Methods: This post hoc analysis assessed data from a 12-week, randomized, double-blind, placebo-controlled phase 3 study (NCT02605837) of budesonide oral suspension (BOS) 2.0 mg twice daily in patients (n=318) aged 11–55 years with EoE and dysphagia. Coprimary efficacy outcomes were histologic (≤ 6 eosinophils per high-power field [eos/hpf]) and dysphagia symptom (≥ 30% reduction in Dysphagia Symptom Questionnaire scores from baseline) responses at week 12.
Key findings:
Histologic responses (≤ 6 and < 15 eos/hpf) were similar regardless of dilation history
Fewer BOS-treated patients with dilation history than no dilation history achieved a dysphagia symptom response (44.0% vs 59.0%)
Discussion Points:
“Esophageal dilation may provide immediate relief from dysphagia (15); symptom improvement has been observed in 95% of dilated patients with EoE (29)…[however] dilation does not affect the underlying inflammation (18).”
“A histologic response (<15 eos/hpf) to swallowed corticosteroids has also been associated with a reduced number of repeat esophageal dilations required to maintain a similar esophageal caliber compared with nonresponse (≥15 eos/hpf)…this supports swallowed corticosteroid use in patients who have undergone esophageal dilation, even in the absence of acute symptom improvement.”
“Study limitations include potential enrollment of patients with severe disease due to stringent inclusion criteria.”
My take: While dilatation alone often improves symptoms, treatment with budesonide may help reduce need for repeat dilatations.
The study by Dellon et al was a 4-year, phase 3, open-label study in patients with EoE who completed up to 52 weeks of BOS therapy (Budesonide oral suspension 2 mg 2/day) in 2 preceding phase 3 studies.
Key findings:
At month 48 of treatment, 50.0% and 58.3% of patients achieved/maintained a histologic response (< or =6 and <15 eosinophils per high-power field, respectively)
Safety:
Treatment-emergent adverse events (TEAEs) occurred in 76.3% of patients; most were mild/moderate in severity and unrelated to study drug.
The most frequently reported BOS-related TEAEs included abnormal adrenocorticotropic hormone stimulation test results (8.4%, 11/131; number of events [m] [ 12) and adrenal insufficiency (2.3%, 3/131; m [ 3). Esophageal candidiasis occurred in 3.1% of patients (4/131)
The study by Biedermann et al explored the use of an orodipsersible tablet for EoE up to 3 years in patients who achieved remission during a 12-week induction. This tablet is not available in the U.S.
Key findings:
At week 96, 80.1% of patients were in histologic remission, defined as peak eosinophils per high-power field of <5, at week 96 vs 91.8% at open label extension baseline
No new safety concerns were observed across 96 weeks of treatment. Suspected symptomatic candidiasis occurred at similar rates to prior BOT studies and was predominantly mild and resolved with treatment
My take: The pharmaceutical budesonide suspension, Eohilia, is labelled by the FDA for use as a 12 week treatment course. Since EoE is a chronic disease, 12 weeks is insufficient. These long-term studies provide data that may address this shortcoming.
Background: “Etrasimod is an oral, once-daily, selective S1P1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of other immune-mediated inflammatory diseases. Etrasimod prevents trafficking of lymphocytes to inflamed mucosal tissue and sites of primary disease manifestation, offering a unique, promising mechanism for the treatment of eosinophilic oesophagitis.”
There were 108 participants in this study: 41 patients received etrasimod 2 mg, 39 received etrasimod 1 mg, and 28 received placebo.
Key findings:
Median percentage changes from baseline in peak eosinophil count (PEC) at week 16:6 were −58·4% for etrasimod 2 mg (p=0·010 vs placebo), −39·4% for etrasimod 1 mg (p=0·29 vs placebo) and −21·5% for placebo.
Significant reductions from baseline in oesophageal PEC were achieved with both etrasimod doses (n=27 for 2 mg n=28 for 1 mg) at week 24 versus placebo (n=19), with a numerically larger reduction seen with the 2 mg dose, which had a median placebo-adjusted difference of –103·9% from baseline in oesophageal PEC. Oesophageal PEC did not decrease further with longer etrasimod treatment during the extension period (to 52 weeks in a smaller subset)
Etrasimod 2 mg was associated with a significant improvement in DSQ score at week 24 versus placebo in patients with no history of dilation (LS mean −21·6 vs –9·6, p=0·031)
No serious treatment-emergent adverse events occurred.
My take (borrowed from the authors): “This [phase 2] study provides the first evidence that targeting the S1P pathway can improve disease activity in eosinophilic oesophagitis. Given that current treatment options for eosinophilic oesophagitis have variable and incomplete response rates, etrasimod presents a promising option.” Larger studies are warranted.
Methods: This was a single center, prospective, observational study with adult patients previously diagnosed with EoE. Thirty EoE patients, receiving off-label swallowed topical corticosteroids (STCs), were consecutively enrolled. “This is the first study to evaluate the clinical, histological, and endoscopic efficacy of the switch from STCs to BOT [Budesonide Orodispersible Tablet]”
Key findings:
The median Dysphagia Symptoms Score decreased from 5 (range 0–9) under STCs therapy to 0 (range 0–6) under BOT therapy (P < .0001)
After switching to BOT, there was a significant increase in the number of patients in histological remission (STCs: n = 19 of 30 [63.3%] vs BOT: n = 27 of 30 [90%]; P = .030) and histological deep remission (STCs: n = 17 of 30 [56.6%] vs BOT: n = 25 of 30 [83.3%]; P = .047)
Another important improvement following the switch was the improved patient satisfaction with the therapy in terms of a faster and easier modality of assumption…favors a better compliance to BOT
There was a “slight increase in oral Candida infection after BOT”
The authors did not include any cost information regarding the switch. In U.S., BOT is not an available treatment option. However, Eohilia, which is a budesonide suspension with a 12-week FDA approval period, costs ~$2100 per month (for 600 mL =30 day supply), whereas budesonide ampules at same dosage cost ~$300 per month (60 1 mg ampules).
My take: BOT therapy, which was targeted for esophageal delivery, was associated with better response rates. However, the cost of targeted FDA approved budesonide therapy in U.S, is exorbitant.
Methods: This was a retrospective cohort study using the UNC EoE Clinicopathologic Database of newly diagnosed patients with EoE treated with a tCS who had a follow-up endoscopy with biopsy. In total, there were 522 patients, including 195 pediatric patients (<18 yr). 122 patients received once daily dosing and 400 patients received twice daily dosing.
At our center, patients are typically treated on a clinical basis with either oral viscous budesonide or fluticasone from a multidose inhaler, with daily doses ranging from 1–2 mg for budesonide and 440–1760 μg for fluticasone based on patient size and at the discretion of the provider.
Key findings:
Global symptomatic response (78% vs 76%; P = .82), posttreatment eosinophil count (20.8 vs 25.6; P = .21), posttreatment EoE Endoscopic Reference Score (2.2 vs 2.2; P = .92), and histologic response (<15 eos/hpf; 56% vs 58%; P = .66) did not differ by dosing frequency
Candida was less frequent with daily dosing (2% vs 8%; P = .04)
My take: This study suggests that once daily dosing can be as effective as twice daily dosing. It may be that the total dose administered may be more important than the frequency. More studies are needed to confirm these results.
This was a retrospective study with children and adults with eosinophilic esophagitis (EoE). Among 1312 patients, there were 657 (50%), 461 (35%), and 194 (15%) with mild, moderate, and severe disease by I-SEE, respectively. Disease activity was categorized as mild (I-SEE 1–6), moderate (I-SEE 7–14), or severe (I-SEE ≥15).
Key findings:
Patients with severe disease were less likely to have histologic response (49% (severe) vs 55% (moderate) vs 64% (mild); P = .03 for <15 eosinophils per high-power field)
Patients with severe EoE also had lower global symptom response rates (53% vs 79% vs 83%, respectively) and higher post-treatment EoE Endoscopic Reference Scores (EREFS; 3.6 ± 2.3 vs 2.4 ± 1.8 vs 1.6 ± 1.6, respectively)
My take: More severe disease is harder to treat with EoE (and most everything else too).
Methods: Using two large administrative databases, MarketScan and Medicare, the authors estimated annual prevalence of EoE, as well as age- and sex-stratified estimates, standardized to the U.S. population. Health care utilization, including medications and endoscopic procedures, was quantified, and annual EoE-associated costs were calculated.
Key findings:
There was a 5-fold increase in prevalence in both databases since 2009.
Standardized to the U.S. population, the prevalence of EoE was 142.5/100,000, extrapolating to 472,380 cases. This equates to ~1 in 700 persons.
Total EoE-associated annual health care costs were estimated to be $1.32 billion in 2024 dollars after accounting for inflation.
PPIs were used more commonly than steroids for treatment. For Marketscan in 2022, PPIs were used in 41% and steroids in 26%.
There has been a 5-fold prevalence increase since 2009Prevalence by State. Overall, ~1 in 700 EoE Prevalence in U.S.
My take: There is likely a true increase in the number of affected individuals, though some changes in prevalence are due to an increased recognition/testing of eosinophilic esophagitis.
Methods: This was a multisite, randomized comparative efficacy trial of a 1-food (milk) elimination diet (1FED) versus 4-food (milk, egg, wheat, soy) elimination diet (4FED) in pediatric EoE. The 12-week study enrolled 63 patients (6-17 yrs). Primary end point was symptom improvement by Pediatric Eosinophilic Esophagitis Symptom Score (PEESS).
Key findings:
1FED vs 4FED: The mean PEESS improved −25.0 versus −14.5 (P = .04), but remission rates (41% vs 44%; P = 1.00), histology scoring system (−0.25 vs −0.29; P = .77), endoscopic reference score (−1.10 vs −0.58; P = .47), and QoL scores were similar between groups.
The 4FED withdrawal rate (32%) exceeded that of 1FED (11%) (P = .0496).
My take: A 4FED diet is difficult to maintain. In this 12 week study, more than 30% of patients withdrew from the 4FED diet. In addition, dairy elimination alone resulted in similar response rates.
Recently, Dr. Sana Syed gave Children’s Healthcare of Atlanta Grand Rounds. She provided an excellent update on the development of artificial intelligence (AI) to select targeted therapies for pediatric gastroenterology diseases. My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of her slides.
Key points:
One of the goals of using AI is to identify the right therapy at the time of diagnosis. Currently, diseases like eosinophilic esophagitis (EoE) and Crohn’s disease have multiple treatment options. However, many patients do not respond to first-line treatments; many develop complications due to not responding to treatment.
Currently we are lacking adequate biomarkers for individualized therapy. AI has the potential to sort through massive amounts of data (histologic, genetic, pharmacokinetics, transcriptome, metabolomics, etc) to allow for precision therapy.
For EoE, machine-learning has already identified three subtypes that may affect clinical management. EoE1 is associated with a normal-appearing esophagus. EoE2 is associated with being steroid refractory. EoE3, when compared to the other two endotypes, is associated with adult-onset and narrow-caliber esophagus or stricturing.
For Crohn’s disease, research has shown that younger age has been associated with an increased risk of not responding to anti-TNF therapy
This is a quote from President Obama when his administration announced massive funding toward precision medicine in January of 2015, that the promise of precision medicine is ”delivering the right treatments at the right time, every time to the right person.” This figure illustrates some of the kinds of data that Dr. Syed had access to as faculty at UVA, including genomics, epigenome, transcriptomics, proteomics, metabolomics, etc.Shoda and colleagues, used a combination of histology data, endoscopic features, histologic and endoscopic scoring indices, and transcripts that make up the eosinophilic esophagitis diagnostic panel, a quantitative PCR assay with 96 EoE representative genes. The key message from all of those visualizations is that they found that EoE can be divided into three distinct endotypes after analyzing transcriptomics changes via partition-around-medoid clustering, a machine-learning method.In this project, the researcher intend to curate a novel metabolic network specific to the ileum, which is relevant to Crohn’s disease, link metabolic processes with Crohn’s disease phenotypes using in silico metabolic network modeling and ‘omics and characterize and target metabolic pathways in an organoid model generated from patient-derived Crohn’s disease tissue.In CoMPAS, the researchers aim to leverage artificial intelligence methods (AI) methods to build predictive models for CD using histology slides and single-cell RNA sequencing, allowing for risk stratification of B1 patients who will respond to anti-TNF therapyThe goal of our project is to create a multi-omics reference dataset with scRNA-seq data coupled with contextual data on tissue morphology, ancestry, social determinants of health, and the environment. The cohort for this study is enrolling patients who have clinical indications for endoscopy like foreign body removal, reflux, abdominal pain
My take: This work is necessary to identify the right treatments for each patient and will lead to better outcomes. We are already seeing the early stages of machine-learning’s impact on clinical care. In many other fields, AI work is much further along (especially in oncology). A recent study in Nature identified JAK inhibitors as potential life-saving therapy with toxic epidermal necrolysis (TEN).
Reference: Nordmann, T.M., Anderton, H., Hasegawa, A. et al. Spatial proteomics identifies JAKi as treatment for a lethal skin disease. Nature (2024). https://doi.org/10.1038/s41586-024-08061-0
Summary from Eric Topol (Ground Truths) focusing on spatial omics: Thierry Nordmann, Matthias Mann and their international consortium, used deep visual proteomics from 3μm PPFE sections of skin biopsies in patients affected by TEN…
More than 5,000 proteins were quantified from single cells—keratinocyte and immune cells—using mass spec, for the 4 different skin conditions (proteome cluster in Figure below, left panel). This led to the finding that the TEN patients had marked increased in Type 1 and 2 interferon signaling and activation of phosphorylated STAT1, which invoked the janus kinase (JAK/STAT) pathway. Subsequent steps were to test JAK inhibitors in cell culture (with live cell imaging) and in two different mouse models, all showing highly potent, dose-dependent impact on inhibition of the intense inflammatory process and disease severity…
They went on to treat seven patients at Fuian Medical University, the course of one patient shown below, treated with a JAKi on day 4 after diagnosis, and manifesting a marked response starting within 48 hours. All 7 patients fully resolved, with no side effects…
For spatial medicine, there are multiple analytical challenges that invoke the need for machine learning and A.I., including segmentation of cell types, automated capture of cells of microdissection, extracting useful information from the >5,000 proteins quantified per cell, and ultimately, as we’ll see more in the future, A.I. powering the construction of high-resolution 3D maps.
gutsandgrowth 