Steroids vs Dietary Therapy to Treat Eosinophilic Esophagitis

 

Abstract and Introduction

Abstract

Purpose of Review. Eosinophilic esophagitis (EoE) is a condition characterized by dense mucosal eosinophilia
in conjunction with symptoms of esophageal dysfunction. Since both the
incidence and prevalence of EoE are on the rise in both children and
adults, understanding the various treatment options available is
imperative in choosing the proper treatment for each patient. This
article will highlight the major strides in both medical and dietary
treatment of EoE in the past year.



Recent Findings. Whereas prior
studies have shown that medical therapy with topical corticosteroids is
effective in treating EoE, this more recent literature highlights some
of the limitations of this approach, raising awareness that development
of better drug delivery models is greatly needed. The review also
describes the recent advances in the field of dietary therapy for this
disease, particularly in adults, and further supports the notion that
the pathophysiology of this disease in children and adults is similar,
with food antigens driving this disease.



Summary. Both medical and dietary
therapy are effective for treating adults and children with EoE.
Choosing the optimal treatment approach should be individualized based
both on patient goals and on available local resources. Future
prospective clinical trials comparing these two treatment modalities are
needed to help understand comparable effectiveness as well as to help
understand potential predictors of response to treatment and identify
optimal therapeutic endpoints.

Introduction

Recent consensus guidelines define
eosinophilic esophagitis (EoE) as a chronic, immune/antigen-mediated
esophageal disease characterized clinically by symptoms related to
esophageal dysfunction and histologically by eosinophil-predominant
inflammation.^[1] The most common symptoms of adults with this condition include dysphagia and food impaction.^[1,2]
Involvement of allergic mechanisms in the pathogenesis of EoE has been
supported by prior studies demonstrating esophageal tissue expression of
allergic mediators such as IgE, eotaxin-3, IL-13, IL-5 and esophageal
involvement by immune cells, including mast cells, dendritic cells and
eosinophils.^[3] Furthermore, esophageal eosinophilia is induced in a murine model following allergen exposure.^[4]
Given the immunological reactivity of the disease, treatment with
anti-inflammatory medications such as oral corticosteroids and swallowed
topical corticosteroids has been shown to be efficacious in both
children and adults.^[5–8]



The concept of food allergens as the main antigenic trigger in EoE
was introduced in a landmark study by Kelly and Sampson in pediatric
patients with symptoms of gastroesophageal reflux disease (GERD) and
histologic features of esophageal eosinophilia, both of which were
unresponsive to acid suppression or fundoplication. After treatment with
an elemental or amino acid based formula, both symptoms and histologic
eosinophilia resolved.^[9,10]
Since this landmark study, numerous series have replicated this
association of food allergens as a trigger in EoE in both the adult and
the pediatric population.^{[2,5,11–13]}
Common food triggers found to cause EoE in both children and adults
include milk, wheat, soy, egg, nuts/peanuts, and fish/shellfish.^[11,12]



The feasible goals of treatment in EoE are still evolving, but
typically include resolution of clinical symptoms, and the achievement
and maintenance of histologic remission. Other important goals include
prevention of complications of the disease (including fibrostenotic
changes such as strictures), avoidance of food bolus impaction and
avoidance of esophageal perforation, which can occur either
spontaneously (from retching during a food impaction) or iatrogenically
(from stricture dilation). Other important therapeutic endpoints include
improvement in the patient's quality of life, improvement of
nutritional deficits in those treated with dietary restrictions, and
prevention of harmful side effects of medications used to treat the
disease. This study highlights the recent strides in both dietary and
medical therapy over the past year.

Comparison of Different Formulations of Topical Corticosteroids

As mentioned, few studies have tried to
identify differences in the effectiveness of EoE medications based on
changes in their formulation or methods of drug delivery. Dellon et al.^[15] performed a randomized trial comparing nebulized and viscous topical steroid preparations in a cohort of adult patients.
Patients received budesonide 1 mg twice daily, either in an aerosolized
form swallowed from a nebulizer or as an oral viscous slurry, for a
total of 8 weeks. Study endpoints included dysphagia improvement based
on MDQ score, reduction in eosinophil counts, and mucosal medication
contact time, which was measured by nuclear scintigraphy with tagged
radiocontrast. The authors found that histologic improvement was
significantly higher in the oral viscous budesonide group (64%) than in
the swallowed nebulizer solution group (27%), although both groups had
comparable improvement in their dysphagia scores. Nuclear scintigraphy
showed that mucosal contact time was much higher in patients treated
with the oral viscous budesonide than the nebulizer solution. This study
showed that the frequency of histologic improvement may be directly
related to mucosal contact time, and has highlighted the importance of
appropriate drug delivery methods in treatment of this disease. It also
shows that complete histologic resolution was achieved in only 64% of
the oral viscous budesonide group, which is a lower percentage than has
been found in prior studies.

Topical Corticosteroids Versus Acid Suppression

In the past year, several studies have
confirmed the effectiveness of medical therapy for EoE, but also have
highlighted some limitations of the current treatment approach. Moawad et al.^[14] recently performed a randomized controlled trial of swallowed fluticasone versus esomeprazole for the treatment of esophageal eosinophilia.
In this study, 42 patients suspected of having EoE (defined by clinical
symptoms of esophageal dysfunction and >15 eos/hpf) underwent
esophageal pH testing with 24 h pH/impedance monitoring. Patients were
then stratified by the presence of GERD and randomized to receive either
fluticasone 440 μg twice daily or esomeprazole 40 mg once daily for 8
weeks. Repeat endoscopy was performed, and the primary outcome was a
histologic response of less than 7 eos/hpf. Secondary outcomes included
clinical change in symptoms using the Mayo Dysphagia Questionnaire (MDQ)
score and interval change in endoscopic features. The investigators
showed that there was no difference in the frequency of resolution of
esophageal eosinophilia between the fluticasone and esomeprazole groups
(19 versus 33%; P = 0.484). They also found that patients with
established GERD (based on pH testing) were much more likely to respond
to proton pump inhibitor (PPI) than fluticasone. Interestingly, they
also found that symptoms improved with PPI treatment, but not with
fluticasone. They concluded that the histologic response with both
treatment options was similar and significantly less than expected
(based on prior studies). This study raises concern about the limited
efficacy of some formulations of swallowed aerosolized topical
corticosteroids, and highlights the importance of using acid suppression
as part of the initial diagnostic and therapeutic strategy for patients
with esophageal symptoms and eosinophilia.

Medical Therapy in Eosinophilic Esophagitis

While prior studies have shown the efficacy
of both systemic and topical corticosteroids in the treatment of EoE,
currently there is no medication specifically approved by the US Food
and Drug Administration (US FDA) for the disease. There have also been
few studies comparing the effectiveness of different types of
pharmacologic therapies. The two most common steroid medications used
for treatment of EoE have been fluticasone and budesonide. Fluticasone
is typically delivered via a metered-dose inhaler whereby the medication
is puffed into the mouth and then swallowed. Starting doses in
published studies have ranged from 440 to 880 μg b.i.d. Budesonide has
been used in the form of oral viscous budesonide, which is a suspension
of the drug in a sucralose binder. Patients are typically counseled on
mixing this medication with multiple packets of sucralose to make a
viscous solution that is swallowed twice daily. A typical starting dose
in adults is 1 mg twice daily.

Placebo-controlled Trials of Swallowed Topical Corticosteroids

Other adult studies also have shown limitations with the use of swallowed topical corticosteroids. For example, Alexander et al.^[16]
performed a double-blind, randomized, placebo-controlled trial of
fluticasone in 42 adult patients with EoE. Patients in the treatment arm
swallowed 880 μg of aerosolized fluticasone (four puffs) twice daily
for 6 weeks. Their therapeutic endpoints were symptomatic (based on the
MDQ-30) and histologic response (based on a criteria of >90% decrease
in mean eosinophil count). They reported complete histologic response
in 11/15 (62%) patients receiving 6 weeks of fluticasone compared with
none of the 15 patients receiving placebo (P < 0.001, based
on intention-to-treat analysis). Dysphagia was reduced in only 57% of
patients receiving fluticasone compared with 33% receiving placebo
therapy (P = 0.22 by intention-to-treat analysis), and esophageal candidiasis
was found in 26% of patients treated with fluticasone. These results
highlight the fact that topical corticosteroids result in less
histologic response than suggested by earlier studies, and have higher
rates of important side effects, including candidiasis, than previously
reported. As in the prior study, the decreased histologic response is
likely due to problems in drug delivery with attempting to swallow an
aerosolized medication, as well as insufficient mucosal contact time.


These recent pharmacologic studies in EoE demonstrate that medical
therapy can result in histologic remission in some patients, but the
limitations shown by the above studies highlight the important unmet
need to identify better medications for the treatment of EoE.

Dietary Therapy in Eosinophilic Esophagitis

Dietary therapy has long been accepted as
first-line therapy in children with EoE, and recently has been shown to
be effective in adults as well. Three approaches to dietary elimination
in EoE patients have evolved. The first is total elimination of all food
allergens by placing patients on an elemental or amino acid-based
formula as their primary nutrition. Patients are usually placed on this
diet for at least 6 weeks. Another approach to dietary therapy has been
allergy-directed diets using the information gained from allergy testing
(e.g. skin prick) to help guide the foods that are to be restricted.
While this approach has been shown to be helpful in some pediatric
cohorts,^[11]
it had limited utility in adult populations due to the lack of
correlation between foods identified by allergy testing and food
triggers in individual patients.^[1,2,13,17]
The last approach of empiric dietary elimination (e.g. six-food
elimination diet) has been shown to be equally effective in children and
adults.^[2,12]

Goals of Diet Therapy

Knowing that dietary therapy is effective in
adults provides the rationale for offering this treatment approach as an
alternative to swallowed topical corticosteroids. It is important to
emphasize that the goals of the dietary therapy are not to stay on a
restrictive diet indefinitely, but, rather, to undergo a process of food
trigger identification to help tailor the diet for long-term
maintenance therapy. Dietary elimination with serial food reintroduction
enables the identification of the actual food triggers of the disease.
This treatment plan should be individualized based on individual
patients and their goals.

Effectiveness of Empiric Elimination Diets in Adults

While dietary therapy has been well
established as an effective first-line therapy in pediatrics for EoE,
this approach has not been extensively studied in adults. Recently,
empiric dietary elimination has been shown to have comparable
effectiveness in adults. Gonsalves et al. prospectively studied
the efficacy of the six-food elimination diet (SFED) in 50 adults (25
M/25 F) with EoE. Seventy percent of patients had histologic response of
less than 10 eos/hpf, 94% had symptomatic improvement and 74% had
endoscopic improvement after completing the diet for 6 weeks. Serial
food reintroduction was undertaken in patients who responded to the
diet. When food triggers were identified, symptoms typically recurred
within 5 days and esophageal eosinophil counts returned to pretreatment
values (P < 0.0001) on follow-up endoscopy. Common food
allergens identified during this process were wheat (60%), milk (50%),
soy (10%), nuts (10%) and egg (5%). The majority of patients had only
one food trigger. Skin prick testing for food allergens was undertaken
prior to the elimination diet, but was predictive of food triggers in
only 13% of cases.


Subsequent to the publication of this study, Lucendo et al.^[13]
from Spain demonstrated similar results in 67 adults with EoE after
empiric elimination of wheat, rice, corn, legumes, peanuts, soy, egg,
milk, fish and shellfish for a similar duration. This approach resulted
in histologic improvement of less than 15 eos/hpf in 73% of the
patients, but required additional foods to be removed.^[11]
Food reintroduction in this study identified the common triggers as
milk (61%), wheat (28%), eggs (26%) and legumes (23%). Unlike the prior
study, the majority of patients in this study were found to have
multiple food antigens as their triggers. A single offending food
antigen was identified in only 36%, two food triggers were found in 31%,
and three or more triggers were found in 33% of patients. Results of
allergy testing in this cohort were also not predictive of their food
triggers. The investigators also found that continued elimination of the
food triggers was effective in maintaining remission.


Noting that milk was one of the most common food triggers in their pediatric cohort, Kagalwalla et al.^[18]
investigated the utility of a single food elimination diet in their EoE
patients. In this retrospective study conducted between 2006 and 2011,
17 patients who had empirically eliminated cow's milk protein from the
diet and had a follow-up endoscopy were included. Sixty-five per cent of
these patients achieved remission as defined by less than 15 eos/hpf
after therapy.^[18]
Although this study has encouraging results, further prospective
studies will be needed in both pediatrics and adults to assess the
generalizability of the approach of single food elimination.

Effectiveness of Allergy-directed Diets in Adults

One of the first studies to attempt a form of
allergy-directed diet in adults was pursued in a small number of adult
patients in Switzerland by Simon et al.^[19]
In this study, based on results of IgE testing to certain foods, few
foods were eliminated from the diet. Despite elimination of these foods,
patients did not respond symptomatically. The one patient who completed
endoscopic evaluation after dietary therapy also did not show a
histologic response. A more recent study undertaken by Molina-Infante et al.^[20]
studied the outcome of an allergy-directed diet using a multimodal
approach including skin prick testing, prick-prick testing and atopy
patch testing to identify allergens in their adult EoE cohort of 22
patients. Disappointingly, they found only a 26% improvement with this
approach. Likewise, allergy testing was not found to be predictive of
food triggers in either the Gonsalves or the Lucendo study. Taken
together, these studies suggest that current allergic testing methods
are not reliable for identifying food triggers in adults with EoE and
should not be used to guide dietary intervention.

Effectiveness of Elemental Diets in Adults

A recent study by Peterson et al.^[21]
evaluated the effectiveness of an elemental diet in a small group of
adults. They found that 50% of adults responded histologically to the
diet with eosinophil counts less than 5 eos/hpf, and 72% had less than
10 eos/hpf, with eosinophil levels on average dropping from 54 to 10
after the diet. Interestingly, patients did not demonstrate symptomatic
improvement, but that may be due to limitations in the dysphagia
assessment tool used in this study. The authors also suspected that the
limited efficacy of elemental diet in this study compared with pediatric
studies might have resulted from poor adherence to the diet in their
adult patient population.

Potential Development of Tolerance After Dietary Therapy

Once a food trigger is identified in EoE, the
mainstay of therapy is continued avoidance of that particular food.
There have not been systematic studies evaluating recurrent food
challenges and the possible development of tolerance over time. One of
the first studies to address this issue was by Leung et al.,^[22]
who performed a retrospective review of their pediatric EoE patients
who were known to have milk as their food trigger. They identified 15
patients who had subsequently reintroduced baked milk back into their
diets for at least 6 weeks, and 11 of them (73%) had maintained
histologic remission despite the reintroduction of baked milk products.
The study did not mention the precise time when reintroduction of baked
milk products occurred in these patients. Despite this limitation, this
study suggests that, over time, some patients with cow's milk-induced
EoE may be able to tolerate milk reintroduction in the form of baked
milk, which would allow a considerable broadening of the diet.


Another study exploring this concept was performed by Lucendo et al.^[23] in adults. This group evaluated the use of a cow's milk-based hydrolyzed formula in patients with cow's milk-induced EoE.^[23]
Seventeen adult patients with cow's milk-induced EoE were administered
this formula over a period of 8 weeks, and repeat endoscopy was
performed. At that time, 88% of patients maintained histologic remission
as defined by less than 15 eos/hpf. This study suggests that some
patients with EoE triggered by a cow's milk protein may tolerate
reintroduction of milk in this reduced antigenic state. While these
formulas are not readily available, this study does provide insight into
the pathophysiologic mechanisms of food allergy that trigger EoE, and
suggests that some patients are tolerant to less antigenic preparations
of their food triggers.

Potential Advantages of Medical Therapy in Adults

Medical therapy has been shown to effectively
induce both symptomatic and histologic remission in some patients with
EoE. Advantages of this approach include the ease of administration of
the medications as well as the limited impact of this treatment approach
on lifestyle. This treatment plan allows patients to eat normally, and
does not mandate dietary restrictions. While an endoscopy after
treatment institution often is performed to ensure that the medication
is working, the medical treatment approach does not require multiple
additional endoscopies, as are often performed in dietary therapy.
Medical therapy does, however, require chronic daily use of medications
with potential side effects.

Potential Advantages of Dietary Therapy

Dietary therapy in adults with EoE has a
number of practical advantages. As prior studies have shown,
discontinuation of swallowed topical corticosteroids in the treatment of
EoE can cause symptomatic and histologic recurrence which may
necessitate chronic daily therapy. Avoidance of food allergens
eliminates the need for chronic medication/corticosteroids to help
control the disease. Oral and esophageal candidiasis
may occur in 5–30% of patients treated with steroids. Other rare side
effects of topical corticosteroids include growth failure in children,
cataracts and adrenal suppression. Unfortunately, these medications have
not been US FDA-approved to be swallowed, which raises concern about
their long-term safety. In addition, long-term use of these medications
may result in a considerable cost to patients with this chronic
condition.


The effectiveness of elimination diet in adults supports the
conceptual definition that EoE is an antigen or immune-mediated
esophageal disease. Therefore, dietary therapy has the advantage of
getting to the root cause of the disease (i.e. food allergen avoidance)
rather than symptom and histologic control with topical corticosteroids.
Current consensus guidelines suggest continued avoidance of food
allergens in patients who are managed with diet therapy,^{[1,2,5,11,12]}
and a targeted, individualized approach to nutrition therapy is
essential to success. Recent studies have suggested that food
reintroduction with altered forms of the food trigger may induce
tolerance and allow more food products to be added. While repeated
endoscopies often are recommended during the food reintroduction
process, recent studies have suggested that other noninvasive testing
methods may become available soon.^[24]

Medical Versus Dietary Therapy: Which to Choose?

When discussing options for therapy with
patients, it is important to review the pros and cons of each treatment
plan and try to identify goals of treatment. It is important to
underscore that the goals of dietary therapy are not to stay on the
elemental diet or SFED indefinitely, but, rather, to undergo a process
of food trigger identification to help tailor the diet for long-term
maintenance therapy. The goals of medical therapy are to help control
symptoms and histology with minimal disruption to daily routine, but
will likely require maintenance therapy to achieve these goals. The
choice on proceeding with medical or dietary therapy should be
individualized based on patient preference as well as available local
resources.

Conclusion

Medical and dietary therapy both are
effective treatments for patients with EoE. While previous studies have
demonstrated the effectiveness of topical corticosteroids, research over
this past year has highlighted limitations of this approach. These
studies have underscored the unmet need for additional therapeutic
options with better drug delivery systems that are specific for EoE.
They have also highlighted the need to better define therapeutic
endpoints (i.e. symptomatic, histologic, or endoscopic response or a
combination of all three). Research is underway to help answer these
basic questions and to develop an important disease activity index
specifically for EoE. Over the past year, several studies have also
highlighted the effectiveness of dietary therapy in adults with EoE, and
have demonstrated that this treatment approach should be considered as
first-line therapy in adults, as it is in children. Knowing that both
medical and dietary therapy is effective provides options for patients,
and highlights the need to individualize treatment plans based on
patient preferences.