IBD Updates November 2019

M Lowenberg et al. Gastroenterol 2019; 157: 997-1006. This LOVE-CD study, a prospective study with 110 patients with active Crohn’s disease, found that treatment with vedolizumab resulted in 29% and 31% corticosteroid-free clinical remission at weeks 26 and 52 respectively (CDAI <150).  Endoscopic remission, based on intent-to-treat analysis, was 33% and 36% at weeks 26 and 52.  Serum vedolizumab levels above 10 mg/L at week 22 were associated with endoscopic remission at week 26.

S Danese et al. Gastroenterol 2019; 157: 1007-18.  This VERSIFY trial, a phase 3b, open-label, single-group study of 101 patients with Crohn’s disease, found that treatment with vedolizumab resulted in 11.9% and 17.9%  endoscopic remission at week 26 and 52 respectively. Remission by MRE was 21.9% and 38.1% at those respective time points. No notable safety issues were reported.

N Khan et al. Clin Gastroenterol 2019; 17: 2262-8. Using a retrospective cohort of 54,919 patients with IBD followed by the VA System (2000-2018), the authors identified 467 patients with incident squamous cell cancer (SCC); median age ~70 years.  11 patients with SCC died from related-complications.  In this group, 8 had been exposed to thiopurines.   Thus, exposure to thiopurines increased mortality related to SCC compared to those exposed to mesalamine therapy, though the absolute risk among the entire cohort was less than 1 in 5000.  My take: Long-term use of thiopurines should be paired with dermatology evaluation and good skin care.

Pics from Mechandise Mart Light Show, Chicago

Waiting for the String Test for Eosinophilic Esophagitis

A recent study (SJ Ackerman et al. American Journal of Gastroenterology: October 2019 – Volume 114 – Issue 10 – p 1614–1625) provides additional data supporting the ‘string’ test to determine whether eosinophilic esophagitis is active or inactive.  Thanks to Ben Gold for sharing this reference.

My take: The string test could be a useful test for monitoring response to treatment, especially if it could garner insurance coverage. When/if will it ever become available clinically? (prior publication as early as 2012: String test for EoE)

Here’s the link to the full-text open-access article: One-Hour Esophageal String Test: A Nonendoscopic Minimally Invasive Test That Accurately Detects Disease Activity in Eosinophilic Esophagitis

Abstract:

OBJECTIVES: Eosinophilic esophagitis (EoE), a chronic food allergic disease, lacks sensitive and specific peripheral biomarkers. We hypothesized that levels of EoE-related biomarkers captured using a 1-hour minimally invasive Esophageal String Test (EST) would correlate with mucosal eosinophil counts and tissue concentrations of these same biomarkers. We aimed to determine whether a 1-hour EST accurately
distinguishes active from inactive EoE or a normal esophagus.

METHODS: In a prospective, multisite study, children and adults (ages 7–55 years) undergoing a clinically indicated esophagogastroduodenoscopy performed an EST with an esophageal dwell time of 1 hour. Subjects were divided into 3 groups: active EoE, inactive EoE, and normal esophageal mucosa. Eosinophil-associated protein levels were compared between EST effluents and esophageal biopsy extracts. Statistical modeling was performed to select biomarkers that best correlated with and
predicted eosinophilic inflammation.

RESULTS: One hundred thirty-four subjects (74 children, 60 adults) with active EoE (n 5 62), inactive EoE (n 5 37), and patient controls with a normal esophagus (n 5 35) completed the study. EST-captured eosinophil-associated biomarkers correlated significantly with peak eosinophils/high-power field, endoscopic visual scoring, and the same proteins extracted from mucosal biopsies. Statistical modeling, using combined eotaxin-3 and major basic protein-1 concentrations, led to the development of EoE scores that distinguished subjects with active EoE from inactive EoE or normal esophagi. Eightyseven percent of children, 95% of parents, and 92% of adults preferred the EST over endoscopy if it provided similar information.

DISCUSSION: The 1-hour EST accurately distinguishes active from inactive EoE in children and adults and may facilitate monitoring of disease activity in a safe and minimally invasive fashion.

First Floor of Hancock Building, Chicago

Precision Prediction of Biliary Atresia Survival

Though young age at the time of Kasai and surgical experience have been identified as factors in the long-term outcome of patients with biliary atresia (BA), why is it that some with timely intervention still fail to respond?  Conceptually, I’ve considered those who had progressive disease as probably having an intrahepatic component of their biliary disease that a Kasai operation cannot help.

New research (Z Luo, P Shivakumar, R Mourya, S Gutta, JA Bezerra. Gastroenterol 2019; 157: 1138-52) identifies genetic factors that are likely a more powerful predictor of Kasai response then the traditional clinical factors.

The science in this study is fascinating –combining genetic heat maps, and survival curves.  The prediction with a 14-gene signature is amplified with serum total bilirubin at 3 months post-Kasai.  In addition, these studies are combined with a mouse model treated with N-acetylcysteine (NAC).  Histologic changes were then assessed.

Key findings:

  • The 14-gene mRNA expression pattern predicted shorter and longer survival times in both the discovery (n=121) and validation sets (n=50) of children with BA (see figure below: red curve vs blue curve)
  • When this 14-gene expression pattern was paired with total bilirubin level 3 months after Kasai, this identified children who survived with their native liver at 24 months with an area under the curve of 0.948 in the discovery set and 0.813 in the validation set (P<.001).
  • In those with transplant-free survival, many of the mRNAs expressed had increased scores for glutathione metabolism.  Subsequently, mice with BA were treated with NAC (which promotes glutathione metabolism) & had reduced bile duct obstruction, liver fibrosis, and increased survival times.
  • In children with lower survival rates, there was increased mRNA expression of proteins encoding fibrosis genes in the liver tissues.

My take: This 14-gene signature has the potential to change our approach to children with BA.  Also, when evaluating surgical success rate, these underlying genetic factors will need to be incorporated.

Image available online

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#NASPGHAN19 Annual Meeting -Plenary Session

Here are some notes and a few slides from NASPGHAN’s plenary session.  There could be errors of transcription in my notes.

Benjamin Gold, NASPGHAN president and part of our GI group, GI Care For Kids, welcomed everyone to the meeting.

Link to NASPGHAN_Annual_Meeting_Program 2019

The first speaker, Jack Gilbert, gave the William F Balistreri lecture.  Dr. Gilbert has written a book on the topic of our ‘magnificent microbiome,’ Dirt is Good.  Here are a few slides:

Related study (not discussed in the talk): A recent study (R Vasapolli et al. Gastroenterology 2019; 157: 1081-91) provided data from 21 healthy adults. Using biopsies from panendoscopy and saliva/fecal samples, the authors found that the fecal microbiome is not representative of the mucosal microbiome.  In addition, each GI region had a different bacterial community.

Christopher Forrest gave the keynote lecture on pediatric learning health systems. By collating data from large pediatric health systems, the researchers can determine more quickly how effective treatments are in all pediatric specialties.

Melvin Heyman, editor of JPGN, provided a good year in review. I only capture a few images.

What is the Calprotectin Threshold for Disease Progression in Crohn’s Disease?

A recent retrospective study (NA Kennedy et al. Clin Gastroenterol Hepatol 2019; 17: 2269-76) with 918 patients with Crohn’s disease (CD) examined calprotectin levels and disease progression. Median followup was 50.6 months.

Key findings:

  • A calprotectin level cut-off of 115 mcg/g was identified as optimal for separation of those with and without disease disease progression.
  • The authors noted: “Several studies have identified a cut-off value of 250 mcg/g as being useful to distinguish active from inactive disease.  In the present study,…a lower threshold of 115 mcg/g (was identified) suggesting that lower levels of inflammatory activity still may be associated with an adverse outcome.”
  • The authors’ figure 2, as estimated by the empiric transition matrix method, shows disease progression over 30 years.  At that point,  the groups were nearly equally divide between stricturing disease, penetrating disease and inflammatory disease; in contrast at disease onset, ~80% had inflammatory disease behavior.

My take: As more effective therapies have become available, our goals for disease control have changed and focus on altering the disease course with more stringent endpoints.  For calprotectin, the lower number (115 compared to 250) indicates a much lower risk for disease progression.

Related blog posts:

Chicago

#NASPGHAN19 Impact of New Technologies on Patient Health

Along with Ragh Varier, I had the privilege of moderating a session on new technologies on patient health.  Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Chicago

 

Dr. Mehta’s lecture focused on wearable health technologies. Key points:

  • It is already in use in some areas (eg. continuous glucose monitoring for diabetes, ECG sensors).
  • She noted that wearable technology dates back to the 1600s with the abacus ring
  • Challenges: Accuracy, Actionability/outcome improvement, Reaching at-risk populations (not just the ‘worried well’ populations), regulation, sustainability (users may abandon quickly), and ethical/privacy concerns
  • Some families taking technology into their own hands, so to speak. #WeAreNotWaiting.  Example: artificial pancreas device system

Dr. Syed’s lecture focused on artificial intelligence in medical-decision making. Key points:

  • AI is already in use in areas like facial recognition
  • AI may be able to increase polyp detection rate in colonoscopy and improve histology reading
  • Her team has been working on using AI to help distinguishing enviromental enteropathy histology from other etiologies
  • Other potential uses: AI to help predict Crohn’s disease progression based on histology

Related study (not discussed in talk): Z Deng, H Shi et al. Gastroenterology 2019; 157: 1044-54. The authors collected more than 113 million images from 6970.  With a deep-learning algorithm, they found that video capsule endoscopy could have higher detection rates and improved reading time with a “CNN-based” reading system (CNN=convolutional neural network).  The mean reading time was reduced from 97 minutes with conventional reading to 6 minutes with CNN-based reading system.  The later had 99.88% sensitivity in per-patient analysis (vs. 74.57% with conventional reading).

The oral abstract presentation, by Sonja Swenson, detailed how machine learning was applied to try to improve transplantation selection/PELD scores.

  • The authors of this abstract (437) used data from 6273 patients with PELD scores and added additional variables to try to identify a more accurate model.
  • Link: All NASPGHAN 2019 Abstracts

Dr. Li, known by some as the ’emperor of emesis,’ presented a lecture on telemedicine. His full slides: Telemedicine NASPGHAN Updated 2019 (B Li)

Key points:

  • When surveyed, patients/families prefer telemedicine over conventional medicine.  Key reason is convenience
  • Lots of issues from health care provider viewpoint: reimbursement, licensing (improving), increased time
  • Many examples of telemedicine/telemonitoring that are ongoing

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.

 

How to Make a Study Look Favorable for Reflux Surgery Compared to Medical Treatment

A recent study (SJ Spechler et al. NEJM 2019; 381: 1513-23) on first glance appears to support surgery as more effective than medical treatment for refractory heartburn.

Only ~20% of enrolled patients were included in the reported outcomes!

Here’s what happened.  Among a cohort of VA patients (n=360, mean age 48 years) who were reportedly refractory to PPI-treatment:

  • 78 were excluded during prerandomization
  • 42 had relief of their heartburn during a 2-week omeprazole lead-in (20 mg BID)
  • 70 did not complete trial procedures
  • 23 had non-GERD disorders
  • 99 had functional heartburn

This left 78 patients who underwent randomization.  All patients in this highly-selected group had undergone endoscopy with biopsy, impedance-pH testing, and esophageal manometry.  18 of 27 (67%) had treatment success with surgery compared to 7 of 25 patients treated with baclofen/PPI and 3 of 26 with control medical treatment (PPI alone).

Key points:

  • Careful evaluation is needed in any patient with refractory heartburn, especially if contemplating surgery.  Most will either respond to PPI treatment or have a disorder other than reflux; the authors note that 122 patients (out of 360 patients) did NOT have reflux –99 had functional heartburn.
  • Careful instruction in PPI use can be helpful.  Omeprazole and similar agents should be taken 30 minutes before meals.
  • The authors noted that in addition to reflux, that reflux hypersensitivity can “respond to fundoplication…treatment success was 71% among the 14 with reflux hypersensitivity and 62% among the 13 with abnormal acid reflux.”

Limitations: The VA population is not representative of the general population; this trial had a predominance of white males. Also, it is hard to exclude that some of the ‘success’ of the procedure could relate to a powerful placebo response.

My take: This trial reinforces the notion that reflux surgery is helpful in very few highly-selected patients.

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