F. Nuti

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn's and Colitis Organisation: Pregnancy and Pediatrics

Women with inflammatory bowel disease (IBD) have similar rates of fertility to the general population, but have an increased rate of adverse pregnancy outcomes compared with the general population, which may be worsened by disease activity. Infertility is increased in those undergoing ileal pouch–anal anastomosis. Anti-tumor necrosis factor therapy in pregnancy is considered to be low risk and compatible with use during conception in men and women and during pregnancy in at least the first two trimesters. Infliximab (IFX) and certolizumab pegol are also compatible with breastfeeding, but safety data for adalimumab (ADA) are awaited. The safety of natalizumab during pregnancy is unknown. For children with Crohns disease (CD), IFX is effective at inducing and maintaining remission. Episodic therapy is not as effective as scheduled infusions. Disease duration in children does not appear to affect the efficacy of IFX. IFX promotes growth in prepubertal and early pubertal Crohns patients. It is also effective for the treatment of extraintestinal manifestations. ADA is effective for children with active CD and for maintaining remission, even if they have lost response to IFX, although there are fewer data. Vaccination of infants exposed to biological therapy in utero should be given at standard schedules during the first 6 months of life, except for live-virus vaccines such as rotavirus. Inactivated vaccines may be safely administered to children with IBD, even when immunocompromised.

Characterization of adherent-invasive Escherichia coli isolated from pediatric patients with inflammatory bowel disease†

Background: Crohns disease (CD) and ulcerative colitis (UC), known as inflammatory bowel diseases (IBD), are characterized by an abnormal immunological response to commensal bacteria colonizing intestinal lumen and mucosa. Among the latter, strains of adherent‐invasive Escherichia coli (AIEC), capable of adhering to and invading epithelium, and to replicate in macrophages, have been described in CD adults. We aimed at identifying and characterizing AIEC strains in pediatric IBD. Methods: In all, 24 CD children, 10 UC, and 23 controls were investigated. Mucosal biopsies, taken during colonoscopy, were analyzed for the presence of AIEC strains by an adhesive‐invasive test. Protein expression of the specific AIEC receptor, the carcinoembryonic antigen‐related cell adhesion molecule 6 (CEACAM6), was evaluated by western blot and immunohistochemistry, while tumor necrosis factor alpha (TNF‐&agr;) and interleukin (IL)‐8 mRNA expression was detected by real‐time polymerase chain reaction (PCR), after bacterial infection. Transmission electron microscopy and trans‐epithelial electric resistance assays were performed on biopsies to assess bacteria‐induced morphological and functional epithelial alterations. Results: Two bacterial strains, EC15 and EC10, were found to adhere and invade the Caco2 cell line, similar to the well‐known AIEC strain LF82 (positive control): they upregulated CEACAM6, TNF‐&agr;, and IL‐8 gene/protein expression, in vitro and in cultured intestinal mucosa; they could also survive inside macrophages and damage the epithelial barrier integrity. Lesions in the inflamed tissues were associated with bacterial infection. Conclusions: This is the first study showing the presence of adhesive‐invasive bacteria strains in the inflamed tissues of children with IBD. Collective features of these strains indicate that they belong to the AIEC spectrum, suggesting their possible role in disease pathogenesis. (Inflamm Bowel Dis 2011)

Rapid test for fecal calprotectin levels in children with Crohn disease.

ABSTRACT Assessment of fecal calprotectin, a surrogate marker of mucosal inflammation, is a promising means to monitor therapeutic response in pediatric inflammatory bowel disease, especially if the result is readily available. We tested the performance of a novel calprotectin rapid test, Quantum Blue, versus the conventional enzyme-linked immunosorbent assay in 134 stool samples from 56 pediatric patients with Crohn disease. The intraclass correlation coefficient analysis reflected good agreement (intraclass correlation coefficient 0.97 [95% confidence interval 0.95–0.98]) but agreement was better in lower values, where dilutions were not required. Using a cutoff of 100 &mgr;g/g for normal values, the percentage agreement between the 2 tests was 87%. The optimal cutoff values to guide clinical decisions in the therapy of inflammatory bowel disease have yet to be determined.

Limitations of fecal calprotectin at diagnosis in untreated pediatric Crohn's disease

Background: Fecal Calprotectin (FC) is a validated screening test for intestinal inflammation in Crohns disease (CD). The objective of the study was to prospectively evaluate the limitations of FC for identifying CD in newly diagnosed untreated pediatric patients and to assess the association of FC levels with disease location and serum inflammatory markers. Methods: Consecutive children with new onset untreated CD participating in the ongoing ESPGHAN GROWTH CD study were evaluated at diagnosis for disease activity, extent, C‐reactive protein (CRP), and FC. Results: In all, 60 children met the inclusion criteria (mean age 12.6 ± 4.6 years,), 25 (42%) with mild disease, 17 (28%) moderate disease, and 18 (30%) severe disease. Twenty‐seven (45%) had small bowel disease only. Median FC levels did not differ between children with small bowel only (2198 &mgr;g/g interquartile range [IQR] 696–2400) and those with colonic involvement (with or without small bowel disease; 2400 &mgr;g/g (IQR 475–2400) (P = 0.76). FC was elevated in 95% of patients, in comparison to CRP (86%) and erythrocyte sedimentation rate (ESR) (83%). Three children (5%) who had normal calprotectin levels also had low or normal CRP and/or ESR. There was no correlation between calprotectin levels and either the pediatric CD activity index (r = −0.11; P = 0.94) or physicians global assessment. Conclusions: FC levels in active disease confined to the small bowel were elevated in the vast majority of children and site of disease was not a confounding factor in this setting. Patients with low FC had a trend toward low levels of inflammatory markers as well. We did not find a significant correlation between FC and clinical indices of activity (Inflamm Bowel Dis 2012)

Role of HMGB1 as a suitable biomarker of subclinical intestinal inflammation and mucosal healing in patients with inflammatory bowel disease.

Background:Noninvasive biomarkers of high- and low-grade intestinal inflammation and of mucosal healing (MH) in patients with inflammatory bowel disease are currently lacking. We have recently shown that fecal high mobility group box 1 (HMGB1) protein is a novel biomarker of gut inflammation. We aimed at investigating in a mouse model if HMGB1 was able to foresee both a clinically evident and a subclinical gut inflammation and if its normalization indicated MH. We also aimed at confirming the results in patients with Crohns disease (CD) and ulcerative colitis. Methods:C57BL6/J mice were treated with increasing doses of dextran sodium sulphate to induce colitis of different severity degrees; 28 with CD, 23 with ulcerative colitis, and 17 controls were also enrolled. Fecal HMGB1 was analyzed by enzyme-linked immunosorbent assay and immunoblotting. Results:Fecal HMGB1 increased by 5-, 11-, 18-, and 24-folds with dextran sodium sulphate doses of 0.25%, 0.50%, 1%, and 4%, respectively, showing that the protein detected a high-grade and a subclinical inflammation. After a recovery time of 4-week posttreatment, HMGB1 returned to control levels, paralleling MH. In patients, fecal HMGB1 significantly correlated with endoscopic indexes (Simple Endoscopic Score for Crohns Disease [SES-CD], endoscopic Mayo subscore), but not with the disease activity indexes (Crohns disease Activity Index, partial Mayo score). Conclusions:Fecal HMGB1 is a robust noninvasive biomarker of clinically overt and subclinical gut inflammation; it can also be a surrogate marker of MH. We suggest the use of fecal HMGB1 to monitor the disease course and assess therapy outcomes in inflammatory bowel disease.

Lymphoma risk in children and young adults with inflammatory bowel disease: analysis of a large single-center cohort.

Background: Prior studies suggest an increased risk of lymphoma in adults with inflammatory bowel disease (IBD). Cases of lymphoma have also been reported in children with IBD. However, the precise risk of lymphoma in relation to drug exposure has not been ascertained in children. Methods: We conducted a single‐center, retrospective study of 1560 children and young adults with IBD evaluated at Childrens Hospital Boston between 1979 and 2008. Of this group, 186 patients were excluded due to incorrect diagnosis, one‐time second‐opinion visits, or missing hospital records. The remaining 1374 patients had charts reviewed to determine whether lymphoma developed while they were receiving their clinical care at our institution and the duration of exposure to various IBD medications. The rate of lymphoma was calculated in patient‐years of exposure for each class of medications utilized in IBD. Results: Of 1374 patients (741 male; age at diagnosis 12.1 ± 4.0 years; 791 Crohns disease [CD], 535 ulcerative colitis [UC], 48 IBD unclassified), we identified two patients who developed lymphoma (one Hodgkin, one anaplastic large cell), in 6624 patient‐years of follow‐up (mean duration follow‐up 4.8 years per patient). Both patients were males (ages 12 and 18 years at time of lymphoma onset) and were receiving thiopurines but had not yet received biologics at the time of their cancer diagnosis. They were both treated with chemotherapy and are alive without cancer 32+ and 76+ months since diagnosis. The absolute incidence rate of lymphoma for patients having received thiopurines was 4.5 per 10,000 patient‐years compared to the expected rate of 0.58 per 10,000 patient‐years, with a standardized incidence ratio (SIR) of 7.51 (95% confidence interval [CI] 0.74–41.98). Conclusions: The overall risk of lymphoma in children with IBD is low, with only two cases seen in our hospital over a 30‐year period. The lymphoma risk (as estimated by SIR) in children receiving thiopurines is comparable to that reported in studies of adults. While there may be an increased risk of lymphoma in children treated with thiopurines, the risk did not reach statistical significance in this large cohort. (Inflamm Bowel Dis 2011;)

Presenting features and disease course of pediatric ulcerative colitis

UNLABELLED Clinical variables and disease course of pediatric ulcerative colitis (UC) have been poorly reported. The aim of this study was to retrospectively describe the phenotype and disease course of pediatric onset UC diagnosed at a tertiary referral Center for Pediatric Gastroenterology. PATIENTS AND METHODS 110 patients with a diagnosis of UC were identified at our Department database. Records were reviewed for disease location and behavior at the diagnosis, family history for inflammatory bowel disease, pattern changes at the follow-up, need of surgery and cumulative risk for colectomy. RESULTS Thirty-five % of patients had an early-onset disease (0-7 years). At the diagnosis, 29% had proctitis, 22% left-sided colitis, 15% extensive colitis and 34% pancolitis. Fifteen % presented with a rectal sparing, while a patchy colonic inflammation was reported in 18%. Rectal sparing was significantly related to the younger age (p: <0.05). Disease extension at the follow up was reported in 29% of pts. No clinical variables at the diagnosis were related to the subsequent extension of the disease. The cumulative rates of colectomy were 9% at 2 year and 14% at 5 years. An extensive disease as well as acute severe colitis and corticosteroid therapy at the diagnosis were significantly associated with an increased risk of colectomy. CONCLUSIONS Pediatric UC is extensive and severe at the diagnosis, with an overall high rate of disease extension at the follow-up. Endoscopic atypical features are common in young children. The colectomy rate is related to the location and severity of the disease at the diagnosis.

A potential role of Escherichia coli pathobionts in the pathogenesis of pediatric inflammatory bowel disease

Through genomic analysis of mucosa-associated Escherichia coli strains, we found a close genetic association among isolates from pediatric inflammatory bowel disease (IBD) patients. A specific E. coli pathovar, adherent-invasive E. coli (AIEC), was found in Crohns disease (CD) adult patients - this pathovar has enhanced adhesive and invasive properties, mainly due to the mannose-bonding FimH protein. We aimed to characterize 52 mucosa-associated E. coli strains isolated from pediatric IBD and non-IBD patients. Eleven E. coli strains, showing a strong similarity in fimH gene sequence to that of E. coli AIEC LF82, were characterized for fimH gene sequence, genomic profiling, adhesive and invasive ability, and phylogrouping. The results were compared with E. coli strains AIEC LF82 and MG1655. The 11 E. coli isolates showed 82.4% ± 1.4% fimH sequence similarity and 80.6% ± 1.3% genomic similarity to strain AIEC LF82. All these strains harbored V27A and S78N FimH mutations, as found in LF82. Nine of them belonged to the more virulent B2 and D phylogroups. Neuraminidase treatment, mimicking inflamed mucosa, enhanced adhesion of all 11 strains by 3.5-fold, but none showed invasion ability. It could be argued that the 11 selected strains could be a branch of an E. coli subpopulation (pathobionts), that could take advantage in an inflamed context because of a suitable genomic and (or) genetic backdrop.

Advances in the medical management of paediatric IBD

IBD includes two classic entities, Crohns disease and ulcerative colitis, and a third undetermined form (IBD-U), characterized by a chronic relapsing course resulting in a high rate of morbidity and impaired quality of life. Children with IBD are vulnerable in terms of growth failure, malnutrition and emotional effects. The aims of therapy have now transitioned from symptomatic control to the achievement of mucosal healing and deep remission. This type of therapy has been made possible by the advent of disease-modifying drugs, such as biologic agents, which are capable of interrupting the inflammatory cascade underlying IBD. Biologic agents are generally administered in patients who are refractory to conventional therapies. However, there is growing support that such agents could be used in the initial phases of the disease, typically in paediatric patients, to interrupt and cease the inflammatory process. Until several years ago, most therapeutic programmes in paediatric patients with IBD were borrowed from adult trials, whereas paediatric studies were often retrospective and uncontrolled. However, guidelines on therapeutic management of paediatric IBD and controlled, prospective, randomized trials including children with IBD have now been published. Here, the current knowledge concerning treatment options for children with IBD are reported. We also highlight the effectiveness and safety of new therapeutic advances in these paediatric patients.

Biological therapy in a pediatric crohn disease population at a referral center

Objective: The antitumor necrosis factor &agr; (TNF&agr;) antibodies infliximab and adalimumab are effective in inducing and maintaining remission in pediatric patients with Crohn disease (CD). The aim of the study was to evaluate the long-term efficacy and safety of biological therapy in pediatric patients with CD followed at a referral center. Methods: This work is a retrospective observational study enrolling patients with CD treated with infliximab or adalimumab beyond the induction protocol. The patients’ data were collected from the units IBD database (maximum follow-up evaluation after 36 months of treatment). The efficacy was evaluated by the Pediatric Crohn Disease Activity Index score and by analysis of the cumulative probability of continuing therapy; the safety was assessed in terms of adverse events. Results: We enrolled 78 patients; the mean therapy duration was 27.2 ± 16.7 months, and the mean age at enrollment was 15 ± 3.1 years. The Kaplan-Meier analysis showed a cumulative probability of continuing therapy of 81%, 54%, and 33% at 1, 2, and 3 years, respectively, from the introduction of therapy. No association between the patients’ baseline characteristics and the long-term outcome was found. The evaluation of the concomitant therapy with immunomodulators and anti-TNF&agr; therapy versus anti-TNF&agr; alone did not show a different outcome. No serious adverse events were recorded. Conclusions: The study indicates that biological therapy is effective and safe in pediatric patients with CD in a longer follow-up period. The response to treatment was not influenced by the patients’ baseline characteristics or by the immunomodulator association.