Eosinophilic esophagitis—established facts and new horizons

Despite dramatic advances in our understanding of the pathogenesis and course of disease in the relatively short timeframe since the discovery and first description of eosinophilic esophagitis (EoE) less than three decades ago, many open questions remain to be elucidated. For instance, we will need to better characterize atypical clinical presentations of EoE and other forms of esophageal inflammatory conditions with often similar clinical presentations, nut fulfilling current diagnostic criteria for EoE and to determine their significance and interrelationship with genuine EoE. In addition, the interrelationship of EoE with other immune-mediated diseases remains to be clarified. Hopefully, a closer look at the role of environmental factors and their interaction with genetic susceptibility often in context of atopic predisposition may enable identifying the candidate substances/agents/allergens and potentially earlier (childhood) events to trigger the condition. It appears plausible to assume that in the end—comparable to current concepts in other immune-mediated chronic diseases, such as for instance inflammatory bowel disease or asthma bronchiale—we will not be rewarded with the identification of a “one-and-only” underlying pathogenetic trigger factor, with causal responsibility for the disease in each and every EoE patient. Rather, the relative contribution and importance of intrinsic susceptibility, i.e., patient-driven factors (genetics, aberrant immune response) and external trigger factors, such as food (or aero-) allergens as well as early childhood events (e.g., infection and exposure to antibiotics and other drugs) may substantially differ among given individuals with EoE. Accordingly, selection and treatment duration of medical therapy, success rates and extent of required restriction in dietary treatment, and the need for mechanical treatment to address strictures and stenosis require an individualized approach, tailored to each patient. With the advances of emerging treatment options, the importance of such an individualized and patient-centered assessment will increase even further

Is There a Role for Topical Swallowed Steroids upon Emergency Room Admission for Suspected Food Bolus Obstruction in Eosinophilic Esophagitis?

Since most pharmacological treatments in case of esophageal food impaction (EFI) are unsuccessful, an endoscopy is usually required to resolve EFI. We present the first results of a budesonide orodispersible tablet (BOT) as a medical treatment option before endoscopy. We evaluated all patients with a suspected EFI to receive BOT before emergent endoscopy at a tertiary hospital between March 2019 and June 2020. A total of eight patients received BOT before endoscopy. Mean age was 50.1 years and 87.5% were male. In 38% (3/8) of patients the EFI resolved without endoscopic intervention. No adverse events occurred. After endoscopy, a diagnosis of EoE was established in 75%. This case series demonstrate the potential of BOT as medical rescue therapy in case of EFI

Close follow-up is associated with fewer stricture formation and results in earlier detection of histological relapse in the long-term management of eosinophilic esophagitis.

BACKGROUND AND AIMS No recommendations exist regarding optimal follow-up schedule in patients with eosinophilic esophagitis (EoE) under maintenance treatment. METHODS We retrospectively evaluated a long-term surveillance concept at the Swiss EoE clinic, where clinical, endoscopic and histological disease activity is assessed annually regardless of EoE symptoms. Data on 159 adult patients under maintenance steroid treatment with available follow-up were analyzed. Patients were classified as having close (duration between visits <18 months) or non-close follow-up (≥18 months). RESULTS We analyzed a total of 309 follow-up visits of 159 patients (123 males, age at diagnosis 38.9 ± 15.4 years). 157 (51%) visits were within a close follow-up schedule (median duration between visits of 1.0 years (interquartile range (IQR) 0.9-1.2)), while 152 visits (49%) were not (median duration between visits 2.9 years (IQR 2.0-4.1)). There was no difference regarding ongoing clinical, endoscopic, and histological disease activity, and adherence to prescribed steroid treatment between the two groups. However, stricture formation was significantly less frequently observed at visits within a close follow-up schedule (22.9 vs. 33.6%, p = 0.038). Absence of close follow-up was a significant risk factor for stricture development in a multivariate regression model. Patients who achieved histological remission and were followed within a close-follow-up schedule had significantly earlier detection of histological relapse compared to patients not within such close follow-up. CONCLUSION Close follow-up is associated with fewer stricture formation and appears to result in earlier detection of histological relapse in patients with eosinophilic esophagitis. We advocate for regular assessment of disease activity (every 12-18 months) in order to detect relapsing disease as early as possible, and therefore potentially minimize the risk for EoE complications

Low serum zinc levels predict presence of depression symptoms, but not overall disease outcome, regardless of ATG16L1 genotype in Crohn's disease patients.

Zinc deficiency (ZD) in Crohn's disease (CD) is considered a frequent finding and may exacerbate CD activity. ZD is associated with depression in non-CD patients. We aimed to assess the prevalence of ZD in CD patients in clinical remission, its association with mood disturbances and to analyze a potential impact on future disease course. Zinc levels from CD patients in clinical remission at baseline and an uncomplicated disease course within the next 3 years ( &lt;i&gt;n&lt;/i&gt; = 47) were compared with those from patients developing complications ( &lt;i&gt;n&lt;/i&gt; = 50). Baseline symptoms of depression and anxiety were measured with the Hospital Anxiety and Depression scale. Mean zinc level in the 97 patients (40.4 ± 15.7 years, 44.3% males) was 18.0 ± 4.7 μmol/l. While no ZD (&lt;11 μmol/l) was observed, we found low zinc levels (&lt;15.1 μmol/l) in 28 patients (28.9%). Males had higher zinc levels compared with females (19.4 ± 5.7 &lt;i&gt;versus&lt;/i&gt; 16.8 ± 3.3, &lt;i&gt;p&lt;/i&gt; = 0.006). Patients with low zinc levels more often reported depression symptoms compared with patients with higher levels (27.3 &lt;i&gt;versus&lt;/i&gt; 9.4%, &lt;i&gt;p&lt;/i&gt; = 0.047). In a multivariate analysis, zinc levels were an independent negative predictor for depression symptoms [odds ratio (OR) 0.727, 95% confidence interval (CI) 0.532-0.993, &lt;i&gt;p&lt;/i&gt; = 0.045]. Zinc levels of patients with a complicated disease course were not different from those of patients without (17.7 ± 4.3 &lt;i&gt;versus&lt;/i&gt; 18.3 ± 5.1, n.s.). Baseline zinc levels did not predict disease outcome regardless of ATG16L1 genotype. Low-normal zinc levels were an independent predictor for the presence of depression symptoms in CD patients. Zinc levels at baseline did not predict a complicated disease course, neither in CD patients overall, nor ATG16L1 &lt;sup&gt;T300A&lt;/sup&gt; carriers

Systematic Review of Outcome Measures Used in Observational Studies of Adults with Eosinophilic Esophagitis.

BACKGROUND Over the last 20 years, diverse outcome measures have been used to evaluate the effectiveness of therapies for eosinophilic esophagitis (EoE). This systematic review aims to identify the readouts used in observational studies of topical corticosteroids, diet, and dilation in adult EoE patients. METHODS We searched MEDLINE and Embase for prospective and retrospective studies (cohorts/case series, randomized open-label, and case-control) evaluating the use of diets, dilation, and topical corticosteroids in adults with EoE. Two authors independently assessed the articles and extracted information about histologic, endoscopic, and patient-reported outcomes and tools used to assess treatment effects. RESULTS We included 69 studies that met inclusion criteria. EoE-associated endoscopic findings (assessed either as absence/presence or using Endoscopic Reference Score) were evaluated in 24/35, 11/17, and 9/17 studies of topical corticosteroids, diet, and dilation, respectively. Esophageal eosinophil density was recorded in 32/35, 17/17, and 11/17 studies of topical corticosteroids, diet, and dilation, respectively. Patient-reported outcomes were not uniformly used (only in 14, 8, and 3 studies of topical corticosteroids, diet, and dilation, respectively), and most tools were not validated for use in adults with EoE. CONCLUSIONS Despite the lack of an agreed set of core outcomes that should be recorded and reported in studies in adult EoE patients, endoscopic EoE-associated findings and esophageal eosinophil density are commonly used to assess disease activity in observational studies. Standardization of outcomes and data supporting the use of outcomes are needed to facilitate interpretation of evidence, its synthesis, and comparisons of interventions in meta-analyses of therapeutic trials in adults with EoE

Budesonide orodispersible tablets for induction of remission in patients with active eosinophilic oesophagitis: A 6-week open-label trial of the EOS-2 Programme

BACKGROUND A novel budesonide orodispersible tablet (BOT) has been proven effective in adult patients with active eosinophilic oesophagitis (EoE) in a 6-week placebo-controlled trial (EOS-1). AIMS To report the efficacy of an open-label induction treatment with BOT in a large prospective cohort of EoE patients within the EOS-2 study. METHODS Patients with clinico-histological active EoE were treated with BOT 1 mg BID for 6 weeks. The primary endpoint was clinico-histological remission (≤2 points on numerical rating scales [0-10] each for dysphagia and odynophagia, and peak eosinophil count <16 eos/mm$^{2}$ hpf (corresponds to <5 eos/hpf)). Further study endpoints included clinical and histological remission rates, change in the EEsAI-PRO score, change in peak eosinophil counts, and deep endoscopic remission using a modified Endoscopic Reference Score. RESULTS Among 181 patients enrolled, 126 (69.6%) achieved clinico-histological remission (histological remission 90.1%, clinical remission 75.1%). The mean peak eosinophil counts decreased by 283 eos/mm$^{2}$ hpf (i.e., by 89.0%). Mean EEsAI-PRO score decreased from baseline by 29 points and deep endoscopic remission was achieved in 97 (53.6%) patients. The majority of patients judged tolerability as good or very good (85.6%) and compliance was high (96.5%). Local candidiasis was suspected in 8.3% of patients; all were of mild severity, resolved with treatment and none led to premature withdrawal from the study. CONCLUSIONS In this large prospective trial, a 6-week open-label treatment with BOT 1 mg BID was highly effective and safe in achieving clinico-histological remission of active EoE and confirmed the results of the placebo-controlled EOS-1 trial

Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease: Prevalence, Presentation, and Anti-TNF Treatment.

There is a paucity of data on extraintestinal manifestations (EIM) and their treatment in pediatric patients with inflammatory bowel disease (IBD). Since 2008, the Pediatric Swiss IBD Cohort Study has collected data on the pediatric IBD population in Switzerland. Data on 329 patients were analyzed retrospectively. A total of 55 patients (16.7%) experienced 1-4 EIM (39 Crohn disease, 12 ulcerative colitis, and 4 IBD-unclassified patients). At IBD onset, presence of EIM was more frequent than in the adult population (8.5% vs 5.0%, P = 0.014). EIM were more frequent in Crohn disease when compared to ulcerative colitis/IBD-unclassified (22.5% vs 10.3%, P = 0.003). The most prevalent EIM were peripheral arthritis (26/329, 7.9%) and aphthous stomatitis (24/329, 7.3%). Approximately 27.6% of all EIM appeared before IBD diagnosis. Median time between IBD diagnosis and occurrence of first EIM was 1 month (-37.5-149.0). Thirty-one of the 55 patients (56.4%) were treated with 1 or more anti-tumor necrosis factor (TNF) agents. IBD patients with EIM were more likely to be treated with anti-TNF compared to those without (56.4% vs 35.0%, P = 0.003). Response rates to anti-TNF depended on underlying EIM and were best for peripheral arthritis (61.5%) and uveitis (66.7%). In a cohort of pediatric patients with IBD, EIM were frequently encountered. In up to 30%, EIM appeared before IBD diagnosis. Knowledge of these findings may translate into an increased awareness of underlying IBD, thereby decreasing diagnostic delay. Anti-TNF for the treatment of certain EIM is effective, although a substantial proportion of new EIM may present despite ongoing anti-TNF therapy

Budesonide orodispersible tablets maintain remission in a randomized, placebo-controlled trial of patients with eosinophilic esophagitis

Background & Aims: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder. Swallowed topical-acting corticosteroids are effective in bringing active EoE into remission. However, it is not clear whether these drugs are effective for long-term maintenance of remission. Methods: We performed a double-blind trial to compare the efficacy and safety of 2 dosages of a budesonide orodispersible tablet (BOT) vs placebo in maintaining remission of EoE. Maintenance of remission was defined as absence of clinical and histologic relapse and no premature withdrawal for any reason. Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given BOT 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks. Results: At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo). Median time to relapse in the placebo group was 87 days. The frequency of adverse events was similar in the BOT and placebo groups. Morning serum levels of cortisol were in the normal range at baseline and did not significantly change during treatment. Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment. Conclusions: In a phase 3 trial, up to 48 weeks of treatment with BOT (0.5 mg or 1.0 mg twice daily) was superior to placebo in maintaining remission of EoE. Both dosages were equally effective and well tolerated. EudraCT number; 2014-001485-99; ClinicalTrials.gov number, NCT02434029

Long-term Efficacy and Tolerability of RPC4046 in an Open-Label Extension Trial of Patients With Eosinophilic Esophagitis

Background & Aims The short-term efficacy of RPC4046, a monoclonal antibody against interleukin-13, has been shown in patients with eosinophilic esophagitis (EoE). We investigated the long-term efficacy and safety of RPC4046 in an open-label, long-term extension (LTE) study in adults with EoE. Methods We analyzed data from 66 patients who completed the 16-week, double-blind, induction portion of a phase 2 study of RPC4046 (180 mg or 360 mg/wk) vs placebo and then completed a 52-week LTE, receiving open-label RPC4046 360 mg/wk. The study was conducted at 28 centers in 3 countries; patients were enrolled between September 2014 and January 2017. Outcomes were stratified by double-blind dose group and included esophageal eosinophil counts, EoE endoscopic reference score, EoE histologic scoring system score, symptom-based EoE activity index score, and safety. Results By week 12 of the LTE, esophageal eosinophil mean and peak counts, total EoE endoscopic reference scores, and EoE histologic scoring system grade and stage scores did not differ considerably between patients who originally received placebo vs RPC4046. Most patients maintained responses through week 52. Symptom remission (symptom-based EoE activity index score, ≤20) increased from 14% at LTE entry to 67% at LTE week 52 in placebo‒RPC4046 patients and from 30% to 54% in RPC4046‒RPC4046 (either dose) patients. Of the 28 patients who did not have a histologic response to RPC4046 during the double-blind induction phase, 10 patients (36%) achieved response during the LTE. The most common adverse events were upper respiratory tract infection (21%) and nasopharyngitis (14%). Conclusions One year of treatment with RPC4046 is generally well tolerated and results in continued improvement and/or maintenance of endoscopic, histologic, and clinical measures of EoE disease activity relative to baseline