Anti IL5 Pathway Therapy

Anti IL5 therapy lowers blood and tissue eosinophils and is used in severe eosinophilic asthma. It also treats eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome and nasal polyps. The agents are mepolizumab, reslizumab and benralizumab.

Mechanism. Mepolizumab and reslizumab bind IL-5 and prevent receptor binding. Benralizumab binds the IL-5 receptor alpha chain and removes eosinophils and basophils by antibody-dependent cell killing, so depletion is almost complete within 24 hours.

Pharmacokinetics. Half lives are about 16 to 22 days for mepolizumab, about 24 days for reslizumab and about 15 days for benralizumab. Clearance is not altered by hepatic or renal impairment.

Mepolizumab. 100 mg subcutaneously every 4 weeks from 12 years, and 40 mg every 4 weeks at 6 to 11 years. For eosinophilic granulomatosis with polyangiitis or hypereosinophilic syndrome, 300 mg every 4 weeks.

Benralizumab. 30 mg subcutaneously every 4 weeks for the first 3 doses, then every 8 weeks. For eosinophilic granulomatosis with polyangiitis, 30 mg every 4 weeks.

Reslizumab. 3 mg/kg intravenously over 20 to 50 minutes every 4 weeks, adults only. It carries boxed-warning level anaphylaxis risk.

Eosinophil thresholds. Mepolizumab: 150 cells/microlitre or more at starting, or 300 cells/microlitre or more in the last 12 months. Benralizumab: 300 cells/microlitre or more in most labels. Reslizumab: 400 cells/microlitre or more.

Differences. Benralizumab gives dosing every 8 weeks after the first 3 doses and depletes eosinophils fully. Reslizumab needs an infusion and observation.

Eosinophilic asthma. Added to high dose inhaled corticosteroid with a long acting beta 2 agonist in patients with repeated exacerbations. Exacerbations fall by about half, and oral corticosteroid requirement falls substantially in dependent patients.

Counting eosinophils. Repeat the count when off oral corticosteroid. Exclude other causes of eosinophilia, including helminth infection, drug reaction, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome and adrenal insufficiency. Treat helminth infection before using the count to select a drug.

Response. Assess at 4 months, continue if exacerbations or oral corticosteroid use fall. Reassess at 12 months. If there is no response, switch to anti IgE or an anti IL-4 receptor drug depending on phenotype.

Not for acute asthma. Anti IL5 therapy does not relieve attacks.

Adverse effects. Headache, injection site reactions, pharyngitis and back pain. Herpes zoster is reported with mepolizumab, so consider vaccination before starting.

Helminth infection. Eosinophils help control helminths, so treat existing infection first. If infection occurs on treatment and does not respond to antihelminthic therapy, stop the drug until it resolves. This matters in endemic areas such as East Africa.

Hypersensitivity. Anaphylaxis is rare with mepolizumab and benralizumab and more frequent with reslizumab, so observe infusions.

Corticosteroid withdrawal. Taper oral corticosteroid slowly and watch for adrenal insufficiency.

Monitoring. Exacerbations, oral corticosteroid dose, FEV1, symptoms, eosinophil count when relevant, and signs of vasculitis.

Special groups. Pregnancy: limited data, use only if benefit outweighs risk. Breastfeeding: IgG in milk is poorly absorbed. Children: from 6 years for mepolizumab. Older adults and organ impairment: no adjustment.

Referral and escalation. Prescribing needs a specialist in severe asthma. New neuropathy, purpura or sinus disease after steroid reduction needs assessment for eosinophilic granulomatosis with polyangiitis.