Clinically Useful Biomarkers for Irritable Bowel Syndrome?

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A selected summary (Gastroenterol 2016; 150: 277-79) provides good insight into the subject of irritable bowel syndrome (IBS) biomarkers.  This summary focuses on a study by Pimental M et al (PLoS One 2015; 10: e0126438).

“In this study, the authors validated 2 serum biomarkers, antibodies (Abs) to cytolethal distending toxin (CdtB) and vinculin, primarily focused on differentiating diarrhea-predominant IBS (IBS-D) from IBD. CdtB is a bacterial toxin commonly produced by Campylobacter jejuni, as well as Escherichia coli, Salmonella, and Shigella…presence of Cdtb seems to be positively associated with the likelihood of developing a postinfectious IBS phenotype…Vinculin is a host cell adhesion protein, with which anti-CdtB Abs are known to cross-react.”

The study recruited 2681 participants (18-65 years) from 180 centers; most (n=2375) had Rome III IBS-D.

Key findings:

  • Anti-CdtB levels were higher in IBS-D 2.53 (± 0.69) compared with Crohn’s disease 1.72 (± 0.81), ulcerative colitis 1.54 (± 0.68), celiac disease 2.23 (± 0.70), and healthy subjects 1.81 (± 0.73)
  • Anti-vinculin Abs were higher in IBS-D as well: 1.34 (± 0.85) compared with Crohn’s disease 1.05 (± 0.91),ulcerative colitis 0.96 (± 0.77), celiac disease 1.07 (± 0.98), and healthy subjects 0.81 (± 0.59)

“Using a cutoff point of >2.80 for anti-CdtB Abs, the sensitivity was 43.7%, specificity was 91.6%.”  The positive likelihood ratio (LR) was 5.2 with this cutoff.  For vinculin, a cutoff of >1.68, resulted in a sensitivity of 32.6%, specificity of 83.8%, and a positive LR of 2.0.

For comparison, the commentary notes that the Rome III criteria in one study had a sensitivity of 68.8%, specificity of 79.5%, and positive LR of 3.35.

“The current study is important for 2 reasons.  First, that these 2 Abs were able to differentiate IBS-D from IBD and healthy controls, with a reasonable degree of accuracy, suggests that a substantial proportion of individuals with IBS may have an overt or subclinical postinfectious trigger, resulting in intestinal microbial disturbances…Second, the ability of these tests, if positive, to rule in IBS-D and rule out IBD is encouraging.”

But…

  • This study may not be representative of a typical primary care population with IBS
  • And,”as a rule of thumb, positive LRs of >10 are very useful in ruling in a disease…the complex, and likely multifactorial etiology of IBS may mean that a single biomarker that can diagnose IBS with the accuracy required for a test to be clinically useful is not possible.”

My take: I would like to see pediatric studies, perhaps this would help determine if a postinfectious mechanism is more common in children and adolescents.

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Plantains

Plantains

Eluxadoline for Irritable Bowel Syndrome with Diarrhea

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A recent study (AJ Lembo et al. NEJM 2016; 374: 242-53) found that eluxadoline, an oral agent with mixed opioid effects was helpful in some with irritable bowel syndrome with diarrhea (IBS-D).

Study methods: 2427 adults with IBS-D received either 75 mg, 100 mg of study medication or placebo twice daily for 26 weeks.  The primary endpoint was a composite response of decreased abdominal pain and stool consistency.

Eluxadoline in IBS

Eluxadoline in IBS.  Primary efficacy end point was defined as the proportion of patients who recorded a reduction of 30% or more from baseline in the daily average score for their worst abdominal pain for at least 50% of days assessed and, on the same days, a daily stool consistency score of less than 5.  Panel A: weeks 1-12.  Panel B for weeks 1-26.

While the absolute difference in response compared to placebo appears modest (see Figure above), the authors note that the treatment effects “were similar to those reported with alosetron and rifaximin.” Adverse effects included nausea (7.5% in 100 mg group compared with 5.1% in placebo), constipation (8.6%% in 100 mg group compared with 2.5% in placebo), and abdominal pain (7.2% in 100 mg group compared with 4.1% in placebo).  Pancreatitis developed in 5 patients in the treatment group (0.3%).

My take: While Eluxadoline helped some with IBS-D, better, more effective treatments are needed.

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“Medical Taylorism” & Zika Link

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An interesting commentary (P Hartzband, J Groopman. NEJM 2016; 374: 106-8) explains the history of trying to achieve better efficiencies in medicine and some of the problems with this.

Frederick Taylor has been described as the “father of scientific management” and the original “efficiency expert.”  He supported the notion that there is one best way to do every task.  This was initially applied to car production but there have been attempts to adopt this idea into medicine.  The authors make several key points:

  • “The standardization integral to Taylorism and the Toyota manufacturing process cannot be applied to many vital aspects of medicine”
  • “There is a certain hypocrisy among some of the most impassioned advocates for efficiency and standardization…they all want a different kind of health care for themselves and their families than they profess for everyone else.  What they want is what every patient wants: unpressured time from their doctor or nurse and individualized care rather than generic protocols for testing and treating.”
  • “Medical Taylorism began with good intentions — to improve patient safety and care. But it has gone too far…we must reject its blanket application…Good medical care takes time, and there is no one best way to treat many disorders.”

Zika NEJM Link (full text): Zika Virus in the Americas Anthony Fauci/David Morens

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Isla Verde, San Juan

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Characteristics of Skin Lesions Associated with Anti-Tumor Necrosis Factor Therapy

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As noted in previous blog posts (see below), anti-tumor necrosis factor (anti-TNF) therapy has been associated with skin problems.  The following study/abstract elaborate on this issue further and indicate that while ~30% of patients with IBD may develop skin reactions, only 28 of 917 (3%) patients required anti-TNF therapy to be discontinued due to skin reactions.

I Cleynen et al. Ann Intern Med. Published online 8 December 2015 doi:10.7326/M15-0729  Characteristics of Skin Lesions Associated With Anti–Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study ONLINE FIRST

 Background: A subgroup of patients with inflammatory bowel disease (IBD) treated with anti–tumor necrosis factor (TNF) antibodies develop skin lesions, but the lesions and their clinical course are not well-characterized.

Objective: To describe patients treated with anti-TNF antibodies who did and did not develop skin lesions.

Design: Retrospective cohort.

Setting: Single IBD tertiary referral center.

Patients: 917 consecutive patients with IBD who initiated anti-TNF therapy.

Measurements: Skin lesions, patient demographic characteristics, treatments, clinical course, and serologic and genetic markers.

Results: During a median follow-up of 3.5 years (interquartile range [IQR], 0.5 to 7.4 years), skin lesions associated with the use of anti-TNF therapy developed in 264 of 917 (29%) patients (psoriasiform eczema, 30.6%; eczema, 23.5%; xerosis cutis, 10.6%; palmoplantar pustulosis, 5.3%; psoriasis, 3.8%; other, 26.1%). Lesions typically developed at flexural regions, genitalia, and the scalp, especially the psoriasiform lesions. Thirty-one percent of women and 26% of men developed lesions. Median cumulative doses (2864 mg/y [IQR, 2203 to 3819 mg/y] and 2927 mg/y [IQR, 2377 to 3667 mg/y]) and trough levels (4.2 µg/mL [IQR, 2.6 to 5.8 µg/mL] and 4.0 µg/mL [IQR, 1.6 to 5.9 µg/mL]) of infliximab were similar in patients with and without lesions. All but 28 patients (11%) were successfully managed without needing to stop therapy because of lesions.

Limitation: Retrospective nature and no matched control group of patients not receiving anti-TNF therapy.

Conclusion: Skin lesions occur frequently in association with anti-TNF therapy but rarely require discontinuation of therapy. Close surveillance and early referral to a dedicated dermatologist are recommended.

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Sleep Duration and Subsequent Obesity

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A provocative study from Brazil (CSE Halal et al. J Pediatr 2016; 168: 99-103) examined a cohort of 4231 infants and assessed sleep duration from 1-4 years of age.

Findings:

  • 10.1% of cohort had short sleep duration at any follow-up
  • At 4 years of age, 201 children (5.3%) were obese and 302 (8%) were overweight
  • Prevalence ratio for obesity/overweight was 1.32 among those who were ‘short-sleepers’

This study introduction notes that studies in adults have suggested an association between poor sleep and weight gain, “possibly through elevation of cortisol and gherlin levels, along with reduction in leptin levels, thereby leading to increased hunger and reduced energy expenditure.”

Normal sleep patterns: for infants 12-15 hours/day, & for toddlers 11-14 hours/day.  At night, average expected sleep is 12 hours at 1 year of age and 11 hours at 4 years of age.

My take: Looking at early sleep patterns helps reduce the likelihood of reverse causation.  This study and others shows an association with less sleep and increased likelihood of weight gain.  Why???

In same issue (AI Wijtzes et al. J Pediatr 2016; 168: 118-25) report that breakfast skipping at age 4 years is associated (ß =1.38) with a higher percent fat mass at age 6 years, though no associations were found with BMI or weight status.  This study involved prospectively collected data from 5914 children in the “Generation R Study” in The Netherlands.

Briefly noted: JA Emond et al. J Pediatr 2016; 168: 158-63. “Greater child commercial TV viewing was significantly associated with more frequent family visits to those fast food restaurants …toy collecting partially mediated that positive association.” This study involved 100 parents with children aged 3-7 in a rural community.

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This graphic identifies commercial entities influencing food choices

This graphic identifies commercial entities influencing food choices

Adolescent Bariatric Surgery Outcomes at 3 Years

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A prospective study (TH Inge et al. NEJM 2016; 374: 113-23) with 242 adolescents from five U.S. centers provides data on outcomes at 3 years. Here’s the scoop:

  • At baseline, mean age was 17 years, 75% were female, 72% were white, and mean BMI was 53.

At 3 years:

  • Mean weight decreased 27% (similar results for gastric bypass and gastric sleeve)
  • 95% had remission of type 2 diabetes (of those with diabetes at baseline)
  • 86% had remission in abnormal kidney function (of those with diabetes at baseline)
  • 74% had remission in elevated blood pressure (of those with diabetes at baseline)

lonnnngg Table 4 details the serious complications:

  • 13% of the participants (n=30, 47 procedures) had undergone additional abdominal procedures. While most of these were related to the procedure, a good number may have occurred regardlessly (eg. 18 cholecystectomies, 2 appendectomies)
  • 13% (n=29) also underwent endoscopic procedures including 9 who needed stricture dilatation.

The most common nutrient deficiency at followup was iron deficiency.  57% had low ferritin levels at 3 years compared with 5% at baseline.  Vitamin B12 deficiency was common; it declined by 35% and 8% had a deficiency at 3 years.  Vitamin A deficiencies increased (16% at 3 years). My take: this study documents the durability of weight loss and its beneficial effects on a multitude of problems.  It also shows that careful followup is needed for nutrient deficiencies and the risks of adverse events. Related blog posts:

Proton Pump Inhibitors Webinar

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For those who missed the live NASPGHAN webinar, it is also available on demand: Link: Proton Pump Inhibitors Webinar. CME credit is available too.

Overall, this is a terrific review and intended for a high level audience. Here are a couple of key points from the talk:

  • Dr. Jennifer Lightdale introduced the webinar.  She noted that there has been a tremendous rise in the use of proton pump inhibitors (PPIs) in children over the past 15 years, including in infants.
  • Preponderance of evidence does not support use of PPIs for reducing GER symptoms or crying in infants.
  • PPIs are extremely effective at acid suppression.
  • Excellent discussion by Dr. Rachel Rosen on Nonerosive Reflux Disease (NERD) and distinguishing this entity from erosive reflux disease, hypersensitive esophagus, and functional heartburn.
  • On a microscopic level, NERD is similar to erosive reflux with microscopic inflammation and dilated intracellular spaces.
  • With regard to testing, it is recommended that for impedance studies, that acid suppression be stopped prior due to improved sensitivity/accuracy.
  • For those at odds with their pulmonologists and ENT colleagues, Dr. Ben Gold reviewed the literature on asthma, cough, and laryngeal-pharyngeal pathology related to reflux. The sensitivity of laryngoscopic findings to identify reflux is poor.  “There is insufficient evidence to recommend for OR against the use of acid suppression therapy.”
  • Dr. Jose Garza reviewed the indications for PPI use which include eosinophilic esophagitis/PPI-REE, erosive esophagitis, NSAID prophylaxis, Upper GI bleeding, and H pylori therapy.
  • Dr. Carlo DiLorenzo provided an in-depth discussion of the potential risks of PPI therapy and explained some of the context as well as absolute risks.  He noted that besides the risk of infection, particularly C difficile, other risks demonstrated in adults have not yet been confirmed in children.
  • “Prolonged acid suppression should be used only when indicated.”  Thus, management should include strategies for treatment discontinuation in the majority of those receiving PPI therapy.

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Isla Verde, San Juan

Isla Verde, San Juan

 

 

 

 

 

 

 

 

 

Turning Conventional Colonoscopy Positioning Upside Down

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A recent article (The American Journal of Gastroenterology 110, 1576-1581 (November 2015) | doi:10.1038/ajg.2015.298) indicates that right-sided positioning rather than left-side down results in quicker and more comfortable colonoscopy.  While it is disconcerting to realize that I had been trained exactly opposite, if this technique works for me, it will be particularly helpful when patients undergo combination procedures since this means that the bed would not need to be rotated.  Thanks to Mike Hart for this reference.

Right Or Left in COLonoscopy (ROLCOL)? A Randomized Controlled Trial of Right- versus Left-Sided Starting Position in Colonoscopy

N Vergis, A K McGrath, C H Stoddart and Jonathan M Hoare

OBJECTIVES:

Colonoscopy is technically challenging and can cause discomfort for patients. We aimed to test whether right-sided starting position for colonoscopy would result in shorter procedure time and greater patient comfort when compared with conventional left-sided starting position.

METHODS:

We conducted a randomized controlled trial in which patients were randomized to begin in either the right- (RL) or conventional left-lateral (LL) position. One hundred and sixty-three adult patients undergoing scheduled colonoscopy were stratified by age, gender, body mass index, and experience of the endoscopist. Patients were then randomized 1:1 in permuted blocks. The primary outcome measure was time to cecal intubation and secondary outcome measures included patient comfort that was evaluated by visual analog comfort scale.

RESULTS:

Median time to reach the cecum was quicker when colonoscopy began with patients positioned RL rather than LL (P=0.0078). Moreover, patients found RL more comfortable than LL (P=0.02). Multiple linear regression confirmed starting position in colonoscopy as an independent determinant of time to reach the cecum (P=0.007). Women and those who had previously undergone abdominal surgery gained the greatest benefit from right-sided positioning (RL vs. LL: 498 vs. 824 s; P=0.03 and 498 vs. 797 s; P=0.006, respectively).

CONCLUSIONS:

Our study reveals that right-sided positioning at the start of colonoscopy results in more comfortable and quicker procedures. Of the factors identified by multiple linear regression to independently have an impact on time to reach the cecum, only starting position is modifiable. Right-sided starting position may therefore be of benefit in colonoscopy, in particular for women and patients who have previously undergone abdominal surgery.

Nummular Eczema due to Infliximab

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An image report (YM Dawkins et al. Clin Gastroenterol Hepatolo 2016; 14: xxxv-xxxvi) describes a 30-year-old with ulcerative colitis who developed nummular eczema two years after the start of infliximab.  He was treated with topical agents and a course of systemic corticosteroids.  The authors note that in a few patients, withdrawal of anti-TNF therapy is needed, but this was not needed in their patient.

SkinRxnNumEczemaIFX

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