Sep 9, 2022
Co-hosts Ryan Piansky and Holly Knotowicz talk with guest Nicole Arva, MD, PhD, about genetics and eosinophilic colitis.
Dr. Arva is a pediatric pathologist at Ann & Robert H. Lurie Children’s Hospital of Chicago. She is also an Associate Professor in the Department of Pathology at Northwestern University Feinberg School of Medicine. She has been a part of more than 50 publications, many of which explore eosinophilic diseases, and recently co-authored a manuscript entitled “Genetics of Eosinophilic Colitis Revealed.”
In this episode, Holly and Ryan discuss with Dr. Arva her recent and upcoming research. They cover the purposes of molecular testing and a new molecular study that concludes that EoC is a unique disease, with specific genetic characteristics that set it apart from other EGIDs, Crohn’s disease, and IBD. Dr. Arva explains how that uniqueness was discovered, and what it means for therapeutic options for EoC. Listen in to learn about this innovative research.
Disclaimer: The information provided in this podcast is designed to support, not replace the relationship that exists between listeners and their healthcare providers. Opinions, information, and recommendations shared in this podcast are not a substitute for medical advice. Decisions related to medical care should be made with your healthcare provider. Opinions and views of guests and co-hosts are their own.
[1:44] Holly shares the topic of this episode, genetics and eosinophilic colitis (EoC), and introduces today’s guest, Dr. Nicole Arva.
[1:51] Dr. Nicole Arva is a Pediatric Pathologist at Ann & Robert H. Lurie Children’s Hospital of Chicago and an Associate Professor in the Department of Pathology at Northwestern University Feinberg School of Medicine.
[2:37] Dr. Arva wanted to understand the mechanisms of diseases to be able to treat them more efficiently. She tells of her professional journey after medical school, studying cancer and leukemia cell lines. She continued her medical training in pathology, specializing in pediatric pathology.
[3:15] Dr. Arva’s work involves assessing laboratory slides from pediatric tissue samples to establish a diagnosis.
[4:05] Dr. Arva explains molecular testing. An increasing number of diseases are found to have genetic abnormalities. Molecular testing can help lead to an accurate diagnosis. Dr. Arva describes getting a tumor diagnosis from molecular testing showing specific chromosomal translocations in correlation with microscopic examination.
[5:23] By performing molecular testing, we can discover gene alterations that can help guide the development of new therapies. Molecular testing can uncover genes that can be targeted.
[5:51] Genetic analysis can also provide insight into how a disease develops and shed light on the pathways that are involved.
[6:35] Dr. Arva describes EoC. EoC affects the large bowel. Eosinophils cause inflammation in the colon. Patients usually have abdominal pain, diarrhea, which can be bloody, and fluid in the abdominal cavity. Patients can become malnourished. They may develop a bowel obstruction or perforation.
[7:25] Studies have been performed on Eosinophilic Gastrointestinal Disorders (EGIDs) and Inflammatory Bowel Disease (IBD). But EoC is a poorly understood condition. When Dr. Arva and her colleagues started their study, they didn’t know whether EoC should be considered to be within the spectrum of EGIDs or as an IBD.
[8:03] The research team was looking to determine where EoC belongs because that would affect the way patients would be treated. Although EoC is similar to other EGIDs because eosinophils drive the inflammation,, EoC has a lower incidence than EGIDs, more severe symptoms, and co-morbidities.
[8:38] EoC is similar to IBDs in that it is an inflammation of the large bowel, but a different type of cell is predominantly involved in IBD (neutrophil) with some eosinophils present.
[9:38] The diagnosis of EoC is challenging. Other, more common conditions can cause colonic eosinophilic inflammation. When pathologists encounter eosinophilia in the large bowel, they have to think of other medical conditions that can cause that. A diagnosis of EoC is established only after other causes of gastrointestinal eosinophilia have been ruled out.
[10:14] IBD, intestinal parasites, autoimmune or connective tissue disorders, and vasculitis can all mimic EoC. Certain medicines can induce eosinophilia. Eosinophils are normally found in the large bowel.
[10:51] Pathologists have to establish eosinophil count values for each segment of the large bowel to best evaluate colonic biopsy; everybody needs to follow the standards when diagnosing EoC.
[11:42] Patients suspected to have EoC may undergo lab testing, imaging, and colonoscopy to reach a diagnosis. The findings may vary, depending on which section of the bowel wall is infiltrated by eosinophils.
[13:02] A biopsy may reveal an increased number of eosinophils. All these test results have to be combined to reach a diagnosis of EoC.
[13:27] The focus of the study was performing molecular testing that was very helpful in diagnosing EoC. They found that nearly 1,000 genes were differentially expressed in EoC compared to normal participants or Crohn’s disease subjects.
[14:30] They found differences in gene expression between EoC and other types of EGIDs, such as eosinophilic esophagitis or gastritis.
[15:02] The main chemotactic factor in EoC seems to be CCL11 (Eotaxin-1). CCL11 is a molecule that attracts eosinophils in the tissue. In eosinophilic esophagitis or gastritis, the main chemotactic factor appears to be CCL26 (Eotaxin-3). All these findings support the idea that EoC is a distinct entity, which is different from other EGIDs and IBD.
[15:37] EoC seems to be driven by a mechanism that does not involve an allergic inflammation. The therapeutic strategy may be much different now that we have a better understanding of EoC.
[16:23] Eosinophilic esophagitis has been shown to run in families and it would be beneficial to test family members with a blood test, allergy testing, or endoscopy if they develop symptoms. As eosinophilic colitis has a different epigenetic mechanism, it is not clear that the same testing is needed for EoC patients or family members.
[17:26] Besides endoscopies and colonoscopies, blood tests looking for high IgE levels, allergy testing, and CT can be useful in testing for various eosinophilic disorders.
[21:07] Dr. Arva explains how many eosinophils are seen in a high-power field of a slide from a colon biopsy to diagnose EoC. They established a normal count of eosinophils for the segment of the colon and the abnormal count would be twice the normal count.
[22:20] Now that a different pathogenic mechanism has been discovered for EoC than for EGIDs and IBD, new treatments can be explored or developed. We are just beginning the research. CLC protein (galectin-10) is upregulated in EoC and may be a target for treatment development. Antibodies may be effective for relieving EoC inflammation.
[23:34] It is challenging to treat EoC because the newly-discovered pathogenic mechanism shows that EoC is unlikely to be allergic in nature, making elimination diets and steroid treatments ineffective. New therapies will be required.
[24:05] All EGIDs can have a significant impact on quality of life. People with EoC can develop serious complications, such as dehydration, malnutrition, intestinal strictures, and bowel obstruction.
[25:04] Dr. Arva considers the difficulties pathologists face in analyzing eosinophilic diseases. There are few patients with EoC. Dr. Arva describes additional challenges.
[26:25] Dr. Arva looks ahead. Most of her research goes in the direction of pediatric gastroenterology. She is working with a clinical colleague, Dr. Josh Weschler, to analyze the role of mast cells in EGIDs. They are finding that eosinophils are not the only offenders in EGIDs and are looking to establish a cohort of EGID patients to study.
[27:43] Holly thanks Dr. Arva for taking the time to talk with us today.
[27:51] Dr. Arva says we are just at the beginning of understanding the etiology of EoC. This study had a small sample size and the results will have to be validated with larger cohorts of patients. The analyses were performed on whole biopsies that contained all types of cells. Future studies using single-cell preparations will be important.
[28:55] Ryan invites listeners to look at apfed.org/eoc to learn more about EoC. Ryan also encourages you to connect with the APFED online community at apfed.org/connections.
[29:25] Dr. Arva thanks Ryan and Holly for having her on the podcast. She is grateful for the opportunity to research EGIDs and benefit patients suffering from these conditions.
Mentioned in This Episode:
“I have always wanted to better understand the mechanisms of diseases because I considered that if we know how an illness occurs, we can treat that entity more efficiently.” — Dr. Nicole Arva
“As testing increases, more and more diseases are found to have recurrent genetic abnormalities. … Molecular testing can help the pathologist to render the correct diagnosis.” — Dr. Nicole Arva
“There are similarities and dissimilarities between EoC and other EGIDs and IBD.” — Dr. Nicole Arva
“Findings support the idea that EoC … seems to be driven by a mechanism that does not involve an allergic inflammation.” — Dr. Nicole Arva