Category Archives: Gastroenterology

Ondansetron for Irritable Bowel with Diarrhea?

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Briefly noted: A selected summary (Gastroenterol 2014; 147: 527-28) reviews the potential utility of ondansetron (median dose in adult participants was 4 mg) for irritable bowel syndrome with diarrhea (IBS-D) based on a recent study (Link to full online journal article: Randomized Trial of Ondansetron for IBS-D in Gut).

Several limitations are discussed including patient dropout, crossover study design, and short term study (in chronic disease).  As such, even though this study provides some evidence that ondansetron may be helpful for IBS-D, this probably needs “to be replicated in large-scale, parallel group, randomized, placebo-controlled trials…with longer duration of therapy..before the true place of ondansetron in the management of IBS-D is known.”

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Barrett’s Esophagus -New Review

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An up-to-date concise review: NEJM 2014; 371: 836-45.

A few key points:

  • “Despite the lack of high-quality evidence to support the practice, medical societies currently recommend endoscopic screening for Barrett’s esophagus in patients with chronic GERD symptoms who have at least one additional risk factor…such as age of 50 years or older, male sex, white race, hiatal hernia, elevated body-mass index…or tobacco use.”
  • If nondysplastic Barrett’s is identified, then followup endoscopy is recommended at intervals of 3 to 5 years.  Though, authors note that surveillance has not been proven to reduce death from esophageal cancer.
  • The authors recommend PPIs even in asymptomatic Barrett’s esophagus.

One other reference: Gastroenterol 2014; 147: 314-23.  “Statin Use is Assciated with a Decreased Risk of Barrett’s”

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Mechanism for FODMAPs diet

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According to a recent study (Gut doi:10.1136/gutjnl-2014-307264 -thanks to KT Park for reference), a low FODMAPs diet changes the microbiome which in turn may relate to improvements in patients with irritable bowel syndrome.

Abstract

Objective A low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) diet reduces symptoms of IBS, but reduction of potential prebiotic and fermentative effects might adversely affect the colonic microenvironment. The effects of a low FODMAP diet with a typical Australian diet on biomarkers of colonic health were compared in a single-blinded, randomised, cross-over trial.

Design Twenty-seven IBS and six healthy subjects were randomly allocated one of two 21-day provided diets, differing only in FODMAP content (mean (95% CI) low 3.05 (1.86 to 4.25) g/day vs Australian 23.7 (16.9 to 30.6) g/day), and then crossed over to the other diet with ≥21-day washout period. Faeces passed over a 5-day run-in on their habitual diet and from day 17 to day 21 of the interventional diets were pooled, and pH, short-chain fatty acid concentrations and bacterial abundance and diversity were assessed.

Results Faecal indices were similar in IBS and healthy subjects during habitual diets. The low FODMAP diet was associated with higher faecal pH (7.37 (7.23 to 7.51) vs 7.16 (7.02 to 7.30); p=0.001), similar short-chain fatty acid concentrations, greater microbial diversity and reduced total bacterial abundance (9.63 (9.53 to 9.73) vs 9.83 (9.72 to 9.93) log10 copies/g; p<0.001) compared with the Australian diet. To indicate direction of change, in comparison with the habitual diet the low FODMAP diet reduced total bacterial abundance and the typical Australian diet increased relative abundance for butyrate-producing Clostridium cluster XIVa (median ratio 6.62; p<0.001) and mucus-associated Akkermansia muciniphila (19.3; p<0.001), and reduced Ruminococcus torques.

Conclusions Diets differing in FODMAP content have marked effects on gut microbiota composition. The implications of long-term reduction of intake of FODMAPs require elucidation.

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Low-FODMAPs with or without Gluten-Free Diet in IBS

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In a small study with 60 patients with irritable bowel syndrome (DDW abstract 374), the response rate to a Low-FODMAPs/Normal gluten diet was as effective as a Low-FODMAPs/Gluten-free diet.  Both diets were more effective in reducing abdominal symptoms than a normal diet.  A summary of this abstract from Gastroenterology & Endoscopy News: Nixing Gluten Offers No Added Benefit To Low-FODMAPs Diet for IBS

According to Lin Chang, MD: “The beneficial effect of low FODMAPs does not appear to be predominantly due to gluten avoidance.”

Related blog post: An Unexpected Twist for “Gluten Sensitivity” | gutsandgrowth

 

Naloxegol for Opioid-Induced Constipation

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Opioid narcotics are ubiquitous therapeutic agents for acute and chronic pain.  In the United States, more than 240 million opioid prescriptions are dispensed per year.  One of the most common sided effects is constipation.  The mechanism of this side effect is the binding of opioid agonists to μ-opioid receptors located in the enteric nervous system.

The recognition of this mechanism has allowed the development of μ-opioid receptor antagonists. A recent study has shown that Naloxegol helps treat constipation related to opioids in patients with noncancer pain (NEJM 2014; 370: 2387-96).  Naloxegol is a pegylated derivative of the μ-opioid receptor antagonist naloxone.  Pegylation limits the ability of naloxegol to cross the blood-brain barrier; hence, the central pain effects of narcotics are not blocked whereas the effects on the enteric nervous system are limited.

This study reported the results of two phase 3, double-blind studies with a combined 1352 participants.  Response to treatment was defined as having ≥3 spontaneous BMs/week and an increase in baseline of ≥1 spontaneous BM/week for ≥9 of 12 week study period and for ≥3 of the final 4 weeks.

Key results:

  • Response to Naloxegol at 25 mg dosing: 44.4% in first study and 39.7% in second study (compared with 29% of placebo treated patients in both studies).
  • Most adverse effects were mild to moderate and included increased abdominal pain, diarrhea, nausea, and flatulence.  Major cardiovascular events were rare and not increased compared to placebo.

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Monotherapy or Combination Therapy with Adalimumab?

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Since the introduction of anti-tumor necrosis factor therapies (anti-TNFs), the benefit of using these agents in combination with immunomodulators or as monotherapy has shifted a few times based on the latest studies.  The most influential recent studies had been SONIC and UC Success which indicated that combination therapy for Crohn’s and Ulcerative Colitis, respectively, was more effective and without more adverse effects than monotherapy. A recent study may create some additional uncertainty in this line of thought (Gastroenterol 2014; 146: 941-49).

The author performed a pooled analysis of data from 1594 patients with Crohn’s disease (CD).  Studies included CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE.  In total, these studies provided 3050 patient-years of exposure. For individual patients, the median followup period was 1.5 years.

Key findings:

  • “Those patients receiving combination therapy had an increased risk of malignancy (other than non melanoma skin cancer [NMSC])” with a relative risk of 2.82.
  • Adalimumab monotherapy was not associated with an increased risk of malignancy other than NMSC
  • Combination therapy was associated with relative risk of NMSC of 3.46

In the discussion, the authors state “the data suggest that the increased risk likely is attributed to the immunomodulator therapy.”

A related editorial (884-86) helps dissect the articles strengths/limitations as well as implications.

Strengths:

  • the study captured data from randomized controlled trials.

Limitations:

  • median followup of 1.5 years –may not be long enough to detect a malignancy signal from anti-TNF therapy
  • unclear how many adalimumab monotherapy patients had been on a thiopurine previously

Implications:

  • “Even if Osterman et al are correct, is this information clinically meaningful enough to swing the mono-combo pendulum back to mono therapy?”
  • “The clinical relevance of the increase in absolute cancer risk from 4 in 1000 with adalimumab monotherapy to 10 in 1000 with combination therapy for cancers other than NMSC is unclear”
  • This difference of 6 in 1000 “translates to 167 patients who are treated before seeing 1 excess cancer”
  • “Most (if not all) of the cancer risk is associated with thiopurine exposure…induction therapy is more effective with combination treatment–>”we propose that we should induce patients into remission with combination therapy, and then consider withdrawing thiopurines at some point.“
  • “Consider treating younger males with thiopurines short term, or alternatively with methotrexate.”  Though the authors note that data from rheumatology brings some concern to methotrexate cancer risk (Semin Arthritis Rheum 2014; 43: 489-97). Source Article: Methotrexate Safety | gutsandgrowth
  • “Consider treating elderly patients with anti-TNF monotherapy to decrease their risk of serious infections”

Also noted: “Risk of Cancer in Patients with Inflammatory Bowel Diseases: A Nationwide Population-based Cohort Study with 30 Years of Follow-up Evaluation” (Clin Gastroenterol Hepatol 2014; 13: 265-73). n=13,756 patients with CD and 35,152 with UC. Key findings –among CD patients, the excess risk was largely due to extra-intestinal cancers such as hematological malignancies (SIR 1.9) and smoking-related malignancies (SIR 1.5).  Associations between UC and gastrointestinal/extraintestinal cancers were weaker (both SIRs were 1.1); the risk of gastrointestinal cancers decreased over the course of the study.

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The Latest on EoE and PPI-REE

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A recent study shows similar clinical, endoscopic and histologic findings between eosinophilic esophagitis (EoE) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) (Aliment Pharmacol There 2014; 39: 603-08 -thanks to Seth Marcus for this reference).

The authors used two databases: one from Walter Reed and one from the Swiss EoE database.  All of these patients were >/=18 years.  Response to PPI was defined as achieving less than 15 eos/hpf and a 50% decrease from baseline following at least 6-weeks of PPI treatment.

Demographics: 63 EoE patients, 40 PPI-REE, mean age 40 years (75% male, 89% Caucasian).

Findings:

  • Similar dysphagia 97% vs. 100% (in EoE and  of PPI-REE cohorts)
  • Similar food impaction 43% vs. 35% (in EoE and  of PPI-REE cohorts)
  • Similar heartburn 33% vs. 32% (in EoE and  of PPI-REE cohorts)
  • Similar duration of symptoms: 6.0 years vs 5.8 years (in EoE and  of PPI-REE cohorts)
  • Similar endoscopic findings too: rings 68% in both groups, furrows 70% in both groups, strictures 49% vs 30% (in EoE and  of PPI-REE cohorts)
  • Similar histology: proximal esophagus 39 vs 38 eos/hpf and distal esophagus 50 vs 43 eos/hpf

Take-home message: EoE and PPI-REE are very similar in presentation and indistinguishable without a PPI trial.

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Marriage, Divorce and Separation with Anti-TNF Therapy

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This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission.  This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married.  Once you committed, you stayed in that relationship indefinitely.  Of course, it is well-known that individuals get divorced.  In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions.  Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this?  The article examines nine studies with a little more than 500 patients.  “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval.  It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.  Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM.  Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.”

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56.  Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease.  This is a useful review with 103 references.

Brief Updates on Colorectal Cancer

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“Low-Dose Aspirin Use After Diagnosis of Colorectal Cancer Does Not Increase Survival: A Case-Control Analysis of a Population-Based Cohort”  Gastroenterol 2014; 146: 700-08.  The authors performed a nested case-control analysis of a cohort of 4794 patients diagnosed with colorectal cancer.  “There was no association between low-dose aspirin usage and colon cancer-specific mortality.”  These study findings contradict previous studies.  More trials are underway.

“Reduced Risk of Colorectal Cancer Up to 10 Years After Screening, Surveillance, or Diagnostic Colonoscopy” Gastroenterol 2014; 146: 709-17.  Conclusion: “In a population-based case-control study, the risk of CRC was strongly reduced up to 10 years after colonoscopy for any indication. Risk was particularly low after screening colonoscopy, even for cancer in the right colon.”  The odds ratio for CRC after screening colonoscopy was 0.09.

NEJM 2014; 370: 1287-97.  Multitarget Stool DNA Testing for Colorectal-Cancer Screening.  Among 9989 average-risk participants, this stool DNA assay identified more cancers than a fecal immunochemical test (FIT) but had more false positives.

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