Anna Dilillo

Premature Subclinical Atherosclerosis in Pediatric Inflammatory Bowel Disease

OBJECTIVES To investigate the risk for developing an early endothelial dysfunction based on increased intima media thickness (IMT) and reduced flow-mediated dilation (FMD) in children with inflammatory bowel disease (IBD), and to evaluate the role of traditional and nontraditional risk factors in determining premature atherosclerosis. STUDY DESIGN We studied 27 patients with Crohns disease (CD) and 25 patients with ulcerative colitis (UC) (mean age, 15.2 years; mean duration of disease, 48.05 months); 31 subjects served as controls. Demographic data (age, sex, family history of diabetes, cardiovascular disease, hypertension, hypercholesterolemia), traditional risk factors for atherosclerosis (blood pressure, body mass index, active and passive smoking, dyslipidemia), and UC and CD activity indexes (Pediatric Ulcerative Colitis Activity Index and Pediatric Crohns Disease Activity Index, respectively) were collected. The IMT of the carotid arteries was measured by high-resolution B-mode ultrasound, and endothelial function was evaluated by FMD in the brachial artery in response to reactive hyperemia. RESULTS Compared with controls, patients with CD had significantly greater exposure to passive smoking and had lower body mass index and high-density lipoprotein cholesterol values. IMT was significantly higher in patients than controls (P < .0001), and the percentage of FMD was significantly lower in both patients with CD (P < .0001) and patients with UC (P < .01) versus controls. In multivariate analysis, diagnosis of IBD was an independent risk factor for atherosclerosis. CONCLUSION Premature endothelial dysfunction occurs in pediatric IBD. This represents a new challenge in the management of pediatric IBD, leading to prevention strategies of cardiovascular disease.

Dipotassium Glycyrrhizate Inhibits HMGB1-Dependent Inflammation and Ameliorates Colitis in Mice

Background High mobility group box-1 (HMGB1) is a DNA-binding protein that is released from injured cells during inflammation. Advances in targeting HMGB1 represent a major challenge to improve the treatment of acute/chronic inflammation. Aim This study is aimed at verifying whether the inhibition of HMGB1 through dipotassium glycyrrhizate (DPG) is a good strategy to reduce intestinal inflammation. Methods Human colon adenocarcinoma cell line, HT29, human epithelial colorectal adenocarcinoma, Caco2, and murine macrophage cell line, RAW 264.7, were cultured to investigate the effect of DPG on the secretion of HMGB1. Acute colitis was induced in C57BL/6 mice through administration of 3% dextran sodium sulphate (DSS); a combined treatment with DSS and 3 or 8 mg/kg/day DPG was used to investigate the effects of DPG on intestinal inflammation. Animals were euthanized at seventh day and colonic samples underwent molecular and histological analyses. Results DPG significantly reduces in vitro the release of HMGB1 in the extracellular matrix as well as expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, by inhibiting HMGB1. Moreover, DPG significantly decreases the severity of DSS-induced colitis in mice. Murine colonic samples show decreased mRNA levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, RAGE and TLR4. Finally, HMGB1, abundantly present in the feces of mice with DSS-induced colitis, is strongly reduced by DPG. Conclusions HMGB1 is an early pro-inflammatory cytokine and an active protagonist of mucosal gut inflammation. DPG exerts inhibitory effects against HMGB1 activity, significantly reducing intestinal inflammation. Thus, we reason that DPG could represent an innovative tool for the management of human intestinal inflammation.

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.

Aortic Intima-Media Thickness as an Early Marker of Atherosclerosis in Children With Inflammatory Bowel Disease.

Objectives: The aims of this study were to determine the presence of endothelial dysfunction by measuring aortic intima-media thickness (aIMT) and carotid intima-media thickness (cIMT) and to evaluate the role of traditional risk factors for premature atherosclerosis in children with inflammatory bowel disease (IBD). Methods: Thirty-four children with IBD (25 Crohn disease [CD] and 9 ulcerative colitis [UC]; mean age 11.1 years) and 27 healthy subjects matched for sex and age were enrolled. In all of the patients, demographic characteristics and risk factors for atherosclerosis (age, sex, body mass index, blood pressure, dyslipidemia, active and passive smoking, and family history for cardiovascular diseases), CD and UC clinical activity scores, and inflammatory markers were evaluated. aIMT and cIMT were measured by high-resolution B-mode ultrasound. Results: aIMT was significantly higher in patients than in controls (P < 0.0005). No significant differences were found for cIMT, although the carotid thickness was higher in patients with IBD than in healthy subjects. At a univariate analysis, inflammatory markers levels and tobacco smoking exposure were significantly related to higher aIMT values, whereas in a multivariate regression model, the inflammatory status was the only independent variable correlated with high aIMT. Conclusions: aIMT is an earlier marker of preclinical atherosclerosis than cIMT in young children with active IBD. The inflammatory status and the smoking exposure are significantly correlated with the premature endothelial dysfunction. These data emphasize the importance of controlling the chronic intestinal inflammation and endorsing smoke-free environments for children and adolescents with IBD.

Ultrasonography of the Colon in Pediatric Ulcerative Colitis: A Prospective, Blind, Comparative Study with Colonoscopy

OBJECTIVES To evaluate the usefulness of colonic ultrasonography (US) in assessing the extent and activity of disease in pediatric ulcerative colitis (UC) and to compare US findings with clinical and endoscopic features. STUDY DESIGN Consecutive pediatric patients (n = 60) with a diagnosis of UC and suspected disease flare-up were prospectively enrolled; of these, 50 patients were eligible for the study. All underwent clinical evaluation, bowel US with color Doppler examination and colonoscopy. Blind US was performed the day before endoscopy in all patients. The US assessed variables were bowel wall thickness >3 mm, bowel wall stratification, vascularity, presence of haustra coli, and enlarged mesenteric lymph nodes. RESULTS The endoscopic extent of disease was independently confirmed in 47 patients by US that yielded a 90% concordance with endoscopy (95% CI 0.82-0.96). Multiple regression analysis showed that US measurements with an independent predictive value of severity at endoscopy were increased bowel wall thickness (P < .0008), increased vascularity (P < .002), loss of haustra (P = .031), and loss of stratification of the bowel wall (P = .021). Each variable was assigned a value of 1 if present. The US score strongly correlated with clinical (r = 0.94) and endoscopic activity (r = 0.90) of disease (P < .0001). CONCLUSIONS Colonic US is a useful first line noninvasive tool to assess the extent and activity of disease in children with UC and to estimate the severity of a flare-up, prior to further invasive tests.

Disease course and efficacy of medical therapy in stricturing paediatric Crohn's disease

BACKGROUND Stricturing is the most common complicated phenotype in paediatric Crohns disease, but only few studies have described its course, while data on the outcome of medical treatment are scanty. AIM To retrospectively describes the course of paediatric stricturing Crohns disease and assess clinical and imaging response to medical therapy. PATIENTS AND METHODS Thirty-six patients with stricturing Crohns disease were identified by our department database. Paediatric Crohns disease activity index, need of surgery and magnetic resonance were evaluated as outcomes at 6, 12, 18 and 24 months after detection of stenosis. RESULTS Strictures were ileal, ileocolonic and colonic in 61%, 28% and 11% of patients. Thirteen (36%) had stricturing disease at the diagnosis of Crohns disease, while 64% developed it at the follow-up. At baseline, 89% had medical treatment, while 11% surgery. At 6, 12, 18, and 24 months, 53%, 50%, 42%, and 35% had complete response to medical treatment, respectively. Overall, 44% were unresponsive to medical therapy and required surgery at the follow-up. Responders and non-responders significantly differed for inflammatory imaging findings at the stenosis detection. CONCLUSIONS A stricturing phenotype is not uncommon at the diagnosis of Crohns disease in children. Medical therapy seems poorly effective in avoiding intestinal resection. Magnetic resonance imaging is valuable in identifying patients who will benefit from medical therapy.

Combined multichannel intraluminal impedance and pH monitoring is helpful in managing children with suspected gastro-oesophageal reflux disease

BACKGROUND Gastro-oesophageal reflux is very common in the paediatric age group. There is no single and reliable test to distinguish between physiologic and pathological gastro-oesophageal reflux, and this lack of clear distinction between disease and normal can have a negative impact on the management of children. AIMS To evaluate the usefulness of 24-h oesophageal pH-impedance study in infants and children with suspected gastro-oesophageal reflux disease. METHODS Patients were classified by age groups (A-C) and reflux-related symptoms (typical and atypical). All underwent pH-impedance study. If the latter suggested an abnormal reflux, patients received therapy in accordance with NASPGHAN/ESPGHAN recommendations, while those with normal study had an additional diagnostic work-up. The efficacy of therapy was evaluated with a specific standardized questionnaire for different ages. RESULTS The study was abnormal in 203/428 patients (47%) while normal in 225/428 (53%). Of those with abnormal study, 109 exhibited typical symptoms (54%), and 94 atypical (46%). The great majority of the patients with abnormal study were responsive to medical anti-reflux therapy. CONCLUSIONS We confirm the utility of prolonged oesophageal pH-impedance study in detecting gastro-oesophageal reflux disease in children and in guiding therapy. Performing oesophageal pH-impedance monitoring in children with suspected gastro-oesophageal reflux disease is helpful to establish the diagnosis and avoid unnecessary therapy.

Investigating the small bowel in pediatric Crohn's disease: Prospective comparative study between small intestine contrast ultrasonography and magnetic resonance imaging

Background: Magnetic resonance imaging (MRI) is considered the gold-standard to evaluate SB in pediatric Crohn’s disease (CD). However, MRI is expensive, requires a strong compliance and a considerable amount of oral contrast to distend intestinal lumen. Small intestine contrast ultrasonography (SICUS) is non-invasive, low cost and generally well tolerated by patients. Objectives: To compare the diagnostic accuracy of SICUS and MRI in detecting presence, site and extension of SB disease and in assessing strictures in pediatric CD. Methods: Pediatric pts with suspected or known CD were prospectively enrolled. All underwent SICUS, MRI and ileocolonoscopy, performed by blind different operators. The SB was subdivided into: jejunum, ileum, terminal ileum (TI). The statistic concordance (k) between the two techniques was calculated. For the TI sensitivity (SE) and specificity (SP) were also assessed, with endoscopy as reference standard. The one-way ANOVA was used to compare the disease extension (cm) in the different segments. Results:66 consecutive patientswere included. The overall k for the presence of lesions was=0.94 (ES 0.06; 95%CI 0.8–1. The k for segments was 0.67 (jejunum), 0.91 (ileum) and 0.91 (TI). SE and SP (%) of SICUS andMRI for TI lesions were 98, 100 and 93, 92, respectively. There was no difference (p ns) in the evaluation of disease extension between the two techniques. The k for SB strictures was 0.62. SE and SP (%) of SICUS andMRI for TI strictures were 100, 100 and 92, 87, respectively. MRI provided 7 false positive results. Conclusions: The diagnostic performance of SICUS is comparable to that ofMRI. SICUSmight represent afirst-line tool in pediatric CD, able to reduce costs and to post-pone or even avoid more invasive investigations.

Mo1724 Disease Course and Outcome of Medical Therapy in Pediatric Stricturing Crohn's Disease

Background and Aim: Stricturing is the most common complicated phenotype in children with Crohn’s disease (CD), but only few studies have described its course and there are no data on the efficacy of medical treatment. The purpose of this study was to retrospectively describe in pediatric stricturing CD the course and assess clinical and radiological response to medical therapy. Patients and Methods: 36 patients (pts) with stricturing CD (64% males, age range: 7.3–20.2 years, median 14.7), were identified by our department database. Records were reviewed for disease duration before detecting stenosis, location of strictures, type of medical treatment received, number of disease recurrences and hospitalizations. Pediatric Crohn’s disease Activity Index (PCDAI), need to change medical treatment or surgery, magnetic resonance imaging or small intestine contrast ultrasonography were used as outcomes and evaluated at 6, 12, 18 and 24 months after diagnosis of stenosis. Results: Strictures were ileal in 61% of pts, ileocolonic in 28% and colonic in 11%; 6 pts (17%) also had proximal jejunal stenosis. Thirteen pts (36%) had a stricturing disease at the time of CD diagnosis, while 64% developed it at the follow-up (2.48±4.12 years after CD diagnosis). Cumulative risk for developing stenosis was 22%, 27% and 28% at 12, 18 and 24 months, respectively. At baseline, 89% of pts underwent medical treatment, while 11% had surgical resection: in a multivariate analysis, only ileal stenosis and severe abdominal pain significantly differed between the two groups (p: 0.05 and p: 0.006, respectively). At 6, 12, 18, and 24 months, 53%, 50%, 42%, and 35% had a complete response to medical treatment, respectively; whereas 34%, 43%, 40%, and 34% had a partial response, defined as a radiological evidence of stenosis requiring a change of their medical therapy. Overall, 44% were unresponsive to medical therapy and required surgery during 24 months followup; responders and non-responders did not statistically differ for clinical variables such as duration of disease, location of stenosis, mean PCDAI at the beginning of the therapy and type of medical treatment. Conclusions: A stricturing phenotype is not uncommon at the diagnosis of CD in children. Medical therapy seems to be poorly effective in avoiding intestinal resection and common clinical variables are not of value in discriminating between responder and non responders to medical therapy. Prospective studies are needed to define the optimal management strategy of stricturing CD and to identify predictive factors of medical treatment failure.

Outcome of Biological Therapy in Pediatric Inflammatory Bowel Disease at a Single Tertiary Center

Background and Aims. Anti-TNFα antibodies Infliximab (IFX) and Adalimumab (ADA) have been shown to be effective agents in inducing and maintaining remission in pediatric patients (pts) suffering from inflammatory bowel disease (IBD). However, data relating to long term outcomes of maintenance therapy are scarce. The aim of our study was to evaluate the long term efficacy and safety of biological therapy in pediatric IBD pts followed at a single center. Methods. All IBD treated with IFX or ADA with a maximum follow-up period up to 36 months for Crohns disease (CD) and 12 months for ulcerative colitis (UC) were enrolled. Pts data were analyzed using the database for IBD pts of the Unit. Efficacy was evaluated by PCDAI and PUCAI clinical scores for CD and UC respectively. Safety was evaluated in terms of side effects and adverse events leading to discontinuation. Seventy two pts (69 CD, 13 UC) were enrolled. Results (mean±SD). Characteristics of pts at the enrollment phase are in Table 1. The main reasons for starting IFX were unresponsiveness to conventional therapies (44%) and perianal disease (37.2%) for CD, unresponsiveness to other therapies (30.8%) and steroid dependency or resistance (53.8%) for UC. ADA was started for disease relapse (34.6%) and unresponsiveness to other therapies (42.2%, 11.5 % unresponsive to IFX). Therapy duration was 14.2 ± 11.4 and 6.8 ± 8.3 months (mts) for CD and UC pts on IFX respectively and 18.6 ± 11.6 mts for ADA pts. Immunomodulator therapy was stopped in 18% of CD pts and in no UC pts on IFX and in 92.3% on ADA during the follow-up period. Corticosteroid free remission at 6 and 12 mts was 71% and 65 % for CD IFX pts, 50% and 66% for UC IFX pts and 69% and 78% for ADA pts. PCDAI at 0, 3, 12, 24, 36 mts and PUCAI at 0, 3 and 12 mts are in Table 2. IFX was stopped in 29 CD pts and 10 UC pts, and ADA was stopped in 10 pts because of: long term remission (45% for CD IFX pts and 27% for UC IFX pts, 11.5% ADA pts), unresponsiveness (3% for CD IFX pts, 36% for UC IFX pts), loss of response (27.6% for CD IFX pts, 16% for UC IFX pts, 11.5% ADA pts) or infections (11.5% ADA pts). Five UC pts required colectomy. At 12 mts, of the 13 CD pts stopping IFX for remission 7 were still in remission, 5 restarted biological therapy (3 ADA, 2 IFX), 1 underwent ileal resection. The 3 pts stopping ADA for remission were inactive at 12 mts. Side effects were reported in 22 pts, of these 7 discontinued therapy. Conclusions. In children with IBD, IFX and ADA are an effective and durable treatment over a 3-year period; biological therapy can also postpone colectomy in UC pts. The safety profile was acceptable for both agents with no serious adverse events or malignancies reported. Table 1