Eosinophilic esophagitis in the "atopic march": dupilumab as an "umbrella" strategy for multiple coexisting atopic diseases

Abstract

Dupilumab is a monoclonal antibody targeting interleukin-4 and interleukin-13, approved for the treatment of multiple T2 diseases and more recently for Eosinophilic Esophagitis (EoE). EoE is a chronic T2 inflammatory disease, believed to be a member of the "atopic march", due to multiple similarities with other atopic diseases, ranging from epidemiology to genetics and pathophysiology. Although often co-existing in the same patient, these diseases are still treated as separated entities by different specialists, resulting in polypharmacy and chronic use of steroids. Thus, a shared-decision approach by a multidisciplinary team composed of different specialists might improve clinical management and outcomes. Yet, prospective data on the effectiveness of dupilumab as a single agent for multiple T2 inflammatory diseases are lacking, since only few case reports and small studies have been published so far reporting outcomes in patients affected by multiple T2 diseases. The purpose of this review is to illustrate the rationale and clinical evidence supporting the possibility of using dupilumab as a single therapeutic agent in those patients affected by multiple T2 diseases in addition to EoE.

Keywords: anti-IL13; anti-IL4; atopic march; dupilumab; eosinophilic esophagitis; eosinophils; esophagitis.

FIGURE 1

Shared immunopathologic mechanisms of the atopic march. Environmental factors (i.e., food, aeroallergens, infections) and the related tissue damage can stimulate the epithelium to release alarmins such as IL-33, IL-25 and TSLP. Alarmins, in turn, activate both ILC2 and DCs which drive naïve T cells toward a Th2 differentiation and production of IL-5, IL-4 and IL-13. IL-5 promotes eosinophils activation and degranulation, whereas IL-4 and IL-13 stimulate the release of eotaxin-3 by epithelial cells. Eotaxin-3 together with IL-5, ultimately lead to eosinophils recruitment, activation, and degranulation. IL-4/IL-13 also promote DC activation, M2 macrophage polarization, IgE class switching by activated B cells and consequently MC and basophils degranulation. Cytotoxic proteins released by granulocytes lead to tissue damage, barrier dysfunction and epithelial remodeling. Finally, IL-4/IL-13 stimulated release of TGFβ1, in synergy with eotaxin-3, promote fibroblast activation and differentiation into myofibroblast, ultimately leading to ECM deposition and smooth muscle cells reduced contractility. Dupilumab, by binding to IL-4Rα, can inhibit the activation of the JAK/STAT6 signaling pathway by IL-4 and IL-13, thus blocking the aforementioned downstream inflammatory processes. EO, eosinophils; DC, dendritic cells; M2, M2 macrophages; MC, mast cells; ILC2, innate lymphoid cell type 2; IL, interleukin; TLSP, thymic stromal lymphopoietin precursor; TH2, T helper 2; TGFβ1, transforming growth factor β1; ECM, extracellular matrix. Created with BioRender.com.

FIGURE 2

Dupilumab as an “umbrella” to treat multiple co-existing diseases. EoE, eosinophilic esophagitis; CRSwNP, chronic rhinitis with nasal polyps. Created with BioRender.com.