Sustained milk consumption after 2 years post-Milk Epicutaneous therapy
for Eosinophilic Esophagitis
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,
PhD1,2
1Division 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, USA
Author 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 items
To 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.3
Epicutaneous 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%.5
As 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,
PhD1,2
1Division 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, USA
Funding Sources: The Children’s Hospital of Philadelphia Eosinophilic
Esophagitis Family Fund
Acknowledgements: JMS, CAL, TBW and MOL are consultants for DBV
Technology.
Correspondence: Jonathan M. Spergel MD, PhD
The Children’s Hospital of Philadelphia
Division of Allergy and Immunology
Wood Bldg 3352D
3401 Civic Center Blvd,
Philadelphia, PA 19104
Email: spergel@email.chop.edu
Phone: 1-215-590-2549
Table 1