Therapeutic Options for Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is an allergy-based disease with a genetic predisposition in which esophageal exposure to food antigens, perhaps primed by respiratory or extraesophageal allergic disease, has been postulated to contribute to a chronic inflammatory state, eventually resulting in fibrosis and stricture formation. As with many allergies, one of the mainstays of treatment for EoE is the use of steroids. Indeed, steroids are the only pharmacologic treatment that has shown clear benefit in EoE across numerous studies. Several studies, including doubleblind, placebo-controlled trials, have demonstrated the efficacy of either systemic or topical steroids in treating EoE.^1–5 With emerging data and growing enthusiasm for understanding and treating this disease, physicians are now asking questions about which steroid preparations are most effective, for how long, and at what dose. Through good anecdotal evidence, the interesting case report by Krishna and associates proposes that viscous budesonide should comprise first-line treatment for patients with EoE.⁶ Before embarking on a discussion of which steroid is most effective, however, it is important to consider several caveats when analyzing this case report and EoE studies in general.

First, several studies evaluating the efficacy of steroids in EoE patients use symptoms as the primary endpoint. Unfortunately, in both children and adults, it has been well demonstrated that symptomatic response may not correlate with histologic response.⁷ This finding may have several explanations. The use of standardized dysphagia scoring systems, which are useful for other dysphagic diseases, may be inadequate for evaluating EoE. Symptoms may be infrequent, particularly in adults, making it difficult to demonstrate a significant difference over a short time period. The effect of short-term steroids on symptomatic fibrotic strictures may be suboptimally appreciated at endoscopy, particularly with diffuse esophageal narrowing.

Second, not all studies agree on how to define histologic remission in response to therapy. For example, some studies define less than 1 eosinophil/high power field (HPF) as a complete response, whereas other studies use 0–6 eosinophils/HPF. Some studies may use scoring systems combining eosinophil counts with other histologic parameters such as basal zone thickness. Moreover, although all studies use HPF as the gold standard field of measurement, the diameter of this field (and, therefore, the eosinophil count) may vary widely among studies. Thus, when analyzing efficacy among various steroid preparations, one should be aware that comparisons may not be of equivalent units.

Third, studies with steroids have used different preparations, dosages, and durations of therapy. For example, a standard dose of 4 puffs of 220 micrograms of fluticasone twice daily is still 240 micrograms less than 2 mg of budesonide once daily. Another study in adults used only 500 micrograms of fluticasone twice daily in adults, which is half of the usual budesonide dose. Other studies vary in their drug trial periods, ranging from 1 to 3 months. Whether these differences are therapeutically significant is unclear.

Finally, much of the success of a steroid preparation for treating patients with EoE rests on the premise that patients in the trial have EoE. With no gold standard for differentiating EoE from gastroesophageal reflux, this presumption may be problematic when comparing studies in which the distribution of these diseases may differ among experimental groups.

On an optimistic note, the use of steroids in EoE is not merely a “me too” phenomenon within the spectrum of allergic diseases. There are clear data demonstrating that steroids effectively and specifically treat the underlying pathophysiology and even improve fibrosis in these patients.⁸ For example, all studies show that steroids effectively reduce and often eliminate eosinophils from esophageal mucosa. Even more interesting is the reduction in other inflammatory and fibrogenic markers. For example, budesonide has been demonstrated to reduce levels of mast cells, tumor necrosis factor-a, and epithelial cell apoptosis, all of which accompany inflammation and lamina propria fibrosis. Moreover, steroids have been shown to decrease transforming growth factor (TGF)-B1 and tenascin C, which are markers of fibrosis and remodeling. Similarly, fluticasone has been shown to reduce tissue levels of monoclonal anti–Ki-67, mast cells, and CD8 T cells. It is also encouraging that topical steroids have been reported to reverse fibrosis (as evidenced by biopsy staining for TGF-B1) and to decrease esophageal wall thickness (as measured by endoscopic ultrasound).^4,8 Tis benefit is far from proven, however; longer-term studies are needed to determine the potential of these therapies for reversing clinically significant esophageal narrowing.

With these points in mind, physicians who treat patients with EoE have to choose their primary and secondary therapies. Can one therapy be deemed superior? If so, why? Certainly, systemic steroids can be held in reserve for patients who are refractory to topical steroids or who cannot tolerate them. As a result, as was nicely discussed in the case by Krishna and colleagues, the most common treatment choices are inhaled fluticasone, inhaled budesonide, and viscous budesonide.⁶ All 3 treatments share several similarities. The pharmacokinetics of these preparations when swallowed have not been well evaluated. In particular, it is possible that swallowed budesonide may not undergo the first-pass metabolism of slow-release budesonide absorbed in the small intestine. All 3 preparations appear to have minimal effect (if any) on the adrenal axis, as documented in asthma patients and several reports of EoE patients. There is a chance (at most, 15%) of developing oropharyngeal or esophageal Candida infection, which is commonly asymptomatic. All 3 preparations have similar rates of clinical and histologic efficacy, though there have not been any direct comparison studies. Both inhaled fluticasone and budesonide are inconvenient to administer, as patients must rinse their mouths with and expectorate water after dosing, as well as avoid eating or drinking for 30 minutes afterwards. Patients may also find it challenging to swallow a medication that is diffusely sprayed over their pharynx. Nevertheless, steroid nebulizers have undergone the most study and use by physicians. They are efficacious and immediately ready for use. However, it is unclear whether a small amount of the sprayed liquid can optimally and completely coat and penetrate an organ with a relatively large surface area. As a result, recent studies have supported the use of viscous budesonide.⁹ This medication is particularly useful in children because of its sweet taste. A recent study of viscous budesonide in children demonstrated complete histologic response in 13 of 15 patients.

The price of these formulations should be considered as well. All of the preparations currently available in the United States are extremely costly. In our area, a 6-week course of fluticasone at 880 mcg BID costs $670, and a 6-week supply of budesonide liquid 2 mg BID taken from respules (Pulmicort, AstraZeneca) costs over $1,200. Cost is a major issue in the treatment of EoE, as the medications currently available are expensive not only initially, but potentially long term, given the nearly universal recurrence of the disease and the likelihood that some patients will require sustained treatment.¹⁰

We are fortunate to have safe and effective medications so early in the life of this disease. Whether futicasone or budesonide will ultimately prove to be more efficacious and/or convenient is unclear. Much of our speculation will ultimately be settled by a double-blind comparison of these 2 medications, though it is likely that several trials will be needed in patients of different ages, as children may have different preferences and responses than adults. It is also likely that we will soon have formulations of these steroids designed specifically for delivery to the esophagus. For now, it is best to take into account the preferences and cost restraints of individual patients when choosing a formulation. As in the case report by Krishna and coworkers, if one formulation fails, another can be attempted, whether a topical or systemic steroid.⁶ Nevertheless, this case report is (hypoallergenic) food for thought and should stimulate more intensive investigation of some of these important questions.