Category Archives: Pediatric Gastroenterology Intestinal Disorder

Celiac Disease, Hepatitis B and Paul Harvey

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Growing up, I heard a number of Paul Harvey broadcasts on the radio. Often there would be an important twist at the end and he would conclude with ‘and that’s the rest of the story.’

This came to mind after reading a recent article on celiac disease and hepatitis B infection:

N Habash et al. JPGN 2022; 74: 328-332. Celiac Disease: Risk of Hepatitis B Infection

Methods:

  • A cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database (2009–2014) 
  • And a retrospective analysis of HBV infection in two cohorts: Mayo Clinic cohort (1998–2021) and the Rochester Epidemiology Project cohort (REP; 2010–2020)

Key findings:

  • Based on NHANES database, the rate of HBV infection in the United States was  0.33%
  • Of 93 patients with CD, 46 (49%) were vaccinated for HBV and of the remaining 19,422 without CD, 10,228 (53%) were vaccinated
  • Twenty-two (48%) vaccinated patients with CD had HBV immunity and 4405 (43.07%) vaccinated patients without CD had HBV immunity
  •  In NHANES data, there were no cases of HBV infection in patients with CD. Among the 3568 patients with CD seen at Mayo Clinic and 3918 patients with CD in the REP database, only four (0.11%) at Mayo Clinic and nine (0.23%) of the REP patients had HBV infection.

This finding is probably applicable to other conditions in which HBV immunity is ascertained.

My take: In contrast to other small studies, this study showed that the “rate of HBV vaccination and immunity was similar in individuals with and without CD.” In addition, there was no increased risk of HBV infection detected in CD patients. Thus, testing for HBV is not necessary in patients with CD.

And that’s the rest of the story.

Related blog post: 

Nonmedical Adalimumab Switches

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G Tapete et al. Inflamm Bowel Dis 2022; 28: 62-69. Effectiveness and Safety of Nonmedical Switch From Adalimumab Originator to SB5 Biosimilar in Patients With Inflammatory Bowel Diseases: Twelve-Month Follow-Up From the TABLET Registry

Methods: Prospective enrollment (n=146) included a ADA and those with a nonmedical switch from the ADA originator (n=98). Clinical remission and safety were assessed at baseline and at 3, 6, and 12 months

Key finding:

  • In the naïve cohort, the overall remission rate at 12 months was 60% (similar to originator adalimumab results); the remission rate in the switching cohort it was 75% with a treatment persistency of 82% at 12 months after the switch
  • No differences were found in terms of ADA serum trough levels at baseline, 3, and 6 months after switching. No patient developed antidrug antibodies after the switch
  • Fecal calprotectin (FC) values trended lower in both cohorts. In the naive cohort, the mean value of FC dropped from 665 (baseline) to 231 at 12 months. In the switch cohort, the mean value of FC dropped from 212 (baseline) to 84 at 12 months

My take: In this cohort, SB5 biosimilar for adalimumab was effective and safe.

Related blog posts:

New Therapy for Crohn’s Disease: Mirikizumab

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Because our office is one of the centers participating in a mirikizumab study for adolescents, I was particularly interested in seeing the published results of a phase 2 study in 191 adults.

BE Sands et al. Gastroenterol 2022; 162: 495-508. Open Access: Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn’s Disease

Summary Video Link (worth a watch!): Summary of Mirikizumab Study (4:25 minutes)

Background: “Mirikizumab (LY3074828) is a humanized immunoglobulin G4 (IgG4)–variant monoclonal antibody that binds specifically to the p19 subunit of IL23 and has demonstrated efficacy in psoriasis and ulcerative colitis, and is currently in phase 3 testing for psoriasis, ulcerative colitis, and CD. We evaluated the efficacy and safety of mirikizumab for the treatment of patients with moderately-to-severely active CD”

Methods: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12.

**approximately two thirds of participants had received biologic therapy and approximately half of all patients in this trial having experienced at least 1 biologic failure

Key findings:

  • At Week 12, endoscopic response was significantly higher for all mirikizumab groups compared with placebo (PBO) (200 mg: 25.8%, P = .079; 600 mg: 37.5%, P = .003; 1000 mg: 43.8%, P < .001; PBO: 10.9 %). 
  • Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C (combined IV groups) and SC (subcutaneous) groups , respectively. See 4th and 6th slides below which show that those with response at 12 weeks continued with response at 52 weeks.
In the Non-Randomized group which included non-improvers and placebo, they received
the highest dose, 1000 mg. A significant number of non-improvers responded at week 52.

My take: In this study of adults, with moderate to severe Crohn’s disease, Mirikizumab showed good efficacy and safety at both 12 weeks and 52 weeks. Because about half of the participants were biologic failures, this indicates that this agent shows promise in those with refractory disease.

Another Obscure Medication Effect: Mesalamine Staining Cleaned Toilet

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D Zeef et al. JPGN Reports: February 2022 – Volume 3 – Issue 1 – p e167 Open Access: Urine Discoloration After Voiding in a Boy With Ulcerative Colitis Using Mesalamine

“The boy noticed the colorization only when he urinated in the toilet at home and this phenomenon was most pronounced after the toilet had been cleaned.” He had a normal urinalysis. “Discoloration of urine by a chemical reaction between mesalamine and sodium hypochlorite bleach has been widely reported in online patient forums, we only found 2 related case reports.”

“Mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, have structural similarity to methyldopa, which is metabolized to melanin-like compounds. In an alkaline environment (the pH of bleach is 11–13), polymerization of these melanin-like metabolites causes a brownish/red discoloration of urine after methyldopa ingestion.”

Case report: Spondylodiscitis After Button Battery Ingestion

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Chris Fritzen and Erica Riedesel passed along a case report: a 16 mo presented to our hospital system with coughing, gagging and hematemesis after an unwitnessed FB ingestion; she was emergently taken to the OR where a button battery was noted to be densely adherent to the posterior wall of the upper thoracic esophagus and removed with a flexible endoscope. Postoperatively, she received 7 days of ampicillin/sulbactam. 14 days after presentation, an MRI revealed esophageal injury was evident at T3 level as well as an abnormal signal was seen within the esophagus spanning C7-T4. In addition, there was edema and enhancement of the intervertebral disc space at T1-T2 and T2-T3 consistent with spondylodiscitis. Prior reports (see below) have emphasized the need for antimicrobial coverage for Staphylococcus and upper respiratory pathogens. Children with spondylodiscitis may present with refusal to walk or limping, back or leg pain, and local stiffness of the neck/spine.

My take: Spondylodiscitis is another rare complication following button battery ingestion.

References:

  • NEO Grey et al. Pediatr Radiol 2021; 51:1856–1866. In this report, 1 of 23 children had spondylodiscitis. Other complications: esophageal perforation (n=11), tracheoesophageal fistula (n=3)
  • V Kieu et al. J Pediatr 2014; 164: 1500-1501. Highlights increased risk from unwitnessed button battery ingestions.
  • H Eshaghi et al. Pediatr Emer Care 2013;29: 368Y370. Spondylodiscitis: A Rare Complication of Button Battery Ingestion in a 10-Month-Old Boy

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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.

IQ and Pediatric Chronic Liver Disease

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DH Leung et al. JPGN: 2022 – Volume 74 – Issue 1 – p 96-103. Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver

In this longitudinal study, the authors evaluated Full Scale Intelligence Quotient (FSIQ) in children with chronic liver disease (mean age 7.6 yrs). Key finding:

  • Patients with Alagille syndrome (ALGS) are at increased risk of lower FSIQ (with 29% <85), whereas our data suggest A1AT and PFIC are not

Related blog posts:

Losartan: Not Effective for Pediatric NAFLD

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M Vos et al. Hepatology 2022; https://doi.org/10.1002/hep.32403. Open Access: Randomized placebo-controlled trial of losartan for pediatric NAFLD (Thanks to Jeff Schwimmer’s twitter feed for this link)

Rationale for study: “A number of studies suggest the utility of losartan in NAFLD.[11–17] In adults, two meta-analyses have found that angiotensin receptor blockers (ARBs) improve insulin sensitivity and reduce the incidence of type 2 diabetes.[18, 19] A large retrospective review of hypertensive patients treated with angiotensin-converting enzyme inhibitors and/or ARBs demonstrated a significant association of renin-angiotensin system (RAS) antagonists with reduced odds of advanced hepatic fibrosis on biopsy.[20] “

Design: 83 participants (81% male, 80% Hispanic) with histologically proven NAFLD were randomized to losartan (100 mg daily) (n = 43) or placebo (n = 40). ALT was chosen as a primary endpoint, because “reduction of elevated serum ALT … has been shown to significantly correlate with improvement in histology in children, including fibrosis”

Key findings:

  • The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: −23.4 U/l; p = 0.01).
  • The authors “found no benefit of losartan on markers of insulin sensitivity, despite an improvement in systolic blood pressure”

My take: This study shows a very low likelihood that Losartan could be beneficial in NAFLD. I would recommend a book (a quick read) to my colleagues: “How I Killed Pluto and Why It Had It Coming.” In this book, the author, Michael Brown, describes years of seemingly-Sisyphean efforts to locate planetoids in our distant solar system; his work ultimately yielded important discoveries.

Related blog posts:

Low Anti-TNF Levels or Antibodies Are Associated with Antibodies to Subsequent Anti-TNF Agent

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NV Castelle et al. Clin Gastroenterol Hepatol 2022; 20: 465-467. Open Access: Patients With Low Drug Levels or Antibodies to a Prior Anti-Tumor Necrosis Factor Are More Likely to Develop Antibodies to a Subsequent Anti-Tumor Necrosis Factor

Design: Retrospective case-control study in 5828 patients (2171 cases, 1445 controls). Subjects needed to have consecutively orders of 2 anti-TNF therapies (infliximab (IFX) prior to adalimumab (ADM) or vice versa).

Key findings:

  • Before switch from IFX to ADM, median (interquartile range) IFX serum concentrations were lower in cases versus control subjects (1.0 μg/mL [1.0–1.0] vs 11.7 μg/mL [4.2–27.1]; P < .0001).
  • As noted in figure below, prior antidrug antibodies ADAb) to anti-TNF agent was associated with development of ADAb with 2nd anti-TNF agent. This risk was >2-fold higher when switching from IFX to ADM (B in Figure) and even more when switching from ADM to IFX (D in Figure)
  • Increasing concentrations of ADAb to IFX were associated with higher proportions of patients developing ADAb to ADM (P < .0001). In contrast, increasing concentrations of ADAb to ADM did not result in a significantly higher proportion of patients developing ADAb to IFX.

My take:

  • In my experience, many patients with subtherapeutic anti-TNF levels, even those with ADAb, can remain on initial anti-TNF with more frequent dosing and often with combination therapy. So before jumping off the initial treatment, make sure it has been optimized.
  • In those who do start a 2nd anti-TNF agent, the authors recommend using combination therapy (with an immunomodulator) which “leads to lower rates of clinical failure and more favorable pharmacokinetics, compared with monotherapy.”
  • “Alternatively, a strategy with optimized monotherapy using proactive TDM may be effective as well, but remains to be assessed in a prospective manner.”
Kaplan-Meier curves representing proportion of patients who developed ADAb when (A) switched from infliximab to adalimumab and (C) switched from adalimumab to infliximab. Difference in rate of ADAb formation between cases (red) and control subjects (teal) for those patients who (B) switched from infliximab to adalimumab and (D) switched from adalimumab to infliximab.

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.

Slinky for Short Bowel Syndrome?

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From GeneralSurgeryNews.com: Open Access: Novel Device Uses Mechanotransduction To Treat Small Bowel Syndrome

An excerpt:

“The basic concept is similar to distraction osteogenesis, which orthopedic surgeons have used for years, applying distraction force to broken bone that will grow up to a millimeter a day,” said Andre Bessette, the CEO and a co-founder of Eclipse Regenesis, Inc…

To regenerate small-bowel tissue, a surgeon inserts the device, which looks like a small, compressed coil, inside the small intestine and secures both ends with plication sutures applied to the outside of the intestine. Over two to three weeks, the device slowly expands to its uncompressed state, stimulating new tissue growth—ultimately two to three times the segment’s original length, about 4 cm...[thus]  they’ll need more than one device applied or more than one procedure.

Once this process is complete, the chromic sutures dissolve over about a month, allowing the device to pass through the body to be excreted...

[The researchers] expect to start these [human] trials in the first half of 2022, and they have identified two primary investigator sites: Boston Children’s Hospital and Cincinnati Children’s Hospital

Preclinical studies: Eclipse’s website at www.eclipseregenesis.com/ publications.

“Do Not Stop Anti-TNF Medications in Children with IBD When They Are Working”

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In 2014, one of the posts on this blog addressed stopping anti-TNF therapy: Marriage, Divorce and Separation with Anti-TNF Therapy. My take at that time was “most patients are better off staying married to their anti-TNF therapy.”

Despite changes in therapeutic options, a recent study and editorial come to the same conclusion in 2022:

In the retrospective study, 78 patients with CD and 56 patients with UC underwent endoscopic reassessment. Key findings:

  • Mucosal healing (MH) was achieved by 32 patients with CD (41%) and 30 patients with UC (53.6%); 26 patients with CD (33.3%) and 22 patients with UC (39.3%) achieved histologic healing (HH)
  • Among 45 patients (n=24 CD, n=21 UC) with both MH & HH, anti-TNF therapy was stopped & patients received either an immunomodulatory or mesalamine. 76% of patients with CD had clinical relapse within 3 years and 17% within 1 year. Importantly, objective markers of relapse, including calprotectin and endoscopy were NOT performed; thus, this is certainly an underestimation of relapse rate and time to relapse.

In the commentary, the authors note the high rate of relapse in other studies with anti-TNF withdrawal (eg. STORI trial) and high rate of surgery in patients with perianal CD who stopped therapy. In the STORI trial, “the best outcomes [for infliximab withdrawal] were those with subtherapeutic infliximab trough levels, ie, those for whom infliximab was not responsible for maintaining their remission.”

The data are less certain for UC. The editorial notes that 85% of the 21 patients in the Scarallo study had limited left-sided colitis and only 17 were followed for at least 1 year. In adult studies on anti-TNF discontinuation with UC (Kennedy et al. Aliment Pharm Ther 2016; 43: 910-23 and Molander et al. Inflamm Bowel Dis 2014; 20: 1021-28), 42% and 35% relapsed within 12 months, whereas another small study (Farkas et al. World J Gastroenterol 2014; 20: 2995-3001) found 100% of patients on combination therapy who stopped anti-TNF agent had to restart anti-TNF therapy.

My take (from editorial): “The totality of the currently available evidence suggests that discontinuing anti-TNF medications in children with IBD is associated with a greatly increased risk of disease exacerbation, especially if the anti-TNF trough level was therapeutic.”

Broadwalk; Hollywood, FL