Recommended Read April 2014

  Education committee is happy to present a special edition of ‘recommended read’. In this edition, we are presenting a compilation of articles under the title ‘The article I liked most in 2013’ which is recommended by the council members.

  Fiona Cameron has recommended this article from JPGN June 2013 - Volume 56 - Issue 6 - p 597–601 Safety, Tolerability, and Clinical Response After Faecal Transplantation in Children and Young Adults With Ulcerative Colitis. Ten children, 7 to 21 years of age, with mild-to-moderate UC received freshly prepared faecal enemas daily for 5 days. Data on tolerability, adverse events, and disease activity were collected during FMT and weekly for 4 weeks after FMT.  No serious adverse events were noted. Mild (cramping, fullness, flatulence, bloating, diarrhoea, and blood in stool) to moderate (fever) adverse events were self-limiting. Average tolerated enema volume by remaining 9 subjects was 165 mL/day. After FMT, 7 of the 9 (78%) subjects showed clinical response within 1 week, 6 of the 9 (67%) subjects maintained clinical response at 1 month, and 3 of the 9 (33%) subjects achieved clinical remission at 1 week after FMT.  This pilot study in a small number of children shows that FMT is feasible and safe in children. However we would need to see the evidence from RCT’s before we can consider FMT in routine clinical practice.

  Paul Henderson has recommended this article published in Cell Host & Microbe Volume 15, Issue 3, 12 March 2014, Pages 382–39  ‘The Treatment-Naive Microbiome in New-Onset Crohn’s Disease’. The authors have studied the microbiome in the largest paediatric CD cohort to date using samples from multiple gastrointestinal locations collected prior to treatment in new-onset cases. The authors have noted that the rectal mucosa-associated, but not faecal, microbiome is a robust disease predictor. Their observation was that an increased abundance in bacteria which included Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales, correlates strongly with Crohn’s disease status. Antibiotics use had amplified the dysbiosis associated with Crohn’s disease.

  Is duodenal histology the gold standard in coeliac disease? Professor Murch has recommended this article Validation of Morphometric Analyses of Small-Intestinal Biopsy Readouts in Celiac Disease. PLoS ONE 8(10): e76163. doi:10.1371/journal.pone.0076163. This study showed that quantitative variables which measure separately gluten-induced morphological changes (villous height: crypt depth) and inflammatory (IEL density) changes are reliable and reproducible. The authors stress the need for correct biopsy orientation (incorrect orientation resulting in cross sectioning of the crypts and the inability to demonstrate crypt hyperplasia) and this is well demonstrated in Figures 2 and 4 in the article. In contrast IEL density assessment is unaffected by orientation of the biopsy specimens (please look at Figure 3 in the article). The ‘gold standard’ investigation in coeliac disease is only credible, if the biopsies are oriented correctly.

  Suzanne Davison has recommended this article ‘Management of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines: Consensus of an expert panel on behalf of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition’ published in Journal of Hepatology 2013 vol 59 814-29. This article provides clear practical advice and also differs from the advice in NICE guidelines in many aspects. Currently, a finite-duration IFN-α therapy remains the treatment strategy of choice for HBeAg-positive children with elevated ALT levels , as in this patient population seroconversion to anti-HBs is the main aim. IFN-α is the only available treatment offering a chance of sustained off-treatment VR. It is likely that, as soon as results of trials using PegIFN in children are available, this medication will become the recommended drug. Nucleoside analogues (NA) used to be second-line therapies because of the high risk of emergence of resistant mutant strains. Nevertheless, the recent FDA approval of NA with higher genotypic barrier to resistance has opened the way for the use of such drugs as first-line treatment for adolescents. As the emergence of resistant mutant strains is becoming a major public health problem, paediatric practitioners should not treat children who are not likely to benefit from a licensed therapy and consider waiting for market approval of more effective drugs. All household contacts of an HBV infected child should be screened for HBsAg, HBsAb, and HBcAb in order to offer vaccination to those without protective antibody levels and diagnose those with a previously unknown infection.

  Alastair Baker has recommended this article Notch signalling and new therapeutic options in liver disease published in Journal of Hepatology Volume 60, Issue 4, April 2014, Pages 885–890. Notch signalling is a developmental pathway that regulates several fundamental cellular processes including cell fate and differentiation and modifying the aberrant activation of the Notch pathway may have therapeutic relevance in many clinical conditions including Crohn’s disease and some of the liver malignancies. In the liver, Notch signalling is critical for biliary tree formation by committing hepatoblasts towards the cholangiocyte-fate and by orchestrating tubulogenesis. Defective notch signalling causes Alagille syndrome with ductopenia and cholestasis. Notch activation appears to be fundamental for regenerating damaged cholangiocytes and bile ductules. Ectopic and persistent Notch activation in the liver may be linked to hepatic cancer. For completion of information, let me add that Notch1 mediates the inhibitory effects of Infliximab and Adalimumab on T cell cycling in patients with IBD and also in healthy individuals.

  Girish Gupte has recommended this article Modulation of the Fecal Bile Acid Profile by Gut Microbiota in Cirrhosis J Hepatol. 2013 May;58(5):949-55. There is emerging evidence that the gut milieu plays an important role in the progression of the complications of cirrhosis. Dysbiosis in the gut microbiota in patients with cirrhosis could have the potential to influence complications such as hepatic encephalopathy. The gut microbiota is known to convert 7α-dehydroxylate primary bile acids and chenodeoxycholic acid (CDCA) & cholic acid (CA) into secondary bile acids lithocholic acid (LCA) & deoxycholic acid (DCA), respectively. Cirrhotic patients have been shown to have a lower proportion of secondary BAs in their bile but the mechanism for this is not clear. The aim of the study was to assess the linkage between faecal bile acid concentrations and the gut microbiota in cirrhotic patients with differing disease severity compared to healthy controls and to define the changes in this correlation after the administration of gut-selective, non-absorbable antibiotic, Rifaximin. 47 patients with cirrhosis (24 advanced) and 14 controls were included. In faeces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and highest primary BAs compared to early cirrhotics and controls. Secondary faecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics. Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae, Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. Post-Rifaximin, six early cirrhotics had reduction and in the secondary/primary BA ratio.

  Nadeem Afzal has recommended this article Methotrexate in Combination with Infliximab Is No More Effective than Infliximab Alone in Patients With Crohn's Disease Gastroenterology. 2014 Mar;146(3):681-688.e1. doi: 10.1053/j.gastro.2013.11.024. In the SONIC trial combination therapy with Infliximab and Azathioprine was superior in achieving and maintaining remission up to one year compared to Infliximab monotherapy or Azathioprine monotherapy. Can we extrapolate that information to Methotrexate combination therapy with Infliximab in Crohn’s disease? The answer is no based on this study. In a 50-week, double-blind, placebo-controlled trial, the authors compared methotrexate and infliximab with infliximab alone in 126 patients with Crohn’s disease who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group. Pre specified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. The authors concluded that the combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone.

  I am taking this opportunity to thank all the contributors to this special edition of ‘recommended read’. Most of these articles could be accessed by your Athens account. Please do send your feedback to . Please also use twitter account of BSPGHAN to share your views.

  Yours sincerely,

Education Committee
April 2014