No Maintenance, No Gain in Long-term Treatment of Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergen-induced/immune-mediated disease that has been rapidly increasing in incidence and prevalence and now accounts for substantial health care costs and utilization.^1-3 The chronicity of EoE has been supported by a number of investigations, including a seminal natural history study by Straumann et al⁴ in which esophageal eosinophilia and dysphagia persisted in EoE patients over a mean follow-up period of more than 7 years without anti-inflammatory treatment. The placebo arms of randomized controlled trials of swallowed topical corticosteroids (STCs) for EoE also have shown no substantial changes in esophageal eosinophil counts, supporting this concept, although these findings were over a much shorter time course.^5,6 In addition, a large retrospective cohort study showed that almost no children “grow out of” EoE,⁷ other studies have shown that disease recurs after nonsteroid therapies as well,^8,9 and a study in adults showed that less than 2% of those who achieved “deep remission” (no symptoms, endoscopic findings, or histologic findings for at least 6 months) could discontinue STCs in the long term; all other patients relapsed after a median of only 22 weeks of discontinuing therapy.¹⁰

A key issue with any chronic disease is understanding the long-term consequences of that disease were it not to be treated. Although there are no reports to date of EoE causing cancer or transforming to either a more diffuse eosinophilic gastrointestinal disorder or hyper-eosinophilic syndrome, we now know that EoE may progress from an inflammatory to a fibrostenotic condition.¹ Schoepfer et al¹¹ studied the concept of diagnostic delay, the interval of time between symptom onset and diagnosis, and found that only 17% of patients diagnosed within 2 years of symptom onset had esophageal strictures, compared with more than 70% with longer than 20 years of symptoms before diagnosis. Several other studies have confirmed this result,^12-16 with 1 study estimating the odds of stricture development doubling with every decade of symptoms. This progression to fibrostenosis is important because esophageal strictures or narrowing are not only complications of EoE, but increase the risk of food impactions and the need for emergency endoscopy, a setting in which esophageal perforation may be more likely.

The chronicity, disease relapse after stopping treatment, and likely progression to fibrosis all support the concept of maintenance therapy in EoE after achieving histologic response.^17,18 However, there have been relatively few studies of this approach. In this issue of Clinical Gastroenterology and Hepatology, Greuter et al¹⁹ from the same Swiss group that has studied the natural history of EoE extensively,^4,10,11,20 provide insight into the role of maintenance therapy. They performed a retrospective cohort study of 226 adults with EoE who were followed up in the Swiss EoE clinic, with the aim of assessing the effectiveness and safety profile of long-term use of STCs in adult EoE patients. Patients were included if they had a baseline and at least 1 follow-up examination at least 1 year apart, had a clinical response (defined as a >50% reduction from baseline symptoms on a 10-point scale) to the initial STC at 1 mg twice daily, and were given a maintenance treatment of 0.25 mg twice daily. For the treatments, either oral viscous budesonide or fluticasone powder (from a blister pack inside of an asthma disk-like inhaler device) could be used, but fluticasone was chosen by most patients because it was more readily available. The primary end points were proportions of clinical remission (absence of any EoE-related symptoms), endoscopic remission (no endoscopic signs of inflammation as reflected exudates, furrows, or edema), and histologic response (peak eosinophil count < 15 eosinophils/high-power field), assessed by the duration and intensity of STC use. Complete remission was defined as the combination of clinical, endoscopic, and histologic remission. Of note, because of variability in the timing of individual patient treatment and follow-up evaluation, the primary analysis was by patient visit.

The median follow-up evaluation period was 5 years, with data from 819 visits analyzed. Of these visits, there were only 62 (8%) in which patients were in complete remission. However, STCs were used in a higher proportion of visits for complete responders compared with noncomplete responders (90% vs 38%; P < .001). Patients used STCs at 336 visits (41%). At these visits, more patients taking STCs compared with those not taking STCs were in clinical remission (31% vs 5%; P < .001), endoscopic remission (49% vs 18%; P < .001), histologic remission (45% vs 18%; P < .001), and complete remission (16% vs 1%; P < .001). At visits during which patients were using STCs, peak eosinophil counts (5 vs 40 eosinophils/high-power field; P < .001) and endoscopic severity score (2 vs 4; P < .001) were improved. There were also increasing clinical and complete remission rates with increasing cumulative STC doses. Longer-term (≥1 y) STC use was associated independently with complete remission, and time to histologic relapse was longer in the STC group (1.5 vs 0.7 y; P = .047). For safety, no esophageal dysplasia or mucosal atrophy was noted. Esophageal candidiasis was noted at 9 of the 336 visits in which STCs were used (3%).

The study by Greuter et al provides welcome data supporting maintenance treatment in adults with EoE and prompts additional questions on this topic.¹⁹ Two key points from their study are that maintenance treatment with STC provides an important clinical benefit, but the doses of STC studied likely are not sufficient for the majority of patients. For visits when patients were on STCs, there were higher rates of clinical, endoscopic, histologic, and complete remission, but patients were on these treatments for less than half of the visits, and remission rates were not universal. Although the article did not explore the reasons for patients not being on STCs, the dose of 0.25 mg twice daily may explain the relatively low response rates. Straumann et al²¹ previously conducted a randomized, placebo-controlled trial of maintenance therapy in EoE. Patients who were in clinicopathologic remission after a 2-week course of swallowed budesonide (2 mg/d) were randomized to receive either swallowed budesonide 0.25 mg twice daily or placebo, and were followed up for 50 weeks. The rates of histologic and symptom response were higher with budesonide compared with placebo (36% vs 0%, and 64% vs 36%, respectively), but there was still substantial relapse compared with the higher initial dose. A similar decrement in histologic response rate has been seen in an open-label extension of a budesonide suspension after a dose decrease from 2 mg twice daily to 2 mg once daily,²² and in a retrospective cohort study assessing longer-term response to maintenance therapy in which STC doses were similarly decreased.²³ From the clinical standpoint, it is possible to say that for many patients a dose of 0.25 mg twice daily is too low, but because there are no dose-ranging studies for maintenance treatment, we do not know the optimal dose for long-term use and this question merits future study. It also is not known whether to maintain the initial induction dose or step down to a lower dose. One approach would be to use the lowest effective dose for each patient, but this dose would need to be individualized using a series of follow-up endoscopies. Treatment algorithms also likely will change as new esophageal-specific STC preparations, which may have higher response rates, become clinically available.²⁴

When interpreting the data in this study, several considerations are appropriate. First, this was a study of adults, therefore the results cannot be applied to children. Similar to the literature in adults, there are few data on maintenance therapy in children, but 2 studies have provided support for this approach. Rajan et al²⁵ performed a retrospective cohort study with a mean follow-up period of 4.5 years, and found that initial STC responders tended to maintain response with ongoing treatment. Andreae et al²⁶ performed a prospective cohort study with a mean follow-up period of 20 months and found that STC treatment was effective for maintaining response with a favorable safety profile. Second, patients were included in this cohort by clinical response, so their baseline histologic response was not known. Dissociation between clinical and histologic response has been well described in EoE,^27,28 and one driver of this is the presence of strictures. In the present study, it is difficult to interpret symptom response in the 15% of visits in which patients underwent esophageal dilation. Indeed, the difference in clinical response between a STC and no STC was less pronounced in those with prior dilation (16% vs 36%) than in those without dilation (4% vs 31%), and the presence of stricture was associated independently with a lack of clinical remission, which has been reported previously.²⁹ Finally, although Greuter et al¹⁹ are to be commended for assessing safety aspects including esophageal mucosal atrophy, candidiasis, and dysplasia, this study did not provide safety information regarding bone health or the adrenal axis, 2 areas in which long-term safety questions remain and should be investigated.

In sum, the study by Greuter et al¹⁹ provides some of the strongest support to date for long-term STC treatment in adults with EoE. In the overwhelming majority of EoE patients, if treatments are not continued, clinical, endoscopic, and histologic disease activity will flare. With ongoing STC treatment, many patients will remain in remission. Although important questions persist about optimal STC dosing and safety, particularly as related to bone health and the adrenal axis, the main message for EoE patients should be: no maintain, no gain.