Eosinophilia Induced by Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes

Abstract

Currently, five biological drugs for uncontrolled severe asthma treatment are marketed. They all block type 2 inflammatory pathways, either by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), or the IL-4/13 pathway (dupilumab). Hypereosinophilia has been observed in between 4% and 25% of patients treated with dupilumab, being transient in most cases, but persistent cases of symptomatic hypereosinophilia consistent with eosinophil granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis or sudden worsening of asthma symptoms have been described. Cases of EGPA have been described with all biologics, including anti-IL-5, and with leukotriene receptors antagonists in publications or in the Eudravigilance database. In many cases of EGPA, it appears during systemic steroids tapering or after switching from an anti-IL-5 biologic to Dupilumab, suggesting that systemic steroids or the anti IL-5 were masking the vasculitis. This review aims to substantiate the plausible mechanisms of dupilumab-induced hypereosinophilia and review symptomatic hypereosinophilia cases associated with dupilumab therapy. Blockade of the IL-4/IL-13 pathway cause a reduction of eosinophil migration and blood accumulation by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in the bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1,500/mL), where an anti-IL-5/IL-5R is preferable. Also, when changing from an anti-IL-5/5R to an anti-IL-4/13R. Close monitoring of blood eosinophils and clinical evolution seems justified in these situations. Nevertheless, dual therapy with anti-IL-5/5R and anti-IL4/IL-13R may be needed for optimal control since both IL-5, and IL-4/13 pathways can simultaneously contribute to airway inflammation.

Two cases with new onset of ANCA-positive eosinophilic granulomatosis with polyangiitis under treatment with dupilumab: coincidence or causality?

“…In contrast to IL-5-inhibitors at least transient hypereosinophilia (>1500/µL) is observed in up to 25% of dupilumab treated asthma patients, which can lead to other eosinophilic diseases such as eosinophilic pneumonia, eosinophilic gastritis or even EGPA 3 4. The blood eosinophilia likely results from impaired migration through the vessel wall due to blockade of IL-4/IL-13-mediated activation of VCAM-1, TARC and eotaxin-3 3…”

Immunopathologic Role of Eosinophils in Eosinophilic Chronic Rhinosinusitis

“…These biologicals can improve the sense of smell, quality of life, nasal polyp scores, and CT score, reducing the need for rescue surgery with somewhat different efficacy and safety [ 87 ]. However, treatment with dupilumab can cause transient blood eosinophilia, which is related to the inhibition of eosinophil migration to the tissue [ 88 , 89 ]. Although most of the eosinophilia is transient and does not develop clinical symptoms, treatment with prednisolone or dual therapy with anti-IL-5/5R monoclonal antibody may be needed in some cases [ 89 ].…”

Response to monoclonal antibodies in asthma: definitions, potential reasons for failure and therapeutic options for suboptimal response

“…In many cases of EGPA, it appears during systemic steroids tapering or after switching from an anti-IL-5 mAb to dupilumab, suggesting that systemic steroids or the anti-IL-5 were masking the vasculitis. Blockade of the IL-4/IL-13 pathway causes a reduction of eosinophil migration and blood accumulation by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis; a plausible explanation of this hypereosinophilia which has been recently reviewed by Olaguibel et al [41].…”