IBD Update -July 2020

X Roblin et al. Gut 2020; DOI: 10.1136/gutjnl-2019-319758 Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial. Key Findings:

  • Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy
  • At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22% versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy

RC Ungaro et al. Clin Gastroenterol Hepatol 2020; 18: 1152-60.  The authors retrospectively analyzed 3178 patients with Crohn’s disease and found that stopping mesalamine therapy in individuals who were starting biologic therapy did NOT increase their risk of adverse clinical events.  They caution that their findings should be validated in a prospective study.

J Wang et al. AP&T. https://doi.org/10.1111/apt.15766. Full Text: Risk factors and treatment outcomes of peristomal pyoderma gangrenosum in patients with inflammatory bowel disease Key finding: “Complete resolution with topical corticosteroids and calcineurin inhibitors alone were low (14% and 13% respectively). Higher rates of complete resolution were reported with anti‐tumour necrosis factor (TNF) agents (63%) and surgical interventions (80%).”

B Verstockt et al. Clin Gastroenterol Hepatol 2020; 18: 1142-51. The authors found that expression of 4 genes in colon tissue could be used to predict which patients will enter endoscopic remission with vedolizumab therapy.  Given the increasing number of expensive therapies for IBD, the ability to predict likely success with treatment rather than selecting empirically would be a huge advance.

ST Leach et al. JPGN 2020; 70: 580-5. The authors found that fecal calprotectin was overall the best fecal biomarker for pediatric Crohn’s disease (=156 patients); however, FA12  (aka S100A12) at 5 mcg/g predicted mucosal healing with greater specificity (87% vs 70%) –though this is related in part to the cut-off values. For calprotectin to have greater specificity (>90%), a cut-off of <100 mcg/g lowered the sensitivity to 63%. FA12 also performs better in younger children as calprotectin levels are higher in this age group in healthy children.

Curcumin Was NOT Effective For Post-operative Crohn’s Disease, Goldman Sachs Take on Masks

NBC/NY Link: Goldman Sachs Says National Mask Mandate Could Slash Infections, Save Economy From 5% Hit


Briefly noted: G Bommelear et al. Clin Gastroenterol Hepatol; 2020; 18: 1553-60. Oral Curcumin No More Effective Than Placebo in Preventing Recurrence of Crohn’s Disease After Surgery in a Randomized Controlled Trial

Methods:

  • Double-blind randomized controlled trial at 8 referral centers in France, from October 2014 through January 2018, with 62 consecutive patients with CD undergoing bowel resection.
  • Patients received azathioprine (2.5 mg/kg) and were randomly assigned to groups given oral curcumin (3 g/day; n = 31) or an identical placebo (n = 31) for 6 months, and were then evaluated by colonoscopy.
  • The primary endpoint: postoperative recurrence of CD in each group (Rutgeerts’ index score ≥i2) at month 6

Key findings:

  • Postoperative recurrence at 6 months: (Rutgeerts’ index score ≥i2): 58% receiving curcumin vs 68% receiving placebo (P = .60).
  • Severe recurrence: 55% receiving Curcumin 55%vs 26% receiving placebo –had a severe recurrence of CD (Rutgeerts’ index score ≥i3) (P = .034).
  • Clinical recurrence of CD (CD activity index score >150) at 6 months: 30% with curcumin compared with 45%  receiving placebo (P = .80)

My take: Curcumin was ineffective in preventing recurrent post-operative Crohn’s disease

Related blog posts:

 

Big Advance for Hepatitis B, Plus One

A recent open-label randomized controlled study (M Bazinet et al. Gastroenterol 2020; 158: 2180-94https://doi.org/10.1053/j.gastro.2020.02.058) showed that the addition of nucleic acid polymers (NAPs) which inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles significantly improved outcomes in a phase 2 HBV trial (n=40).

Full text: Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy

NAP therapy was administered intravenously once a week.

Key findings:

  • During the first 24 weeks of tenofovir (TDF) and peg-Interferon (pegIFN) administration, significantly higher proportions of patients in NAP groups had decreases in HBsAg to below 1 IU/mL (P < .001 vs control) and HBsAg seroconversion (P = .046 vs control).
  • At the time patients completed the TDF + pegIFN + NAP regimen, HBsAg levels were 0.05 IU/mL or lower in 24/40 participants
  • During 48 weeks of treatment-free follow-up, virologic control persisted in 13 of 40 participants (2 lost to follow-up after 24 weeks), whereas functional cure persisted in 14 of 40 participants (all completing 48 weeks of follow-up) with persistent HBsAg seroconversion

The associated editorial (pg 2051-4 by D Durantel, T Asselah) makes the following points:

  • The authors call for larger multicenter studies with longer followup.  They note that more evaluation is needed to determine if seroconversion is sustained.
  • It remains unclear whether PEG-IFN is needed. TDF/NAP therapy without PEG-IFN was not studied.
  • They state that more information about flares during treatment are needed.  In this study, flares were safe and associated with beneficial outcomes.  It is not clear if therapy flares would be detrimental in those with advanced fibrosis.
  • Optimistically, they state that there are multiple competing therapies being studied (eg. small interfering RNA, and small molecule HBs-RNA destabilizer) which could be more easily administered.

My take (borrowed from authors): In a phase 2 randomized trial, “we found that addition of NAPs to TDF + pegIFN did not alter tolerability and significantly increased rates of HBsAg loss and HBsAg seroconversion during therapy and functional cure after therapy.”

A related commentary (Gastroenterol 2020; 158: 2028-32) calls for investment/study of treatment for immune-tolerant patients along with curative therapy when it becomes available.  The authors also argue for a study of long-term viral suppression with either entecavir or tenofovir alafenamide.

Plus one: N Rodriguez-Baez et al. JPGN 2020; 71: 99-105.  This study examined liver histology from 134 liver biopsies from treatment-naive children with chronic hepatitis B infection. 60% acquired infection vertically, 69% were HBeAg-positive.   Interface hepatitis was mild in 31%, moderate in 61% and severe in 6%; lobular inflammation was mild in 54%, moderate in 29% and severe in 7%. Fibrosis: 18% had no fibrosis, 59% had portal fibrosis without bridging, 19% had bridging fibrosis and 4% had cirrhosis. Alanine amnotransferase was a fairly good indicator of the severity of hepatic inflammation and extent of fibrosis.

Related blog posts:

Liver Shorts -June 2020

SH Ibrahim et al. Hepatology 2020; 71: 1474-85.  Thorough review of liver diseases in the perinatal period and relationship of the maternal-infant interactions.  Liver diseases discussed include GALD which has “strikingly normal or near normal transaminases” despite liver failure (most common etiology).  Treatment for GALD includes IVIG (1 g/kg) along with subsequent double-volume exchange transfusion.  The review covers maternally-transmitted viral infections, fatty liver disease, and acute fatty liver disease of pregnancy (AFLP); AFLP is most commonly caused by LCHAD but can be caused by other defects in fatty acid oxidation.

RT Khalaf, RJ Sokol. Hepatology 2020; 71: 1486-98. This review focuses on intestinal failure-associated liver disease (IFALD).  The review provides an in-depth discussion of intravenous lipid emulsions and other factors implicated in the pathogenesis.

  • Risk factors: bacterial overgrowth, central line infections, recurrent sepsis, prematurity, parenteral nutrition composition, and micronutrient imbalances
  • Protective factors: early enteral nutrition, cycled parenteral nutrition, glucagon-like peptide 2, preservation of ileocecal valve, small bowel lengthening when appropriate
  • While the authors acknowledge that lipid minimization often improves cholestasis, they advise caution due to concern for both essential fatty acid deficiency and detrimental effects on brain growth.
  • Prevention of central line infections with use of ethanol locks is important and effectively reduces the rate by more than 80% (though currently costs of ethanol locks have skyrocketed: FDA Safety Initiative Complicit in Ethanol Costing $30,000 for 1 oz)
  • The authors note that long-term survival from intestinal transplantation is only 40% at 10 years indicating benefit of ongoing parenteral nutrition management if feasible.

Related blog posts:

PL Valentino et al. JPGN 2020; 70: 547-54. This article discusses potential management of Wilson disease diagnosed in infancy based on ATP7B genetic testing. Very little evidence presented.  Suggests starting Zinc therapy at an early age and monitoring for copper deficiency along with efficacy.  More precise recommendations regarding urine copper goals for children would be helpful as well.

Large (n=112, median age 38 years) prospective observational study of Acute Hepatic Porphyria. L Gouya et al. Hepatology 2020; 71: 1546-58. Key findings from EXPLORE group:

  • Chronic symptoms were noted in 65%; 46% had daily symptoms. Symptoms including body pains, trouble sleeping/tiredness, anxiety, GI symptoms (eg. nausea) and weakness.
  • During the 2-year study period, 88% experienced a total of 483 attacks; 77% of these attacks required treatment at a health care facility or hemin administration
  • Median annualized attack rate was 2.0
  • UrineDelta-aminolevulinic acid (ALA) and porphobilinogen (PBG) compared with upper limit of normal at baseline and increased further during attacks.
  • At baseline, 16% had elevations of liver aminotransferases
  • Related reference: M Balwani et al. Hepatology 2017; 66: 1314-22. Acute Hepatic Porphyrias -Review. Current recommendations include gene sequencing to confirm all biochemical cases. Biochemical tests are spot urine testing of porphobilinogen (PBG), 5-aminolevulinic acid (ALA), and porphyrins. A normal urine PBG in symptomatic patients “excludes the three most common acute hepatic porphyrias.”  For those with abnormal studies, this reference is a handy.

Automated ascites pump. F Wong et al. Liver Transplantation 2020; 26: 651-61. In this study with 30 patients, interventional radiology placement of an “alfapump” helped manage refractory ascites in cirrhosis.

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Weekend News: Elevators, Maskne, Fraudulent Mask Exemptions, Vaccine Optimism, and Taking Healthcare from Millions

Weekend News:

:NY Times: Maskne Is the New Acne, and Here’s What Is Causing It

Maskne — the most common kind of which is acne mechanica, a.k.a. the type of acne a football player may get where the helmet rubs — is also enough of a thing that the Covid-19 task force of the American Academy of Dermatology (A.A.D.) felt compelled to release advice on the subject.

The article describes how mask can trigger acne and ways to prevent/treat this.

Related: American Academy of Dermatology: 9 WAYS TO PREVENT FACE-MASK SKIN PROBLEMS

NY Times: Don’t Whistle on the Elevator. Don’t Even Talk. (print version article title)

“The good news is: If you don’t like small talk in the elevator, those days are over,”…“Imagine if you have a 30-story office building in New York City and you’re trying to get 5,000 people in between 7 and 9 in the morning,”

From NPR:

This administration should present its ‘plan’ and pass it before taking healthcare insurance from millions.

 

How Very Early Onset-Inflammatory Bowel Disease is Different, Plus One

A recent retrospective study (JR Kelsen et al. Inflamm Bowel Dis 2020; 26: 909-18) compares children diagnosed with inflammatory bowel disease at different age points and their outcomes.  During a 9 year study span (2008-16), there were 229 subjects diagnosed as very-early onset (<6 years, VEO), 221 diagnosed as intermediate onset (6-10 years), and 521 diagnosed as older onset (> 10 years)

Key findings:

  • VEO-IBD patients were significantly more likely to have had a diverting ileostomy and colectomy than the older patients.  Diverting ileostomy rates: 12.2%, 4.1%, and 1.2% respectively.  Colectomy rates: 7.4%, 4.1%, and 1.7% respectively.
  • Ileocecal resections were significantly higher in the older-onset IBD population. In the older group, these resections were noted in 64/521 (12.2%) compared to 1/229 (0.4%) in the VEO group and 10/221 (4.5%) in the intermediate group.
  • VEO-IBD patients had higher medication failure rates at 1 year into treatment and were more frequently readmitted to the hospital. For infliximab (IFX), failure rates were 62.4% for VEO subjects compared to 14.6% for older-onset subjects.  For adalimumab, the respective rates were 53.2% vs. 7.2%.
  • Targeted therapy was successfully used almost exclusively in the VEO-IBD population

My take: Children with VEO-IBD have a more severe disease course than older children.  Since monogenetic disorders occur in ~8% of the VEO population, targeted therapies are more likely; however; ~2% of older children also have a monogenetic disorder and as such, targeted therapy could be important in this group as well.

Related review article: J Ouahed et al. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis 2020; 26: 820-842.  This is a useful review.  A couple of key points:

  • “There are no quality studies assessing the use of nutritional approaches in VEO-IBD”
  • Stem Cell Transplantation NOT efficacious in these disorders (per Table 3): TTC7A, STXBP2, IKBKG (NEMO)

Related blog posts:

ACG Review (Zobair Younassi, MD): NAFLD and NASH

For PDF copy of slides: NAFLD and NASH

Dr. Zobair Younassi gave a recent virtual grand rounds –here are some of the slides:

Epidemiology:

Natural History:

  • Progression of disease is not linear
  • Fatty liver disease is a multisystem disorder.  Cardiovascular disease is leading cause of death in patients with fatty liver disease
  • Fatigue (~50%) is common with fatty liver disease

Main treatment:

  • Weight loss -Mediterranean diet may be helpful
  • Exercise
  • No FDA-approved treatments, though pioglitizone supported by AASLD for biopsy-proven NASH
  • Public health interventions are needed

Iodine Deficiency in Extremely Low Gestational Age Newborns Receiving Parenteral Nutrition

Briefly noted: N Kanike et al. Nutrients 202012(6), 1636; https://doi.org/10.3390/nu12061636 (from Kipp Ellsworth Twitter feed)

Full text: Risk of Iodine Deficiency in Extremely Low Gestational Age Newborns on Parenteral Nutrition

Background/Methods: Extremely Low Gestational Age Newborns (ELGAN) do not receive Iodine supplementation while on parenteral nutrition (PN)….We measured urine iodine levels and thyroid function tests in 50 mother–infant dyads at birth, at 1 week, 1, 2, 3 months and near discharge. In our study, 64% of mothers were iodine deficient at the time of delivery.

Key findings:

  • At 1 month of age, ELGAN on PN developed iodine deficiency (p = 0.017) and had high thyroglobulin levels of 187 (156–271) ng/mL
  • Iodine levels improved with enteral feeds by 2 months of age (p = 0.01).

My take: The authors note that “Iodine supplementation during pregnancy and postnatally should be considered to avoid iodine deficiency.”  In addition, in those at risk, there needs to be monitoring and treatment of hypothyroidism.

Related blog posts:

Blog Case Report: Colonic Polyp & Elevated Calprotectin

Last week, a 7 year old with a 6 month history of loose stools and rectal bleeding underwent a panendoscopy.  Prior to endoscopy, she had a calprotectin level of 1000 mcg/gram.

  • Findings: Huge (>5 cm) multilobulated polyp which was removed at stalk.  A second pass to revise stalk was completed subsequently. The histology report noted that the polyp was a benign juvenile polyp.

This case was interesting to me due to the unusual size/configuration of the polyp and the very elevated calprotectin.  I was aware of elevated calprotectin levels with polyposis (in part from a recent review of our experience with ~400 colonoscopies in our center: Full Text Link: Diagnostic Yield Variation with Colonoscopy among Pediatric Endoscopists)

Two views of large polyp from scope in descending colon

Related blog posts:

 

Data on Mask Efficacy and COVID-19 Safety –How U.S. Compares

According to this ranking, U.S. is 58th in the world:

From Health Affairs, Full Text: Community Use Of Face Masks And COVID-19: Evidence From A Natural Experiment Of State Mandates In The US

Related blog posts: