Shorts: Hep E in Urine, Genetics in Autoimmune Enteropathy, EndoFlip Findings in EoE

Posted on June 7, 2023 by gutsandgrowth

D Ying et al. Hepatology 2023; 77: 1722-1734. Urine is a viral antigen reservoir in hepatitis E virus infection

Key findings: HEV Ag was specifically taken up by renal cells and was disposed into urine, during which the level of Ag was concentrated >10‐fold, resulting in the higher diagnosing sensitivity of urine Ag than serum Ag. Moreover, Ag in urine appeared 6 days earlier, lasted longer than viremia and antigenemia, and showed good concordance with fecal RNA in a rabbit model.

F Charbit-Henrion et al. Clin Gastroenterol Hepatol 2023; 21: 1368-1371. Open Access! Genetic Diagnosis Guides Treatment of Autoimmune Enteropathy

Background: Autoimmune enteropathy (AIE) is a severe form of enteropathy characterized by chronic diarrhea refractory to any exclusion diet and associated with autoimmunity…In a recent cohort of 40 AIE patients, anti-enterocyte antibodies were reported in only 14% (4/28) of the cases, likely caused by the high frequency of patients with primary hypogammaglobulinemia…30%–50% of adult AIE can display anti-transglutaminase antibodies. The common histopathologic presentation of AIE includes intestinal villous atrophy with variable lymphocytic infiltration and various features of follicular lymphoid hyperplasia, cryptitis, graft-versus-host disease-like lesions, and loss of Paneth and goblet cells.

Key findings: Pathogenic variants were identified in 20/48 adult patients (41.6%); most common variants: CTLA4, LRBA, STAT3, and STAT1; 12/20; 60% of those with variants. Thus, specific therapeutics were available for more than half of the patients who received a molecular diagnosis

**Representative endoscopic aspects in patients with** *CTLA4* **variants and AIE.**

NV Hoffmann et al. Clin Gastroenterol Hepatol 2023; 21: 1188-1197. Esophageal Distensibility Defines Fibrostenotic Severity in Pediatric Eosinophilic Esophagitis

Key finding: In this prospective pediatric cohort (n=59) with EoE, distensibility index (DI) <4.5 mm²/mmHg predicted grade 2 rings on endoscopy. Lower DI was associated with increased risk of food impaction but did not correlate with eosinophilic count. DI was “superior to diameter in assessing fibrostenotic severity.”

One If By Colon and Two If By Capsule For Clostridioides difficile

Posted on June 6, 2023 by gutsandgrowth

Well, this study is not exactly Paul Revere territory; nevertheless, the blog title seemed better than “Eat Shit for C diff.”

BP Vaughn et al. Clin Gastroenterol Hepatol 2023; 21: 1330-1337. Effectiveness and Safety of Colonic and Capsule Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection

Methods: Clinical outcomes and adverse events after FMT performed for rCDI at 6 sites (n=269) were captured in a prospective registry. FMT was performed using either freeze-dried/encapsulated or frozen-thawed/liquid.

The authors note that the cohort with a mix of academic and private practices reflects real-world use of FMT. Since the study products were free of charge, providers and patients selected treatment based on their preference (65% selected oral capsule).

Key findings:

At 1 month, rCDI cure rate was 91% for FMT-colonoscopy and 84% for FMT-capsule (no significant difference, p=0.12)
At 2 months, rCDI were 83% and 81% for FMT-colonoscopy and FMT-capsule respectively
Use of non-CDI antibiotics increased failure rates: 28% at 2 months compared to 10% who did not receive antibiotics
One serious adverse event was related to colonoscopy (aspiration pneumonia), otherwise no new safety signals were identified

My take: This study indicates similar effectiveness of FMT-capsule to FMT-colonoscopy. FMT-capsule is easier and avoids risks associated with colonoscopy. But, it does require patients to eat (encapsulated) feces

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More Pics from Tucson -above picture near Wasson Peak

Bridge Therapy for Ustekinumab with Acute Severe Ulcerative Colitis

Posted on June 5, 2023 by gutsandgrowth

P Veyard et al. Clin Gastroenterol Hepatol 2023; 21: 1354-1355. Efficacy of Induction Therapy With Calcineurin Inhibitors in Combination With Ustekinumab for Acute Severe Ulcerative Colitis

This small retrospective study with 10 adults examined the efficacy of using a calcineurin inhibitor (cyclosporin (n=9) or tacrolimus (n=1)) as a bridge therapy for long-term ustekinumab treatment. Most patients had failed infliximab (90%) and vedolizumab (80%). Patients received an induction of ustekinumab (6 mg/kg) followed by every 8 week treatment. Calcineurin inhibitor use was used for a median of 45 days.

Key finding:

None of the patients underwent a colectomy at 6 months
One patient remained on steroids at 6 monhts and one patient failed to obtain a clinical response or remission

My take (borrowed from authors): This small retrospective study shows that bridging therapy with a calcineurin inhibitor followed by maintenance therapy with ustekinumab is feasible. Bridging therapy has also been used for vedolizumab (Pellet et al. Clin Gastroenterol Hepatol 2019; 17: 494-501; Ollech et al. Aliment Pharmacol Ther 2020; 51; 637-643)

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In Tucson, we stayed adjacent to a bunch of animals that we fed each morning.

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Choosing Health Insurance -Humor

Posted on June 4, 2023 by gutsandgrowth

Dr. Glaucomflecken: Choosing a health insurance plan

“if it made sense it wouldn’t be US healthcare”

VTE Protocol for Hospitalized Kids with IBD

Posted on June 2, 2023 by gutsandgrowth

LG Hamant et al JPGN 2023; 76: 610-615. Venous Thromboembolism Prophylaxis in Pediatric Inflammatory Bowel Disease Patients Hospitalized With a Central Line

This article reviews the results of a venous thromboembolism (VTE) protocol that was implemented in 2018 in children with inflammatory bowel disease (IBD). A total of 313 hospitalizations across 187 different patients were identified that met criteria including IBD and central venous access. This retrospective review focused on children with IBD and and central venous catheter (CVC) Key findings:

VTE prophylaxis increased from 5.24% (n = 12) prior to the intervention to 63.10% (n = 53) after the intervention
Rate of Doppler US increased from 9.17% (n = 21) prior to the intervention to 17.86% (n = 15) after the intervention
Diagnosis of VTE increased from 0.87% (n = 2) prior to the intervention to 7.14% (n = 6) after the intervention (attributed to better detection)

This article provides an algorithm for implementing VTE prophylaxis, recommending prophylaxis if 2 or more risk factors –both IBD and CVCs are risk factors. Mechanical prophylaxis (along with frequent ambulation, if feasible) is generally recommended if there are at least 2 risk factors, whereas anticoagulation prophylaxis is generally recommended if there are at least 4 risk factors. Other risk factors include being post-pubertal, obese, prolonged surgery (>90 minutes) within 2 weeks, altered mobility, and mechanical ventilation (see full protocol in article).

My take: In children at increased risk, the approach to reducing VTE in this article is quite sensible. Nevertheless, more research, especially with regard to institution of anticoagulation, is needed.

Related blog posts:

When Will Intestinal Ultrasound for IBD Become Practical?

Posted on June 1, 2023 by gutsandgrowth

M Allocca et al. Gastroenterol 2023; 164: 851-855. Open Access! Intestinal Ultrasound in the Assessment and Management of Inflammatory Bowel Disease: Is It Ready for Standard Practice?

This short article outlines the indications, availability, technical skills, cost-effectiveness and potential value of intestinal ultrasound (IUS). Some key points:

Goal: “IUS is used as a first-line investigation and can avoid or delay the need for more invasive and expensive testing (CT, MRI, or colonoscopy). Thus, costs are minimized and patient convenience is optimized”
Availability: “IUS is quite widespread in many European countries, but its uptake has been significantly less in other parts of the world, including the United States. Limitations to its use include the absence of standardized and reproducible protocols, lack of local expertise, and the perception that IUS is an operator-dependent tool, feasible only by highly experienced operators. In reality, however,…. studies specifically addressing sonographer variability demonstrate substantial agreement for color Doppler signals and almost perfect agreement for bowel-wall thickness, as the most relevant IUS parameter.”
Expertise: Trainees “have to perform at least 300 supervised ultrasound examinations in Italy and 400 in Germany to achieve full competency…It is believed that learners can achieve competency in IUS after approximately 200 supervised examinations, but it is important to acknowledge that a formal learning curve and the criteria for competency assessment have not yet been fully defined”

My take: Despite all the interest in this useful point-of-care tool, for IUS to become more widespread in the U.S. it will need to be incorporated in training programs. The threshold for competency is not achievable with a weekend seminar. It will be interesting to see how this test affects cost, management, and outcomes. Will it reduce or increase other cross sectional imaging testing? Is the information from IUS more useful than a calprotectin (stool biomarker) which could also be a point-of-care test?

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The Oro Valley/Tucson Loop shared use bike path extends over 130 car free miles throughout unincorporated Pima County, Marana, Oro Valley, and Tucson.

ARCH Study: Higher Doses of Infliximab in Acute Severe Ulcerative Colitis

Posted on May 31, 2023 by gutsandgrowth

KG Whaley et al. Clin Gastroenterol Hepatol 2023; 21: 1338-1347. Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis

This was a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified (n=38).

Key findings:

Compared to previous publications of pediatric ASUC, there was a low colectomy rate in this cohort of 2.7% at week 26 and 10.8% at 2 years
Median initial IFX dose was 9.9 mg/kg
Early rapid clearance was strongly associated with colectomy
Faster clearance was associated with higher WBC, presence of antibodies to infliximab and lower albumin. Higher platelets were associated with increased volumes of distribution. Concomitant immunomodulator use (26% with methotrexate, 13% thiopurine) “was not a significant covariate for PK parameters”

Discussion points:

Higher IFX dosing (10 mg/kg) may sufficiently optimize early outcomes in pediatric ASUC. Prior retrospective studies of adult and pediatric ASUC patients have supported lower colectomy rates with intensified induction regimens compared to standard induction regimens
The availability of vedolizumab may also have contributed to a lower colectomy rate
WBCs, “specifically neutrophils, may participate in the elimination of IFX”
Limitations: observational study, lack of dose standardization, lack of endoscopic outcomes

My take: Especially in pediatric patients, there is ample data to support using 10 mg/kg dosing for infliximab in patients with more severe inflammatory bowel disease, both ulcerative colitis and Crohn’s disease.

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Durability of Biologics in Children with Inflammatory Bowel Disease

Posted on May 30, 2023 by gutsandgrowth

JL Kaplan et al. JPGN 2023; 76: 567-575. Open Access! Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort

Methods: The authors analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry (n= 17,649) between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation

Key findings:

7585 (43%) were treated with a biologic agent before age 18. 50% of children with Crohn’s disease (CD) received a biologic compared to 25% of children with ulcerative colitis (UC)
First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab)
Probability of remaining on first biologic in patients with CD: 93% at 6 months, 85% at 12 months, 79% at 24 months, and 74% at 36 months
Probability of remaining on first biologic in patients with UC: 84% at 6 months, 75% at 12 months, 66% at 24 months, and 55% at 36 months
First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%).

My take: This is an important study that shows that anti-TNF therapy durability was 79% in patients with CD and 66% in patients with UC at 2 years. This pediatric-specific information will help with counseling families when starting biologic therapy. There was improvement in durability after 2013 compared to prior -so perhaps perhaps even better durability is occurring in 2023. It is a little ironic that this study is from ImproveCareNow given that the results are quite dated. There have been a lot of changes in the last seven years. These include the widespread use of dose optimization/therapeutic drug levels and the approval of several new classes of targeted medications.

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Landmark Study: Oral Biologic for Crohn’s –Upadacitinib

Posted on May 29, 2023 by gutsandgrowth

EV Loftus et al. N Engl J Med 2023; 388:1966-1980. Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease

This study is the basis for the FDA’s approval of updacitnib (Rinvoq) for Crohn’s disease in adults: New FDA Rinvoq (upadacitinib) Indication: Oral Treatment For Crohn’s

This publication describes the results of two multicenter, double-blind, randomized, placebo-controlled induction trials (n=1021 adults,U-EXCEL, U-ECEED) and one maintenance trial (n=502, U-ENDURE) with Upadacitinib (Rinvoq). The induction trials involved an early mandatory glucocorticoid taper.

Key findings:

A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons).
There was a rapid onset of action with a difference in clinical response compared to placebo at 2 weeks

Maintenance Trial of clinical responders: At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons).

Adverse effects included gastrointestinal perforations (6 in study medication, 1 in placebo), neutropenia in up to 2.6%, and increased Herpes Zoster infections in patients receiving study medication (1.5% to 3%).

A good commentary of this study is in the same issue: M Abreu. N Engl J Med 2023; 388:2005-2009. It is noted that upadacitinib showed a good response even though a different JAK inhibitor, tofacitinib, had disappointing results for patients with Crohn’s disease. Other points:

“It is hard to compare findings across studies because of differences in the characteristics of patients and end points. That being said, the incidences of clinical remission observed by Loftus et al. were greater than those observed in most studies of biologic drugs to treat Crohn’s disease. Moreover, upadacitinib was more likely than placebo to resolve extraintestinal manifestations.”
“They did not find evidence of cardiovascular or thromboembolic complications, which were previously observed in patients with rheumatoid arthritis treated with tofacitinib and which led to a black-box warning.¹⁰ However, the treatment of greater numbers of patients for a longer duration will be required to determine whether upadacitinib is asssociated with a risk of such complications.”
“Among the most common upadacitinib-specific adverse events were anemia [6.9%] and acne [6.3%]. The increase in anemia may be due to off-target effects of upadacitinib on erythropoietin signaling through JAK2.”

My take: This is great news for patients with Crohn’s disease. In addition to having a new option for refractory disease, this option does not require IV administration. When will pediatric data be available?

New FDA Rinvoq (upadacitinib) Indication: Oral Treatment For Crohn’s

Posted on May 28, 2023 by gutsandgrowth

5/18/23: FDA approves first oral treatment for moderately to severely active Crohn’s disease

“Patients should start with 45 mg of Rinvoq once daily for 12 weeks. Following the 12-week period, the recommended maintenance dosage is 15 mg once a day. A maintenance dosage of 30 mg once daily can be considered for patients with refractory, severe, or extensive Crohn’s disease.”

“The most common side effects of Rinvoq as indicated for Crohn’s disease are upper respiratory tract infections, anemia, fever, acne, herpes zoster, and headache…. Serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis have occurred with JAK inhibitors such as Rinvoq.”