Briefly noted: L Waters et al. Annals Int Med 2020; doi:10.7326/L20-0497. Celiac Disease Remission With Tofacitinib
The authors describe a male with a well-documented case of celiac disease and alopecia areata. He was placed on tofacitinib off-label for his alopecia areata and it was discovered that his celiac disease had developed “complete histologic and serologic remission…while he was still on a gluten-containing diet.” Prior to medication, he had confirmation of both severe histologic changes and high tTG IgA titers.
The authors note that tofacitinib inhibits CD8+ T-cell mediated enteropathy in a transgenic mouse model.
My take (borrowed from authors): Tofacitinib has many potential adverse effects but may considered for further study, especially in refractory celiac disease.
Table –From Annals of Internal Medicine Twitter Feed
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Emilio J. Laserna‐Mendieta et al. AP&T 2020; https://doi.org/10.1111/apt.15957. Full article link: Efficacy of proton pump inhibitor therapy for eosinophilic oesophagitis in 630 patients: results from the EoE connect registry
“This cross‐sectional study collected data on PPI efficacy from the multicentre EoE CONNECT database.” Overall, 630 patients (76 children) received PPI as initial therapy (n = 600) or after failure to respond to other therapies (n = 30)
- PPI therapy achieved eosinophil density below 15 eosinophils per high‐power field in 48.8% and a decreased symptom score ≥50% from baseline in 71.0% of patients.
- More EoE patients with an inflammatory rather than stricturing phenotype accomplished clinico‐histological remission after PPI therapy (OR 3.7; 95% CI, 1.4‐9.5)
- PPI treatment is more effective in achieving clinico‐histological remission of the disease when used in higher instead of standard or lower doses (50.8% vs 35.8%), and when the duration of therapy is prolonged from 8 to 12 weeks (50.4% vs. 65.2%)
My take: This study confirms previous studies which have generally found that PPIs are effective in 40-50% of patients with eosinophilic esophagitis. Higher doses of PPIs are needed to achieve the highest response rates.
“Bar chart for histological (A) and symptomatic (B) responses for proton pump inhibitor (PPI) mono‐therapy to induce and maintain remission in patients with eosinophilic oesophagitis. For induction of remission, patients were classified according to the PPI dosage prescribed: high dose was double dosage or higher, and low dose was standard dosage or lower. For maintenance therapy, only patients with dosage reduction from that used for induction were included. eos/hpf: eosinophils per high power field”
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A recent study (H-C Lien et al. Clin Gastroenterol Hepatol 2020; 18: 14-66-74) adds a bit more insight into the topic of larygnpharyngeal symptoms (related blog post: Gastroestophageal Reflux Phenotypes and Where ‘Rome, Lyon, and Montreal Meet’ provides more information on treatment outcomes).
Methods: In this prospective multi-center observational study with adults aged 20-70 years, n=142 completed study), enrollment required chronic laryngitis symptoms >3 months and “laryngoscopic” signs suggestive of reflux. Subsequently, patients were examined with multiple modalities, including 24-pH testing, manometry, and Bernstein test followed by treatment with omeprazole 40 mg twice a day.
- Pathologic reflux was identified in 146/252 (58%) of those meeting inclusion criteria. Thus, approximately 40% did NOT have objective findings of reflux despite suspicion of laryngopharyngeal reflux (LPR); this is similar to other studies.
- In those with documented reflux, those with and without typical reflux symptoms had improvement in LPR with omeprazole therapy: 57% and 63% respectively; whereas, omeprazole therapy was effective in 32% in those without objective (pH probe) findings of reflux. In previous studies, reflux laryngitis response to PPIs has been similar to placebo.
My take: Typical reflux symptoms are not needed for patients with LPR to respond to PPIs. However, more than 40% of individuals with LPR do NOT have objective evidence of reflux; in this subset, response to PPI therapy is low.
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In the June issue of Gastroenterology (158: 2015-16), a tribute to George Sachs (1935-2019) recognizes his work in the field of gastroenterology and his development of proton pump inhibitors (PPIs).
Much more work remains as ~30% of patients with gastroesophageal reflux remain symptomatic despite PPI therapy. In the same issue, IW-3718, a bile acid sequestrant colsevelam with a gastric-retentive formulation was studied in 280 patients (MF Vaez et al. Gastroenterol 2020; 158: 2017-19).
Methods: The authors performed a multicenter, double-blind, placebo-controlled 8-weel treatment trial (2016-17); patients received the study drug (500, 1000, 1500 mg) or placebo twice daily. The authors enrolled symptomatic patients (≥4 times per week) with erosive esophagitis or pathologic reflux based on Bravo study (pH<4 for ≥4.2% during at least one 24-hour period). They continued PPI therapy which they had been receiving for a minimum of 8 weeks prior to starting study medication.
- Improvement in heartburn severity scores for placebo, 500, 1000, and 1500 mg groups: 46%, 49%, 55%, and 58%. The 11.9% difference between 1500 mg group compared to placebo reached statistical significance (P=.04)
- There was an improvement in weekly regurgitation frequency score as well from baseline to week 8 in 1500 mg group of 17.5% compared to placebo.
- No serious drug related serious adverse events were identified. Constipation was noted in 8% of study drug recipients compared 7% for placebo recipients.
Limitations: lack of a centralized review for endoscopy images, high placebo response rate, once daily use of PPI in study, and problems with overlap of functional symptoms
My take: This study shows why a placebo control is needed in reflux studies. While IW-3718 at higher doses was effective, its response appears much less notable when compared with placebo-recipients.
From The Onion: Dumbass Dog Wearing Face Mask All Wrong
From The Onion
A recent study (ID Croall, et al. Gastroenterol 2020; 158: 2112-22), using a UK Biobank with 500,000 adults, compared 104 participants with celiac disease to 198 healthy age-matched controls (mean age 63 years).
The authors examined cognitive outcomes, mental health outcomes and imaging data (MRI, diffusion tensor imaging).
- The celiac cohort had significant deficits in reaction time (P=.004), anxiety (P=.025), depression (P=.015), thoughts of self-harm (P=.025), and health-related unhappiness (P=.01)
- Imaging studies showed white matter changes “which match up well anatomically with the regions affected in the celiac-related neurologic syndrome gluten ataxia.”
Limitations: study lacked data on celiac treatment status –whether better control or earlier diagnosis/treatment would reduce CNS complications is uncertain. Also, whether these findings are more or less prevalent in individuals with undiagnosed celiac disease is unclear.
My take: This study provides further evidence that celiac disease results in significant neurologic problems and further reasons for those with celiac disease to adhere to a strict gluten-free diet (as other studies of neurologic outcomes indicate that a GFD can improve/reverse neurologic morbidities).
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Here is link to original study: Increased Risk of COVID-19 Among Users of Proton Pump Inhibitors
Almario CV, Chey WD, Spiegel BMR. Increased risk of COVID-19 among users of proton pump inhibitors. Am J Gastroenterol 2020 (pre-print posted online July 7, 2020)
From ACG: Information Sheet and FAQs About Proton Pump Inhibitors (PPIs) and Risk of COVID-19
This study shows an association but does not prove that PPIs increase risk of COVD-19. Patients taking PPIs may have other attributes that increase their risk compared to those who are not taking PPIs.
Here is some more information on twitter thread of this topic:
Here is a link to the EPUB draft of AGA clinical report (G Su et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2020.05.059): AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders
Here is a link to the pre-draft technical review by GA Preidis et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2020.05.060 AGA Technical Review on the Role of Probiotics in the Management of Gastrointestinal Disorders
- The report recommends NOT using probiotics outside of clinical trials for irritable bowel syndrome, Clostridium difficile infection treatment, Crohn’s disease, and gastroenteritis.
- It recommends a specific probiotic for pouchitis and for prevention of necrotizing enterocolitis in preterm infants <37 weeks and 3 probiotics for patients who are receiving antibiotics (to prevent Clostridium difficile infection)
CNN summary: Probiotics don’t do much for most people’s gut health despite the hype, review finds
“While our guideline does highlight a few use cases for probiotics, it more importantly underscores that the public’s assumptions about the benefits of probiotics are not well-founded,” said Dr. Grace L. Su, a professor of medicine and chief of gastroenterology at the University of Michigan, Ann Arbor, in a news statement. She was the chair of the panel that issued the new guidance….
“The industry is largely unregulated and marketing of product is often geared directly at consumers without providing direct and consistent proof of effectiveness,” said the new guidelines. “This has led to widespread use of probiotics with confusing evidence for clinical efficacy,” it said…
“Not all probiotics are created equal. Some probiotic strains and mixtures are very effective for some types of diseases and should not be overlooked due to studies that lump all probiotics together as one”
My take: Probiotics are overhyped and underperform for most conditions. This report suggests that most people should NOT be taking probiotics.
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A recent systematic review and network meta-analysis (CJ Black, et al. Clin Gastroenterol Hepatol 2020; 18: 1238-39) reviewed the relative efficacy of medications for irritable bowel syndrome with constipation. In total, the 14 trials randomized 9113 patients.
- All treatments were significantly more effective than placebo
- Linaclotide was ranked most effective; however, indirect comparison of active treatments revealed no significant differences between the individual drugs
Interesting article: Full Text: SARS-CoV-2 RNA concentrations in primary municipal sewage sludge as a leading indicator of COVID-19 outbreak dynamics
M Sahin-Toth. Gastroenterology 2020; 158: 1538-40. Full Text Link: Channelopathy of the Pancreas Causes Chronic Pancreatitis
Excerpt from editorial:
In this issue of Gastroenterology, Masamune et al report a landmark discovery, the genetic association of functionally defective TRPV6 channel variants and chronic pancreatitis. The authors investigated the TRPV6 gene in Japanese and European patients with nonalcoholic chronic pancreatitis using targeted sequencing followed by functional analysis of the identified variants. In the Japanese discovery cohort, they found functionally defective variants in 4.3% of the patients and in 0.1% of the controls (odds ratio 48). In the European replication cohort, 2% of the patients carried a defective variant and none was found in controls.
Original research study: A Masamune et al. Gastroenterology 2020; 158: 1626-41. Full text: Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis
TRPV6 variants are globally associated with early-onset nonalcoholic CP. To our knowledge, TRPV6 is a novel pancreatitis-associated gene beyond the pancreatic digestive enzyme/enzyme inhibitor system, and it is the first gene that directly regulates Ca2+ homeostasis. Our findings open a completely new avenue by emphasizing the potential role of ductal cells and, especially, calcium channels in the pathophysiology of pancreatitis, which might lead to the development of personalized medicine targeting TRPV6 channel activity.
From editorial by Sahin-Toth
Visual abstract for research study by Masamne et al.
From NEJM Journal Watch (5/8/20): A New First-Line Treatment Regimen for H. pylori Infection
In this industry-funded, phase III trial conducted in the U.S., 455 H. pylori-treatment–naive patients with dyspepsia and a confirmed H. pylori diagnosis were randomized to treatment with capsules containing rifabutin, amoxicillin, and omeprazole or capsules containing amoxicillin and omeprazole for 14 days. Participants took 4 capsules every 8 hours. The eradication rate in the rifabutin-based therapy group was significantly higher (84%) compared with the comparison group (58%). In patients with confirmed adherence to treatment, the eradication rates were 90% versus 65%, respectively. No H. pylori resistance to rifabutin was detected, and side effects were similar between groups.
My take: More treatment options are needed due to drug resistance. Also, “further studies are needed to compare this new triple therapy with current quadruple therapies.”
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