# Shedding Light on FIRE Syndrome: An Overview of a Novel Condition in Eosinophilic Esophagitis
## 7 Potential Management Strategies and Challenges
### Biologic Therapies  
7.3.1. Anti-IL-4/IL-13 Therapy: Dupilumab  
Targeting type 2 cytokine signaling pathways may be beneficial in FIRE syndrome, particularly where there is overlap with EoE and other allergic disorders where mast cells may play a central role [87]. Dupilumab, a fully human monoclonal antibody directed against the subunit alpha of the shared IL-4/IL-13 receptor, is approved for several allergic conditions, including moderate-to-severe atopic dermatitis, chronic rhinosinusitis with nasal polyposis, asthma, and eosinophilic esophagitis [88]. It showed significant benefit in alleviating symptoms and improving both histopathologic and endoscopic aspects of EoE [89]. By looking into its capacity to suppress inflammatory responses initiated by IL-13 and IL-4, including the production of proinflammatory cytokines, chemokines, and IgE, Dupilumab could prove to be a useful instrument in FIRE syndrome management [90]. In addition, by downregulating inflammatory genes, Dupilumab can reduce the probability of mast cell activation, reinforcing its potential use in this syndrome [91]. 7.3.2. Anti-IgE Therapy: Omalizumab  
Additionally, considering the probable role of IgE in inducing an immediate hypersensitivity reaction in FIRE syndrome, a potential approach could involve the use of anti-IgE therapy. Omalizumab, a humanized monoclonal antibody that binds to the C\(\epsilon\)3 domain of circulating IgE, inhibits its ability to bind to FcRI, thus reducing serum IgE levels and downregulating FcRI on mast cells and basophilis [92; 93]. It is approved for the treatment of multiple atopic conditions including asthma in patients 6 years and older, urticaria from the age of 12, and chronic rhinosinusitis with nasal polyposis in adult patients [88]. Notably, in food allergy, Omalizumab showed significant benefit, used in monotherapy as adjuvant to oral immunotherapy (OIT) [94; 95]. It increased reaction thresholds for various foods such as milk, eggs, wheat, and peanuts, reducing food-induced reactions while also improving the quality of life [94; 95]. The promising results of the OUtMATCH study, which investigated the safety and effectiveness of Omalizumab as monotherapy in patients with multiple food allergies, led to the FDA approval, dated February 2024, for the use of Omalizumab for IgE-mediated food allergy in adults and children 1 year or older [96; 97]. In contrast with its success in food allergy, Omalizumab did not demonstrate therapeutic benefit in eosinophilic esophagitis, a disease with a complex pathophysiology [98]. Its application in FIRE syndrome remains theoretical. However, if FIRE syndrome can be considered a distinct phenotype in EoE, with its potential IgE-driven mechanism, future studies evaluating the use of Omalizumab could yield significant benefit for patients. 7.4. Allergen Immunotherapy  
Considering the potential role of IgE-mediated mechanisms in FIRE syndrome and its frequent coexistence with PFAS and atopic disease, allergen immunotherapy (AIT) may represent an interesting therapeutic direction. AIT may have a role in reducing symptoms by raising the reaction threshold while also reducing esophageal inflammation associated with EoE, in cases where PFAS and FIRE syndrome overlap. While EoE appears as a complication of OIT in approximately 5% of cases, epicutaneous immunotherapy (EPIT) has the potential to reduce eosinophil esophageal inflammation [28]. A study involving pediatric patients with EoE induced by milk examined the impact of EPIT on reducing eosinophil infiltration [99]. The study revealed a 47% remission rate, with sustained response at 2-year follow-up, showing that EPIT could be an effective treatment in some patients with EoE [99; 100]. Additionally, another study on peanut-sensitized mice demonstrated that EPIT prevented esophageal eosinophilic infiltration and consequently influenced esophageal inflammation [101].