Astor Rodrigues

A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease

Aliment Pharmacol Ther 2011; 33: 946–953

Management of Crohn's disease

Crohns disease (CD) is rapidly increasing in children so an up to date knowledge of diagnosis, investigation and management is essential. Exclusive enteral nutrition is the first line treatment for active disease. The vast majority of children will need immunosuppressant treatment and around 20% will need treatment with biologics. Recent guidelines have helped make best use of available therapies.

Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN.

Background Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with inflammatory bowel disease [IBD], but the data in paediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-centre paediatric IBD cohort. Method Retrospective review of children [aged 2-18 years] treated with vedolizumab from 19 centres affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was Week 14 corticosteroid-free remission [CFR]. Results In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range 14-38; range 6-116]); 41 [64%] cases of ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U] and 23 [36%] Crohns disease [CD]. All were previously treated with anti-tumour necrosis factor [TNF] [28% primary failure, 53% secondary failure]. Week 14 CFR was 37% in UC, and 14% in CD [P = 0.06]. CFR by last follow-up was 39% in UC and 24% in CD [p = 0.24]. Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate [42% vs 35%; p = 0.35 at Week 22]. There were three minor drug-related adverse events. Only 3 of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%). Conclusions Vedolizumab was safe and effective in this cohort of paediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC.

Contemporary Outcomes for Ulcerative Colitis Inpatients Admitted to Pediatric Hospitals in the United Kingdom

Background:Pediatric ulcerative colitis (UC) care is variable with a lack of appropriate guidelines to guide practice until recently. Methods:UC inpatients <17 years old admitted to 23 U.K. pediatric hospitals had clinical details collected between September 2010 and 2011. Comparative data for 248 patients were available from a previous audit in 2008. Results:One hundred and seventy-six patients (98 males) of median age 13 years (interquartile range, 10–13) were analyzed; 23 were elective surgical admissions, 47 new diagnoses, and 106 needed acute medical care for established UC. Median length of stay was 6 days (interquartile range, 3–10) with no deaths. Eighty-eight of 126 patients (70%) with active disease had standard stool cultures performed (3 [2%] were positive), and 57 (45%) had Clostridium difficile toxin tested (none positive). Twenty-five of 66 (38%) emergency admissions had an abdominal x-ray on admission, and 13 of 66 patients (20%) had a Pediatric Ulcerative Colitis Activity Index score. There were 3 cases of toxic megacolon and 2 thromboses. Eighty-one of 116 patients (71%) responded to steroids. Nineteen patients who did not respond adequately to steroids received rescue therapy (7 infliximab, 11 ciclosporin, and 1 both) with overall response rate of 90%; 7 patients needed surgery acutely, 5 without previous rescue therapy. Compared with the 2008 data, stool culture rates improved significantly (86 of 121 [71%] versus 76 of 147 [52%], P = 0.001) as did heparinization rates (15 of 150 [10%] versus 5 of 215 [2%], P = 0.002) and rescue therapy usage (17 of 33 [52%] versus 10 of 38 [26%], P = 0.03). Conclusions:There were signs of improving UC care with significantly increased rates of stool culture and rescue therapy. The majority of sites, however, did not use Pediatric Ulcerative Colitis Activity Index scores.

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

G204(P) Can Taurolidine-Based Catheter Locks Reduce Central Venous Catheter Related Blood Stream Infections In Children On Long-Term Home Parenteral Nutrition?

Objectives and study To compare the incidence and characterise the type of catheter-related blood stream infections (CRBSIs) in children with intestinal failure on long-term home parenteral nutrition (PN), using heparin-saline based catheter locks versus those using taurolidine-based catheter locks. There is growing body of evidence that taurolidine-based catheter locks, which have a broad-spectrum antimicrobial and antifungal action, is associated with a decreased incidence of CRBSIs children on home PN. Methods All children referred to a tertiary paediatric gastroenterology service with temporary or on-going intestinal failure requiring long-term PN or preparation for home PN between 2005–2011 were included. Children were given a single-bag system of PN with each infusion via central venous catheter. Parents were formally trained in aseptic techniques and to instil heparin-saline or taurolidine-based solution into the catheter after completion of each infusion. CRBSIs were defined as a laboratory-confirmed blood stream infection from with a peripheral or central venous sample. Results were excluded if evidence that the source of infection was from a second site. All cultures results were confirmed through the microbiology database and clinical records. Research ethics committee approval was sought, but ethical review was not deemed necessary. Results 32 children (18 boys, 14 girls) were identified who required PN for intestinal failure for combined total of over 12,500 PN days. 9 children had no positive blood cultures. There were 126 positive blood cultures (27 organisms isolated) in the remaining 23 children. Of the 21 children who used a heparin-saline based catheter lock, 86% had one or more CRBSI. 11 children used a taurolidine-based catheter lock, with only 45% having one or more CRBSI. Conclusion There was a significant reduction in the incidence of CRBSIs in those children using taurolidine-based catheter locks (TauroLock™) compared to heparin locks. There was an absolute risk reduction of 40.3% (95% CI 7.25 – 73.3%) with a numbers needed to treat (NNT) of 3 (95% CI 1.4–13.8). The use of taurolidine locks on all children on long-term home PN could reduce morbidity and morality, and have a significant impact on the associated costs of CRBSIs. Taurolidine-based catheter locks should be considered for all children on long-term PN.

Improved Medical Treatment and Surgical Surveillance of Children and Adolescents with Ulcerative Colitis in the United Kingdom.

Background Pediatric ulcerative colitis (UC) presents at an earlier age and increasing prevalence. Our aim was to examine morbidity, steroid sparing strategies, and surgical outcome in children with active UC. Methods A national prospective audit was conducted for the inpatient period of all children with UC for medical or surgical treatment in the United Kingdom (UK) over 1 year. Thirty-two participating centers recruited 224 children in 298 admissions, comparisons over 6 years were made with previous audits. Results Over 6 years, recording of Paediatric Ulcerative Colitis Activity Index (PUCAI) score (median 65)(23% to 55%, P < 0.001), guidelines for acute severe colitis (43% to 77%, P < 0.04), and ileal pouch surgery registration (4% to 56%, P < 0.001) have increased. Corticosteroids were given in 183/298 episodes (61%) with 61/183 (33%) not responding and requiring second line therapy or surgery. Of those treated with anti-TNFalpha (16/61, 26%), 3/16 (18.8%) failed to respond and required colectomy. Prescription of rescue therapy (26% to 49%, P = 0.04) and proportion of anti-TNFalpha (20% to 53%, P = 0.03) had increased, colectomy rate (23.7% to 15%) was not significantly reduced (P = 0.5). Subtotal colectomy was the most common surgery performed (n = 40), and surgical complications from all procedures occurred in 33%. In 215/224 (96%) iron deficiency anemia was detected and in 51% treated, orally (50.2%) or intravenously (49.8%). Conclusions A third of children were not responsive to steroids, and a quarter of these were treated with anti-TNFalpha. Colectomy was required in 41/298 (13.7%) of all admissions. Our national audit program indicates effectiveness of actions taken to reduce steroid dependency, surgery, and iron deficiency. 10.1093/ibd/izy042_video1izy042.video15769503407001.

Real-life Anti-tumour Necrosis Factor Experience in > 500 Paediatric United Kingdom Inflammatory Bowel Disease Patients

Objective: The aim of this study was to measure the effectiveness, safety, and use of anti-tumor necrosis Factor (TNF) therapy in pediatric inflammatory bowel disease in the United Kingdom (UK). Methods: Prospective UK audit of patients newly starting anti-TNF therapy. Disease severity was assessed using Physician Global Assessment +/or the Paediatric Crohn Disease Activity Index. Results: A total of 37 centers participated (23/25 specialist pediatric inflammatory bowel disease sites). A total of 524 patients were included: 429 with Crohn disease (CD), 76 with ulcerative colitis (UC), and 19 with IBD unclassified (IBDU). Eighty-seven percent (488/562) of anti-TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co-immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (interquartile range 0.63–2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by Physician Global Assessment compared to 41% (88/217) by Paediatric Crohn Disease Activity Index (Kappa (&kgr;) 0.28 = only “fair agreement”; P < 0.001. Where documented, 77% (53/69) of patients with CD responded to induction; and 65% (46/71) entered remission. A total of 2287 infusions and 301.96 years of patient’ follow-up (n = 385) are represented; adverse events affected 3% (49/1587) infliximab and 2% (2/98) adalimumab infusions (no deaths or malignancies). Peri-anal abscess drainage was less common after anti-TNF initiation (CD), that is 26% (27/102) before, 7% (3/42) after (P = 0.01); however, pre and post anti-TNF data collection was not over equal time periods. Conclusions: Anti-TNFs are effective treatments, usually given with thiopurine co-immunosuppression. This study highlights deficiencies in formal documentation of effect and disparity between disease severity scoring tools, which need to be addressed to improve ongoing patient care.