Therapeutic Topics
Medical Treatment: When can we Expect Approval of Topical Corticosteroids?
In a multitude of studies, swallowed topical corticosteroids (budesonide and fluticasone) have demonstrated efficacy in bringing EoE successfully into clinicopathological remission. It is therefore astonishing that, currently, no drug therapy has been approved by regulatory authorities. There are several reasons for this: (1) performing controlled randomised clinical trials in EoE is still difficult because no instrument for assessing EoE-related symptoms has been approved; (2) some therapeutic studies with swallowed topical steroids have shown a correlation between EoE-related symptoms and histological changes, whereas other trials have documented an isolated histological, but not a symptomatic, response; the use of various mostly unvalidated symptom assessment instruments might explain these discrepant results; and (3) there is still a debate as to whether the major focus of efficacy should be directed towards symptom relief, anti-inflammatory activity or even both. There is a realistic hope that the intensive and constructive discussions among researchers, pharmaceutical companies and regulatory authorities will soon culminate in a definition of meaningful endpoints. Regarding the sequelae of unbridled chronic eosinophilic inflammation such as stricture formation and food impaction, it is likely that patient-reported items as well as biological markers will ultimately be included in the readouts.
Despite all these concerns, there are currently a total of 33 trials evaluating anti-eosinophil medications—swallowed topical corticosteroids and alternative drugs—for EoE registered on the clinicaltrials.gov website. Six of these trials are currently actively recruiting patients. This multitude of trials demonstrates that the search for EoE therapies represents a field of intense research. So far, swallowed topical corticosteroids have proved efficacious in reducing oesophageal eosinophil counts and in improving EoE-related symptoms in several trials, whereas alternative drugs have shown rather limited efficacy. Swallowed topical corticosteroids are therefore currently considered first-line drug therapy. There are not yet any results published on trials comparing fluticasone with budesonide, but both compounds seem to be effective. It is likely that the formulation providing an intensive and long-standing contact between the drug and the oesophageal surface is more relevant than the specific type of corticosteroid. Dellon and colleagues have shown that a viscous form of budesonide was more efficient in reducing eosinophil counts than the nebulised swallowed formulation. In addition, the authors demonstrated a longer oesophageal contact time for the viscous budesonide compared with the nebulised form. The use of topical steroids is usually safe. Candida oesophagitis has been reported in up to 30% of patients, with many being noted incidentally during follow-up endoscopy. Long-term safety data regarding potential adrenal suppression and bone mineral density are still awaited.
In conclusion, swallowed topical corticosteroids are highly efficient in treating active EoE and represent the first-line drug therapy for EoE. The challenge is to develop an oesophageal-adjusted formulation. Despite all the above-mentioned hurdles, approval of swallowed topical steroids designed for the treatment of EoE can be expected within the next few years.
Dietary Treatment: A Reasonable Therapeutic Modality?
Since the early days of EoE, allergen avoidance by dietary measures has been an established appropriate treatment. Today, three dietary modalities are available whose characteristics are illustrated in Table 2. The first strategy, elemental diet, consists of a total elimination of all food allergens by an amino acid-based formula. Among all the dietary regimens, this elemental diet represents the most reliable and, ultimately, the most effective strategy for use in children (ie, symptom resolution and histological improvement), with success rates exceeding 80%. In adults this approach seems to be less successful, achieving a remission rate of <50% in one study. The second strategy, individually-targeted elimination diets, consists of an elimination of food allergens that have been identified by allergy testing. Targeted elimination diets have the lowest efficacy of all hypoallergic diets, with remission rates between 53% and 72% in the paediatric population. In the adult population the results are even poorer, achieving remission rates between 22% and 32%. The third strategy, the empirical elimination diet, does not consider the individual allergic status of a patient. It is based on the concept that the empirical avoidance of the food categories that are most commonly associated with immediate hypersensitivity (ie, milk, wheat, eggs, soy, peanuts/nuts, fish/shellfish) would be valuable in treating EoE. After adhering to this so-called six-food elimination diet (6-FED) for 6 weeks, remission rates of more than 70% were found in children as well as in adults. Of interest, controlled food reintroduction procedures revealed milk and wheat as the most common triggers for EoE. Finally, the first long-term study has also shown that an empirical 6-FED was not only able to induce clinical and histological remission of EoE, but also to maintain it up to 3 years. We can therefore conclude that all available allergen avoidance approaches have proven efficacy in treating EoE using a non-pharmacological principle.
Regarding these respectable results, one may pose the question as to why the dietary approaches are not more popular. An elemental diet entails the drawbacks of being costly and usually requires a feeding tube. The 6-FED includes several staple foods and therefore requires a fundamental change in nutritional habits. All dietary modalities might have a negative impact on patients' quality of life, and adherence remains an ongoing problem as it has been shown that, as soon as these regimens are no longer followed, EoE returns. These drawbacks limit the wide use of this regimen.
In order to minimise these obstacles, less restrictive diets have also been evaluated as valuable therapeutic options in treating EoE. In children with a simple milk-free diet, Kagalwalla and colleagues have achieved a remission rate of 65% and Lucendo and colleagues have demonstrated that, after identification of the causative food categories by a controlled reintroduction procedure, an individually restricted elimination of the identified causative food is sufficient to maintain EoE in remission. In one-third of patients only one food category had to be eliminated, in one-third two food categories were involved and, in the last third, three food categories had to be excluded.
Taken together, there is realistic hope that, in the near future, studies evaluating a step-down principle will identify dietary approaches that are easier to follow. This could make diets more popular and provide a valuable therapeutic alternative to swallowed topical steroids in motivated patients desiring a non-pharmacological treatment.
Dilation: Still a Therapeutic Option?
Oesophageal dilation, either performed using through-the-scope inflatable balloons or wire-guided Savary bougies, represents a valuable therapeutic option for stricturing EoE. It has been clearly demonstrated that unbridled eosinophilic inflammation leads to the formation of oesophageal strictures. Strictures are, at least in part, responsible for EoE-typical swallowing difficulties and represent the main risk factor for food impactions.
As illustrated by several studies, oesophageal dilation can offer longlasting symptom improvement. A recently reported meta-analysis on 860 patients with EoE, of whom 525 underwent at least one oesophageal dilation and 992 dilations in total, showed a clinical improvement in 75% of patients. In general, patient acceptance of dilation is good; however, dilation has the drawback that it does not influence the underlying eosinophilic inflammation and that, post-dilation, most patients suffer from marked chest pain for several days. In addition, in EoE, dilation has the reputation of posing a not insignificant risk of oesophageal perforation. However, two meta-analyses including 671 and 992 dilations have recently reported perforation rates of 0.1% and 0.3%, respectively. These rates are comparable with perforation rates for dilation of strictures due to causes other than EoE. In general, considerable symptomatic improvement is achieved when an oesophageal diameter of 16–18 mm has been reached. Nevertheless, in consideration of the inherent EoE oesophageal wall rigidity, it is recommended that the progression steps per dilation session be limited to a maximum of 3 mm. Mucosal tears following dilation should not be reported as a complication as they represent a desired therapeutic effect. Post-dilation bleeding necessitating an endoscopic intervention is a rare event.
In conclusion, oesophageal dilation of stricturing EoE is still a valuable therapeutic option and may lead to long-lasting symptom improvement. However, it does not influence the underlying eosinophilic inflammation and, today, the main effort should be towards preventing stricture formation by an early and consistent medical treatment.