New Treatment for Eosinophilic Gastritis and Duodenitis

ES Dellon et al. NEJM 2020; 383: 1624-1634. Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis

Background: AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells.

Methods: In this phase 2 trial, the authors randomly assigned adults (n=65) who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo

Key findings:

  • The mean percentage change in gastrointestinal eosinophil count was −86% in the combined AK002 group, as compared with 9% in the placebo group
  • Treatment response  (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo
  • The authors note that AK002 “also resulted in alleviation of dysphagia in patients with a history of concomitant eosinophilic esophagitis.”
  • Limitations: Small study and 10% developed antibodies to drug

My take: Larger phase 3 studies with AK002 are underway (NCT04322604 & NCT04322708). AK002 looks promising for eosinophilic gastrointestinal diseases.

Change in total symptom score over 14 weeks. “Shown is the least-squares mean percentage change from baseline in total symptom score over time.” The total symptom score ranges from 0 to 80, with higher scores indicating greater symptom severity. Each of eight symptoms are given a score of 0 to 10: abdominal pain, nausea, vomiting, early satiety, loss of appetite, abdominal cramping, bloating and diarrhea.

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#NASPGHAN19 Postgraduate Course (Part 5)

Here are some selected slides and notes from this year’s NASPGHAN’s postrgraduate course.  There may be errors in omission or transcription on my part.

Link to the full NASPGHAN PG Syllabus 2019 (Borrowed with permission)

– Intestinal Inflammation Session

192 David T. Rubin, MD, University of Chicago Positioning the new IBD therapies: Merging experience with evidence

Some key points:

  • Ustekinumab escalation can increase response. Optimization in CD patients with loss of response led to recapture of response in 69% of patients
  • Tofacitinib –given black warning, will likely be used in more refractory patients
  • May be able retry a previous therapy (Chicago protocol in slide below)

As an aside, while Dr. Rubin is an excellent speaker, my view is that there are so many terrific pediatric IBD specialists, I would favor having a pediatric IBD specialist give this talk at our postgraduate course.  (Some might argue that adult IBD specialists would have more experience with emerging therapies.)

204 Anne Griffiths, MD, FRCPC, Hospital for Sick Children Immunosuppressive therapy in IBD: Can we de-escalate therapy?

  • High rate of relapse when biologic therapy is stopped.  Use of an immunomodulator may reduce the relapse rate when stopping an anti-TNF agent

215 Stacy Kahn, MD, Boston Children’s Hospital When it is not IBD … rare forms of intestinal inflammation

  • For patients with milder microscopic colitis, antidiarrheal agents can be given.  For more severe disease, budesonide is effective.

223 Edaire Cheng, MD, UT Southwestern Medical Center  Eosinophilic inflammation beyond the esophagus

 

Disclaimer: NASPGHAN/gutsandgrowth assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version.

Vedolizumab -Could it Work for Eosinophilic Gastroenteritis?

A recent study with only five patients (HP Kim et al. Clin Gastroenterol Hepatol 2018; 16: 1992-4) examined the use of vedolizumab for eosinophilic gastroenteritis.. The rationale was that α4β7 integrin may play an important role in eosinophilic localization in IBD and that blocking α4β7 may inhibit eosinophil recruitment to intestinal mucosa.  In addition, there are few proven therapies for EGE beyond steroids and dietary treatments.  The five patients in this study had been tried on numerous prior treatments and had a disease course of 6-17 years prior to vedolizumab.

Key findings:

  • Two of the five patients were able to wean/discontinue steroids, reported symptom improvement and had normal gastric and small bowel biopsies.  The median time to histologic followup was 2.2 months.
  • A third patient reported symptom improvement but declined a followup biopsy.

My take: A larger study of vedolizumab is needed for EGE.

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Calgary

How Many Eosinophils Indicate Eosinophilic Gastroenteritis or Colitis?

A recent study (Z Kiss et al. JPGN 2018; 67: 6-12) provides more data on normative values for eosinophil counts in the GI tract.  For their report, the authors reviewed 3 databases for a systematic search of the literature. They screened 1316 abstracts but found only 8 articles with complete/relevant data.  Among these 8 articles, data regarding each segment of the GI tract was present in as few as 3 articles and as many as 6 articles. The authors provide confidence intervals (CIs) and prediction intervals (PIs); the latter account for the wider uncertainty due to insufficient data.

Key points:

Normal eosinophil cell number per high-power field (HPF area = 0.2 mm squared):

  • Duodenum 8.26 with CI 4.71-11.8 and PI of 0 to 20.57
  • Terminal ileum 11.52 with CI 7.21-15.83 and PI of 0 to 60.64
  • Cecum 14.12 with CI 9.05-19.19 and PI of 0 to 38.64
  • Ascending colon 13.25 with CI 8.65-17.86 and PI of 0 to 35.42
  • Transverse colon 11.52 with CI 7.80-15.23 and PI of 0 to 25.85
  • Descending colon 10.32 with CI 7.22-13.42 and PI of 0 to 49.10
  • Sigmoid colon 8.80 with CI 6.82-10.77 and PI of 0 to 32.49
  • Rectum 7.39 with CI 4.20-10.59 and PI of 0 to 22.33

Other points:

  • The authors note that eos/HPFis a flawed measurement due to technical parameters of the microscope.  Some HPFs are bigger than others –this could affect eosinophil count up to 5-fold.  The authors specify an HPF to be =0.2 mm squared.
  • Obtaining appropriate mucosal samples for normal number of eosinophil counts can be difficult.  Even patients with functional disorders like irritable bowel syndrome and nonulcer dyspepsia could have abnormal numbers of eosinophils.

My take: These numbers of expected eosinophil counts for pediatric histology are a good starting point.  The prediction intervals remain large due to insufficient data.

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Gibbs Gardens

Why Did the Young Woman’s Heartburn Keep Getting Worse?

Mystery NY Times Case: Why Did the Young Woman’s Heartburn Keep Getting Worse?

An excerpt:

The radiologist who read the scan made an interesting observation. In each of the three visits to the E.R., the patient’s blood had been tested. All three tests showed an elevated white-blood-cell count. That could suggest an infection — but in her tests a quarter of those white blood cells were a cell type known as eosinophils, which normally make up only a tiny fraction of the white blood cells in the circulation. ..

When the radiologist saw the elevated level of eosinophils, however, he recalled an unusual and relatively new disorder known as eosinophilic gastroenteritis (EGE). He added this rarity to the list of possible causes of the patient’s abnormal CT findings on his report…

EGE is thought to be an unusual type of allergic reaction to foods. Food exposure triggers the recruitment of eosinophils to the gut, but once they have a toehold, repeated exposure isn’t necessary to keep them there. The disorder was first described in a series of patients in the United States in 1993 but since then has been found to occur throughout the developed world. Because it’s a relatively new disease, and because our understanding of allergy is still emerging, it’s not well understood. As recognition of the disorder expands, so, too, do the number of cases. Patients are usually started on an elimination diet and given steroids to further suppress the immune system. An elimination diet — one in which the foods most frequently linked to allergic reactions, like milk, eggs and wheat, are not consumed — has been shown to be helpful up to 90 percent of the time.

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Epidemiology of Eosinophilic Disorders

Jensen et al. JPGN 2016; 62: 36-42.  The researchers used a large database (>75 million individuals) representative of US commercially-insured population to provide estimates of the prevalence of several eosinophilic disorders:

  • Eosinophilic gastritis 6.3 per 100,000
  • Eosinophilic gastroenteritis 8.4 per 100,000
  • Eosinophilic colitis 3.3 per 100,000

In the associated commentary by Furuta et al (pg 1), clinicians are encouraged to urge patients with EGID to register on the Consortium for Eosinophilic Gastrointestinal Disease Research registry: https://www.rarediseasesnetwork.org/cms/CEGIR

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Anti-TNF Therapy for Eosinophilic Gastroenteritis

A recent report highlights the use of anti-TNF therapy (eg. infliximab (IFX) and adalimumab [ADA])  for eosinophilic enterocolitis/eosinophilic gastroenteritis in eight patients who had not responded to other treatments (JPGN 2013; 56: 492-97).

The mean age of these patients was 8 years with a range of 1 to 14 years.  Prior to use of IFX therapy, multiple therapies had been used.  Four patients had been treated with complete elemental diet; medications that were used included montelukast, hydroxyzine, sodium cromogylcate, budesonide, amitriptyline, prednisone, ketotifen, cyproheptadine, thiopurines, and methotrexate (Table 1 in study).

Complete clinical remission was noted to occur in 6 (75%) with IFX induction treatment; this was associated with mucosal healing in 3, mucosal improvement in 2, and unknown in 1 patient.

The six responders were followed for a median of 7 years.  During that timeframe, four of six had secondary loss of response and were switched to ADA.  Three of these four maintained a clinical response with ADA using high doses (80 mg EOW).

Additional References:

  • -Clin Gastroenterol Hepatol 2011; 9: 950.  40% of Eosinophili gastroenteritis resolved.
  • -JPGN 2010; 51: 723. n=91.  Incidental gastric eosinophils does not predict a worse response to fluticasone then isolated EoE.
  • -NEJM 2009; 361: 1387.  Description of a case of eosinophilic gastroenteritis.
  • -Gut 2009; 58: 721-32. Review of primary Eos d/o of GI tract.
  • -JPGN 2008; 47: 234-8.  EGIDs.