Is IL-5 Inhibition Effective in NSAIDs-Exacerbated Respiratory Disease?

ATLANTA, GA—Marek Kowalski, MD, PhD, presented at the 2017 AAAAI Annual Meeting that anti-interleukin 5 (IL-5) treatment may be effective in patients with NSAIDs-exacerbated respiratory disease (N-ERD). Studies assessing anti-IL 5 efficacy for asthma in N-ERD patients are inadequate, stated Dr. Kowalski. 

IL-5 is a cytokine involved in the maturation, activation, proliferation, and survival of eosinophils. Its cellular sources include Th2 lymphocytes, CD+NK cells, Type 2 innate LC, mast cells, and eosinophils. Dr. Kowalski explained, “IL-5 receptors are activated by dimerization of alpha (ILRα) and βc subunits.” Patients with asthma have airways that overexpress IL-5 in bronchial tissue in a parallel manner to the severity of eosinophilic inflammation. Patients with a dual allergic response show an increased expression of IL-5 mRNA and IL-5 is also increased i induced sputum during asthma. 

“Inhibition of IL-5 synthesis is one of the major mechanisms underlying effectiveness of corticosteroids in asthma,” explained Dr. Kowalski. There are currently 3 anti-IL-5/IL5R treatments: mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab that is currently in development. Mepolizumab and reslizumab have shown to decrease severe asthma exacerbations, improve FEV1, and allow for oral corticosteroid reduction in severe asthmatics. A positive response to anti-IL 5 treatment may be through measuring peripheral blood eosinophils. Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) exhibit TH2-type inflammation with high levels of tissue eosinophilia and increased activation of eosinophil markers. Both systemic and topical corticosteroids are effective in treating CRSwNP. 

A clinical study enrolled 30 patients with severe nasal polyposis randomized to 2 IV injections of mepolizumab 750mg or placebo. The data showed a significant reduction in the polyp score in 60% of patients with parallel reduction in CT score; this effect was sustained for over 1 year. Dr. Kowalski then went on to describe the clinical characteristics of NERD, which include: hypersensitivity to aspirin, CRSwNP, and bronchial asthma.  

The rationale that anti-IL 5 treatment would be effective for asthma in N-ERD patients was supported by the fact that more than there is significant 10-fold upregulation of the number of eosinophils infiltrating bronchial tissue. Also, IL-5 is overexpressed in bronchial tissue in parallel to severity of eosinophilic inflammation. Similarly, the rationale that anti-IL 5 treatment would be effective for CRSwNP in N-ERD patients was supported by the fact that there is intense sin-nasal/polyp tissue infiltration with eosinophils and mast cells. There are also significantly higher concentrations of IL-5 in NP tissue homogenates from N-ERD vs. aspirin-tolerant asthma (ATA) patients. 

There are, however, several “arguments against effectiveness of anti-IL 5 treatment in N-ERD,” described Dr. Kowalski. These points include the clinical and pathophysiological heterogeneity of the N-ERD syndrome, production of mixed TH1/TH2 cytokine profile, and the possibility of involvement of mechanisms other than IL-5, “pro-eosinophilic” mechanisms.Based on study data of 201 patients with aspirin-exacerbated respiratory disease (AERD), certain phenotypes were distinguished: 

• Class 1: asthma with moderate course, intensive upper airway symptoms, and blood eosinophilia
• Class 2: asthma with a mild course, relatively well controlled and with low healthcare use 
• Class 3: asthma with a severe course, poorly controlled, and with severe exacerbations and airway obstruction 
• Class 4: poorly controlled asthma with frequent and severe exacerbations in female subjects 

Mepolizumab was studied in a Phase 2, double-blind, randomized, multicenter, placebo-controlled study to evaluate the use of mepolizumab 750mg IV every 4 weeks for 6 doses in adults with severe bilateral nasal polyposis for the need for surgery at Week 25. Then, a post-hoc analysis of the need for surgery in patients with concurrent asthma (n=77) was performed. The study data showed more mepolizumab-treated patients vs. placebo-treated patients no longer required surgery at Week 25 (33% vs. 10%, respectively).  

A separate post-hoc summary on the need for surgery at Week 25 among patients with aspirin sensitivity (n=44) was performed. Like the main analysis, “a greater proportion of aspirin-sensitive subjects treated with mepolizumab compared with those treated with placebo no longer required surgery at Week 25 (37% vs. 8%).In general, anti-IL 5 treatment appeared to be effective in patients with eosinophilic asthma and/or CRSwNP, study authors concluded. 

Based on the pathophysiological and clinical characteristics of N-ERD, anti-IL 5 therapy may be effective in this patient subgroup. Dr. Kowalski added, “In future studies on anti-IL 5 treatment in N-ERD patients, heterogeneity of this syndrome should be considered.”