Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology
Source: CD4+ T cells (TH2).
Receptor: IL-5R heterodimer induces Jak2 and STAT 3 signaling pathway. The receptors for IL-3, IL-5, and GM-CSF share a common β chain. All 3 cytokines stimulate the development of eosinophils.
The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.
(click to enlarge the image)
- Eosinophils: activation, increased production
- B cells: proliferation, IgA production
IL-5 is the key regulator of eosinophil proliferation.
Humanized mAb against IL-5. Promising results in hypereosinophilic syndrome and eosinophilic esophagitis. Larger trials ongoing. Disappointing early clinical trials in asthma. 2 asthma studies published in NEJM in March 2009.
Emerging appreciation of asthma heterogeneity. Identification of "eosinophilic asthma" with tissue eosinophils, greater airway remodeling, more exacerbations.
Three concepts in NEJM studies:
1. inhibition of IL-5 reduces eosinophilic inflammation
2. not all asthma is eosinophilic
3. reduction in eosinophils associated with a decreased rate of exacerbations
Unlike previous studies of anti-IL-5, the NEJM trials included patients highly eosinophilic asthma (sputum eosinophils gerater than 3%, 16% in one group).
Eosinophilic asthma occurs in less than 5% of adult-onset asthma.
Average age at asthma onset was the mid-to-late 20s. Screened hundreds to get 20 in one study. Reduction of eosinophils had no effect on FEV1, symptoms, and asthma control.
Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma, NEJM 2009
RCT, 61 subjects, sputum eosinophils greater than 3% despite high-dose ICS. Infusions of mepolizumab (29) or placebo (32) monthly for 1 year. Primary outcome: number of severe exacerbations. Secondary outcomes: symptoms, AQLQ (1-7), FEV1, airway hyperresponsiveness,eosinophils - blood and sputum.
Fewer severe exacerbations (2.0 vs. 3.4 per subject; relative risk, 0.57; P=0.02). Improvement in AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; P=0.02). Lower eosinophil counts in the blood (P lower than 0.001) and sputum (P=0.002). No significant differences: symptoms, FEV1, airway hyperresponsiveness.
Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984.
Mepolizumab for Prednisone-Dependent Asthma with Sputum Eosinophilia, NEJM 2009
RCT, persistent sputum eosinophilia (greater than 3%) and symptoms despite oral CS. Less than 3% of the 800 adult patients with severe asthma in the practice (McMaster University, Hamilton, ON, Canada). 9 patients received mepolizumab (5 monthly infusions), 11 placebo.
12 asthma exacerbations in 10 placebo patients. Only one mepolizumab patient had an exacerbation, not associated with sputum eosinophilia (P=0.002). Mepolizumab patients able to reduce prednisone dose by a mean of 84% of their maximum possible dose, as compared with 48±40.5% in placebo (P=0.04). Improvements in eosinophil numbers, asthma control, FEV1 for 8 weeks after last infusion.
Small pilot study.
- higher sputum eosinophil count at baseline in the mepolizumab group (16.6 vs 4)
- no significant difference in final prednisone doses in the two study groups
- most on LABAs: did not retest for albuterol reversibility or methacholine in all patients
- some investigators aware of study-group assignments - aware of sputum-cell counts
Nair P, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993
Receptors for each of the following cytokines share the common gamma chain except which one?
Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007;176:1062-1071.
Sally E. Wenzel, M.D. Eosinophils in Asthma — Closing the Loop or Opening the Door? NEJM, Volume 360:1026-1028, March 5, 2009, Number 10.
Monoclonal antibody reslizumab improves lung function in asthma subtype with eosinophilic airway inflammation - ACAAI, 2010. http://goo.gl/UJJHG
Anti-IL5 Antibody Reslizumb (mAb) Looks Promising for Severe Eosinophilic Asthma http://goo.gl/mlGkL
Azithromycin Inhibits IL-5 Production of T Helper Type 2 Cells from Asthmatic Children. http://1.usa.gov/171oIN