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Gastroenterology & Hepatology: Open Access

Research Article Volume 14 Issue 1

The role of biologics in the pathogenesis and treatment of eosinophilic esophagitis

Nightingale Syabbalo

Department of Physiology and Medicine, Nabanji Medical Centre, Zambia

Correspondence: Professor Nightingale Syabbalo, Department of Physiology and Medicine, Nabanji Medical Centre, P. O. Box 30243, Lusaka, Zambia, Tel +260 966 486117

Received: December 20, 2022 | Published: February 16, 2023

Citation: Syabbalo N. The role of biologics in the pathogenesis and treatment of eosinophilic esophagitis. Gastroenterol Hepatol Open Access. 2023;14(1):27-29. DOI: 10.15406/ghoa.2023.14.00539

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Abstract

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disorder characterized by inflammation, and intraepithelial infiltration of eosinophils in the esophageal epithelium. It is associated with unbearable symptoms, such as dysphagia, and bolus impaction which affect the nutritional status, and quality of life of the patients. It is diagnosed from a thorough medical history, and confirmed by endoscopy and esophageal biopsy. Traditionally, it has been treated with elimination diet, proton pump inhibitors, and swallowed topical corticosteroids. However, several of the patients with EoE are refractory to the treatment. Eosinophilic esophagitis like eosinophilic asthma is a T helper type 2 lymphocyte (Th2)-mediated allergic disease. During an allergic inflammation Th2 cells secrete cytokines, such as interleukin-5 (IL-5). IL-4, and IL-13 which play a key role in the pathogenesis of EoE. Th2 cytokines promote eosinophilopoiesis, differentiation, proliferation, maturation and activation of eosinophils. Activated eosinophils liberate several cytotoxic cationic proteins, and reactive oxygen species which cause epithelial injury, inflammation, and remodeling, which later progresses to esophageal fibrosis. Dupilumab (dupixent®)is a monoclonal antibody which target the IL-4 receptor (IL-4Rα) which signals for both IL-4 and IL-13. Dupilumab is the only biologic which is effective, and approved for the treatment of EoE in adults and children 12 years and older. Treatment with dupixent® has been shown to improve dysphagia, dilate and relax the gullet, and allow patients to enjoy their cherished dish. Biologics such as dupilumab should be administered early in patients with EoE in order to prevent the menacing complications of the disease, such as esophageal stricture, and esophageal perforation, which necessitate surgical esophageal dilatation, and repair.

Keywords: eosinophilic esophagitis, endoscopic dilatation, pharmacological therapy, straumann dysphagia instrument, esophageal epithelium, chronic rhinosinusitis

Abbreviations

EoE, eosinophilic esophagitis; CRSwNP, chronic rhinosinusitis and nasal polyps, Th2, T-helper type 2, MBP, major basic protein, ECP, eosinophil cationic protein, EDN, eosinophil-derived neurotoxin

Eosinophilic asthma

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disorder characterized by inflammation, and intraepithelial infiltration of eosinophils in the esophageal epithelium.1,2 Eosinophilic esophagitis is a relative new disorder, which was initially described in the early 1990s.3 The incidence of EoE is about 30-100/100 000 in adult population, and 29-42/100 000 in the children population, and its prevalence is increasing in North America and Europe.4,5 EoE affects both adults and children, with a peak incidence between 30-50 years. It is more common in males than females,6 with a male-to-female ratio of 3:1.7

The symptoms of of EoE are due to esophageal dysfunction and narrowing, and include dysphagia, bolus impaction, gastroesophageal reflux, vomiting, central chest pain, and epigastric pain.

The pathophysiological mechanisms of EoE are similar to those of the diseases of the ”atopic match” which include atopic dermatitis, allergic rhinitis, eosinophilic asthma, and chronic rhinosinusitis and nasal polyps (CRSwNP).8-10 Eosinophilic esophagitis is the fifth and the last member in the atopic match.11 Table 1 show the allergic diseases associated with eosinophilic esophagitis.

Food allergy

Allergic dermatitis (eczema)

Allergic rhinitis

Eosinophilic asthma

Chronic rhinosinusitis with nasal polyps

Aspirin exacerbated respiratory disease

Table 1 Allergic diseases associated with eosinophilic esophagitis

Eosinophilic esophagitis is an allergic disease due to sensitization to food antigens. It is caused by T-helper type 2 cell (Th2), and innate group 2 lymphocyte (ILC2) responses to food antigens in contact with the esophageal epithelium. Activation of Th2 and ILC2 result in Th2 inflammatory response which leads to secretion of Th2 cytokines, such as interleukin-5 (IL-5), IL-4, and IL-13, chemokines, adhesion molecules, and growth factors.12,13. Th2 cytokines are also secreted by haematopoietic, and non-haematopoietic cells, such eosinophils, basophils, mast cells, fibroblasts, and myofibroblasts. The Th2 cytokines lead to eosinophilopoiesis, differentiation, proliferation, maturation, recruitment, and activation of eosinophils in the esophageal mucosa. Additionally, Th2 cytokines prolong eosinophil survival by preventing apoptosis.14 Chemokines, such as RANTES, MCP-3, MCP-4 and eotaxins stimulates eosinophilic migration to the inflamed esophageal mucosa, amplifying the eosinophilic inflammation.

Activated eosinophils degranulate and liberate four cytotoxic cationic proteins, such as major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and eosinophil-derived peroxide (EDPX)15 (Table 2). The cytotoxic cations are very injurious and damaging to the esophageal epithelium which results in intense eosinophilic inflammatory, and remodeling,14 followed by healing and fibrosis.4,16 Fibrosis causes esophageal lumen narrowing, and the esophagus to be less distensible.

Cationic proteins

Major basic protein (MBP)

Eosinophil cationic protein (ECP)

Eosinophil-derived neurotoxin (EDN)

Eosinophil-derived peroxide (EDPX)

Reactive oxygen species (superoxide, peroxide, and hypobromite)

Leukotrienes (LTC4, LTD4, LTE4)

Prostaglandins (PGE2)

Cytokines  (IL-2, IL-3, IL-4, IL-5, IL-9, IL-13, IL-23, IL-25, IL-33, and TNFα)

Chemokines (CXC-, CC-, CX3C, and XC)

Enzymes (elastase)

Growth factors (TGF-β1, VEGF, and PDGF)                                                                                                                                                                                                                                                                                                           

Table 2 Eosinophil-derived inflammatory mediators in eosinophilic esophagitis
Abbreviations: IL, interleukin; LT, leukotriene; PG, prostaglandin; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor, PDGF, platelet-derived growth factor; CXCL, C-X-C motif chemokine ligand

Diagnosis of EoE is from thorough history of esophageal dysfunction, but esophagogastroscopy is required to obtain biopsies from six different locations of the esophageal lining, in order to confirm the diagnosis. Histologic diagnosis of EoE is based on the presence of at least 15 eosinophils per high-power (eos/hpf) field in the absence of other gastrointestinal diseases associated with esophageal eosinophilia, such as achalasia, gastroesophageal reflux disease, and eosinophilic gastritis.6. Other endoscopic changes of EoE demonstrate mucosal oedema, exudates, mucosal rings (tracheolization), linear furrows, and strictures.17.

Treatment of EoE comprises of dietary restriction, proton pump inhibitors, such as omeprazole, lansoprazole, esomeprazole, and pantoprazole,1,18,19 and swallowed topical corticosteroids,20 including viscous budesonide slurry.21,22, fluticasone from a multi-dose inhaler,23,24 and mometasone.25,26 However, this standard of care is not effective in most patients. Severe esophageal is inevitably treated with endoscopic dilatation, in patients with severe dysphagia, bolus impaction, and in those who do not respond to pharmacological therapy.17. Table 3 shows the pharmacological and biological treatment of eosinophilic esophagitis.

Proton pump inhibitors

Omeprazole

Lansoprazole

Esomeprazole

Pantoprazole

Corticosteroids

Budesonide

Fluticasone

Mometasone

Ciclesonide

Biologics

Dupilumab

Table 3 Pharmacological and biologic treatment of eosinophilic esophagitis

Treatment of eosinophilic asthma with biologics targeting IL-5, IL-4, and IL-13, and their receptors is well established, and is very effective. Currently, there has been attempts to repurpose some of these biologics for the treatment of eosinophilic asthma to treat EoE. However, targeting IL-5 with mepolizumab and reslizumab, two anti-IL-5 antibodies that block the biological effects of IL-5 did not reach end points in clinical trials. Both biologics in the studies in children and adults with EoE resulted in reduction in esophageal tissue and blood eosinophils, but no significant reduction in esophageal symptoms.27

In the MESSINA clinical trial which studied 210 patients with histological active EoE, benralizumab an IL-5R blocking monoclonal antibody (mAb) was associated with significant improvement in the histology of EoE. However, treatment with benralizumab did not improve symptoms of EoE, such as dysphagia.28

The duet sister cytokines IL-4 and IL-13 have a 25% homology, and signals through a common IL-4Rα signaling chain, and have similar biological and immunological functions. They play a central role in the pathogenesis of several allergic diseases, such as atopic dermatitis, allergic rhinitis, eosinophilic asthma, and chronic rhinosinusitis with nasal polyps.

Dupilumab (Dupixent®) is a fully humanized IgG4 monoclonal antibody targeting the IL-4Rα, which mediate signalling for both IL-4 and IL-13, thereby inhibiting their biological effects. Clinical trials have shown that treatment subcutaneous dupixent® significantly reduces the           (SDI) patient-reported outcome (PRO) score. It has also been demonstrated to reduce the peak esophageal intraepithelial eosinophil count. Furthermore, treatment with dupilumab has been reported to reduce the EoE-histologic scoring system (HSS) severity score, and the endoscopic reference score. Noteworthy, dupilumab has been shown to increase esophageal distensibility, and ameliorate dysphagia.29 Dupilumab has also been associate with improvement in esophageal symptoms, such as dysphagia when use for the treatment of other allergic diseases.30 Dupixent® was approved by the Food and Drug Administration for the treatment of moderate-to-severe eosinophilic asthma in adults and children 12 years and older on May 20, 2022.

Dupilumab is a master biologic which is approved for the treatment of eczema, eosinophilic asthma, chronic rhinosinusitis with nasal polyps, and EoE. It is very beneficial in the treatment of patients with severe, uncontrolled eosinophilic asthma with the above comorbid diseases because it effective also in treating the associated diseases.

Conclusion

Eosinophilic esophagitis is a chronic immune-mediated disorder characterized by inflammation, and intraepithelial infiltration of eosinophils in the esophageal epithelium. It is associated with debilitating symptoms, such as dysphagia, and bolus impaction which affect the nutrition, and health related quality of the patients. The standard of care of EoE includes dietary restrictions, proton pump inhibitors, and swallowed topical corticosteroids. However, the disease remains refractory to the SoC in some of the patients. Th2 and ILC2 cytokines, such as IL-5, Il-4, and IL-13 play a key role in the pathogenesis of eosinophilic esophagitis. Attempts to block the immunopathological effects of IL-5 in order to treat EoE have not been successful. Dupilumab is a mAb which target the IL-4 receptor (IL-4Rα) which signals for both IL-4 and IL-13, it is the only biologic which is effective and approved for the treatment of EoE. Treatment with dupixent®is associated with improvement in distressing dysphagia, dilate and relax the gullet, and allow patients to swallow their cherished meals. Patient with eosinophilic esophagitis may benefit from early treatment with biologics, such as dupilumab, in order to prevent the menacing complications of the disease, such as esophageal stricture, and esophageal perforation, which necessitate surgical esophageal dilatation, and repair.

Acknowledgments

None.

Conflicts of interest

None.

Funding

The author declares that the publication was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Dellon ES, Hirano I. Epidemiology and natural history of eosinophilic esophagitis. Gastroenterology. 2018;154:319–332.
  2. Reed CC, Dellon ES. Eosinophilic esophagitis.  Med Clin North Am. 2019;103(1):29–42.
  3. Staumann A, Katzka DA. Diagnosis and treatment of eosinophilic esophagitis. Gastroenterology. 2018;154(12):346–359.
  4. Dellon ES. Epidemiology of eosinophilic esophagitis. Clin North Am. 2014;43(2):201–218.
  5. Arias A, Perez–Martinez I, Tenias JM, et al. Systematic review with meta–analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population–based studies. Aliment Pharmacol Ther. 2016;43:3–15.
  6. Muir A, Falk GW. Eosinophilic esophagitis. A review. JAMA. 2021;326(13):1310–1318.
  7. Hruz P. Epidemiology of eosinophilic esophagitis. Dig Dis. 2014;32:40–47.
  8. Hill DA, Spergel JM. Atopic march: critical evidence and clinical relevance. Ann Allergy Asthma Immunol. 2018;120(2):131–137.
  9. Hill DA, Grundmeier RW, Ram G, et al. The epidemiologic characteristics of healthcare provider–diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study. BMC Pediatr. 2016;16:133–016–5540673–z.
  10. Syabbalo N. Anti–interleukin biologics for the treatment of the atopic match diseases. Open J Pulm Respir Med. 2021;3:1–27.
  11. Hill DA, Grundmeier RW, Ramos M, Spergel JM. Eosinophilic esophagitis is a late manifestation of the allergic march. J Allergy Clin Immunol Pract. 2018;6(5):1528–1533.
  12. 12. Barnes PJ. Targeting of cytokines to treat asthma and chronic pulmonary disease. Nat Rev Immunol. 2018;18(7):454–566.
  13. Lambrecht BN, Hammad H, Fahy JV. The cytokines of asthma. Immunity. 2019;50(4):975–991.
  14. Hogan SP, Rosenberg HF, Moqbel R, et al. Eosinophil: biological properties and role in health and disease. Clin Exp Allergy. 2008;38(5):709–750.
  15. 15. Sherrill JD, Rothenberg ME. Genetic and epigenetic underpinnings of eosinophilic esophagitis. Gastroenterol Clin North Am. 2014;43(2):269–280.
  16. Schoepfer AM, Safroneeva E, Bussmann C, Kuchen T, Portmann S, Simon HU, et al. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time–dependent manner. Gastroenterology. 2013;145(3):1230–1236.e1–2.
  17. Lucando AJ, Arias A, Molina–Infante J, Arias–Gonzalez C. The role of endoscopy in eosinophilic esophagitis: from diagnosis to therapy. Expert Rev Gastroenterol Hepatol. 2017;11(12):1135–1149.
  18. Gomez–Torrijos E, Garcia–Rodriguez R, Castro–Jimenez A, et al. The efficacy of step–down therapy in adult patients with proton pump inhibitor–response oesophageal eosinophilia. Aliment Pharmacol Ther. 2016;43(4):534–540.
  19. Gutierrez–Junguera C, Fernandez–Fernandez S, Cilleruelo ML, et al. Long–term treatment with proton pump inhibitors is effective in children with eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2018;67(2):210–216.
  20. Rajan J, Newbury RO, Anilkumar A, et al. Long–term assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids. J Allergy Clin Immunol. 2016;137(1):147.e8–156.e8.
  21. Staumann A, Conus S, Degen L, et al. Long–term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2011;9(5):400.e1–409.e1.
  22. Dellon ES, Collins MH, Katzka DA, et al. Improvements in dysphagia and pain with swallowing in patients with eosinophilic esophagitis receiving budesonide oral suspension. Clin Gastroenterol Hepatol. 2021;47(3):261–270.e4.
  23. Andreae DA, Hanna MG, Magid MS, et al. Swallowed fluticasone propionate is an effective
  24. long–term maintenance therapy for children with eosinophilic esophagitis. Am J Gastroenterol. 2016;111(8):1187–1197.
  25. Dellon ES, Lucendo A, Schlag C, et al. 30345 Safety and efficacy of long–term treatment of EoE with fluticasone orally disintegrating tablets (APT:1011): results from 40 weeks treatment in phase 2b randomized doble–blind placebo–controlled trial. Am J Gastroentero.  2020;115(1):S169–S170.
  26. Tytor J, Larson H, Bove M, et al. Topically applied mometasone furoate improves dysphagia in adult eosinophilic esophagitis – results from a double–blind, randomized, placebo–controlled trial. Scand J Gastroenterol. 2021;56(6):629–663.
  27. de Rooij WE, Dellon ES, Parker CE, et al. Pharmacotherapies for the treatment of eosinophilic esophagitis: State of the art review. Drugs. 2019;79(13):1419–1434.
  28. Straumann A, Conus S, Grzonka P, et al. Anti–interleukin–5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomized, placebo–controlled, double–blind trial. Gut. 2010;59(1):21–30.
  29. https://www.astrazeneca.com/media–centre/press–releases/2022/update–on–messina–phase–iii–trial.html
  30. Dellon ES, Rothenberg ME, Collins MH, et al. Dupilumab in adults and adolescents with eosinophilic esophagitis. N Engl J Med 2022;387(25):2317–2330.
  31. Spergel BL, Ruffner M, Godwin B, et al. Improvement in eosinophilic esophagitis when using dupilumab for other indications or compassionate use. Ann Allergy Asthma Immunol. 2022;128(5):589–593.
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