IBD Updates: Treat-to-Target Uptake, Long-Term Data on Ustekinumab Intensification, and Low Rates of C diff with Tofacitinib (& Clinical Pearl)

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JL Yang et al. Inflamm Bowel Dis 2023; 29: 735-743. Utilization of Colonoscopy Following Treatment Initiation in U.S. Commercially Insured Patients With Inflammatory Bowel Disease, 2013-2019

In this study with 39,734 commercially-insured initiators of IBD medications (18-64 year old), 34% had a colonoscopy by 12 months and 42% at 15 months. The authors state that “it is evident that patients without any colonoscopy during this interval are not being followed under an optimal long-term T2T (treat-to-target) paradigm.”

RS Dalal et al. Inflamm Bowel Dis 2023; 29: 830-833. Long-Term Outcomes After Ustekinumab Dose Intensification for Inflammatory Bowel Diseases

This retrospective study examined 123 patients with Crohn’s disease and 40 with ulcerative colitis who had dose intensification with ustekinumab (to either every 4 weeks, n=91, or every 6 weeks, n=72). Dose escalation was effective in both achieving and maintaining corticosteroid-free clinical remission for 61% of patients with Crohn’s disease and 40% with ulcerative colitis at 24 months; endoscopic remission was noted in 43% with Crohn’s disease and 55% with ulcerative colitis.

EV Loftus et al. Inflamm Bowel Dis 2023; 29: 744-751. Open Access! Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program 

Using data from multiple studies with 1157 patients, only 9 tofacitinib patients developed Clostridioides difficile infection (CDI) which was lower than the placebo group. CDI were all mild–moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. The low rate of infection was likely in part due to screening for CDI prior to treatment. In addition, “it is possible than the lower rates of CDI …may be due to better-controlled disease…, thus reducing susceptibility to infection.”

One clinical pearl in the discussion: “When considering treatment [for CDI], initial therapy with oral vancomycin should be considered instead of metronidazole, and treating for at least 21 days should also be considered [in patients with IBD due to]…lower rates of CDI recurrence.”

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.

Lego Art at Tucson Botanical Gardens

Linaclotide -Now FDA-Approved for Children

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FDA 6/12/23: FDA approves first treatment for pediatric functional constipation

“FDA has approved Linzess (linaclotide) capsules to treat functional constipation in pediatric patients 6 to 17 years of age. Linzess is the first treatment for pediatric functional constipation. The recommended dosage in pediatric patients 6 to 17 years is 72 mcg orally once daily.”

“The efficacy of Linzess for the treatment of functional constipation in pediatric patients 6 to 17 years of age was established in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from adequate and well-controlled trials in adults with chronic idiopathic constipation (constipation that persists and isn’t connected to an underlying illness).”

Safety:

  • Most common adverse effect was diarrhea
  • Avoid in patients with known or suspected mechanical gastrointestinal obstruction (bowel blockage)
  • “Linzess contains a boxed warning that the medication should not be taken by patients less than 2 years of age”
  • See full prescribing information for additional information on risks associated with Linzess.

My take: While this is good news to have the first FDA-approved treatment for pediatric functional constipation, it is worth remembering that the estimated cost for a monthly supply is between $514-$536 (in Atlanta pharmacies per GoodRx.com).

Related blog posts:

Data on Fecal Microbiota Transplantation for Ulcerative Colitis and Case Report of Vancomycin for Refractory Ulcerative Colitis

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NEH Chehade et al. Inflamm Bowel Dis 2023; 29: 808-817. Efficacy of Fecal Microbiota Transplantation in the Treatment of Active Ulcerative Colitis: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials

HS Almomen, B Al-Bawardy. Inflamm Bowel Dis 2023; 29: 837-838. Oral Vancomycin Induced and Maintained Clinical and Endoscopic Remission in Ulcerative Colitis and Primary Sclerosing Cholangitis Post-liver Transplantation

In the first study by Chehade et al, the authors analyzed six RCTs involving 324 patients. Key findings:

  • Compared with placebo, FMT has significant benefit in inducing combined clinical and endoscopic remission (odds ratio, 4.11; 95% confidence interval, 2.19-7.72; P < .0001)
  • clinical remission with FMT was 46.2% compared 22.5% for placebo
  • clinical response with FMT was 51.6% compared to 30.1% for placebo
  • endoscopic remission with FMT was 18.9% compared to 6.1% for placebo
  • endoscopic response with FMT was 36.7% compared to 22.4% for placebo

Discussion Points:

  • “The studies included in our article indicate that there is a shift in the microbiota composition of responders in the FMT group to resemble the profile of healthy donors”
  • FMT delivery via upper GI tract was equally effective as delivery via lower GI tract in these studies in inducing combined remission
  • “The understanding of FMT effectiveness for IBD is in its infancy.”

In the case report by Alomomen et al, a 34 year old with refractory ulcerative colitis and PSC (post-transplant) had not responded to infliximab, vedolizumab, adalimumab, tofacitinib or 10 months of ustekinumab (every 4 weeks). In addition, he was receiving tacrolimus therapy due to his liver transplant. His colonoscopy demonstrated a continuous Mayo 3 colitis. Subsequently, vancomycin therapy was added to his treatment (500 mg BID); he continued ustekimumab. Six months afterwards, his fecal calprotectin had dropped to 277 from 1600 and his CRP and hemoglobin had normalized. Repeat colonoscopy demonstrated complete endoscopic healing.

My take: There are many patients who do not respond to current IBD therapies. These two studies show that both FMT and vancomycin could be useful in selected patients.

Related blog posts:

Lego Art at Tucson Botanical Gardens
Lego Lion
Lego Panther

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.

Comparing Outcomes Between PEG Placement and Surgical GT Placement

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K Tazi et al. JPGN Reports 4(2):p e316, May 2023. | DOI: 10.1097/PG9.0000000000000316. Open Access: Complications of Percutaneous and Surgical Gastrostomy Placements in Children: a Single-Centre Series.

In this retrospective single-center pediatric (n=124) study, the authors analyzed complications that occurred up to 1 year after placement. Key findings:

  • Fifty-nine patients (47.6%) underwent endoscopic placement, 59 (47.6%) surgical placement, and 6 (4.8%) laparoscopic-assisted percutaneous endoscopic gastrostomy. 
  • 29 (14.4%) major and 173 (85.6%) minor complications were reported
  • This study highlights at least 1 complication (regardless of severity) in 106 (85.5%) patients and reports a significantly lower complication rate in the PEG group (major and minor combined) compared to the surgical group (laparoscopy and laparotomy) (OR, 0.3; 95% CI, 0.07–0.9) (P = 0.001).
  • In the endoscopic group, patients with concomitant neurological disease had significantly more early complications (25.8 vs. 3.6%; OR, 9.1)
  • In the surgical group, patients with undernutrition had significantly more major complications (12.1% vs. 40%; OR, 4.7; 95% CI, 1.2–18; P = 0.01)

Discussion:

  • The authors note that although their results found fewer complications in the PEG group, other studies have reported lower complications in surgically-placed GTs. “Baker et al (4). report, like Sanderg et al (9)., an advantage of the laparoscopic technique compared to the endoscopy technique in terms of major complication (OR, 0.29; 95% CI, 0.17–0.51; P = 0.0001). Several other studies (9,20,21) show similar results.”
  • “Although a single prophylactic antibiotic therapy with cefazolin is systematically administered before each procedure, the rate of infectious complications remains high: 13 cases of abdominal wall abscess or cellulitis (6.4% of total complications) and 33 cases of minor infection (16.3% of total complications) requiring local treatment.”
  • The strengths of this study are an exhaustive collection of detailed data permitting a precise analysis of complications

My take: The majority of studies suggest that laparoscopic GT placement is safer, unlike this study. A more definitive answer would require a randomized prospective study with rigorously-collected data. Also, GT complications are common, ~85% in this study; thus, family education is important both before and after GT placement.

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.

Skinny Babies with Cleft Lips and/or Cleft Palates

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CM McKinney et al. J Pediatr 2023; 255: 181-189. A Cross-Sectional Study of the Nutritional Status of Infants with Orofacial Clefts in the First 6 Months of Life

In this cross sectional study (2010-2022) the authors calculated the proportion of infants (n=883) underweight and wasting with z scores below −2 SDs monthly from birth to 6 months of age at a single tertiary care center. Key findings:

  • Compared with expected proportion of underweight infants (2.3%), a larger proportion of infants with orofacial clefts were underweight between birth and 1 month (10.6%), peaking between 2 and 3 months (27.1%), and remaining high between 5 and 6 months (16.3%). 
  • Compared with the expected proportion of infants with wasting (2.3%), a higher proportion of infants with orofacial clefts experienced wasting between birth and 1 month (7.3%), peaking between 2 and 3 months (12.8%), and remaining high between 5 and 6 months (5.3%).
  • Similar findings were observed for all cleft types and regardless of comorbidities.
  • “The mean prevalence of underweight in our sample exceeded that observed in children in African countries such as Tanzania and Uganda.”

My take: This study shows a high prevalence of underweight and wasting in infants with orofacial clefts.

Lego Art at Tucson Botanical Gardens:

More Proof That Transpyloric Feeds Protect the Lungs

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B Srivatsa et al. J Pediatr 2023; 255: 175-180. Transpyloric Feeding is Associated With Improved Oxygenation Compared With Gastric Feeding Among Nonintubated Extremely Low Birth Weight Infants

As noted in a previous blog, transpyloric (TP) feedings are equivalent to a fundoplication in reducing reflux. As such, it is not surprising that it is used in premature infants to minimize reflux-associated respiratory problems including aspiration and potentially mitigate bronchopulmonary dysplasia.

In this retrospective study with 56 extremely low birth weight infants, the authors analyzed oxygen saturation (SpO2) and action of inspired oxygen (FiO2) data (measured at 1-minute intervals) for 96 hours before and after institution of TP feeds.

Key findings:

  • No significant differences were observed in any oxygenation measures during TP vs gastric feeding among 14 intubated infants.
  • Among 42 nonintubated patients, significant improvements were observed in the median SpO2/FiO2 ratios (P = .001), median titration index (P = .05), median number of hypoxemic episodes (P = .02), and median severity of hypoxemic episodes (P = .008) after TP tube placement.

Discussion:

  • The authors note that a prior study (J Perinat Med 2021; 49: 383-387) had shown improvement in SpO2/FiO2 ratios in intubated patients (n=33). This discrepancy between the two studies could be due to differences in patient population, ventilation technique (high frequency vs conventional) and higher level of power due to more intubated subjects in the prior study.
  • The exact mechanism of improvement in oxygenation is a matter of speculation. “Does TP feeding in nonventilated patients result n fewer or less severe GER events, leading to less pulmonary microaspiration or laryngospasm?…Does aerophagia, more common among nonintubated patients on positive pressure support, exacerbate GER events and is it ameliorated with TP feedings?” It is also possible that TP feedings result in improvement due to a reduction in esophageal reflux mediated bronchoconstriction.

My take: TP feedings have been very helpful in clinical practice, especially in infants with feeding difficulties, reflux, and respiratory issues. Most of these problems are transitory. This study provides granular data showing the significant improvements in oxygenation following the initiation of TP feedings among non-ventilated ELBW.

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How Long to Hold Biologics and Small Molecule Drugs Perioperatively

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BL Cohen et al. Clin Gastroenterol Hepatol l2023; 21: 1148-1151. How to Manage Targeted Immune Suppressants (Biologics and Oral Small-molecule Drugs) Perioperatively for Inflammatory Bowel Disease and non-Inflammatory Bowel Disease surgery

This article makes pragmatic recommendations with regard to surgery timing in individuals taking medications that target the immune system.

Key points:

  • Several recent large studies have “observed no association between biologic exposure and postoperative infectious outcomes.”
  • The primary risk factor for infectious complications has been corticosteroid/glucocorticoid use.
  • For IBD Surgery: “If patients are deriving therapeutic benefit, including reducing the need for steroids, we propose continuing treatment until surgery…It may be practical to perform the surgery mid to late dosing interaval in the case of biologics with longer half-lives…Our expert opinion is that therapy may be resumed 14 days postoperatively or when recovered from infectious complications.”
  • For Non-IBD surgery: “Expert opinion suggests medications may be re-dosed by 14 days postoperatively if there have been no complications. Consideration should be given to resuming oral small molecules earlier given their short half-lives.”
  • Emergency or urgent surgeries “should be performed promptly regardless of targeted immune suppressant use.”
David Yetman Trail (Tucson)

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.

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

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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.”

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Seronegative Villous Atrophy

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

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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