Category Archives: Uncategorized

Fewer Surgeries with Crohn’s Disease

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Briefly noted: NE Burr et al. Clin Gastroenterol Hepatol 2019; 17: 2042-49.

In a retrospective cohort (1994-2013) using a primary care database from England, the authors identified decreasing risk of surgeries with Crohn’s diseae (CD).

  • From 1994-2003, the risk of first surgery dropped from 44% to 21%.
  • The risk of a second resection dropped as well, from 40% in 1994 to 17% in 2003 (with 10-year followup)

The reasons for this reduction are not certain but could include better clinical care or reduction in other risk factors (like smoking).

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Quantifying the Risk of Autoimmunity for Celiac Disease

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A recent study (MR Khan et al. JPGN 2019; 69: 438-42) examined the rates of autoimmune disorders (AD) among patients with celiac disease (CD) (n=249) compared to a control group (n=498) over an 18 year period (1997-2015). The authors utilized the  a database of medical records via the Rochester Epidemiology Project (Mayo Clinic/Olmstead County).

Key findings:

  • Five years after the index date, 5.0% of CD patients and 1.3% of controls had a de novo AD diagnosis
  • In the pediatric age group, there was an increased risk of AD: 5/83 (7.3%) of CD patients and 0/179 (0%) developed a AD diagnosis at the 5-year mark
  • The authors note that they observed a lower rate of Hashimoto thyroiditis after the diagnosis of CD, likely indicating a protective role of a gluten-free diet
  • Thyroid disorders, type 1 DM, psoriasis/psoriatic arthritis and rheumatoid arthritis were the most common AD identified in patients with CD

Limitations:

  • Retrospective study
  • Adherence with GFD was not assessed

My take: Screening for AD periodically is worthwhile in patients with CD, particularly thyroid disorders and type 1 diabetes which accounted for ~80% of the autoimmune conditions identified.

Briefly noted: R Ahawat et al. JPGN 2019; 69: 449-54. In this study with 38 newly-diagnosed CD, the authors found a high prevalence of low vitamin D (25OHD) levels (65.8%) -defined as <30 ng/mL; however, the control population had a higher rate of 79.3%.  While the authors advocate checking vitamin D levels due to the risk of bone disease, it is noted that bone mineral density and vitamin deficiencies frequently improve with a gluten-free diet (Related post: Celiac studies)

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Vedolizumab versus Adalimumab for Ulcerative Colitis (part 2)

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A previous blog post (Vedolizumab More Effective Than Adalimumb for Ulcerative Colitis) highlighted a preliminary report on the “VARSITY” study. The full report has now been published (BE Sands et al NEJM 2019; 381: 1215-26) and a little nuance is needed.

This double-blind, double-dummy randomized trial included 769 patients who underwent randomization to receive at least one dose of one of the study medications.

Key findings:

  • At week 52, clinical remission was higher in the vedolizumab group: 31.3% compared to 22.5% for adalimumab
  • Endoscopic improvement was better for vedolizumab: 39.7% compared to 27.7%
  • Corticosteroid-free remission was better for adalimumab: 21.8% compared to 12.6% for vedolizumab

Limitations:

  • dose escalation was not allowed during the study –this limitation likely favors vedolizumab compared to adalimumab
  • previous exposure to an anti-TNF agent was allowed in up to 25% of patients

My take:  In two of three key measures, vedolizumab outperformed adalimumab.  This study provides a rationale for vedolizumab to be considered a first-line agent.  That being said, in my clinical experience, infliximab is a much more frequently used anti-TNF agent in moderate-to-severe ulcerative colitis.  So a head-to-head study with infliximab would be of interest.

The image below shows histologic remission differences at week 52

 

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What to Tell Patients About Ranitidine From AGA

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Here’s the link: Talking to your patients about ranitidine  Thanks to John Pohl for sharing this information.

Oct. 3, 2019

Talking to your patients about ranitidine

The recent FDA safety alert might be causing concern among your patients about their heartburn treatment.

The FDA recently released several safety alerts on ranitidine formulations, including the brand-name drug Zantac, that were found to contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests and animal studies. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. This contaminant is similar to was recently found in losartan, an angiotensin II receptor blocker used to treat hypertension, that was recalled by the FDA.

The FDA is continuing to test ranitidine products from multiple manufacturers and is assessing the potential impact on patients who have been taking ranitidine. 

With the voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., as well as the voluntary recall of over-the-counter (OTC) ranitidine tablets (75 mg and 150 mg), labeled by Walgreens, Walmart, and Rite-Aid and manufactured by Apotex Corp, your patients might be asking a lot of questions about whether to continue to using their medicines and what alternatives are available. 

TALKING TO YOUR PATIENTS 

The FDA safety alerts have been covered by various media outlets since early September. This may cause your patients to question whether they should stay on or start using ranitidine products. When discussing the recall with your patients, let them know that: 

  • Ranitidine is an H2 blocker (antihistamine) — available OTC and in prescription strength — used to prevent and relieve heartburn associated with acid ingestion and sour stomach. It reduces stomach acid and works longer but not as quickly as antacids.
  • Not all ranitidine medicines marketed in the U.S. are being recalled and the FDA is not recommending individuals stop taking all ranitidine medicines at this time.
  • It might be prudent to hold off taking Zantac until a final FDA conclusion.
  • Multiple drugs are approved for the same or similar uses as ranitidine. Other treatment options are available, both prescription and OTC, for patients who are concerned about ranitidine.
  • Life-style modifications may reduce or eliminate the need for heartburn drugs for long-term use. These may include weight loss, avoiding tobacco or a change in eating patterns. Share AGA’s patient education content on gastroesophageal reflux disease (GERD) for more tips for your patients.

Related blog post: Preliminary Recommendations from NASPGHAN on Ranitidine Warnings

Ustekinumab for Ulcerative Colitis (UNIFI Trial)

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A landmark study (BE Sands et al. NEJM 2019; 381: 1201-14) shows that ustekinumab (Stelara) can be an effective therapy for moderate-to-severe ulcerative colitis (UC); it is already an approved, established therapy for Crohn’s disease. This randomized placebo-controlled study included an 8-week induction trial (n=961) followed by a 44-week maintenance trial (n=523) for patients with response.

Clinical remission was defined as a total socre of ≤2 on the Mayo scale (range 0-12) and no subscore >11 on any of the four Mayo scale components.

Key findings:

  • During induction, there was a similar clinical remission rate between those who received 130 mg fixed intravenous dose compared to those who received 6 mg/kg: 15.6% and 15.5% compared to 5.3% for placebo group.
  • During maintenance, among patients receiving 90 mg every 8 weeks the clinical remission rate at 44 weeks was 43.8%, in those with 90 mg every 12 weeks the rate was 38.4%; placebo group was 24.0%.
  • The response to ustekinumab occurred in those with or without previous treatment failure with biologic agents, though response was lower in both induction and maintenance in those with prior treatment failure.  In both phases, at least 59% of participants had failed either or both anti-TNF agents or vedolizumab.
  • In this study, there were similar serious adverse events with ustekinumab compared to placebo.  In the treatment groups, there were two deaths (one from ARDS, one from esophageal varices) and 7 cases of cancer (3 nonmelanoma skin cancer, two colon cancer, one prostate, one renal).  There was one death from testicular cancer in the placebo group. Also four patients in the ustekinumab group had opportunistic infections including CMV in two, legionella in one and HSV in one.

In terms of dosing, the authors note that there was greater improvement in calprotectin values during induction in the group who received 6 mg/kg compared to those who received 130 mg.  At week 44, using more objective and stringent end points (eg. endoscopic improvement), greater clinical benefit was observed with the every 8 week regimen.

Visual abstract from NEJM Twitter Feed:

The following image depicts patients response during the maintenance phase –the lightest color is placebo, followed by every 8 weeks, and then the darkest color is every 12 weeks.  The x-axis measures (left to right) are clinical remission, maintenance of clinical response at week 44, endoscopic improvement, corticosteroid-free remission, and remission at 44 weeks in those with remission after induction.

My take: Ustekinumab is more effective for placebo in patients with ulcerative colitis.  More experience is needed to understand its long-term safety.

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“Bystander Effect” –Not the Norm

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A recent study has cast some “shade” on the concept of the “bystander effect.”

From Washington Post: Forget What You May Have Been Told. New Study Shows Strangers Help 90 Percent of the Time

An excerpt:

Bystanders will intervene 9 times out of 10 to assist the victim in a public fight, an international team of researchers found in a study called “Would I be helped?,” published in American Psychologist this summer. After reviewing surveillance footage of more than 200 violent altercations around the world, the researchers concluded that having more bystanders around makes it more likely that someone will intervene…

On average, at least three people chose to intervene — and every additional bystander present increased the odds that the victim would receive assistance by roughly 10 percent.

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PPIs: Good News on Safety (Part 2)

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Earlier this year, I noted that a recent publication provided reassurance on PPI safety. (related blog post: PPIs: Good News on Safety).  In the journal issue with the printed version, a detailed editorial provides useful context.

DA Corley. Full Text Link: “Safety and Complications of Long-Term Proton Pump Inhibitor Therapy: Getting Closer to the Truth” Gastroenterol 2019; 157: 604:-7.

The Table 1 contrasts the useful information from this large double-blind randomized study and prior data/data quality.

The new study found NO ASSOCIATION between PPI use and kidney disease, dementia, bone fractures, myocardial infarction, pneumonia, or gastrointestinal malignancies.

An excerpt:

Recent publications have summarized both the evidence and evidence-based approaches toward teasing out whether proton pump inhibitors cause certain diseases or are only associated with them through other pathways (e.g., confounding).  Helpful strategies include using the classic criteria for evaluating causation such as the:

  • strength of the association
  • consistency of the findings between studies
  • specificity when an outcome happens almost exclusively from a specific exposure
  • temporality such that the exposure comes before the outcome
  • biological gradient whereby higher exposure doses or longer durations increase risk of the outcome
  • biological plausibility for the proposed association
  • coherence such as between observed effects and known biology of disease
  • experiment such as randomized trials that decrease confounding; and
  • analogy to similar exposure–disease associations known to be causal…

This massive undertaking included >17,000 patients from 33 countries who were randomized to pantoprazole versus placebo, followed for a median of approximately 3 years, and evaluated prospectively for potential complications. The study found an increased risk of enteric infections among pantoprazole users, a result found in both the intention-to-treat and “as-treated” analyses, which excluded people who stopped their medications. This association makes sense—stomach acid markedly decreases bacterial load in food, so decreasing stomach acid may increase the risk of enteric bacterial infections. The authors found no increased risk for several of the most feared associations previously reported, such as cardiovascular disease, kidney disease (directly measured using estimated glomerular filtration rate), dementia, pneumonia, fracture, and all-cause mortality.

My take: (borrowed from editorial): The current study would indicate, from the strongest study design available,… that there is an increased risk of gastrointestinal infections and no detectable excess risk for several other potentially important clinical events…Given known problems with overprescribing and overuse, patients and clinicians should maintain appropriate vigilance in prescribing acid suppression only to persons with defined indications and at the lowest effective dose and duration.

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AGA Guidelines for Evaluation of Functional Diarrhea and IBS-D

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W Smalley et al. Gastroenterol 2019; 157: 851-54. Full Text Link: AGA Clinical Practice Guidelines on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D)

Clinical support tool on pg 855, Patient Summary 856-57, and Technical Review 859-80.

These guidelines/recommendations (listed below) do NOT apply to patients with any of the following:

  • Alarm features such as gross blood, weight loss, anemia, and hypoalbuminemia
  • Family history of of IBD, colon cancer, or celiac disease
  • Travel to areas with high prevalence of infectious diarrhea
  • Immune suppression
  • Ingestion of medications or substances known to cause diarrhea

 

Table 3  Summary of Recommendations of the American Gastroenterological Association on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults
Statement Strength of recommendation Quality of evidence
Recommendation 1: In patients presenting with chronic diarrhea, the AGA suggests the use of either fecal calprotectin or fecal lactoferrin to screen for IBD. Conditional Low
Recommendation 2: In patients presenting with chronic diarrhea, the AGA suggests against the use of ESR or CRP to screen for IBD. Conditional Low
Recommendation 3: In patients presenting with chronic diarrhea, the AGA recommends testing for Giardia. Strong High
Recommendation 4: In patients presenting with chronic diarrhea with no travel history to or recent immigration from high-risk areas, the AGA suggests against testing stools for ova and parasites (other than Giardia). Conditional Low
Recommendation 5: In patients presenting with chronic diarrhea, the AGA recommends testing for celiac disease with IgA-tTG and a second test to detect celiac disease in the setting of IgA deficiency Strong Moderate
Recommendation 6: In patients presenting with chronic diarrhea, the AGA suggests testing for bile acid diarrhea. Conditional Low
Recommendation 7. In patients presenting with chronic diarrhea, the AGA makes no recommendation for the use of currently available serologic tests for diagnosis of IBS None Knowledge gap

For recommendation #6, the authors note that tests for bile acid mediated diarrhea in the U.S. include total bile acid in a 48-hour stool collection and serum fibroblalt growth factor 19.

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IBD Shorts: September 2019

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S Olivia et al (including Stanley Cohen from GI Care for Kids) Clin Gastroenterol Hepatol 2019; 17: 2060-7. “A Treat to Target Strategy Using Panenteric Capsule Endoscopy in Pediatric Patients with Crohn’s Disease”  In this prospective study with 48 children with Crohn’s disease, pan-enteric capsule endoscopy (PCE) detected inflammation in 34 (71%) at baseline, 22 (46%) at week 24, and 18 (39%) at week 52.  PCE results were used to manage treatment and resulted in change in therapy in 71% at baseline and 23% at week 24.  Furthermore, PCE increased the proportions of patients in deep remission, up to 58% at week 52.

M Wright, et al. J Pediatr 2019; 210: 220-5. This case report of a 4 year-old boy with a perianal abscess and granulomatous colitis identified a NCF4 mutation causing severe neutrophil dysfunction.  He developed osteomyelitis with anti-TNF therapy and did not respond to vedolizumab. He had an excellent outcome following a hematopoietic stem cell transplantation. This study reinforces the potential benefit of investigating VEO-IBD which could allow more targeted therapy. Related blog post:

P Zapater et al. Inflamm Bowel Dis 2019; 25: 1357-66. This study with 112 patients with Crohn’s disease showed that serum interleukin-10 levels were directly related to infliximab and adalimumab levels.  This suggests that serum anti-TNF levels are significantly influenced by immunological activation.

JE Axelrad et al. Clin Gastroenterol Hepatol 2019; 17: 1311-22.  This study, using the Swedish National Patient Register, showed that gastrointestinal infection increased the odds of developing IBD in a nationwide case-control study.  “Of the patients with IBD, 3105 (7%) had a record of previous gastroenteritis compared with 17,685 control subjects (4.1%). IBD cases had higher odds for an antecedent episode of gastrointestinal infection (aOR 1.64), bacterial gastrointestinal infection (aOR 2.02) and viral gastrointestinal infection (aOR 1.55)…a previous episode of gastroenteriitis remained associated with odds for IBD more than 10 years later (aOR 1.26).”  The authors note that they cannot formally exclude misclassification bias, but it appears that enteric infections contribute to the development of IBD in susceptible individuals.

Polyposis in Pediatric Patients -Review

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A recent review article (SP MacFarland et al. JPGN 2019; 69: 273-80) provides clearcut guidelines on polyposis syndromes in pediatric patients.

Table 1 lists the syndrome, the mutated gene (s), and recommended screening (onset & interval). The article and table provide more nuance/guidance but the basic recommendations are noted as follows:

  • For Familial Adenomatous Polyposis (FAP), the authors recommend onset of colonoscopy at 10 years and with 1 year intervals.  “Colectomy recommended by 20 to 25 years.”  EGD is recommended at 18 to 20 years. Thyroid ultrasound is recommended at 18 years.  Alpha-fetoprotein levels to check for hepatoblastoma are recommneded every 3-6 months in infancy up to 5 years of age.
  • For Juvenile Polyposis Syndrome, EGD and Colonoscopy are recommended at 15 years with interval evaluations at 1-3 years.
  • For Peutz-Jeghers syndrome, EGD and Colonoscopy are recommended at 8 to 10 years (along with small bowel evaluation with either MRE or video capsule).  Interval followup is recommended every 2-3 years.

Table 2 provides suggestions for familial screening in pediatric polyposis syndromes.

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