How HLA DQA1*05 and Combination Therapy Modulate Treatment Outcomes in Children with Crohn’s Disease

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J Adler et al. Am J Gastroenterol 2025; 120: 1076-1086. HLA DQA1*05 and Risk of Antitumor Necrosis Factor Treatment Failure and Anti-Drug Antibody Development in Children’s with Crohn’s Disease.

This was a prospective, double-blind, placebo-controlled trial with 204 patients examining the clinical outcomes of anti-TNF with or without methotrexate (COMBINE).

Key findings:

  • Treatment failure in HLA DQA1*O5: A trend toward increased treatment failure among HLA DQA1*05-positive participants was not statistically-significant (hazard ratio 1.58; P = 0.08).
  • HLA DQA1*05 and Treatment Failure Rate: During the followup period, HLA DQA1*05-positive patients had a 35% failure rate compared to 26% for those who were HLA DQA1*05-negative (P=0.098). The overall failure rate was 30%
  • Methotrexate Combined with HLA DQA1*05 Effect: Patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13-0.70; P = 0.005).
  • Anti-TNF Medication Comparison: Treatment failure was similar between infliximab and adalimumab, 29% and 33% respectively
  • Antidrug antibodies (ADA): A trend toward increased ADA development among HLA DQA1*05-positive participants was not significant (odds ratio 1.96, P = 0.09). The addition of methotrexate to the treatment regimen mitigated the risk of treatment failure among individuals positive for HLA DQA1*05 and reduced the odds of developing ADA by 90%.
  • Rate of ADA: “After further stratification, HLA DQA1*05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05-positive patients on placebo (odds ratio 0.12; P = 0.008).”

Discussion Points:

  • “A retrospective by Fuentes-Valenzuela et al …found that if patients underwent proactive TDM, there was no increase in the rate of treatment discontinuation among those who were HLA DQ-A105 positive compared with HLA DQ-A105 negative”
  • “The totality of evidence suggests that HLA DQ-A1*05 seems to confer a risk of both immunogenicity and treatment failure, particularly among infliximab-treated patients. Furthermore, this risk may be mitigated by the use of proactive TDM and/or concomitant immunomodulators.”

My take (borrowed in part from authors):  “40% of patients were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate.” The use of combination therapy (methotrexate with anti-TNF) was associated with the lowest failure rates.

Also, unrelated article: DA Carlson et al. Gastroenterology 2025; 168: 1114-1127. A Standardized Approach to Performing and Interpreting Functional Lumen Imaging Probe Panometry for Esophageal Motility Disorders: The Dallas Consensus. Congratulations to Dr. Garza from our group who was one of the authors

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Dr. Arun Singh: Tips and Tricks to Managing Celiac Disease

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Recently Dr. Arun Singh gave our group a terrific update on Celiac Disease. I have taken some notes and shared some slides. There may be inadvertent omissions and mistakes in my notes.

Key points:

  • Celiac disease (CD) global prevalence is about 1.4%, though there are ‘pockets’ with much higher rates (~3% prevalence in Colorado). This equates to more than 3 million Americans with CD
  • There is a huge gluten free diet market of ~$7 billion. This market includes CD, nonceliac gluten sensitivity (NCGS) and those with wheat allergies
  • Many patients have atypical symptoms which can include ADHD, brain fog, headaches, and elevated LFTs. Many have silent CD with no symptoms
  • Higher risk groups include family members (~10% risk for 1st degree, ~80% risk for identical twin), autoimmune diseases (thyroid, diabetes, others), and genetic disorders (Down syndrome, Williams syndrome, Turner syndrome)
  • Transient elevation of TTG IgA is common. In TEDDY study, 19% had TTG IgA spontaneously normalize. Thus, a single abnormal lab is not reliable
  • Genetic testing can be a useful adjunct in a few specific situations, including prior to instituting a gluten challenge
  • 1-3% of those with celiac disease may be negative for HLA-DQ2 and HLA-DQ8
  • If a gluten challenge is needed, 12 weeks is ideal. However, if poorly tolerated, then consider endoscopy earlier and Dr. Singh recommends checking in with family 4-6 weeks into the challenge
  • Endoscopy recommendations: Taking a single biopsy per pass can improve orientation when obtaining duodenal biopsies (bulb and distal portion, 5-6 in total)
  • NASPGHAN has not updated comprehensive guidelines for CD in 20 years
  • A survey of NASPGHAN members indicated that ~40% utilize a “no-biopsy” approach in patients. Dr. Singh noted that the accuracy of this approach, based on data from North America, may be about 96%
  • Drug trials for CD require a biopsy-confirmed diagnosis
  • Surveillance practice is quite variable. Important to follow growth and serology. CHOP approach includes surveillance for type 1 DM
  • Followup endoscopy to assess mucosal healing is not the current standard of care but could be helpful in some patients
  • Among patients with potential CD, about 30% develop CD over time. Thus, these patients should be monitored (yearly labs, f/u scope after 2 years)
  • Nonresponsive/refractory CD: start with nutrition assessment, often needs a f/u scope before consideration of budesonide therapy (9 mg x 12 weeks) or gluten contamination elimination diet

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Risks of GLP-1RA Therapy Related to Endoscopy: Three Studies and GLP1RA Nutrition Pearls

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A recent Nutrition Pearls with one of our nutritionists, Baily Koch, as a moderator was very good: Christy Figueredo – Navigating GLP-1 Use in Pediatrics (episode 33, 58 minutes)

A Faccisorusso et al. Clin Gastroenterol Hepatol 2025; 23: 715-725. Open access! Effects of Glucagon-Like Peptide-1 Receptor Agonists on Upper Gastrointestinal Endoscopy: A Meta-Analysis

This is one of three articles discussing the issue of GLP-1RAs and potential complications with upper endoscopy. Faccisourruso et al performed a meta-analysis that included 13 studies (of 177 studies) involving a total of 84,065 patients.

Key findings:

  • Patients receiving GLP-1RA therapy exhibited significantly higher rates of retained gastric contents (RGC) (OR, 5.56)
  • Rates of aborted and repeated procedures were higher in the GLP-1RA user group. The absolute risk of aborted procedure was 1% in GLP-1RA users compared to 0.3% in non-users. The absolute risk of a repeated procedure was 2% vs 1% respectively.
  • No significant differences were found in AE and aspiration rates between the 2 groups (OR, 4.04 and OR, 1.75 respectively). The absolute risk of aspiration was 0.3% in GLP1-RA users compared to 0.2% in non-GLP1-RA group
  • Adverse events were higher in GLP-1RA users (0.3%) compared to non-users (0.1%)

In their discussion, the authors note that an “individualized approach based on the indication of GLP-1RA use (withholding the drug in patients with diabetes could lead to more harm)…a potential stragegy could be to place patients on a liquid diet the day before endoscopy, thus prolonging the duration of fasting for solid for at least 12 hours.”

The related articles:

My take: The totality of these studies confirms the increased risk of retained gastric contents in patients receiving GLP-1RAs. This in turn increases the need to abort/reschedule cases and may result in very a low increased risk of aspiration. To mitigate this risk, it may be sufficient to implement a liquid diet the day before endoscopy (avoiding solid foods for at least 12 hours prior to endoscopy). This is in agreement with the recent AGA Rapid Clinical Practice Update (see post below).

Related article on utility of GLP-1RAs: David Kessler, NY Times  5/7/25: In a World of Addictive Foods, We Need GLP-1s

“Like millions of others, I was caught between what the food industry has done to make the American diet unhealthy and addictive and what my metabolism could accommodate.

We may now be at the brink of reclaiming our health. New and highly effective anti-obesity medications known as GLP-1s have revolutionized our understanding of weight loss and of obesity itself. These drugs alone are not a panacea for the obesity crisis that has engulfed the nation, and we should not mistake them for one. But their effectiveness underscores the fact that being overweight or obese was never the result of a lack of willpower…

GLP-1s are revolutionary drugs that can drastically reduce caloric intake and improve health in a way I didn’t expect I would ever see. Now we need to complete that revolution by taking on the food industry and its engineered foods that are contributing to some of the most harmful health issues America faces today.”

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Disclaimer: This blog, 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. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog 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.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

VISION 5-Year Study Results: Safety of Vonoprazan in Erosive Esophagitis

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N Uemura et al. Clin Gastroenterol Hepatol 2025; 23: 748-757. Open Access! Vonoprazan as a Long-term Maintenance Treatment for Erosive Esophagitis: VISION, a 5-Year, Randomized, Open-label Study

Background: Potassium-competitive acid blockers, such as vonoprazan, provide more potent gastric acid suppression than proton pump inhibitors. However, long-term safety data are lacking for vonoprazan in patients with healed erosive esophagitis. This study with 208 patients provides long-term data on the use of a vonoprazan.

Methods: Open-label study. Patients with erosive esophagitis (EE) received induction therapy (once daily vonoprazan 20 mg or lansoprazole 30 mg; ≤8 weeks). Those with healed EE received maintenance therapy (once daily vonoprazan 10 mg or lansoprazole 15 mg) for 260 weeks (2:1). 

Key findings–Adverse effects:

  • No malignant alterations or gastric neuroendocrine tumors (NETs) were observed; there was 1 adenoma in each group
  • At week 260, significantly more patients taking vonoprazan vs lansoprazole had parietal cell hyperplasia (97.1% vs 86.5%) and foveolar hyperplasia (14.7% vs 1.9%)
  • proportions of patients with ECL cell hyperplasia (4.9% vs 7.7%) and G-cell hyperplasia (85.3% vs 76.9%) were similar
  • Median serum gastrin levels were higher with vonoprazan treatment vs lansoprazole (625 pg/mL vs 200 pg/mL)

Key finding –Efficacy:

  • Overall, the cumulative EE recurrence over 260 weeks was lower in the vonoprazan group (10.8% ) vs the lansoprazole group (38.0%) (P = .001)  

Discussion Points:

  • “Annual endoscopies and biopsies performed in the VISION study are considered objective approaches for detecting upper gastrointestinal diseases and variable lesions, as well as gastric mucosa morphological changes in areas without endoscopically apparent lesions…Although the proportions of patients with parietal cell protrusion and foveolar hyperplasia were higher in the vonoprazan group than in the lansoprazole group over 5 years, the clinical significance of these findings is unclear.”
  • “The safety profiles of vonoprazan and lansoprazole were also comparable, suggesting that long-term use of vonoprazan is as safe as PPIs.”

My take: This study provides some reassurance regarding the risk of using vonoprazan & other potassium-competitive acid blockers. The benefits of controlling erosive esophagitis may outweigh potential safety risks of long-term use. Nevertheless, it will be a while before this class of medications is used extensively in the pediatric age group.

Related blog posts:

Disclaimer: This blog, 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. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog 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.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Head-to-Head: Tirzepatide Outperforms Semaglutide

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LA Aronne et al. NEJM 2025; DOI: 10.1056/NEJMoa2416394. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity

Methods: In this phase 3b, open-label, controlled “SURMOUNT-5” trial, adult participants (n=751) with obesity but without type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks

Key findings:

Discussion Points:

“With both treatments in our trial, as weight reduction increased, greater improvements occurred in cardiometabolic risk factors, including blood pressure, glycemia, and lipid levels, which is consistent with the findings in previous reports.17 The mean differences between tirzepatide and semaglutide in the cardiometabolic risk factors may be clinically relevant considering that reductions in systolic blood pressure of 2 to 5 mm Hg have been shown to reduce the risk of cardiovascular events.”

” As typically observed with incretin-based therapies, gastrointestinal adverse events were predominantly mild to moderate in severity, occurred mostly during dose escalation, and led to treatment discontinuation more often with semaglutide than with tirzepatide.”

My take (borrowed from the authors):  “Treatment with tirzepatide, a dual GIP and GLP-1 receptor agonist, was superior to treatment with semaglutide, a selective GLP-1 receptor agonist, with respect to reduction in body weight and waist circumference.”

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Upadacitinib’s Effectiveness for Perianal Fistulizing Crohn’s Disease

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J-F Colombel et al. Clinical Gastroenterology and Hepatology, Volume 23, Issue 6, 1019 – 1029. Open Access! Efficacy and Safety of Upadacitinib for Perianal Fistulizing Crohn’s Disease: A Post Hoc Analysis of 3 Phase 3 Trials

Methods: This post hoc analysis evaluated upadacitinib outcomes in patients with fistulizing disease in the following studies: phase 3 induction (U-EXCEL, U-EXCEED) and maintenance (U-ENDURE) trials. It was noted that there were 1021 patients in U-EXCEL and U-EXCEED; 143 (14.0%) had any fistulas at baseline (66 draining). Most (n = 128) had perianal fistulas (56 draining).

Key findings:

  • Fistulizing disease (primarily perianal) treated with upadacitinib achieved higher rates of resolution of drainage, closure of external openings, clinical remission, and endoscopic response vs placebo
These slides from Figure 1 show the resolution of drainage in perianal draining fistulas, closure of external perianal fistula openings, and closure of external openings for any fistula at week 12 of the induction trials and week 52 of the maintenance trial.

Discussion points:

  • Patients with draining fistulas often experience higher disease burden
  • Most patients in U-EXCEL and U-EXCEED had failed at least 2 prior biologic treatments (which often included anti-TNF therapy), reflecting a more refractory and difficult-to-treat population in CD
  • Despite the presence of perianal disease, patients with fistulizing CD treated with upadacitinib showed concurrent improvements in CD symptoms (CDAI, SF, and APS), luminal disease (endoscopic response and SES-CD), and markers of inflammation

My take: This study shows that upadacitinib is more effective than placebo; however, the majority of patients continued with ongoing perianal disease.

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Increase in Irritable Bowel Syndrome During COVID Pandemic

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CV Almario et al. Neurogastroenterology and Motility; https://doi.org/10.1111/nmo.70020. Trends in Prevalence of Rome IV Disorders of Gut-Brain Interaction During the COVID-19 Pandemic: Results From a Nationally Representative Sample of Over 160,000 People in the US

Methods: From May 2020 to May 2022, the authors performed a series of cross-sectional online surveys among a representative sample of adults ≥ 18 years old in the US (n=160,154). We administered Rome IV gastroduodenal and bowel DGBI questionnaires.

Key findings:

  •  During the COVID-19 pandemic, the prevalence of irritable bowel syndrome (IBS) increased from 6.1% [May 2020] to 11.0% [May 2022]
  • In addition, the prevalence of chronic idiopathic constipation (CIC) increased mildly from 6.0% [May 2020] to 6.4% [May 2022]
  • No changes in prevalence were seen for the other examined gastroduodenal and bowel disorders of gut-brain interaction (DGBI)

My take: This study identified increases in the prevalence of IBS during COVID. Increases in IBS following other enteric infections (eg. norovirus, shigella, campylobacter) has been shown previously as well.

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Rice Fields in Northern Thailand

David Rubin: Linking Inflammatory Bowel Disease and Mental Health Through the Gut Microbiome

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At this year’s DDW, Dr. David Rubin discussed the connection between inflammatory bowel disease and mental health via the microbiome. He shared his slides: Linking Inflammatory Bowel Disease and Mental Health Through the Gut Microbiome

Here are 15 of his 37 slides:

The Guardian: UnitedHealth Secretly Paid Nursing Homes to Reduce Hospital Transfers

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The Guardian 5/21/25:
Revealed: UnitedHealth secretly paid nursing homes to reduce hospital transfers

An excerpt:

UnitedHealth Group, the nation’s largest healthcare conglomerate, has secretly paid nursing homes thousands in bonuses to help slash hospital transfers for ailing residents – part of a series of cost-cutting tactics that has saved the company millions, but at times risked residents’ health, a Guardian investigation has found…

Those secret bonuses have been paid out as part of a UnitedHealth program that stations the company’s own medical teams in nursing homes and pushes them to cut care expenses for residents covered by the insurance giant.

In several cases identified by the Guardian, nursing home residents who needed immediate hospital care under the program failed to receive it, after interventions from UnitedHealth staffer…UnitedHealth said the suggestion that its employees have prevented hospital transfers “is verifiably false”. It said its bonus payments to nursing homes help prevent unnecessary hospitalizations that are costly and dangerous to patients and that its partnerships with nursing homes improve health outcomes…

To reduce residents’ hospital visits, UnitedHealth has offered nursing homes an array of financial sweeteners…

Two current and three former UnitedHealth nurse practitioners told the Guardian that UnitedHealth managers pressed nurse practitioners to persuade Medicare Advantage members to change their “code status” to DNR even when patients had clearly expressed a desire that all available treatments be used to keep them alive...

UnitedHealth’s insurance arm covers millions more Medicare Advantage seniors than any of its rivals

Commentary from Dr. Glaucomflecken account on X: https://x.com/i/status/1925348490680340979

My take: Healthcare insurance companies are incentivized to act as financial institutions and gatekeepers/third party administrators. This often compromises and delays patient care.

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Essential Summer Safety Tips for Preventing Drowning

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Yesterday, a ICU colleague indicated that she really does not like to work on summer holiday weekends. While she is a hard worker, what she doesn’t like is seeing kids with drowning and firework injuries. All of a sudden a happy time becomes tragic. With that in mind, here are a few tips to prevent drowning.

From Strong4Life: “Practicing water safety for kids of all ages is crucial because drowning is a leading cause of death in children from birth through the teen years. And drowning is often quick and silent.”

Also, firearm deaths are the leading cause of death in children in the U.S. and motor vehicle accidents are second. So, firearms need to be secured and drive safely on the way to the pool, lake, river or beach.

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