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:

 

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.

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

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:

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:

 

Healthy Microbiome: A Work in Progress, Plus Microbiome-Drug Metabolism

A recent study (G Galazzo, N Van Best, et al. Gastroenterol 2020; 158: 1584-96) highlights the changes in microbiota diversity from birth until 11 years of age.

Full text: Development of the Microbiota and Associations With Birth Mode, Diet, and Atopic Disorders in a Longitudinal Analysis of Stool Samples, Collected From Infancy Through Early Childhood

Methods: We collected 1453 stool samples, at 5, 13, 21, and 31 weeks postpartum (infants), and once at school age (6–11 years), from 440 children (49.3% girls, 24.8% born by cesarean delivery; all children except for 6 were breastfed for varying durations; median 40 weeks; interquartile range, 30–53 weeks).

Key findings:

  • Most bacteria within the Bacteroidetes and Proteobacteria phyla were already present at 5 weeks after birth, whereas many bacteria of the Firmicutes phylum were acquired at later times in infancy.
  • At school age, many new Actinobacteria, Firmicutes, and Bacteroidetes bacterial taxa emerged.
  • The largest increase in microbial diversity occurred after 31 weeks of life.
  • Vaginal, compared with cesarean delivery, was most strongly associated with an enrichment of Bacteroides species at 5 weeks through 31 weeks.
  • From 13 weeks onward, diet became the most important determinant of microbiota composition; cessation of breastfeeding, rather than solid food introduction, was associated with changes.
  • When we adjusted for confounding factors, we found fecal microbiota composition to be associated with development of atopic dermatitis, allergic sensitization, and asthma. Members of the Lachnospiraceae family, as well as the genera Faecalibacterium and Dialister, were associated with a reduced risk of atopy.

My take: We are still learning a lot about the microbiome.  Though a ‘healthy’ microbiome is still not straight-forward determination, a good diet with plenty of fruits and vegetables has been associated with more favorable attributes.

Plus One: Bahar Javdan, et al. Personalized Mapping of Drug Metabolism by the Human Gut MicrobiomeCell, 2020; DOI: 10.1016/j.cell.2020.05.001

In this study, the authors found how variations in the microbiome had unique effects on drug metabolism.  From ScienceDaily, Can gut microbiome alter drug safety and efficacy?  The authors tested 575 FDA-approved drugs to see if they are chemically modified by one of the 21 cultured microbiomes, and then tested a subset of the drugs with all the cultured microbiomes. Here, they found microbiome-derived metabolites that had never been previously reported

Related blog posts:

 

Reducing Gastrostomy Tube Placement in Children with Aspiration & COVID-19 Tracking

From The COVID Tracking Project: Effective Reproduction Number

These are up-to-date values for Rt, a key measure of how fast the virus is growing. It’s the average number of people who become infected by an infectious person. If Rt is above 1.0, the virus will spread quickly. When Rt is below 1.0, the virus will stop spreading.  All 50 states listed below (but hard to see) -these numbers adjust for testing frequency:

The site has each state -here are Georgia and Florida:


A recent study (McSweeney M, Meleedy-Rey P, Kerr J, Yuen JC, Fourneir G, Norris K, Larson K, Rosen R. A quality improvement initiative to reduce gastrostomy tube placement in aspirating patients. Pediatrics. 2020, 145: e20190325; DOI: https://doi.org/10.1542/peds.2019-0325) was highlighted by John Pohl in Practical Gastroenterology:

Full text summary: Reducing Gastrostomy Placement in Children with Aspiration

An excerpt:

Children equal to or less than 2 years of age with aspiration demonstrated on VFSS were included in the study…If a VFSS was abnormal and the child was less than 52 weeks gestational age, then the child either was admitted to the hospital for a trial of nasogastric (NG) breastmilk or oral thickened formula with NG breast milk. The patient then continued to work with SLP… If a repeat VFSS showed improvement in the swallowing mechanism, then work with SLP and trialing with thickened feeds continued until the aspiration had resolved as demonstrated by VFSS. However, if a repeat VFSS still showed aspiration, a child was considered a candidate for gastrostomy placement…

In total, 6125 patients at 2 years of age or less underwent a VFSS during the 4-year study period, and 1668 of these patients had aspiration or penetration… 94 of the patients with aspiration or aspiration and penetration on their first VFSS (12.2%) and 31 of the patients with penetration only on their first VFSS (3.4%) eventually required gastrostomy placement…

Gastrostomy placement in this patient population fell from 10.9% at the beginning of the study to 5.2% at the end…

The number of emergency room visits and hospitalizations in the patient group without gastrostomies did not increase during the study with this same patient group having significantly less emergency room visits and hospitalizations compared to those children who had undergone gastrostomy placement

My take: This study shows that conservative therapy allows most children (<2 yrs) to avoid gastrostomy tube placement

Related blog posts:

 

Can Microscopic Colitis Lead to Crohn’s Disease or Ulcerative Colitis?


A recent prospective cohort “ESPRESSO” study (H Khalili et al. Gastroenterol 2020; 158: 1574-83) from 1990-2017 examined the risk of incident inflammatory bowel disease (IBD) in subjects with microscopic colitis, n=13,957 (& each matched with 5 controls). ESPRESSO = Epidemiology Strengthened by histoPathology Reports in Sweden.

Key findings:

  • In the microscopic colitis group, there were 323 incident cases of ulcerative colitis (UC) and 108 cases of Crohn’s disease (CD)
  • Mean times to diagnosis were 3.2 years for UC and 3.3 years for CD
  • Microscopic colitis was associated with an aHR of 12.6 for CD and 17.3 fo rUC
  • The absolute excess risk compared to matched control over a 10-year period were 2.6% for UC and 0.9% for CD

My take: Individuals with microscopic colitis are at increased risk of developing UC and CD.

Related blog post/related article:

 

IBD Briefs June 2020

SA Draiweesh et al. Safety of Combination Biologic and Antirejection Therapy Post-Liver Transplantation in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2020; 26: 949-59. In this case series of 19 patients, 14 who had liver transplantation for PSC, there was no increased risk of serious infections among patients receiving biologic therapy in combination with antirejection medications.

A Malian et al. Pedictors [sic] of Perianal Fistula Relapse in Crohn’s Disease. Inflamm Bowel Dis 2020; 26: 926-31. In this retrospective study with 137 patients, fistula relapse rates were not different in patients receiving infliximab or adalimumab (P = 0.66). In patients treated by anti-TNF at inclusion, discontinuation of anti-TNF therapy (odds ratio 3.49, P = 0.04), colonic location (OR 6.25, P = 0.01), and stricturing phenotype (odds ratio 4.39, P = 0.01) were independently associated with fistula relapse in multivariate analysis.

M-H Wang et al. Unique Phenotypic Characteristics and Clinical Course in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis: A Multicenter US Experience. Inflamm Bowel Dis 2020; 26: 774-81. Among 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001).  In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar.

B Barberio et al. Matrix Metalloproteinase 3 Predicts Therapeutic Response in Inflammatory Bowel Disease Patients Treated with Infliximab. Inflamm Bowel Dis 2020; 26: 756-62. Retrospectively, 73 IBD patients who had received IFX for at least 1 year were enrolled: 35 patients were responders and 38 were nonresponders at 52 weeks…The MMP3 levels were similar at baseline (19.83 vs 17.92 ng/mL), but at postinduction, patients who failed to respond at 1 year had significantly higher levels than patients who responded (26.09 vs 8.68 ng/mL, P < 0.001); the difference was confirmed at week 52 (29.56 vs 11.48 ng/mL, P < 0.001)…The MMP3 serum determination may represent an early marker of response to infliximab.