: 1198-1207Crossref PubMed Scopus (1514) Google Scholar Briefly, patients 12 years or older with SEA (defined as asthma requiring regular treatment with high-dose inhaled corticosteroids and additional controller medication,4Global strategy for asthma management and prevention 2019.https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdfDate accessed: January 27, 2010Google Scholar plus a blood eosinophil count ≥150 cells/μL at screening or ≥300 cells/μL in the previous year) and a history of 2 or more exacerbations requiring systemic corticosteroids in the year preceding enrollment received standard care plus mepolizumab 100 mg subcutaneously, or placebo, every 4 weeks for 32 (MENSA) or 24 (MUSCA) weeks. In both studies, the presence of NP was determined from patients' medical records and/or external nasal examination at baseline. MUSCA assessed the mean change from baseline in the SinoNasal Outcomes Test (SNOT-22) score at the end of treatment (week 24); we analyzed this post hoc using mixed model repeated measures. The SNOT-22 is a 22-item patient-reported outcome tool developed for use in patients with chronic rhinosinusitis (CRS) with and without NP, assessing upper airways/nasal symptoms and HRQOL impacts of CRS; the established minimally clinically important difference (MCID) representing an improvement is an 8.9-point decrease.5Hopkins C. Gillett S. Slack R. Lund V.J. Browne J.P. Psychometric validity of the 22-item Sinonasal Outcome Test.Clin Otolaryngol. 2009; 34: 447-454Crossref PubMed Scopus (968) Google Scholar A shared outcome of both studies was the mean change from baseline in the annual rate of clinically significant exacerbations (asthma worsening requiring systemic corticosteroids and/or hospitalization, and/or an emergency room visit). Annualized exacerbation rates were analyzed using a negative binomial regression model, and treatment differences for each study were combined using an inverse variance weighted fixed-effects meta-analysis. For the MUSCA post hoc analysis, of 551 patients included in the modified intent-to-treat population, 105 (19%) had NP at baseline. Overall, 422 patients completed the SNOT-22 questionnaire at baseline (and were therefore included); 80 (19%) had NP. Mean baseline SNOT-22 scores were 43.6 ± 22.3 and 31.1 ± 20.2 for patients with and without NP. This is consistent with the reported SNOT-22 scores of patients undergoing surgery for NP and/or CRS,5Hopkins C. Gillett S. Slack R. Lund V.J. Browne J.P. Psychometric validity of the 22-item Sinonasal Outcome Test.Clin Otolaryngol. 2009; 34: 447-454Crossref PubMed Scopus (968) Google Scholar indicating greater disease burden among patients with versus without NP. Among patients with NP, mepolizumab and placebo reduced the mean (SE) SNOT-22 score by −13.7 (2.6) and −1.9 (3.0) from baseline to week 24. The treatment difference of −11.8 (95% CI, −19.8 to −3.9) (Fig 1) exceeded the MCID, indicating a clinically meaningful improvement.5Hopkins C. Gillett S. Slack R. Lund V.J. Browne J.P. Psychometric validity of the 22-item Sinonasal Outcome Test.Clin Otolaryngol. 2009; 34: 447-454Crossref PubMed Scopus (968) Google Scholar In patients with SEA without NP, the impact of mepolizumab was less, with a treatment difference of −4.9 (95% CI, −8.3 to −1.6). However, improvements in HRQOL related to lower airway symptoms (as measured by the SGRQ [St George's respiratory questionnaire] score) with mepolizumab were evident in both groups, with treatment differences (95% CI) of −14.6 (−21.4 to −7.7) and −6.5 (−9.6 to −3.5) in those with and without NP; these both exceeded the MCID of 4.0. This shows that mepolizumab has greater benefit in the upper and lower airways in patients with NP and SEA versus SEA alone. For the meta-analysis of MENSA/MUSCA, of 936 patients included, 166 (18%) had NP at screening. Patients with NP had higher baseline geometric mean (SD log) eosinophil counts than did those without NP (440 [0.938] vs 290 [1.010] cells/μL). Mean baseline annual exacerbation rates were 3.1 ± 2.1 and 3.2 ± 2.3 for patients with and without NP. Mepolizumab versus placebo reduced the annual rate of clinically significant exacerbations in patients with SEA regardless of NP status, but to a greater extent in patients with NP (80%) than in without NP (49%) (Fig 2). Overall, our results suggest that patients with SEA and comorbid NP have a higher disease burden, as reflected by the SNOT-22 and SGRQ scores, and greater systemic eosinophilic inflammation than do those with SEA but no diagnosis of NP. Furthermore, in support of other studies of biologics in SEA,6Castro M. Mathur S. Hargreave F. Boulet L.P. Xie F. Young J. et al.Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study.Am J Respir Crit Care Med. 2011; 184: 1125-1132Crossref PubMed Scopus (565) Google Scholar,7Bleecker E.R. Wechsler M.E. FitzGerald J.M. Menzies-Gow A. Wu Y. Hirsch I. et al.Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma.Eur Respir J. 2018; 52: 1800936Crossref PubMed Scopus (140) Google Scholar clinical improvements with mepolizumab were greater in patients with SEA and NP than in those without NP. It should be noted that in this analysis NP was identified on the basis of patients' medical records and/or external nasal examination, which may not be as reliable as performing a standardized physical examination. Nonetheless, these data suggest that patients with the clinical phenotype of SEA plus NP may have an even greater response to treatment with mepolizumab due to their morbidity. Consistent with this it is known that mepolizumab, as a systemic therapy, impacts on the upper airways, with improvement in NP size and HRQOL in patients with NP.8Bachert C. Sousa A.R. Lund V.J. Scadding G.K. Gevaert P. Nasser S. et al.Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial.J Allergy Clin Immunol. 2017; 140: 1024-1031. e14Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar The local generation of IL-5 within the upper and lower airways in patients with SEA with NP may explain the higher circulating blood eosinophil levels compared with patients with SEA without NP.9Bachert C. Zhang N. Holtappels G. De Lobel L. van Cauwenberge P. Liu S. et al.Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma.J Allergy Clin Immunol. 2010; 126 (968. e1-6): 962-968Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar Because higher blood eosinophil counts are a predictive biomarker of better response to mepolizumab in SEA,2Chupp G.L. Bradford E.S. Albers F.C. Bratton D.J. Wang-Jairaj J. Nelsen L.M. 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: 390-400Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar,3Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. et al.Mepolizumab treatment in patients with severe eosinophilic asthma.N Engl J Med. 2014; 371: 1198-1207Crossref PubMed Scopus (1514) Google Scholar it may not be surprising that mepolizumab has greater benefit in reducing severe exacerbations in patients with SEA plus NP. However, it is important to demonstrate that this phenotype is associated with an enhanced response to mepolizumab in the clinical setting. In conclusion, although patients with SEA demonstrated improvements in HRQOL and exacerbations with mepolizumab treatment regardless of the presence of NP, patients with SEA and concomitant NP have a phenotype that demonstrates greater benefit with mepolizumab therapy compared with patients with SEA in the absence of NP. These results suggest that mepolizumab may directly affect upper airway type 2 inflammatory conditions, with prospective studies required to demonstrate this further. Editorial support (in the form of writing assistance, including development of the initial draft on the basis of a detailed online written by the lead author, assembling tables and figures, collating authors comments, grammatical editing, and referencing) was provided by Kerry Knight, PhD, at Fishawack Indicia Ltd, UK, and was funded by GlaxoSmithKline. Eosinophil paradox with mepolizumab in chronic rhinosinusitis with nasal polyposisJournal of Allergy and Clinical ImmunologyVol. 146Issue 3PreviewWe were intrigued to read the post hoc analysis by Howarth et al1 suggesting that 100 mg mepolizumab given subcutaneously may reduce disease burden in the upper and lower airways of patients with severe eosinophilic asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Pointedly, the diagnosis of CRSwNP was not based on either sinonasal endoscopy or computed tomography scan. The subgroup of patients in the MUSCA trial who completed the 22-item Sino-Nasal Outcome Test (SNOT-22) exhibited a mean treatment effect of −11.8 with mepolizumab, which exceeded the minimal clinically important difference of −8.9. Full-Text PDF