Orodispensable Budesonide Tablets for Eosinophilic Esophagitis

Full Text Link (courtesy of AGA twitter feed):Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial  AJ Lucendo et al. Gastroenterol 2019; 157: 74-86. https://doi.org/10.1053/j.gastro.2019.03.025

Abstract:

Background & Aims

Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE.

Methods

We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0–10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily).

Results

At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P< .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent.

Best Approach for Identifying Eosinophilic Esophagitis

A recent study (K Radicic, RF Stokes. Clin Gastroenterol Hepatol 2019; 1408-9) indicated that taking biopsies from three esophageal areas (proximal, mid, and distal)  improved the likelihood of identifying eosinophilic esophagitis (EoE).

Key findings:

  • In their study, among 96 patients with EoE, 55.2% were positive (>15 eos/hpf) in only 1 of the 3 levels.
  • 17 patients (17.7%) were positive in the mid-esophagus alone, and 6 patients (6.3%) were positive in the proximal esophagus alone.

The authors state that a 2-level biopsy protocol missed the diagnosis of EoE in roughly 1 of 5 patients.

My take: This study is provocative. However, the reasons why 3 levels improved their yield could be related to other factors rather than location.

  1. Prior studies have shown higher yield when taking 5 or 6 biopsies rather than fewer biopsies; thus, the location of biopsies may not be as important as the number of specimens
  2. Prior studies have shown that having another pathologist review the slides can increase the yield by ~20%; this indicates that careful review of specimens by itself is helpful.  Perhaps, more specimen containers will increase the time that a pathologist reviews the biopsies.

My view is that if adequate numbers of biopsies are taken from several locations, a single jar for all the specimens should suffice (& reduce costs) –though a formal study could be beneficial to confirm this.

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From NASPGHAN 2014 EoE Slide Set

Highest Reported Prevalence Rates for Eosinophilic Esophagits

A recent retrospective study (J Robson et al. Clin Gastroenterol Hepatol 2019; 17: 107-14) utilized a pathology database encompassing the vast majority of Utah pediatric cases to determine the incidence and prevalence of eosinophilic esophagitis (EoE) from 2011 to 2016.

The authors determined cases of EoE by looking for symptomatic children with isolated esophageal eosinophilia (more that 14 eos/hpf) in the absence of other comorbid conditions.

Key findings:

  • 1060 children met the criteria for a new diagnosis of EoE
  • Average annual incidence of EoE was 24 per 100,000 children; this is nearly double the previously reported rate 12.8 per 100,000 from Hamilton County, Ohio in 2003.
  • Prevalence of EoE was 118 per 100,000 children

The authors speculate on several factors that produced this increased incidence rate –all related to EoE risk factors:

  • Predominant non-Hispanic White population
  • High rates of atopy
  • Increased capture rate of their database
  • Also, the authors did NOT exclude PPI-responsive esophageal eosinophilia (which is a subtype of EoE and not a different disease

The authors note that “there is reason to believe that this [high incidence rate] is a conservative estimate:”

  • ~2% of pathology reports had 10-14 eos/hpf.  Further review of these cases would likely have identified some which have exceeded the >14 threshold
  • Some pediatric EoE cases are diagnosed by adult gastroenterologists who did not use the pathology databases

My take: This study shows high rates of EoE but comes as no surprise.  And, there are likely a large number of individuals with mild EoE which has not been diagnosed.  In my experience, families and physicians often overlook altered eating habits as related solely to behavior.  Useful questions to uncover dysphagia include the following: how long does it take your child to eat? does your child have to drink a lot of liquids when eating? does food get stuck frequently?

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Surprising Findings in Prospective Budesonide-Eosinophilic Esophagitis Study

A recent study (ES Dellon et al Clin Gastroenterol Hepatol 2019; 17: 666-73) prospectively followed patients in a 24 week open-label extension of a randomized, double-blind, placebo-controlled trial of budesonide oral suspension (BOS) for eosinophilic esophagitis (EoE). The authors defined histologic response as ≤6 eos/hpf. During the extension, the dosage of BOS was reduced from 2 mg twice daily to 2 mg once a day.

Key findings:

  • No new safety signals. One patient in placebo/BOS arm (n=37) developed oral candidiasis and one patient in the BOS/BOS arm (n=45) did as well. In addition, four patients in placebo/BOS developed esophageal candidiasis. No clinically relevant changes in morning serum cortisol levels were identified.
  • Histologic response was observed in 49% (16/33) in placebo/BOS arm and 23% (9/39) of BOS/BOS arm. 58% of placebo/BOS and 28% of BOS/BOS patients had ≤15 eos/hpf.
  • Mean peak eosinophil count decreased in placebo/BOS arm from 119 to 29 and increased in BOS/BOS arm from 38 to 72.
  • Overall, only 42% of patients who responded to BOS during double-blind 12 week study maintained a histologic response.

While this study shows that BOS is effective for many patients with EoE, it also shows that many lose a response.  In addition, most patients who “did not respond to treatment during the double-blind phase did not gain a histologic or endoscopic response with longer-term treatment.”  Only 1 of 26 patients (4%) gained a response. This has several important implications:

  • Some patients may develop corticosteroid resistance
  • In patients who respond to induction, it may be prudent to continue with the same induction dose rather than reducing the dosage
  • In patients who do not respond to induction, further treatment is not beneficial

My take: Though the response to BOS was not very high in this study, the population studied was highly symptomatic and had histologically-severe EoE.  Thus, in a more typical population of patients with EoE, the response rate is likely to be more favorable. Also, many patients will not maintain a response to BOS at a lowered dose.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

What Happens When Topical Steroids Are Stopped in Eosinophilic Esophagitis

A recent retrospective study (T Greuter et al. Clin Gastroenterol Hepatol 2019; 17: 419-28) shows that patients with eosinophilic esophagitis who continued to take swallowed topical corticosteroids (STC) did much better than patients who did not.

Using the Swiss EoE database, the authors analyzed 229 patients with a mean age of 39 years at diagnosis.  Median followup was 5 years.  The authors initiated STC, almost all received fluticasone, at 1 mg BID for 2-4 weeks followed by maintenance treatment indefinitely.

Key findings:

  • There was frequent discontinuation of STC by patients, such that patients were actually taking STC at only 41% of visits.
  • Higher proportions of patients taking STCs were doing well compared to those not taking STCs:
    • clinical remission was 31% compared to 4.5% respectively (P<.001),
    • endoscopic remission was 49% compared to 18% respectively (P<.001)
    • histologic remission was 45% vs 10% respectively (P<.001)
    • complete remission was 16% vs 1% respectively (P<.001)
  • No dysplasia or mucosal atrophy was detected.  Esophageal candidiasis was observed in 2.7% of visits in patients taking STC

My take: This study shows that patients who maintained STC therapy had better esophageal outcomes than patients who stopped their treatment.  What is not known is the optimal long-term dose.

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Increased Risk of Eosinophilic Esophagitis in Esophageal Atresia Patients

Briefly noted: U Krishnan et al. Analysis of eosinophilic esophagitis in children with repaired congenital esophageal atresia. JACI 2018. Published online Oct 24, 2018.

This retrospective, single-center study examined 4 eosinophilic esophagitis (EoE) study cohorts and identified EoE in 20 of 110 patients (18%) who had surgically-repaired esophageal atresia.

This association has been seen previously: . 2014 Dec 21; 20(47): 18038–18043.  This case study stated ” We are suggesting that EoE is a frequent concomitant problem in patients with history of congenital esophageal deformities, and for this reason any of these patients with refractory reflux symptoms or dysphagia (with or without anastomotic stricture) may benefit from an endoscopic evaluation with biopsies to rule out EoE.”

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Association and Causation: Early Life Risk Factors for Eosinophilic Esophagitis

A recent case-control study (CP Witmer et al. JPGN 2018; 610-5) using the Military Health System Database examined 1410 cases of eosinophilic esophagitis (EoE) and matched them with 2820 controls; the study period was 2008-2015.

  • The authors found that early exposure to proton pump inhibitors (PPIs), histamine-2 receptors (H2RAs), and antibiotics were all associated with an increased risk of developing EoE with adjusted odds ratios of 2.73, 1.64, and 1.31.
  • In addition, among atopic problems, milk protein allergy had an adjusted odds ratio of 2.37 and eczema 1.97. –for developing EoE.

My take: This study does not determine whether the use of PPIs, H2RAs or antibiotics are involved in causation of EoE or whether patients with EoE simply receive these medications more frequently.  Nevertheless, the findings reinforce the idea that these medications should be used less frequently in infants.

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