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Background: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). Methods: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. Results: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. Conclusion: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226

Background Etrolizumab, a humanized anti-β7 antibody, has not been studied in children. Here, we evaluate the pharmacokinetics, pharmacodynamics, and safety of etrolizumab in children with inflammatory bowel disease. Methods Patients age 4 to 17 years with moderately to severely active ulcerative colitis or Crohn’s disease were randomized 1:1 to receive 1.5mg/kg of etrolizumab subcutaneously every 4 weeks (q4w) or 3.0mg/kg every 8 weeks (q8w) for 16 weeks in this open-label phase 1 trial. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results Of the 24 patients treated, 21 completed the study. In the groups of 1.5mg/kg q4w and 3.0mg/kg q8w, respectively, mean (SD) maximum concentration (Cmax) was 9.8 (4.86) µg/mL and 18.1 (6.25) µg/mL; and mean (SD) area under the curve within a dosing interval (AUCtau) was 167 (86.9) and 521 (306) μg·day/mL after the last dose. The Cmax increased dose proportionally. The AUC over an 8-week period was slightly higher in the 3.0mg/kg q8w dose group. Median half-life was similar for both dosing regimens. Median numbers of free β7high gut-homing T and B cell subsets declined below 10% of baseline, confirming β7 target engagement and complete/near-complete receptor occupancy. Adverse events were consistent with the safety profile in adults. Approximately 60% of patients achieved a clinical response. Conclusions Etrolizumab showed a dose-proportional increase in Cmax and a slightly greater than dose-proportional increase in AUCtau. Both regimens achieved complete/near-complete β7 receptor occupancy, with a similar relationship to concentration as adults. Etrolizumab was well tolerated and demonstrated clinical activity in children.

Background & aims This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). Methods This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor–naive patients with active ulcerative colitis (total Mayo score 6–12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220–450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. Results Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37–1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. Conclusions The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Background: Magnetic resonance enterography (MRE) is an excellent way to study the small bowels. During such an examination, the colon is also seen within the field of study. The aim of this study was to evaluate the effectiveness of MRE in detecting characteristics of active inflammatory bowel disease (IBD) in the colon, in comparison to different features seen in colonoscopies. Methods: This retrospective study was conducted with 41 children. Features of active inflammation we considered were wall thickening; contrast enhancement; incorrect signal in the DWI sequence in the MRE; and presence of ulceration, erosion, erythema, spontaneous bleeding and a decrease of the vascular pattern seen in colonoscopy. The colon was divided into six segments: caecum, ascending, transverse, descending, sigmoid and rectum. Results: The sensitivity of MRE was, on average, 50–75%, and as high as 92–100%, depending on the segment. The most important feature for which there was the most dependencies was ulceration. In the analysis of intestinal wall thickness, the AUC value >0.8 was detected as ulceration (segments: cecum, ascending, descending colon, sigmoid), spontaneous bleeding (ascending colon and sigmoid) and decreased vascular pattern (ascending, transverse, descending colon). Conclusions: Evaluation of qualitative structural changes in MRE distinguishes patients with inflammation in colonoscopy from patients without lesions, with high diagnostic accuracy, albeit higher specificity than sensitivity.

Background: Recent data indicate that increased intestinal permeability plays a key role in the pathogenesis of inflammatory bowel diseases (IBD) and correlates with disease flare. Since zonulin related proteins (ZRP) are the proteins that increase permeability in the epithelial layer of the small intestine by reversibly modulating the intercellular tight junctions, they may serve as a new, noninvasive biomarker of disease activity. The aim of this study was to investigate fecal ZRP in pediatric IBD patients as well as its correlation with disease activity and fecal calprotectin (FCP). Methods: Ninety-four individuals: 47 Crohn’s disease (CD) patients, 41 ulcerative colitis (UC) patients, and 6 healthy controls were examined for fecal ZRP. Values were correlated to IBD type, disease activity for IBD patients, and FCP for all children included in the study. A stool specimen was collected the day before the visit to the hospital, then fecal ZRP and FCP were tested using the ELISA test. Non-parametric statistical tests were used for data analysis. Results: The level of fecal ZRP was higher among IBD patients compared to the control group (CG): medians for CD—113.3 (53.6–593.6) ng/mL; UC—103.6 (50.7–418.3) ng/mL; and CG—46.9 (31.8–123.0) ng/mL (p < 0.05). No difference in fecal ZRP concentration was observed between children with CD and those with UC (p = 0.55). A slight correlation between disease activity (PCDAI for CD and PUCAI for UC) and the fecal ZRP level was found for CD (p = 0.03/R = 0.33), but not UC (p = 0.62/R = 0.08), patients. A correlation between fecal ZRP and FCP was observed (R = 0.73, p = 0.00). Conclusions: Fecal ZRP levels are increased among those with IBD, are associated with CD activity, and strongly correlate with FCP. Further research into the role of intestinal permeability in IBD and the clinical usefulness of ZRP in IBD is warranted.

In recent years, there has been a significant increase in the incidence of Crohn’s disease. Despite significant medical progress, the treatment options available today do not meet the needs of all patients. Recent reports indicate that external environmental factors, including diet, are key in the pathomechanism of the disease. It was proven that the so-called Western dietary pattern is associated with an increased risk of disease. In the pediatric population, exclusive enteral nutrition is the only nutritional therapy option recommended today with proven high efficacy in inducing remission. Recent publications that indicate at least comparable efficacy and significantly better tolerability of a specialised elimination diet, the Crohn’s Disease Exclusion Diet (CDED), provide the basis for a change in recommendations. This article discusses the mechanism of action, principles of use, and scientific evidence evaluating the efficacy of CDED in the treatment of children with Crohn’s disease.

Background: Infusion reactions (IRs) are the most common adverse events (AEs) of infliximab (IFX) treatment in patients with inflammatory bowel disease (IBD). Prophylactic premedication (PM) with corticosteroids or antihistamines prior to IFX infusions has been used in clinical practice, but its efficacy is not known. The aim of this study was to assess the influence of steroid PM on IR incidence in pediatric patients with IBD receiving IFX. Methods: We performed a case–control study that included pediatric patients with IBD receiving IFX. Patients were divided into four subgroups according to the agent and PM they received: Remicade (original drug) + PM, and two biosimilars—Reshma +/− PM, and Flixabi—PM. At our site, until 2018, PM with steroids was used as a part of standard IFX infusion (PM+); however, since then, this method has no longer been administered (PM−). IRs were divided into mild/severe reactions. Differences between subgroups were assessed with the appropriate chi-square test. Multivariate logistic regression was used to assess associations between PM and IR incidence, correcting for co-medication usage. Results: There were 105 children (55 PM+, 44 male, mean age 15 years) included in the study who received 1276 infusions. There was no difference between the PM+ and PM− subgroups, either in incidence of IR (18.2% vs. 16.0% of patients, p > 0.05) or in percentage of infusions followed by IR (2.02% vs. 1.02% of infusions, p > 0.5). The OR of developing IR when using PM was 0.34, and the difference in IRs ratio in PM+ and PM− patients was not statistically significant (95% CI, 0.034–1.9). There were 11/18 (61.1%) severe IRs (anaphylactic shock) reported in all patients (both PM+ and PM−). Conclusion: At our site, the incidence of IR was low, and PM did not decrease the incidence of IR in pediatric patients with IBD receiving IFX. These results indicate that PM with steroids should not be a standard part of IFX infusion to prevent IR.

The incidence and prevalence rate of chronic inflammatory disorders is on the rise in the pediatric population. Recent research indicates the crucial role of interactions between the altered intestinal microbiome and the immune system in the pathogenesis of several chronic inflammatory disorders in children, such as inflammatory bowel disease (IBD) and autoimmune diseases, such as type 1 diabetes mellitus (T1DM) and celiac disease (CeD). Here, we review recent knowledge concerning the pathogenic mechanisms underlying these disorders, and summarize the facts suggesting that the initiation and progression of IBD, T1DM, and CeD can be partially attributed to disturbances in the patterns of composition and abundance of the gut microbiota. The standard available therapies for chronic inflammatory disorders in children largely aim to treat symptoms. Although constant efforts are being made to maximize the quality of life for children in the long-term, sustained improvements are still difficult to achieve. Additional challenges are the changing physiology associated with growth and development of children, a population that is particularly susceptible to medication-related adverse effects. In this review, we explore new promising therapeutic approaches aimed at modulation of either gut microbiota or the activity of the immune system to induce a long-lasting remission of chronic inflammatory disorders. Recent preclinical studies and clinical trials have evaluated new approaches, for instance the adoptive transfer of immune cells, with genetically engineered regulatory T cells expressing antigen-specific chimeric antigen receptors. These approaches have revolutionized cancer treatments and have the potential for the protection of high-risk children from developing autoimmune diseases and effective management of inflammatory disorders. The review also focuses on the findings of studies that indicate that the responses to a variety of immunotherapies can be enhanced by strategic manipulation of gut microbiota, thus emphasizing on the importance of proper interaction between the gut microbiota and immune system for sustained health benefits and improvement of the quality of life of pediatric patients.

The aim of this study was to compare the clinical efficacy and tolerance of polyethylene glycol 3350 (PEG) and lactulose for the treatment of functional constipation in infants and children.This randomized, multicenter study covered 12 weeks of treatment and 4 weeks of follow-up of patients with functional constipation. Patients were randomized (central randomization) to receive either PEG or lactulose. The primary end points were the number of defecations per week after 12 weeks of treatment and improvement in stool consistency of at least 2 points in the Bristol scale. The secondary end point was the presence of adverse events. Bowel movements ≥3 per week and stool consistency ≥2 (Bristol scale) were considered as successful treatment.We enrolled 102 patients (M 57, F 45) aged 3.62 ± 1.42 years and 88 completed the study. At week 12, good clinical outcome was achieved in 98% (PEG) and 90% (lactulose). The PEG group had more defecations per week compared with the lactulose group (7.9 ± 0.6 vs 5.7 ± 0.5, P = 0.008) and both groups had similar frequency of defecation with pain (5% vs 5%, P = 0.9), stool retention (7% vs 10%, P = 057), large volume of stools (30% vs 31%, P = 0.9) and hard stools (7% vs 13%, P = 0.58). There were more patients with side effects in the lactulose group (15 vs 23, P = 0.02), mostly bloating and abdominal pain.PEG 3350 is more effective and causes fewer side effects than lactulose in the treatment of constipation in infants and children.

Background and Aims The study investigates the practical utility of whole-blood gene expression profiling to diagnose inflammatory bowel diseases [IBDs]. Methods The discovery cohorts included 102 and 51 paediatric IBD patients and controls, and 95 and 46 adult IBD patients and controls, respectively. The replication cohorts included 447 and 76 paediatric IBD patients and controls, and 271 and 108 adult IBD patients and controls, respectively. In the discovery phase, RNA samples extracted from whole peripheral blood were analysed using RNA-Seq, and the predictive values of selected biomarkers were validated using quantitative polymerase chain reaction [qPCR]. Results In all, 15 differentially expressed transcripts [adjusted p ≤0.05] were selected from the discovery sequencing datasets. The receiver operating characteristic curves and area under the curve [ROC-AUC] in replication analyses showed high discriminative power [AUC range, 0.91–0.98] for 11 mRNAs in paediatric patients with active IBD. By contrast, the AUC-ROC values ranged from 0.63 to 0.75 in comparison among inactive paediatric IBDs and active/inactive adult IBDs, indicating a lack of discriminative power. The best multi-mRNA diagnostic classifier showed moderate discriminative power [AUC = 0.81] for paediatric inactive IBD, but was not able to discriminate active or inactive adult IBD patients from controls. The AUC-ROC values did not confirm an ability of the mRNAs abundances to discriminate between active ulcerative colitis and active Crohn’s disease in paediatric or adult populations. Conclusions This study identifies and validates blood transcriptional biomarkers that could be used in clinical settings as diagnostic predictors of IBD clinical activity in paediatric, but not adult, IBD patients.

Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis.The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557.93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period.Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis.AbbVie.

Background OX40 (CD134) plays a role in the maintenance of late T-cell proliferation and survival. KHK4083 is a monoclonal antibody directed against OX40. We aimed to assess the safety and preliminary efficacy of KHK4083 in patients with moderately active ulcerative colitis (UC). Methods In this multicenter, double-blind, parallel-group, phase 2 study, patients with moderately active UC patients were randomized to ascending doses of intravenous KHK4083 (1, 3, or 10 mg/kg) or placebo every 2 weeks for 12 weeks. The primary endpoint was safety. The primary efficacy end point was the change from baseline in mean modified Mayo endoscopy subscore at week 12. Treatment with KHK4083 or placebo was continued every 4 weeks for up to 52 weeks in responders. Results Long-term treatment with KHK4083 was well tolerated, with treatment-related adverse events being predominantly transient mild-to-moderate infusion-related reactions. Exploratory analysis of biopsy samples showed the virtually complete elimination of OX40+ cells in colon mucosa after 12 weeks of KHK4083 treatment. There were no significant differences between any of the randomized KHK4083 dose groups and placebo for the mean change in Mayo endoscopy subscore from baseline to week 12. Conclusions KHK4083 can be safely administered intravenously at doses up to 10 mg/kg every 2 or 4 weeks for up to 52 weeks. Proof of pharmacodynamic action was confirmed by depletion of the elevated levels of the OX40+ cells associated with UC at all tested doses. Clinical response and mucosal healing (endoscopic improvement) in this population was not correlated with ablation of OX40+ T cells.

Summary Objective Constipation is one of the most common problems among children, with a prevalence ranging from 7 to 30%. It is treated with defecation training and laxative medications. However, many patients do not respond to the standard therapy. There is, therefore, an increasing interest in probiotics for the treatment of functional constipation. Study design The aim of this study was to assess the effectiveness of Lactobacillus reuteri DSM 17938 as an adjunct to macrogol in the treatment of functional, intractable constipation in children. A double-blind, placebo-controlled, randomized, multicentre trial involved a group of 129 children with functional constipation who were treated with a poor effect for at least two months prior to the study. Patients were randomly assigned to one of the two groups: 1. L. reuteri DSM 17938 and macrogol or 2. macrogol and matching placebo for 8 weeks. Results 121 patients completed the study. Almost all patients (119/129) increased their bowel movements in both groups (59 vs 60, ns.) and there was no statistically significant difference in the number of bowel movements per week in week 8 between the study and the placebo group (7.5 ± 3.3 vs 6.9 ± 2.5, respectively). Additionally, there were no significant differences between groups in the numbers of patients complaining of pain during defecation (13/47 vs 8/53), abdominal pain (19/41 vs 25/36), withholding stools (15/45 vs 13/48), passing hard stools (7/53 vs 3/58) or large stools (14/46 vs 12/49), and faecal incontinence (17/43 vs 11/50). Conclusion L. reuteri DSM 17938 supplementation as an additional therapy to macrogol did not have any beneficial effect on the treatment of functional constipation in children aged 3–7 years.

markdownabstractBackground: This European Crohn's and Colitis Organisation [ECCO] topical review focuses on the transition of adolescents with inflammatory bowel disease [IBD] from child-centred to adult-oriented care. The aim was to provide evidence-supported, expert consensus for health professionals taking part in the transition. Methods: An online survey determined the areas of importance for health professionals involved in the transition of adolescents with IBD. Thereafter an expert panel of nine paediatric and five adult gastroenterologists was formed to identify the critical elements of the transition programme, and to prepare core messages defined as 'current practice points'. There is limited literature about transition, therefore this review is mainly based on expert opinion and consensus, rather than on specific evidence. Results: A total of 21 practice points were generated before the first [online] voting round. Practice points that reached > 80% agreement were accepted, while those that did not reach 80% agreement were refined during a consensus meeting and subjected to voting. Ultimately, 14 practice points were retained by this review. Conclusion: We present a consensus-based framework for transitional care in IBD that provides a guidance for clinical practice.

Background Two randomised controlled trials of a novel subcutaneous (SC) formulation of infliximab in patients with active rheumatoid arthritis1 and in patients with active Crohn’s disease (CD) and ulcerative colitis (UC)2 confirmed comparable clinical efficacy and safety of CT-P13 SC with CT-P13 intravenous (IV) up to Week 30. We now present the efficacy, pharmacokinetics (PK) and safety of CT-P13 SC over 1-year in the active CD and UC trial, including the outcomes of switching from CT-P13 IV to CT-P13 SC. Methods After loading doses of IV 5 mg/kg at Weeks 0 and 2, patients were randomised at Week 6 to receive either SC 120 mg ( Results A total of 131 patients were randomised (66 to the SC arm and 65 to the IV arm); of whom, 105 (80.2%) patients completed the Week 54 visit (55 in the SC arm and 50 in the IV arm). The mean CDAI and partial Mayo scores decreased over time in the 2 arms until Week 30 and comparable improvement in clinical activity was observed at Week 54 after switching the remaining IV patients to SC (Figure 1 and 2). The rates of clinical response and remission were also maintained at Week 54 and the rate of mucosal healing in combined CD and UC was further improved at Week 54 (Table 1). The mean pre-dose serum concentrations in the IV arm increased to a similar level to SC arm after switching and maintained consistent levels until Week 54 (Figure 3). The safety profiles during the maintenance phase and on or after Week 30 were generally comparable between the 2 arms (Table 1). All of the localised injection site reactions were grade 1 or 2 in intensity and majority of patients recovered without any treatments. Conclusion These results of CT-P13 SC 1-year study in active CD and UC show comparable efficacy and safety of the SC and IV formulations, which were not affected by a switch of IV patients to SC route. The PK as manifested by trough concentrations of the drug, increased after switching from IV to SC. These observations support the first infliximab SC formulation as a viable therapeutic agent to expand patients’ treatment options. References

Biosimilars of infliximab were first approved by the European Medicine Agency in 2013,1 , 2 based on pre-clinical studies on biosimilarity and on clinical data coming from two randomised controlled trials conducted in rheumatoid arthritis [RA] and ankylosing spondylitis [AS].3 , 4 Initially the European Crohn’s Colitis Organisation [ECCO] raised some caution on the use of biosimilars.5 This cautious approach was also supported by several national inflammatory bowel disease [IBD] societies5–12 [Table 1]. An insufficient understanding of the characteristics and use of biosimilars became evident in a web survey among ECCO members in the same period.13 View this table: Table 1. Available society guidelines. Since biosimilars were introduced in the EU market in early 2015, more data from IBD patients14–19 have supported the biosimilarity of biosimilar infliximab CT-P13 and the reference product, with no significant differences in terms of efficacy or safety, in either naive or switched patients in cohort studies. Importantly, a study showed clear cross-reactivity between the infliximab originator and CT-P13.20 Recently, a large nationwide Norwegian randomised controlled trial [NOR-SWITCH] on patients with immune-mediated diseases [Crohn’s disease; ulcerative colitis; psoriasis; psoriatic arthritis; RA and AS] found no differences in terms of clinical response, maintenance of remission, or adverse events in patients receiving CT-P13 compared with those receiving originator infliximab.21 Consideration of these findings22 together with a better understanding of the process of biosimilar development and regulatory approval, have contributed to a change in the perception of IBD experts, who now prescribe biosimilars with significantly more confidence.23 A task-force including Governing Board representatives and one representative from pertinent ECCO Committees performed a literature search and made relevant statements to summarise their shared position. The proposed statements were then discussed, agreed and approved in a Consensus meeting. The licensing of any biosimilar medication …

To evaluate the diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) in the detection of chronic pancreatitis (CP)-specific changes in the pediatric population.The study included 48 children with pancreatic disorders subjected to both endoscopic retrograde cholangiopancreatography (ERCP) and MRCP within a 1- to 4-month interval. The sensitivity, specificity, positive predictive value, and negative predictive value of MRCP in the detection of CP-specific changes were determined using ERCP as a diagnostic standard.Diagnostic ERCP pancreatograms were obtained in 41 (85.4%) of 48 patients and diagnostic MRCP images in all 48 children. The sensitivity and positive predictive value of MRCP were 77.1% and 90%, respectively, and its specificity and negative predictive value amounted to 50% and 27.3%, respectively. The patients with consistent results of MRCP and ERCP (ie, true-positive and true-negative cases) and individuals with incompatible results of the tests (ie, false-positive and false-negative cases) differed in terms of their median age at MRCP (14.17 vs 10.33 years) and median CP stage according to the Cambridge Scale (4 vs 2).Magnetic resonance cholangiopancreatography provides diagnostic information equivalent to ERCP in a large percentage of pediatric patients with CP and should be used as the imaging method of choice, especially if the likelihood of therapeutic intervention is low.

Supplemental Digital Content is Available in the Text. Article first published online 7 March 2016., Background: The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Methods: Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW

Introduction The clinical efficacy of infliximab (IFX) for induction of remission in both adults and children with active Crohn's disease (CD) has been well documented. Recently, so-called "deep remission" defined as mucosal healing has become the ultimate endpoint of the most recent therapeutic advances for CD. However, endoscopic evidence of mucosal healing is not necessarily associated with histological evidence of suppression of inflammation. Aim Since data on that issue are limited, especially in the paediatric population, the aim of this study was to assess the impact of induction therapy with IFX on deep microscopic remission in paediatric patients with CD. Material and methods Fifty-six children (32 boys and 24 girls) aged 13.0 ±9.3 years with moderate to severely active CD diagnosed at the mean age of 5.5 ±0.83 years were included into the study. Colonoscopy and gastroscopy with sample collection were performed in all patients before and after three injections of IFX. Clinical activity of the disease was assessed using the Paediatric Crohn's Disease Activity Index (PCDAI), and the endoscopic activity was scored using the Simple Endoscopic Score (SES-CD). Histological changes were evaluated by a previously described numerical scoring system. Results Thirty-nine (69.6%) patients reached clinical remission (PCDAI ≤ 10). When comparing data at baseline and at week 10, a significant decrease was observed in median PCDAI, and in SES-CD score between the initial and control colonoscopies. We also reported a decrease in histological scale. However, the difference was not statistically significant (p = 0.63). Three (5.4%) patients had a score of zero in the control histological examination. The correlation was found only between histological score and SES-CD score. Clinical remission correlated better with mucosal healing expressed by a decrease in SES-CD score than with microscopic changes. Conclusions Biological therapy with infliximab enables mucosal healing in paediatric patients with CD, which is not necessarily associated with histological evidence of suppression of inflammation. Mucosal healing correlates better than microscopic healing with clinical remission.

Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are heterogeneous chronic autoimmune diseases that may share underlying pathogenic mechanisms. Herein, we compared simultaneously analyzed blood transcriptomes from patients with PBC, PSC, and IBD. Microarray-based measurements were conducted using RNA isolated from whole blood samples from 90, 45, 95 and 93 patients with PBC, PSC, CD, and UC, respectively, and 47 healthy controls. Expression levels of selected transcripts were analyzed by quantitative reverse-transcribed PCR using an independent cohort of 292, 71 and 727 patients with PBC, PSC, and IBD, respectively. Of 4026, 2650 and 4967 probe sets differentially expressed (adjusted p-value

The introduction of biological treatments has changed disease outcomes for patients with inflammatory bowel disease. Biologicals have high efficacy, and can induce and maintain remission after failed responses to conventional immunosuppressive and/or steroid therapy. The increasing occurrence of severe disease at diagnosis has resulted in infliximab being more often introduced as the first-line treatment in a "top-down" approach. Besides their favourable efficacy and safety profile, biologicals have one significant disadvantage, which is their high cost. This results in many patients stopping therapy prematurely, with the maintenance phase being too short. This often leads to disease exacerbation shortly after treatment cessation. Every newly started course of biological therapy can induce production of anti-drug antibodies, which can result in treatment failure and possible allergic/anaphylactic reactions. The introduction of biological biosimilars was intended to greatly reduce therapy costs thus increasing the availability of these agents to more patients. It was also anticipated that biosimilars would prevent premature termination of therapy. Analyses of paediatric data suggest that biosimilar infliximabs are equally effective as the reference infliximab. Safety patterns also seem to be similar. Paediatric experience places cost-therapy reductions at around 10%-30%.

Introduction In recent years, monoclonal antibodies against tumor necrosis factor α (TNF-α), infliximab (IFX), and adalimumab (ADA) have gained increasing popularity in Crohn's disease (CD) management. Many clinical trials have shown that biologics are a generally well-tolerated and safe treatment. However, the follow-up time with regards to safety is too short, and data on that issue are still limited. Aim To report the cumulative safety profile of biologic therapy with IFX and/or ADA, up to 8 years, in Polish children with moderately to severely active CD. Material and methods We performed a retrospective analysis of 110 children, aged 13.0 ±9.3 years, diagnosed with CD, and treated with IFX and/or ADA, within a period of 8 years between 2005 and 2013. Safety data for all treated patients were collected throughout the entire treatment period and were included in the safety analyses. Results The cumulative rates of treatment-related adverse events (AE) (TRAEs) in all patients were 67 events - 43 (64.17%) events for IFX and 24 (35.83%) for ADA, respectively. The majority of TEAEs were mild-to-moderate in intensity. The most frequently reported ones were: anaemia in 17 (20.23%) IFX patients and 9 (23.08%) ADA patients, and mild infections in 9 (10.7%) IFX patients and 5 (12.8%) ADA patients, respectively. We did not report any serious AE (sAE). Conclusions Biologic therapy with infliximab and/or adalimumab is generally well tolerated and safe, and does not cause any sAEs.

In recent years, a novel biologic therapy with monoclonal antibodies against tumor necrosis factor-alpha has revolutionized the treatment of Crohn's disease. Infliximab, the first biologic agent, has been demonstrated to considerably improve both clinical and endoscopic outcomes. In view of the growing popularity of infliximab in the management of Crohn's disease, we review the profile of the agent in the treatment of this disease in a pediatric setting.

Objective: The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis. Methods: Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of ≥10 to ≤55 and a truncated Mayo Score of ≥1 for both rectal bleeding and stool frequency, were enrolled. They received body weight–dependent doses of oral, delayed-release mesalamine for 6 weeks in a low- (27–71 mg · g−1 · day−1) or high-dose group (53–118 mg · g−1 · day−1). The primary endpoint was treatment success, defined as the proportion of patients who achieved remission (PUCAI score

Chronic pancreatitis (CP) is a rare disease in childhood. Although ERCP is commonly performed in children, the effect of pancreatic duct stenting therapy in children with CP is unknown.To investigate the efficacy of pancreatic duct stenting in children with CP.Retrospective analysis.National referral center.A total of 208 children with CP hospitalized between 1988 and 2012.ERCP with pancreatic duct stenting.Results of endoscopic therapy and number of pancreatitis episodes per year before and after treatment.A total of 223 pancreatic duct stenting procedures were performed in 72 children. The median number of stent replacements was 3 (range 1-21). A statistically significant decrease in the number of pancreatitis episodes per year was observed: from 1.75 to 0.23 after endoscopic treatment (P.05). Pancreatic duct stenting was performed more frequently in patients with hereditary pancreatitis (61.5%) and in children with CP and anatomic anomalies of the pancreatic duct (65%; P.05).Retrospective analysis with the assessment of adverse events based on medical history.Pancreatic duct stenting therapy is a safe and effective procedure in children with CP. This therapy should be recommended especially for children with hereditary pancreatitis and patients with anatomic anomalies of the pancreatic duct.

Although the current doctrine of IBD pathogenesis proposes an interaction between environmental factors and gut microbiota in genetically susceptible individuals, dietary exposures have attracted recent interest and are, at least in part, likely to explain the rapid rise in disease incidence and prevalence. The D-ECCO working group along with other ECCO experts with expertise in nutrition, microbiology, physiology, and medicine reviewed the evidence investigating the role of diet and nutritional therapy in the onset, perpetuation, and management of IBD. A narrative topical review is presented where evidence pertinent to the topic is summarised collectively under three main thematic domains: i] the role of diet as an environmental factor in IBD aetiology; ii] the role of diet as induction and maintenance therapy in IBD; and iii] assessment of nutritional status and supportive nutritional therapy in IBD. A summary of research gaps for each of these thematic domains is proposed, which is anticipated to be agenda-setting for future research in the area of diet and nutrition in IBD.

Introduction Chronic pancreatitis (CP) is of a rare occurrence in childhood. The aetiology of CP in children is varied and includes anatomic anomalies, gene mutations, metabolic disorders and others. The aim of this study was to investigate the etiological aspects of CP in children from well-defined homogenous single-centre cohort. Methods 313 children with CP (aged: 0.6–18 years; mean 8.8; F-171, M-140) hospitalised between 1988 and 2016 were enrolled into the study. Clinical and epidemiological data were recorded and analysed. All patients were screened for gene mutations predisposing to CP. All children had preceding imaging studies, including US, CT, MRCP and/or ERCP. Results Gene mutations were found in 194 children (61%) (PRSS1 mutation in 42 children, CFTR in 46 patients, SPINK1 in 76 children, CTRC in 78 patients, CPA1 in 2 children). Anatomic anomalies of pancreatic duct were diagnosed in 51 patients (16%) (31-pancreas divisum, 10-ansa pancreatica, 4-ABPU, 2-two main pancreatic ducts, 4-other). Toxic-metabolic risk factors were found in 41 patients (13%), with dominance of lipid disturbances (21 children). CP was associated with biliary tract diseases in 26 patients (8.3%). Autoimmune pancreatitis was diagnosed in 6 children (1.9%). History of trauma was present in 20 cases (6.4%). Idiopathic CP was diagnosed in 50 children (16%). Conclusions 1. Gene mutations and anatomic anomalies of pancreatic duct are the most common etiologic factors of CP in children. 2. Our data demonstrate the need for genetic testing in children with CP.

In most European countries, an infliximab biosimilar (CT-P13) is currently in common use. In vitro and in vivo studies have proved a high similarity between CT-P13 and the reference infliximab. CT-P13 was licensed for use in patients with Crohn disease (CD) based on the extrapolation of data from preclinical studies and clinical trials in rheumatology indications. The aim of this study was to assess the similarity between CT-P13 and the originator infliximab in induction therapy in CD paediatric patients.Thirty-six CD paediatric patients from 3 Polish academic centres who started biological therapy with CT-P13 were enrolled in this prospective, observational study. Patients received 3 induction doses (5 mg/kg) of CT-P13 at weeks 0, 2, 6. Assessment was performed before the first infusion and at week 14.Overall 34/36 (94.4%) patients completed induction therapy with CT-P13. A clinical response or remission after 3 initial doses was achieved in 31/36 (86%) and 24/36 (67%) of patients, respectively. Clinically and statistically significant decreases in Paediatric Crohn's Disease Activity Index, C-reactive protein, and erythrocyte sedimentation rate were observed in the responders group. An allergic reaction during infusion, which led to treatment discontinuation, was observed in one case.Induction therapy with CT-P13 in children with CD is effective. The profile appears similar to that reported for the reference infliximab. No unexpected adverse events occurred.

Clinically effective therapies now exist for remission maintenance in both ulcerative colitis [UC] and Crohn's Disease [CD]. For each major class of IBD medications [5-aminosalicyclates, immunomodulators, and biologic agents], used alone or in combination, there is a risk of relapse following reduction or cessation of treatment. A consensus expert panel convened by the European Crohn's and Colitis Organisation [ECCO] reviewed the published literature and agreed a series of consensus practice points. The objective of the expert consensus is to provide evidence-based guidance for clinical practice so that physicians can make informed decisions in partnership with their patients. The likelihood of relapse with stopping each class of IBD medication is reviewed. Factors associated with an altered risk of relapse with withdrawal are evaluated, and strategies to monitor and allow early identification of relapse are considered. In general, patients in clinical, biochemical, and endoscopic remission are more likely to remain well when treatments are stopped. Reintroduction of the same treatment is usually, but not always, successful. The decision to stop a treatment needs to be individualized, and shared decision making with the patient should take place.

Gastroesophageal reflux is one of the most common reasons for referrals to paediatricians or paediatric gastroenterologists. Gastric acid-buffering agents, mucosal surface barriers and gastric anti-secretory agents are the main groups of medications currently used for treating gastroesophageal reflux disease (GERD) in children. Recently, the use of proton pump inhibitors (PPIs) for the treatment of GERD in children has increased considerably. Their effectiveness in healing erosive oesophagitis in paediatric subjects and in improving GERD symptoms has been established in many studies. However, the effectiveness in other clinical conditions and the long-term safety of PPIs for paediatric GERD have not been fully established yet and thus are still under debate. Therefore, the aim of this article is to provide a comparative review of the efficacy, safety and tolerability of PPIs in paediatric GERD. The available data suggest that short-term use of PPIs is well tolerated. Adverse events tend to be of a mild-to-moderate nature, with headache being the most frequently reported treatment-related adverse event. However, further well-designed trials and observational studies are still needed to clarify the efficacy and safety of PPIs in the paediatric population, especially in infants under the age of 12 months.

Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn’s disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P = 5.2 × 10−11 and odds ratio (OR) = 2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity-associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components.

Evaluate the efficacy and safety of rabeprazole in children, 1 to 11 years old, with endoscopically/histologically proven gastroesophageal reflux disease (GERD).Children were randomized to 0.5- or 1.0-mg/kg rabeprazole granule formulation for 12 weeks. The dose was further determined by weight: children 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children ≥15 kg (high-weight cohort) received 10 or 20 mg. The primary endpoint was endoscopic/histologic healing at week 12 (defined as grade 0 on the Hetzel-Dent classification scale and/or grade 0 on the Histological Features of Reflux Esophagitis scale).Overall, 81% (87/108) achieved endoscopic/histologic healing at week 12 with higher healing in the low-weight cohort (82% [5-mg dose], 94% [10-mg dose]) compared with high-weight cohort (76% [10-mg dose], 78% [20-mg dose]). There was a significant (P0.001) decrease in the mean Total GERD Symptoms and Severity score from 19.7 points (baseline) to 8.6 points (week 12), with 26% fewer children reporting GERD symptoms at week 12. The average frequency of symptoms per child decreased from 7.7 (week 1) to 4.7 (week 12). The GERD Symptom Relief score showed that 71% of children felt better, 81% were rated "good to excellent" on the Global Treatment Satisfaction scale by the investigator; 77% were rated "good to excellent" on the Clinical Global Impressions-Improvement scale by the parent/caregiver. The most common (10%) treatment-emergent adverse events included cough and vomiting (14% each), abdominal pain (12%), and diarrhea (11%).Rabeprazole was effective and safe in 1- to 11-year-old children with GERD.

Background/aims Defecation disorders are one of the most common problems in pediatric gastroenterology. Treatment includes changes in the diet, pharmacotherapy, and biofeedback therapy. The aim of the present study was to evaluate the effectiveness of biofeedback therapy as assessed by clinical improvement as well as by changes in manometric parameters in children with constipation and pelvic floor dyssynergia (PFD). Materials and methods A total of 44 children with constipation and PFD hospitalized between 2000 and 2015 were enrolled in this retrospective study. All patients underwent anorectal manometry, and in case of diagnosed PFD, the patient qualified for biofeedback therapy. Amplitudes between extreme and basic pressures during defecation maneuvers in the first and last sessions as well as the difference between them were compared between groups with and without clinical improvement after the last session. Results A clinical improvement was achieved in 38 (86%) patients. There were no significant differences found in the amplitudes in the first session (mmHg), 94, 65, 115 vs. 112, 55, 170 (median, first quartile, third quartile, respectively; NS: not significant); last session, 36, 27, 52 vs. 41, -38, 66, respectively; or between them, 71, 11, 124 vs. 81, 17, 109, respectively, in the group with versus the group without clinical improvement, respectively. Conclusion Biofeedback therapy has high clinical efficacy, and despite the lack of manometric improvement, it should be used as a treatment method in children in whom dietary and pharmacological procedures do not work, even if we consider the exercises more as a form of psychological training.

OBJECTIVES The etiological factors of chronic pancreatitis (CP) in children differ from those in adults. To date, no study has assessed the clinical course of CP in young children. The aim of our study was to evaluate the etiology and the clinical presentation of the disease in children with disease onset before 5 years of age in comparison to later-onset of CP. METHODS A total of 276 children with CP, hospitalized from 1988 to 2015, were enrolled in the study. Data on presentation, diagnostic findings, and treatment were reviewed. Two hundred sixty patients were screened for the most frequent mutations in major pancreatitis-associated genes, such as cationic trypsinogen/serine protease gene (PRSS1), serine protease inhibitor, Kazal type 1 gene (SPINK1), and cystic fibrosis transmembrane conductance regulator gene (CFTR). RESULTS The disease onset before the age of 5 years occurred in 51 patients (group 1), the later onset in 225 patients (group 2). We found no significant discrepancies in distribution of the etiological factors between groups. The youngest patients (group 1) had more pancreatitis episodes (median 5.0 vs 3.00; P

Infliximab was the first monoclonal antibody used in the treatment of inflammatory bowel disease (IBD). Over several years, this antitumour necrosis factor (TNF) treatment proved its efficacy in both induction and maintenance therapy. In many cases this biological treatment stopped the progression of the disease, probably also decreasing morbidity and hospitalization rates, and improving patients’ comfort. When the patent on infliximab started to expire, the first biosimilar of a monoclonal antibody was introduced onto the pharmacological market. Biosimilar infliximab was studied in rheumatology and proved a high similarity to the reference drug. Based on extrapolation, biosimilars were approved to treat adult and paediatric IBD patients. Biosimilar infliximab, mainly because of its lower cost, has started to be in common use in Europe. The first studies have shown a similar efficacy and safety profile in comparison with reference drug. Biosimilar infliximab is raising hopes for improving the availability of this effective treatment.

Introduction: Infliximab (IFX) is currently registered for use in Crohn’s disease (CD) in children over 7 years of age. So far, there are not enough satisfactory data on maintenance therapy with IFX in children with CD from Eastern and Medium Europe. Aim: Therefore, we carried out this trial in order to assess the benefit of maintenance therapy with infliximab in paediatric patients with active Crohn’s disease who responded to induction therapy with 3 doses of infliximab. Material and methods: The study group consisted of 32 CD children aged 14.8; 12.9; 16.3 (median; Q1; Q3) with active Crohn’s disease (Crohn’s Disease Activity Index (PCDAI) > 30) who have finished induction therapy with infliximab (5 mg/ kg) in three repeated infusions. After assessment of remission at week 10, patients were assigned repeat 5 mg/kg infliximab every 8 weeks thereafter until week 46; weeks 14, 22, 30, 38, 46. The clinical activity of the disease by means of the PCDAI and endoscopic activity by means of the SES-CD together with laboratory tests were assessed at week 10 and 50. Adverse events monitoring had been conducted. Descriptive data analysis was performed with Statistica (StatSoft Polska) ver. 5.11 software package. A non-parametric statistical hypothesis test, Mann-Whitney U test, was used to assess whether two independent samples of observations had equally large values. Value of p < 0.05 was regarded as significant. Streszczenie

The primary objective of this study was to characterize the pharmacokinetic profile of pantoprazole delayed-release granules in infants and children aged 1 month to6 years with gastro-oesophageal reflux disease (GORD). The studies described in this manuscript were conducted to fulfil the requirements of the paediatric written request for pantoprazole by the US FDA.Two randomized, open-label, multicentre studies were conducted in infants aged 1 month to12 months (study 1) and children aged 1 year through6 years (study 2) with GORD. Patients were randomly assigned to either the low-dose pantoprazole group (0.6 mg/kg equivalent) or the high-dose pantoprazole group (1.2 mg/kg equivalent) in a 1 : 1 fashion. Pantoprazole granules were administered approximately 30 minutes before breakfast for at least five consecutive doses. Blood samples were obtained at prespecified intervals. Plasma pantoprazole concentration-time data were analysed by non-compartmental methods. Descriptive statistics were calculated for pharmacokinetic parameters. Patients in study 2 additionally received pantoprazole for 28 days. Safety was monitored throughout.In study 1, 43 patients were randomized; 42 were included in the single-dose pharmacokinetic evaluation (15 females, 27 males; mean postnatal age 6.3 months). In study 2, 17 patients were randomized, and all were included in the single-dose pharmacokinetic evaluation (6 females, 11 males; mean age 3.2 years). In both studies, exposure increased with dose. Mean (standard deviation) maximum (peak) plasma concentration values for the low and high doses were 503 (506) ng/mL and 1318 (1307) ng/mL, respectively, in study 1, and 229 (196) ng/mL and 653 (645) ng/mL, respectively, in study 2. Area under the plasma concentration-time curve values for the low and high doses were 1046 (1043) ng · h/mL and 3602 (3269) ng · h/mL, respectively, in study 1, and 293 (146) ng · h/mL and 2448 (2170) ng · h/mL, respectively, in study 2. There was a trend for increasing clearance with increasing age across the ages 1 month through6 years. There was no evidence of drug accumulation after multiple doses. On-treatment adverse events (AEs) occurred in 19 of 43 patients in study 1 and in 11 of 17 patients in study 2. Serious AEs occurred in two patients in study 1 (gastroenteritis in one patient and acute gastroenteritis from rotavirus infection resulting in discontinuation of one patient); the serious AEs resolved and were not considered by the investigators to be drug related. No other safety-related discontinuations occurred in either study.Exposure increased with increasing doses of pantoprazole granules, even though wide interindividual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was similar in study 1 and slightly lower in study 2. Pantoprazole was generally well tolerated in infants and children aged 1 month through6 years with GORD. Trial registration numbers (ClinicalTrials.gov): NCT00259012 (study 1) and NCT00141817 (study 2).

Introduction: Assessment of nutritional status of children with portal hypertension is an important prognostic factor which plays a significant role in the efficacy of their treatment. Aim: To assess the nutritional state of paediatric patients with portal hypertension through various methods of nutritional assessment and to investigate the usefulness of the techniques. Material and methods: The study group included 31 children with portal hypertension classified into 3 sub groups: patients with portal vein obstruction, biliary cirrhosis and post-hepatitic cirrhosis. The following anthropometrics data were measured: weight, body mass index (BMI), Cole’s index and body mass rate (BMR). The body fat (BF) and fatfree mass (FFM) were measured by skin fold bioelectrical impedance assessment (BIA) and dual-energy X-ray absorptiometry (DEXA). The total body water percentage (TBW%) and extracellular fluid content were measured by bioelectrical impedance (BIA). Laboratory parameters such as albumins, cholesterol, vitamin levels (A, E and D), and trace elements (Fe, Zn) together with other biochemical markers were also assessed. The control group consisted of healthy children selected according to their age. Results and conclusions: Malnutrition, based on Cole’s index and BMI < 10th percentile, was detected in 60% of children with biliary cirrhosis, 55.5% of those with posthepatitic cirrhosis and 45.5% of those with portal vein obstruction, respectively. Fat-free mass, measured by different methods, remained stable in each group (r = 0.97). For BF, the correlation between anthropometry, BIA and DEXA was significantly lower. Total body water percentage was higher in children with biliary cirrhosis than in other groups (p < 0.05). Vitamin A concentration was decreased in each Streszczenie Wstep: Stan odzywienia u dzieci z nadciśnieniem wrotnym odgrywa wazną role w skuteczności terapii oraz rokowaniu. Bardzo wazne znaczenie ma wczesne wykrycie zaburzen stanu odzywienia i odpowiednie leczenie zywieniowe w tej grupie pacjentow. Cel: Ocena stanu odzywienia u dzieci z nadciśnieniem wrotnym z zastosowaniem roznych metod, a takze określenie ich przydatności w diagnostyce. Material i metody: Grupe badaną stanowilo 31 dzieci z nadciś nieniem wrotnym, ktore podzielono na 3 podgrupy, w zalezności od etiologii choroby: pacjentow z blokiem przedwątrobowym, marskością zolciową oraz marskością pozapalną. We wszystkich grupach wykonano nastepujące badania: pomiary antropometryczne (masa ciala i wysokośc), wskaźnik masy ciala (BMI), wskaźnik Cole’a i wspolczynnik masy ciala (WMC). Dodatkowo u wszystkich obliczono beztluszczową mase ciala (BMC) oraz mase tluszczową na podstawie pomiaru 4 faldow skornych (nad mieśniami: dwuglowym, trojglowym oraz pod lopatką i nad kolcem biodrowym). Oceny dokonano metodą bioelektrycznej analizy impedancji (BIA) oraz metodą podwojnej absorpcji promieniowania X (DEXA). Zawartośc wody calkowitej (CW) i wody zewnątrzkomorkowej (ZW) w organizmie oszacowano metodą bioelektrycznej analizy impedancji (BIA). Wykonano rowniez badania laboratoryjne z krwi: oznaczenie stezenia albumin, cholesterolu, witaminy A i E, 25-hydroksycholekalciferolu oraz pierwiastkow śladowych (Fe, Zn). Grupe kontrolną stanowily zdrowe dzieci w podobnym przedziale wiekowym. Wyniki i wnioski: Niedozywienie, opierając sie na wskaźnikach Cole’a i BMI < 10. percentyla, zidentyfikowano u 60% dzieci z marskością zolciową, 55,5% z marskością pozapalną i 45,5% z blokiem przedwątrobowym. Oceniając BMC roznymi metodami, uzyskano zblizone wyniki, nierozniące sie staty

Ulcerative proctitis constitutes a large portion of newly diagnosed ulcerative colitis cases.1–4 It is defined as disease limited to the distal colon (the rectum), not extending beyond 15–20 cm proximal to the anal verge. The first line treatment for ulcerative proctitis is 5-aminosalicylic acid (5-ASA/mesalamine), administered as an oral medication or as rectal suppositories (1 g/day), enemas, foams, or gels (1–4 g/day).5–7 The therapeutic effect of mesalamine is attributed to its local concentration on the intestinal mucosa and not to its serum levels, which are very low due to a rapid metabolism of mesalamine into its main acetylated metabolites excreted in urine.8 Studies have shown that higher concentrations of the drug in inflamed colonic mucosa enhance response to treatment.9,10 Current treatment options aim at inducing and maintaining remission of disease-related symptoms and decrease the risk of drug-related adverse events.11 Mesalamine 500 mg suppositories have been used worldwide for more than 20 years with proven safety and efficacy in the adult population.5,12–16 Most adult patients respond to a twice daily dosing, in the morning and at bedtime. However, about 20% of ulcerative colitis patients have disease onset before 20 years of age.17–19 Pediatric patients will thus require long-term maintenance therapy with 5-aminosalicylate (5-ASA).20 Even though the presenting symptoms and therapeutic management options are similar in adults and children, data on the efficacy and safety of short- and long-term mesalamine treatment in pediatric patient populations are lacking.21 Clearly, clinical trials are needed for pediatric patients with inflammatory bowel disease (IBD) in general and ulcerative proctitis in particular. This is especially true considering the recently documented increase in the incidence rate of IBD among pediatric patients (from 9.5 per 100,000 in 1994 to 11.4 per 100,000 in 2005).19 In the present study we evaluated the clinical efficacy and safety of mesalamine 500 mg suppositories in a population of pediatric patients with ulcerative proctitis.

Limited data on proton pump inhibitors in infants led regulatory agencies to request sponsors to conduct pediatric studies. To determine the pharmacodynamic response to pantoprazole in infants with GERD to aid the dose selection for an efficacy study. In two open-label studies, neonates and preterm infants (study 1, ~1.2 mg/kg [high dose]) and infants 1 through 11 months (study 2, ~0.6 [low dose] or ~1.2 mg/kg [high dose]) received once-daily pantoprazole. Twenty-four-hour dual-electrode pH-metry parameters were compared between predose and steady state (≥5 days) (two-sided paired t test). Treatment was administered for ≤6 weeks. In studies 1 and 2, 21 and 24 patients, respectively, were enrolled for pharmacodynamic evaluation. The high dose provided similar responses in the two studies and improved these parameters significantly: mean gastric pH and percent time gastric pH > 4 increased (p