Safety Net for Celiac Disease?

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JA Murray, JA Syage et al.Gastroenterol 2022; 163: 1510-1521. Open access! Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge

Background: Latiglutenase (IMGX003) is an investigational dual-enzyme drug candidate that acts to degrade gluten in vivo when consumed with a meal. The authors note that “despite strict adherence to a GFD, about half of CD patients show evidence of persistent small intestinal mucosal injury (Marsh grades II–III);’ thus, there is a need to improve treatment with other measures in addition to diet.

Methods: 43 patients (IMGX003, n = 21; placebo, n = 22) completed this double blind and placebo controlled study which assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease (CD) exposed to 2 g of gluten per day for 6 weeks study

Key findings:

  • In IMGX003-treated patients, there was less damage to mucosa. The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was –0.04 vs –0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). 
  • Measurements of gluten-immunogenic peptides (GIP) in urine indicated 95% gluten degradation in the stomach by latiglutenase.

The 2 g dose per meal of gluten allowed used in the study, “would likely substantially exceed that accidently occurring while on a GFD, 4 supporting such an approach for management for gluten-triggered symptoms in treated patients.”

Graphical abstract:

In both the placebo and IMGX003 groups, there was an increases in symptoms, but this was blunted in the treated group–Figure 2:

My take: This study shows the potential for latiglutenase to act as a ‘safety net’ to protect from CD from accidental gluten exposure. The findings reinforce the idea that this agent is not likely to be effective in the absence of gluten restriction. As an aside, I would be interested in finding out whether patients with presumed non-celiac gluten sensitivity would improve on this therapy.

Related blog posts:

IBD Updates: Understanding Newest IBD Therapies for Kids- Bowel Sounds, Hispanic Patients with IBD, More on Intestinal Ultrasound

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Bowel Sounds Link: Joel Rosh talks small molecules and biologics

This is another good chat. Dr. Rosh provides a lot of information about the newest IBD agents. Overall, the episode indicates a very enthusiastic experience with IL-23 targeting agents like risankizumab (perhaps the ‘Michael Jordan’ of biologics) and with JAK agents like tofacitinib and upadacitinib. Dr. Rosh’s experience with regard to safety of these newer agents has been very positive. For tofacitinib, the typical dosing alluded to in the podcast was 10 mg twice a day (not three times a day). The potential adverse effects, though unlikely in the pediatric population, are carefully discussed with families and monitored.

So far, Dr. Rosh has not found a niche for ozanimod. In addition, he briefly discusses therapeutic drug monitoring. With regard to using vedolizumab as a first-line agent for ulcerative colitis, he often uses the VARSITY study (BE Sands et al NEJM 2019; 381: 1215-26) to justify this to payers. There is a sad element to the podcast though –Dr. Rosh admits to being a lifelong Mets fan!

Related blog posts:

NH Nguyen et al. Clin Gastroenterol Hepatol 2023; 21: 173-181. Open Access! Effectiveness and Safety of Biologic Therapy in Hispanic Vs Non-Hispanic Patients With Inflammatory Bowel Diseases: A CA-IBD Cohort Study

Key findings in this retrospective study with 240 Hispanic patients:

  • Within 1 year of biologic initiation, Hispanic patients had higher rates of hospitalizations (31% vs 23%; adjusted hazard ratio [aHR], 1.32; 95% CI, 1.01–1.74) and IBD-related surgery (7.1% vs 4.6%; aHR, 2.00; 95% CI, 1.07–3.72), with a trend toward higher risk of serious infections (8.8% vs 4.9%; aHR, 1.74; 95% CI, 0.99–3.05).
  • The authors state “these findings suggest that biologic agents may not be as effective or safe in Hispanic patients as they are in non-Hispanic Caucasians… Besides biological factors, socioeconomic factors related to costs and access to care, which contribute to delayed initiation of biologics, and/or limited postinitiation monitoring, leading to higher rates of unplanned health care utilization.”

T Kucharzik et al. Clin Gastroenterol Hepatol 2023; 21: 153-163. Open Access! Early Ultrasound Response and Progressive Transmural Remission After Treatment With Ustekinumab in Crohn’s Disease (STARDUST study)

Key findings:

  • IUS showed that ustekinumab-treated CD patients achieved progressive IUS response (46.3%) and transmural remission (24.1%) through week 48, with a more robust response in the colon and biologic-naive patients
  • Fair/moderate reliability (κ = 0.21–0.51) was observed between week 4 IUS response and week 48 overall endoscopic response and fecal calprotectin/complete biomarker outcomes.

What’s Wrong with Noncompete Clauses

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NY Times (1/9/23): Lina Khan: Noncompetes Depress Wages and Kill Innovation

This editorial provides a rationale for the FTC’s proposal to eliminate non-compete clauses.

Background: “When you’re subject to a noncompete clause, you lose your right to go work for a competing company or start your own, typically within a certain geographic area and for a certain period of time…In theory, noncompete clauses promote investment and innovation by assuring companies that their employees can’t run off with valuable secrets. And, again in theory, workers should be paid more in exchange for agreeing to sign a contract that restricts their autonomy. But the reality looks very different.”

Key points:

  • About 1 in 5 U.S. workers are subject to noncompete clauses.
  • “Noncompete clauses systemically drive down wages, even for workers who aren’t bound by one.”
  • Employees do not receive additional compensation for signing a noncompete clause. “Employers often spring them on workers after they’ve accepted a job, when their bargaining power is effectively zero.”
  • “Noncompetes reduce entrepreneurship and start-up formation…and keep innovative ideas from breaking into the market.”
  • “Noncompetes are the type of restriction that Section 5 of the F.T.C. Act, a federal law passed by Congress more than a century ago, is supposed to prevent.”
  • There are alternative ways to protect company secrets like nondisclosure agreements
  • California does not allow noncompete clauses (since 19th century) and this “hasn’t kept the California economy — the world’s fifth-largest — stuck in the Stone Age.”

My take: Elimination of noncompete clauses would be good for doctors (and other workers) and for the economy as well. Established business with market dominance will need to use other ways besides coercion to keep talented employees when noncompete clauses go away.

Siesta Key Beach, FL

Meds for Obesity: AAP Guidelines

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Selected recommendations:

  • In children 10 y and older, pediatricians and other PHCPs should evaluate for lipid abnormalities, abnormal glucose metabolism, and abnormal liver function in children and adolescents with obesity (BMI ≥95th percentile) and for lipid abnormalities in children and adolescents with overweight (BMI ≥85th percentile to <95th percentile). 
  • Pediatricians and other PHCPs should provide or refer children 6 y and older (Grade B) and may provide or refer children 2 through 5 y of age (Grade C) with overweight (BMI ≥85th percentile to <95th percentile) and obesity (BMI ≥95th percentile) to intensive health behavior and lifestyle treatment.
  • Pediatricians and other PHCPs should offer adolescents 12 y and older with obesity (BMI ≥95th percentile) wt loss pharmacotherapy, according to medication indications, risks, and benefits, as an adjunct to health behavior and lifestyle treatment. 
  • Pediatricians and other PHCPs should offer referral for adolescents 13 y and older with severe obesity (BMI ≥120% of the 95th percentile for age and sex) for evaluation for metabolic and bariatric surgery to local or regional comprehensive multidisciplinary pediatric metabolic and bariatric surgery centers. 

My take: As with the AGA, the AAP has now recommended the widespread adoption of pharmacologic therapy for use in patients with obesity. It appears that treatment would be required indefinitely, though, given the likelihood of weight gain when treatment is stopped (reviewed on a future post).

Related blot posts:

 Garden Lights, Holiday Lights at Atlanta Botanical Gardens

The Onion’s Take on the New AAP Guidelines:

“A Smarter Way to Reduce Gun Deaths” Plus Two

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N Kristof, NY Times (1/24/23): A Smarter Way to Reduce Gun Deaths

Some excerpts:

In 2021 a record 48,000 Americans were killed by firearms, including suicides, homicides and accidents. So let’s try to bypass the culture wars and try a harm-reduction model familiar from public health efforts to reduce deaths from other dangerous products such as cars and cigarettes.

Harm reduction for guns would start by acknowledging the blunt reality that we’re not going to eliminate guns any more than we have eliminated vehicles or tobacco, not in a country that already has more guns than people. 

Recommendations from article:

  • We can try to keep firearms from people who are under 21 or who have a record of violent misdemeanors, alcohol abuse, domestic violence or some red flag that they may be a threat to themselves or others
  • To keep ineligible people from buying firearms, we need universal background checks
  • A pillar of harm reduction involving motor vehicles is the requirement of a license to drive a car. So why not a license to buy a gun?… In Massachusetts, which has one of the lowest gun mortality rates in the country, an applicant who wants to buy a gun must pay $100 for a license, be fingerprinted, undergo a background check and explain why he or she wants a gun. If the permit is granted, as it typically is after a few weeks, the bearer can then go to a gun store and buy the firearm. There is then an obligation to store it safely and report if it is stolen.
  • Smoking and alcohol cause more deaths in U.S. –both are regulated, not banned. “Because we’ve worked to reduce vehicle deaths and haven’t seriously attempted to curb gun violence, firearms now kill more people than cars.”
  • Background checks to purchase ammunition… this should be possible without creating burdens for gun owners who have already gone through background checks to buy weapons
  • Waiting periods and limits on how many guns one can purchase at a time may also help. We also need to crack down on untraceable ghost guns and on firearms made by 3-D printers; ghost guns are already a growing source of weapons for criminals
  • Warning labels: One proposed ammunition label has a photo of a bloody face and states that a gun increases the risk of someone in a home being killed
  • Increase costs of ownership to cover the damage associated with weapons: raise cost of guns through taxes/fees

This article proposes a lot of practical interventions that if implemented would likely reduce gun violence.

Related article: NPR Jan 24, 2023: Gun violence deaths: How the U.S. compares with the rest of the world The chart below shows how the U.S compares to gun violence in countries with low levels of gun violence. The U.S. compares favorably with Mexico, El Salvador, Guatemala, Venezuela, The Phillipines and Iraq. However, many violent places have lower gun violence than U.S. including Syria, Somalia, Afganistan, Iran, Pakistan, Yemen, and Libya.

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Atlanta Botanical Gardens

From NPR article.

Aslo, gun violence is widespread and is more common in ‘red’ states than ‘blue’ states despite the widely-held notion that gun violence occurs mainly in large urban centers.

Axios 1/27/23: Not an anomaly: 2020’s red states have higher murder rates Murder rates in red states have outpaced blue states by an average of 23% over the past two decades.

2023 ACG Celiac Guidelines for Adult and Children

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A Rubio-Tapia et al. Am J Gastroenterol 2023;118:59–76. Open Access! American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease Thanks to Ben Gold for this reference.

Here are some of the recommendations from updated ACG Celiac Guidelines:

Comments: The authors favor a non-biopsy approach for Celiac diagnosis in children with very elevated serology but not in adults. In adults, they cite a paucity of literature. “One multicenter international study of adults found that a 10-fold elevation of TTG IgA had a positive predictive value of 95% for CD (50). Given the life-long treatment implications of a GFD, this may be unacceptably low.”

The authors suggest assessing for mucosal healing after 2 years of treatment in all patients though they indicate a low quality of evidence for this recommendation. In those undergoing endoscopy, biopsies of the duodenal bulb along with at least 4 post-bulbar biopsies are recommended.

Figure 3 provides an algorithm for non-responsive celiac disease.

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Liver Briefs: HLH in Infancy, Maralixibat for Alagille Syndrome, Liver Disease Due to Inborn Errors of Immunity

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N Hadzic et al. J Pediatr 2022; 250: 67-74. High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy In this retrospective study of pediatric acute liver failure (PALF, n=78) in children <24 months of age: Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The mortality in this group was 33% (n=10). The authors conclude that targeted genetic analysis (ie perforin, SIAP, XIAP, and GRA) or whole exome sequencing should become a standard part of PALF workup.

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BM Kamath et al. J Pediaatr 2023; 252: 68-75. Open Access! Maralixibat Treatment Response in Alagille Syndrome is Associated with Improved Health-Related Quality of Life. Twenty of the 27 patients (74%), all with moderate-to-severe pruritus at enrollment, achieved an Itch-Reported Outcome (Observer) treatment response at week 48. “The significant improvements in pruritus seen with maralixibat at week 48 of the ICONIC study are clinically meaningful and are associated with improved HRQoL.”

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D Sharma et al. Hepatology 2022; 76: 1845-1861. Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity This articles reviews inborn errors of immunity (IEI) and their liver manifestations. This includes the following:

  • T-cell/B-cell deficiency: SCID, CD40 ligand deficiency, DOCK8 deficiency, IL-21R deficiency, and Activated P13K delta syndrome
  • Antibody deficiency: CVID, X-linked aggamoglobulinemia
  • Phagocytic disorders: CGD
  • Primary Immune Regulatory Disorders: STAT1 GOF, STAT3 GOF, IPEX, APECED
  • Others: Wiskott-Aldrich syndrome, Immunodeficiency-centromeric instability-facial anomalies syndrome, Hepatic veno-occlusive disease with immunodeficiency, STAT3-deficient hyper IgE syndrome

In patients with IEIs with liver abnormalities, one needs to consider infectious etiologies (eg. HAV, HBV, HCV, HEV, CMV, EBV, HSV, cryptosporidium, liver abscess), autoimmune disorders (eg. AIH), drug-induced liver disease, and sclerosing cholangitis

Royal Terns at Siesta Key, FL