Eosinophilic esophagitis. Beyond the diet.

Mechanism of action

The mechanisms by which PPIs work to reduce eosinophilia in EoE have been the subject of considerable debate and research effort[1],[4]. Proposed mechanisms include PPI-induced gastric acid suppression leading to a restoration of esophageal barrier function and, on the other hand, a direct anti-inflammatory effect, inhibiting the production of proinflammatory cytokines such as interleukin 4 (IL-4), interleukin 5 (IL-5), and most prominently IL-13[5].

IL-13 plays a crucial role in the pathogenesis of EoE, since it promotes the expression of eotaxin-3, a chemokine responsible for the recruitment of eosinophils to the esophageal mucosa. This anti-inflammatory action is achieved by acting at 4 levels[6]: blocking the expression of cell surface adhesion molecules, inhibiting the migration of inflammatory cells to the esophageal epithelium; blocking STAT6-mediated eotaxin-3 (transcription factor) expression, reducing eosinophil recruitment to the esophageal epithelium; stimulation of the aryl hydrocarbon receptor, normalizing the expression of genes involved in barrier function, including filaggrin, loricrin and involucrin, through inhibition of the IL-4/IL-13-STAT6 pathway; and inhibition of ATP12A, non-gastric H-type P2, K-ATPase activity. IL-4-mediated induction of eotaxin-3 secretion is sensitive to ATP12A inhibition.

What dose of PPIs do we use to induce remission?

According to clinical guidelines, standard PPI therapy for EoE would be the standard twice-daily dose of either PPI[7]; however, there are limited data directly comparing PPI dose combinations for the treatment of EoE.

In a recent study involving a total of 305 patients with EoE, various doses of PPIs were evaluated for at least 8 weeks[8]. They found that the twice-daily prescribed PPI dose induced higher histologic response rates compared with the once-daily PPI dose, even when the total daily dose was equivalent. Histological response rates were higher with the twice-daily dosing regimen (moderate 52.8 % / high 54.3 %) compared to once-daily (standard 11.8 % / moderate 10 %) (P < 0.0001). In addition, double-dose treatment (40 mg omeprazole twice daily) did not appear to provide additional benefit over the moderate twice-daily dose (20 mg twice daily).

Therefore, based on the results of this study, the standard twice-daily PPI dose (20 mg omeprazole twice daily or equivalent) may be the optimal PPI regimen for inducing remission in EoE

How long should one treat with PPIs to induce remission?

According to the recommendation of clinical practice guidelines, PPI treatment should be maintained for a minimum of 8 weeks before endoscopic evaluation[7]. However, a more recent study compiling data on the efficacy of PPIs from the multicenter EoE CONNECT database examines whether the duration of PPI treatment influences the effectiveness in achieving clinical-histologic remission of EoE[3]. The results they obtained show that PPI treatment duration of 8 to 10 weeks (56-70 days) provides a remission rate of 50.4 %; by prolonging treatment between 71 and 90 days (10 to 12 weeks), the remission rate increases to 65.2 %; however, treatment beyond the third month (>90 days) decreases effectiveness to 44.1 %, possibly due to lower patient adherence. Therefore, according to the results obtained in this study, we could consider that treatment duration of up to 12 weeks correlates with a higher probability of inducing EoE remission compared to treatments shorter than 10 weeks.

History and evolution of dietary treatment of EoE

The first study employing dietary treatment in patients with EoE was published in 1995 by Kelly [10]. In this study, 10 children were treated with an elemental diet, achieving complete histologic remission in 8 of them and clinico-histologic improvement in the remaining 2. These findings demonstrated that EoE is caused by a food allergy.

Eleven years later, in 2006, the first study on the empirical six-food elimination diet was published, showing somewhat lower response rates than the elemental diet, but reaching 74%[11].Since then, numerous studies have confirmed the effectiveness of this dietary strategy in the treatment of EoE.

The six-food elimination diet is the most studied and has demonstrated the highest response rates[12]. However, it is a highly restrictive diet that requires a prolonged diagnostic period (at least 42 weeks) and the performance of up to seven gastroscopies. Therefore, less restrictive alternatives have been developed, such as four-food, two-food, and single-food elimination diets (Table 1).

In 2018, Molina-Infante proposed the Step-Up strategy for diagnosis and treatment by empiric diet in patients with EoE. This strategy starts with a two-food elimination diet and, in case of no response, is progressively increased to four and six foods[13].

Protocol for the dietary management of EoE[12]

Once treatment is initiated with the elimination diet agreed with the patient, a gastroscopy with biopsies will be performed at 6-8 weeks. In case of lack of response (no histological remission), a more restrictive diet or a change to pharmacological treatment will be considered. Otherwise, food will be reintroduced, starting from the least allergenic (fish and seafood) to the most allergenic (milk of animal origin). After the reintroduction of the first food, a new gastroscopy will be performed after 4-6 weeks. If histological remission persists, the next food will be added, with endoscopic control at 4-6 weeks. In case of recurrence of the eosinophilic infiltrate after the introduction of a food, it will be identified as a trigger and definitively withdrawn. After a washout period of 4-6 weeks, another food will be introduced. This cycle will be repeated until all foods initially eliminated have been evaluated. Definitive treatment will consist of permanent exclusion of the food(s) identified as triggering the disease.

Food elimination diets based on allergy tests

Food elimination diets based on allergy tests (such as skin prick test, patch test or serum Ig test) have shown lower efficacy compared to empirical diets, as evidenced by three meta-analyses[14]-[16]. Currently, these tests are not recommended, as mentioned in the latest published guideline on EoE[17]. This is because these tests detect IgE-mediated allergies, whereas EoE is a lymphocyte-mediated type 2 immunity disorder characterized by delayed hypersensitivity, in which IgE does not play a relevant role. In those patients with suspected IgE-mediated food allergy, as well as before the reintroduction of food after a long period of dietary restriction, an evaluation by Allergology will be necessary, especially in children, because cases of severe immediate reactions, such as anaphylaxis, have been documented.

Effectiveness of topical corticosteroids in EoE

Topical corticosteroids, such as budesonide and fluticasone, have been shown to be highly effective in the treatment of EoE through numerous prospective, retrospective studies and up to 13 randomized, double-blind, placebo-controlled clinical trials in adults and children[18]-[23]. Its mechanism of action is based on the reduction of esophageal inflammation mediated by eosinophils and other inflammatory mediators through inhibition of proinflammatory cytokines, reduction of the production of key interleukins in Th2 inflammation (IL-4, IL-5 and IL-13), which promote eosinophil activation and survival; modulation of transcription factors that inhibit nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1), responsible for the transcription of proinflammatory genes; reduction of eosinophilic chemotaxis (they decrease the expression of eotaxin-3, a chemokine essential for the recruitment of eosinophils to esophageal tissue); induction of eosinophil apoptosis; inhibition of Th2 differentiation; and enhancement of the epithelial barrier, promoting tissue repair, which contributes to reducing chronic damage and progression to fibrostenosis. These molecular and histological actions are essential to control chronic inflammation and prevent complications arising from fibrosis in disease progression[24].

Different formulations have been used for the treatment of EoE with topical corticosteroids (Table 2), initially with devices designed for the treatment of other organs such as inhalation devices or nasal drops. Subsequently, budesonide or viscous fluticasone preparations have been used, and are still used today, either magistral formulas prepared by pharmacists or home-made solutions. Recently, budesonide orodispersible tablets have been developed, which have shown clinical, endoscopic and histologic response rates above 95%[18]. Similar formulations of fluticasone are in phase 3 development. A recent study showed that switching to orodispersible tablets improves quality of life, treatment satisfaction, and histologic outcomes (<15 eosinophils/CGA and even <6 eosinophils/CGA), as well as endoscopic response [25]. In addition, topical corticosteroids have been shown to be more effective than PPIs and diets in both first- and second-line treatments[26]. They also achieve high long-term histologic response maintenance rates of greater than 60%, with excellent treatment adherence and low rate of adverse effects[27]. According to data from the European CONNECT registry[26], fluticasone is used more frequently than budesonide (6:4 ratio). Nasal drops are the most common presentation of fluticasone, whereas for budesonide master formulations predominate, followed by orodispersible tablets. The analysis also showed that budesonide is more effective than fluticasone, budesonide orodispersible tablets are more effective than other formulations, high doses (2 mg budesonide, 0.8 mg fluticasone) are more effective than low doses, and that the severity of symptoms is inversely proportional to the response to topical corticosteroid treatment.

Adverse effects[5]

Topical corticosteroids are safe in the long term, as evidenced by a study of nearly 1,000 patients, where adverse effects were mainly mild to moderate [28]. The most common was oral and esophageal candidiasis, frequently asymptomatic and rarely requiring discontinuation of treatment. Its management includes topical (clotrimazole) or systemic (fluconazole) antifungal agents, dose reduction or temporary suspension in severe cases. Adrenal insufficiency is a rare complication. Although adrenal function monitoring is not required in short treatments, it could be considered in prolonged therapies. Biologic treatment. Dupilumab

Efficacy

The evaluation of the efficacy of dupilumab in EoE is based on a randomized, double-blind, multicenter, placebo-controlled, phase 3 clinical trial[31]. The study consisted of 3 parts: A, B, and C. Parts A and B each consisted of a 24-week double-blind treatment period. After this treatment period, patients in parts A and B had the option to enter part C, which consisted of a 28-week treatment extension period, the objective of which was to evaluate safety and efficacy up to 52 weeks of treatment with dupilumab. The results they obtained were that the proportion of patients achieving histological deep remission < 6 eos/CGA was significantly higher in patients treated with dupilumab, regardless of receiving dupilumab weekly or every 2 weeks versus the placebo group.

In contrast, when analyzing clinical improvement in dysphagia, they found that patients receiving weekly dupilumab achieved greater symptom control after 4 weeks of treatment when compared with the placebo group. However, such clinical improvement was not obtained in the group of patients who were administered every 2 weeks.

Therefore, taking into account these results, and the fact that the histological remission rates are similar when prescribed weekly or every 2 weeks, the use of dupilumab could be evaluated in one way or another depending on the patient's symptoms.

Safety

Clinical trials and post-marketing studies have shown that dupilumab has a favorable safety profile in patients with EoE, similar to that observed in other indications (such as atopic dermatitis or asthma). Most of the adverse effects reported are mild to moderate, mainly injection site reactions (erythema, pain, inflammation). Among patients with EoE, the frequency of conjunctivitis was low and similar between the dupilumab or placebo group and there were no cases of keratitis[31],[32].

Other emerging biologic therapies

Currently an area of intense research activity, there are a large number of biologic drugs that could be used for the treatment of EoE and other gastrointestinal eosinophilic diseases. The drawback is that we do not know the medium- and long-term efficacy and safety of the new molecules. Nor have they demonstrated the ability to modify the natural history of EoE.

These therapies target different cytokines involved in the inflammatory response in EoE. Ongoing studies of agents targeting IL-5, such as mepolizumab, reslizumab, and benralizumab should provide more information on whether targeting this pathway is feasible. It is expected that ongoing studies evaluating agents targeting other novel pathways, such as Siglec-8 (lirentelimab), IL-13 (cendakimab), sphingosine 1-phosphate receptor (etrasimod), and TSLP blocker (tezepelumab) will provide additional options for chronic management of EoE[33],[34].

Issues to be resolved in the management of the patient with EoE.

We know, therefore, that EoE is a chronic immune-mediated disease that, in the absence of treatment, presents a high probability of recurrence and can progress to structural complications, such as fibrostenosis, with the primary goal of treatment being to achieve clinical, histologic, and endoscopic remission of the disease[40].

One of the major outstanding issues in EoE is the lack of robust evidence on the efficacy and safety of long-term maintenance therapy. Currently, there are few studies designed to evaluate how to maintain clinical and histologic remission without exposing the patient to prolonged side effects or compromising treatment adherence. Furthermore, there is no consensus on the optimal time to perform revision endoscopies, either in the context of therapeutic de-escalation or during the maintenance phase[41]. Finally, doubts persist as to whether it is possible to discontinue treatment in certain patients who achieve sustained remission, and what would be the criteria for making this decision safely. These unknowns underscore the need for long-term prospective studies and more personalized approaches to disease management.

1. What is the optimal clinical and endoscopic follow-up?

The scientific evidence on the follow-up of patients with EoE is limited. However, there is a consensus document developed by North American and European experts that provides recommendations on how to perform this follow-up[42].

Monitoring in EoE seeks to determine whether the patient is improving, but this poses challenges due to the chronic nature of the disease, its recurrence upon discontinuation of treatment, and the potential loss of therapeutic efficacy over time. Long-term follow-up is required, evaluating symptoms, endoscopic and histologic findings to get a complete picture of disease activity. Symptoms, although fundamental, have limited correlation with the biological parameters of the disease. They may improve while active inflammation persists, due to avoidance behaviors or esophageal dilations, or they may persist even after controlling inflammation due to factors such as undetected strictures, esophageal hypervigilance, or feeding dysfunction. It is essential to inquire in detail about dysphagia, feeding behaviors and feeding dysfunction. The EREFS system is recommended to assess endoscopic response. Complete normalization corresponds to a score of 0, although a score ≤2 is a reasonable goal. Comparing pre- and post-treatment findings helps to assess evolution. Histologically, the goal is to achieve <15 eos/hpf (<60 eos/mm²), so biopsies should be taken at each follow-up endoscopy.

The ideal concept of "deep resolution" combines symptom resolution and endoscopic and histologic normalization. However, it is achievable in few patients; for example, only 9.4% of patients in a Swiss study achieved this remission, and the median relapse was 22 weeks after stopping treatment. This highlights the need for continued follow-up even in patients in remission.

The follow-up interval varies according to treatment and individual characteristics. We will perform endoscopy after 8-12 weeks of starting PPIs, topical corticosteroids or elimination diet. Dupilumab requires 12-24 weeks to evaluate response. If there are no complications (impaction, perforations, malnutrition), clinical follow-up can be regular. However, a gap in care longer than 2 years increases the risk of fibrostenosis.

Although up to now biopsies are still essential, less invasive methods are being explored such as transnasal endoscopy that reduces costs and exposure to anesthesia, especially in children, cytosponge which is a capsule with a cytological brush that collects tissue when extracted; it has good tolerance and acceptable sensitivity, esophageal String Test that manages to detect inflammatory markers by absorbing them during their stay in the esophagus and other techniques such as mucosal impedance and EndoFLIP, which evaluate biomechanical and structural characteristics during endoscopies.

2. Is it possible to interrupt treatment in EoE?

EoE is a chronic immune-mediated disease that requires continuous management to prevent persistent inflammation and structural complications, such as fibrosis and stenosis. For this reason, treatment discontinuation is a topic of debate in the scientific and clinical community, especially in patients who achieve sustained clinical and histologic remission.

Current management guidelines, such as those of the American Gastroenterological Association (AGA)[43] and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)[44], recommend a continuous treatment approach for most patients, given the risk of disease recurrence and progression. Several studies have evaluated the impact of withholding specific treatments, such as diet and medical treatment.

The results show that most patients experience clinical and histological relapse after discontinuation, even in those with sustained remission.

However, we believe that in certain selected cases a "suspension test" could be considered, especially in patients with mild EoE (no fibrostenotic pattern) and those who have maintained clinical and histologic remission for a prolonged period (>12 months). In these scenarios, discontinuation should be performed with close follow-up with periodic clinical and endoscopic evaluation to detect early relapses. This decision to discontinue treatment should be based on an individualized assessment that considers disease activity, risk of complications, and patient preferences. Future studies will help to better define patient subgroups that could benefit from therapeutic de-escalation strategies.