W Sandborn et al. N Engl J Med 2017; 376:1723-1736 May 4, 2017DOI: 10.1056/NEJMoa1606910
Abstract from NEJM:
Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.
We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.
In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.
In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo.
Families are often surprised to learn my opinion about probiotics. The “truth” about probiotics is that they are poorly regulated/lack rigorous production standards and are mostly ineffective for many of the conditions for which they have been promoted. Even in conditions in which there is some effectiveness (eg. antibiotic-associated diarrhea), the number of persons needed to treat for one person to benefit is fairly high.
In addition, when someone says that they are taking a probiotic, many families do not understand the idea of “strain” specific effects. I tell families that if they see a “dog in yard” sign that they do not know if that is a poodle of a pit bull. With probiotics, similarly you often do not know if you are getting a pit bull or a poodle.
As a consequence, I think negative studies like a recent report (K Wojtyniak et al. J Pediatr 2017; 184: 101-05) are helpful. In this study, the authors examined the effectiveness of Lactobacillus casei rhamnosus Lcr35 (Lcr35) in the management of constipation.
This randomized, double-blind, placebo-controlled trial was conducted in 94 children <5 years of age. Dose: 8 x10 to the 8th CFU twice daily x 4 weeks.
- “Lcr35 as a sole treatment was not more effective than placebo in the management of functional constipation.” In fact, the placebo group had a greater increase in bowel movement frequency than the treatment group.
- Both groups had improvement -more than half in each group (total 52 of 81 who completed study) had reached endpoint of 3 or more BMs/week without soiling.
My take: Probiotics often are ineffective. This study showed that Lcr35 was NOT helpful for pediatric constipation.
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Claude Monet, La Rue Montorgueil
A recent study (E Lionetti et al. J Pediatr 2017; 184: 81-6) did NOT find an association between mode of delivery and the development of celiac disease (CD).
After a telephone interview to confirm mode of delivery, the authors identified 431 children at high risk for CD and compared the rates of celiac autoimmunity (serology-positive) and overt CD that developed by age 5 years:
- CD autoimmunity –cesarean vs vaginal: 24% and 19% (P=.2)
- Overt CD –cesarean vs vaginal: 19% and 14% (P=.2)
While neither reached statistical significance, there was a higher rate in those born by cesarean mode. The lack of a statistical association could be a reflection on sample size or the specific population that was studied. However, more likely, this suggests that “the role of intestinal microbiota at birth in the pathogenesis of immune mediated disorders has been overestimated.”
La Source, Jean Auguste Dominque Ingres, Musee d’ Orsay
Conventional wisdom and previous studies have indicated that negative testing for HLA-DQ8 and HLD-DQ2.5 alleles makes a diagnosis of celiac disease (CD), now or in the future, very unlikely. While ~60% of the population has one of these alleles, testing negative for these alleles has been regarded as having a high negative predictive value (>99%) and can be valuable in cases of equivocal diagnosis.
The authors of recent report (F Fernandez-Banares et al. Clin Gastroenterol Hepatol 2017; 15: 594-96) challenged this wisdom, noting that there is expected to geographical variation in the presence of these alleles. The goal of their study was to assess the prevalence of HLA-DQ2.5/8 among CD patients in Spain by reviewing previous studies; 12 studies were included. To be included, patients had to have villous atrophy, positive serology and available genotyping.
- Among 2963 Spanish CD patients, 3% “might be negative for HLA-DQ2.5/8.”
This is a brief report. It is expected that limitations would relate to the accuracy of genotyping and of excluding other causes of villous atrophy.
My take: (from the authors) “This information highlights the need to be cautious when ruling out CD only on the basis of genetics.”
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L Kivela et al. J Pediatr 2017; 183: 115-21. This study divided children with CD into those identified via screening (n=145) and those identified due to clinical symptoms (n=359). Key findings:
- There were no differences in serology or histology between the two groups
- More than half (51.8%) of screen-detected patients had symptoms at diagnosis, but typically these were milder than in the clinically-detected group.
- Anemia was more common in the ‘clinical group’ 22.9% vs 7.1% (screen group) as was poor growth (36.9% vs. 15.7%).
AJ Irvine et al. Am J Gastroenterol 2017; 112: 65-76. (Thanks to Ben Gold for this reference) In this systemic review with 15,256 individuals (& 9,275 with irritable bowel), “prevalence of positive celiac serology and biopsy-proven CD was significantly higher in subjects with symptoms suggestive of IBS vs. healthy controls.” The odds ratio for serology-positive and/or biopsy-proven CD ranged from 2.75 to 4.48, though there was no significant increase in these ORs for North American studies.
Palace of Versailles
A recent study (A Butwicka et al. J Pediatr 2017; 184: 87-93) describes an increased rate of childhood psychiatric disorders among children with celiac disease (CD).
The authors used a nationwide registry (in Sweden) with 10,903 children with celiac disease, 12,710 siblings, and more than 1 million control patients. The median age at diagnosis was 3 years and median duration of followup was 9.6 years.
- CD patients had a 1.4 fold greater risk of psychiatric disorders, including mood disorders, eating disorders, behavioral disorders, and ADHD.
- CD siblings did not have an increased risk.
- 7.7% of children with CD were diagnosed with a psychiatric disorder
Limitation: The actual reported incidence of psychiatric disorders seems low in both the CD patients and controls. It is possible that some of the difference could be related to selection bias. Patients with (undiagnosed) psychiatric disorders may be more likely to be anxious, and seek out medical attention for their GI complaints; this could precede a diagnosis of CD.
Strengths: This study has large numbers of patients and the data was prospectively obtained.
The association with increased psychiatric problems could have a biologic basis or be related to the toll of chronic gastrointestinal symptoms prior to diagnosis and the difficulty of managing CD.
My take: This is an intriguing study and suggests that patients with CD are more likely to be diagnosed with a psychological disorder. Whether CD itself or the preceding symptoms trigger this diagnosis is uncertain.
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Paris from Notre Dame
According to a recent study (P Mehta et al. JPGN 2017; 64: 546-49), propofol was safe in pediatric patients with eosinophilic esophagitis (EoE) and food allergy.
This finding was based on a retrospective study of 1365 upper endoscopies (2013-2014). Though, propofol was used less frequently, “there was no difference in complication rates relative to propofol use.”
Specifically, egg or soy allergy patients had 38 procedures; 114 children had EoE (without known egg or soy allergy) and 27 and EoE and egg or soy allergy.
This study is important because propofol is used frequently in patients with egg and soy allergies despite a contraindication warning on the package insert. Nevertheless, this study does not provide a definitive answer due to the very low rates of allergic reactions to propofol (~1:10,000 to 1:20,000). In addition, the diagnosis of food allergy in this study relied on review of the medical record.
My take: This study is limited in scope but did not identify any significant safety concerns with propofol in patients who had EoE and/or egg/soy allergies.
Palace of Versailles
A recent study (P Tandon et al. Inflamm Bowel Dis 2017; 23: 551-60) was a systemic review regarding the accuracy of blood-based testing for predicting colonic CMV reactivation in patients with inflammatory bowel disease. The review identified 9 studies. The overall sensitivity of blood-based testing (either pp65 antigenemia or blood PCR) for CMV was 50.8% and the specificity was 99.9%. Blood PCR was better at 60% sensitivity.
My take: Blood-based tests are not sensitive enough to exclude colonic CMV reactivation. The authors recommend the use of immunohistochemistry or tissue PCR for detecting CMV reactivation in inflammatory bowel disease.
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Palace Gate, Versailles