Guts and Valentines?

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I learned this week that the Crohn’s & Colitis Foundation of America (CCFA) was founded in part  based on a love story:

From CCFA: Irwin M. Rosenthal, one of the visionary co–founders of CCFA, and Suzanne were due to be married in a few months time when suddenly Suzanne became very ill. Motivated by her struggle with Crohn’s disease, Irwin, along with William and Shelby Modell, and Dr. Henry D. Janowitz, established the Foundation for Research in Ileitis, now known as the Crohn’s & Colitis Foundation of America.

To send an CCFA eValentine: CCFA Valentine E-card

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What We Should Not Worry About

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A few useful studies provide reassurances regarding exposures in the prenatal period and perinatal period that we should NOT worry about.

CN Bernstein et al. Clin Gastroenterol Hepatol 2016; 14: 50-7.

In this study with 1671 individuals with inflammatory bowel disease and 10,488 controls, “people with IBD were not more likely to have been born by cesarean section than controls or siblings without IBD.  These findings indicate that events of the immediate postpartum period that shape the developing intestinal microbiome do not affect risk for IBD.”

J Julvez et al. Am. J. Epidemiol. (2016) Full Text Link: doi: 10.1093/aje/kwv195. First published online: January 5, 2016 (thanks to Mike Hart for this reference)

For parents of autistic kids who avoid fish, this article provides information indicating that this is counter-productive.  ” Seafood consumption during pregnancy is thought to be beneficial for child neuropsychological development, but to our knowledge no large cohort studies with high fatty fish consumption have analyzed the association by seafood subtype.” The authors “evaluated 1,892 and 1,589 mother-child pairs at the ages of 14 months and 5 years, respectively, in a population-based Spanish birth cohort established during 2004–2008…” Key finding: “Consumption of large fatty fish during pregnancy presents moderate child neuropsychological benefits, including improvements in cognitive functioning and some protection from autism-spectrum traits.”

My take: We often worry about the wrong things.  These articles provide reassurance that mode of birth and consumption of seafood during pregnancy are things we should not worry about.

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Value of Calprotectin

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A large study (WJ Sandborn et al Gastroenterol 2016; 150: 96-102) focuses on the question of how well calprotectin values correlate with clinical outcomes.  As part of a double-blind, placebo-controlled phase 2 trial of 194 patients who received various doses of tofacitinib or placebo, the authors obtained data on fecal calprotectin (FCP).  Here were the key findings:

  • Week 8 FCP levels were significantly lower in those with a clinical response: 156 vs 725 mg/kg, in clinical remission: 64 vs 617 mg/kg, in endoscopic remission: 44 vs 489 mg/kg and in mucosal healing: 127 vs. 753 mg/kg.
  • On an individual level, FCP showed only moderate agreement for these measures.

For clinical remission, FCP concentration:

  • At 50 mg/kg, the specificity was 0.91, sensitivity was 0.43
  • At 150 mg/kg, the specificity was 0.79, sensitivity was 0.68

For endoscopic remission, FCP concentration:

  • At 50 mg/kg, the specificity was 0.88, sensitivity was 0.52
  • At 150 mg/kg, the specificity was 0.75, sensitivity was 0.79

For mucosal healing, FCP concentration:

  • At 50 mg/kg, the specificity was 0.92, sensitivity was 0.29
  • At 150 mg/kg, the specificity was 0.85, sensitivity was 0.54

The authors speculate that the only fair to good accuracy of FCP in classifying clinical and endoscopic outcomes of individual patients could be related to day-to-day variability in FCP levels and due to residual microscopic inflammation.

My take: While a single normal calprotectin value is not entirely reassuring, I would not be surprised if these values outperform the PGA (physician global assessment).  It is likely that serial calprotectin values will be helpful in tracking clinical progress.

In brief:

Agardh et al. JPGN 2016; 62: 43-46.  Authors show that fecal calprotectin levels were markedly elevated (median 844 mg/kg) in 11 of 12 patients with juvenile polyps and that these levels normalized after polypectomy.  These levels were similar to their cohort (n=129) of children with active IBD (median values of 962 mg/kg).

Heida et al. JPGN 2016; 62: 47-49.  The investigators retrospectively examined 80 children who had endoscopy due to suspected inflammatory bowel disease.  In all 10 of the children with calprotectin levels less than 50 (mcg/g), IBD was excluded.

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Old Town, San Juan

Old Town, San Juan

In brief: Pediatric HCV trial, Exercise for NAFLD, and Urso for Unconjugated Hyperbilirubinemia

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Schwarz et al. JPGN 2016; 62: 93-96.  This study showed that all 21 children who had achieved a sustained virological response with PEG-interferon/ribavirin maintained an SVR during followup of 4.4-7.0 years.  Hopefully, new direct-acting highly effective oral agents will be approved in pediatrics and make this study less relevant.

U.S. Food and Drug Administration approved Zepatier (elbasvir and grazoprevir) Jan 28, 2016

Anderson et al. JPGN 2016; 62: 110-17.  Participants (n=2612) from a large longitudinal study with prospectively collected data were followed. “The adolescents who are more active in late childhood have lower risk of ultrasound scan fatty liver and lower ϒ-gluamyl transferase levels.”  In addition, they showed that more activity was correlated with lower fat mass in adolescence.

Saki et al. JPGN 2016; 62: 97-100. In a double-blind randomized clinical trial of 80 neonates with unconjugated hyperbilirubinemia, treatment with added ursodeoxycholic acid (5 mg/kg/dose BID) resulted in improved clearance of bilirubin compared to phototherapy alone. At 12, 24 and 48 hours, total bilirubin in the treatment group was 12, 10 and 9.8 respectively compared with 14.4, 12.5, and 10.1 for the control group.  Furthermore, the mean time for phototherapy to decrease bilirubin to <10 was 15.5 hours in the treatment group compared with 44.6 hours in the control group.  This study, if confirmed, could result in shorter hospital stays.

Old Town, San Juan

Old Town, San Juan

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

Isla Verde, San Juan

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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