Sustained milk consumption after 2 years post-Milk Epicutaneous therapy for Eosinophilic EsophagitisJonathan M. Spergel, MD, PhD1,2; Amanda B. Muir, MD2,3; Chris A. Liacouras, MD2,3;Deirdre Burke1, CRA; Megan O. Lewis, MSN, RN, CPNP1; Terri Brown-Whitehorn, MD1,2, Antonella Cianferoni, MD, PhD1,21Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, PA, USA, 2Department of Pediatrics, The Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA, 3Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, PA, USAAuthor contribution:JMS-study design, writing manuscript, interpreting data; ABM-writing manuscript, study visits, data interpretation; CAL-writing manuscript, study design, interpreting data; DB-writing manuscript, regulatory coordinator, coordination and collection of data, study visits; MOL-writing manuscript, collection of data, study visits; TBW-writing manuscript, collection of data and study visits, AC-interpreting data, collection of data, study visits, regulatory itemsTo the Editor:Eosinophilic Esophagitis (EoE) is an allergic disease of the esophagus without any curative therapy. Typical symptoms of EoE are feeding difficulties, vomiting, abdominal pain and dysphagia and vary by age, with a diagnosis confirmed on esophageal biopsy with> 15 eosinophils/high power field (eos/hpf).1 The two treatment options for pediatric EoE2 are: 1) topical swallowed steroids, which is effective in inducing EoE remission in 50-90% of patients, depending on the dose, formulation and medication used; 2) dietary elimination of the causative allergen/s which is effective in 50-70% of patients with selective food elimination, and 95% with elemental diets3. Cow’s milk (CM) is the most common food allergen causing disease in up to 65% of patients.4 When either treatment is discontinued, inflammation and symptoms recur.3Epicutaneous immunotherapy (EPIT) is an investigational immunotherapy using low dose allergen exposure through the skin to induce desensitization. In the randomized controlled clinical trial,Study of Efficacy and Safety of Viaskin® Milk for CM-induced EoE (SMILEE Study) , 20 pediatric participants with CM-induced EoE were randomized to receive EPIT with Viaskin® Milk (n=15) or placebo (n=5)(details in appendix). After CM-induced EoE was confirmed, EPIT therapy was applied daily for 9 months during a CM-free period, followed by CM-containing diet for 2 months (Figure 1). At 11 months, subjects completed an upper endoscopy with biopsy to evaluate tissue eosinophilia as the primary endpoint. In the pre-defined per-protocol population (7 patients-Viaskin® Milk, 2 patients- placebo), Viaskin® Milk treated subjects had a lower number of eosinophils/high power field (eos/hpf) on biopsy (25.57 ± 31.19) compared to placebo (95 ± 63.64). After the blinded phase, 19 subjects were eligible to enroll in the open-label extension (additional 11 months of therapy) and had repeat endoscopy and biopsy. At the end of the open-label phase, 6/19 subjects had < 6 eos/hpf (32% response rate); 3/19 subjects had 7-14 eos/hpf for total response rate of 47%.5As part of routine clinical care, we continue to follow all 19 subjects who completed the open-label extension (currently 2 years after the end of Viaskin® Milk therapy) to understand whether CM continued in their diet without symptoms. Four of 5 subjects who had <6 eos/hpf after milk introduction were able to continue with approximately 2 servings of CM/day without any symptoms (Table 1). One of these patients had a clinically indicated endoscopy and biopsy that had 0 eosinophils. Two subjects, who had 6-14 eos/hpf during the study, continued to tolerate CM, including one subject who continued to have 6-14 eos/hpf on repeat endoscopy. In addition, 4 subjects who had significant symptoms ingesting CM and had > 15 eos/hpf during the initial SMILEE study were able to add CM back into their diet without having symptoms, as either baked CM (n=2) or regular CM with concomitant swallowed steroids therapy (n=2).The follow-up of this pilot study for the use of EPIT for milk-induced EoE suggests that the treatment effect can persist for 2 years after stopping therapy; six out of 7 patients in the responder and partial responder groups remain completely symptom-free while consuming an average of 2 servings/day of CM. In contrast to the current therapies of diet elimination or swallowed topical steroids where symptoms return when therapy is stopped, EPIT has demonstrated a persistent effectiveness. These findings align with EPIT’s proposed mechanism of action, by directly targeting and reprogramming the immune response to allergen.3 EPIT may induce true tolerance, as is observed in murine models, where Foxp3(+) CD25(+) CD4(+) T regulatory cells are induced and can transfer tolerance.6 Further longer-term studies are needed to examine this possibility and confirm these unique findings.Reference:1. Spergel JM, Dellon ES, Liacouras CA, et al. Summary of the updated international consensus diagnostic criteria for eosinophilic esophagitis: AGREE conference. Ann Allergy Asthma Immunol.2018;121:281-284.2. Spergel JM, Brown-Whitehorn TA, Muir A, Liacouras CA. Medical algorithm: Diagnosis and treatment of eosinophilic esophagitis in children. Allergy. 2020;75:1522-1524.3. Nhu QM, Aceves SS. Medical and dietary management of eosinophilic esophagitis. Ann Allergy Asthma Immunol.2018;121:156-161.4. Kagalwalla AF, Amsden K, Shah A, et al. Cow’s milk elimination: a novel dietary approach to treat eosinophilic esophagitis.J Pediatr Gastroenterol Nutr. 2012;55:711-716.5. Spergel JM, Elci OU, Muir AB, et al. Efficacy of Epicutaneous Immunotherapy in Children With Milk-Induced Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2020;18:328-336 e327.6. Dioszeghy V, Mondoulet L, Dhelft V, et al. The regulatory T cells induction by epicutaneous immunotherapy is sustained and mediates long-term protection from eosinophilic disorders in peanut-sensitized mice. Clin Exp Allergy. 2014;44:867-881.Sincerely,Jonathan M. Spergel, MD, PhD1,2; Amanda B. Muir, MD2,3; Chris A. Liacouras, MD2,3;Deirdre Burke1, CRA; Megan O. Lewis, MSN, RN, CPNP1; Terri Brown-Whitehorn, MD1,2, Antonella Cianferoni, MD, PhD1,21Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, PA, USA, 2Department of Pediatrics, The Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA, 3Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, PA, USAFunding Sources: The Children’s Hospital of Philadelphia Eosinophilic Esophagitis Family FundAcknowledgements: JMS, CAL, TBW and MOL are consultants for DBV Technology.Correspondence: Jonathan M. Spergel MD, PhDThe Children’s Hospital of PhiladelphiaDivision of Allergy and ImmunologyWood Bldg 3352D3401 Civic Center Blvd,Philadelphia, PA 19104Email: [email protected]: 1-215-590-2549Table 1