Physical Training and Healthy Diet Improved Bowel Symptoms, Quality of Life, and Fatigue in Children With Inflammatory Bowel Disease.

OBJECTIVES: Physical activity programs have been suggested as adjunctive therapy in adult inflammatory bowel disease (IBD) patients. We assessed the effects of a 12-week lifestyle intervention in children with IBD. METHODS: This study was a randomized semi-crossover controlled trial, investigating a 12-week lifestyle program (3 physical training sessions per week plus personalized healthy dietary advice) in children with IBD. Endpoints were physical fitness (maximal and submaximal exercise capacity, strength, and core stability), patient-reported outcomes (quality of life, fatigue, and fears for exercise), clinical disease activity (fecal calprotectin and disease activity scores), and nutritional status (energy balance and body composition). Change in maximal exercise capacity (peak VO 2 ) was the primary endpoint; all others were secondary endpoints. RESULTS: Fifteen patients (median age 15 [IQR: 12-16]) completed the program. At baseline, peak VO 2 was reduced (median 73.3% [58.8-100.9] of predicted). After the 12-week program, compared to the control period, peak VO 2 did not change significantly; exercise capacity measured by 6-minute walking test and core-stability did. While medical treatment remained unchanged, Pediatric Crohn's Disease Activity Index decreased significantly versus the control period (15 [3-25] vs 2.5 [0-5], P = 0.012), and fecal calprotectin also decreased significantly but not versus the control period. Quality of life (IMPACT-III) improved on 4 out of 6 domains and total score (+13 points) versus the control period. Parents-reported quality of life on the child health questionnaire and total fatigue score (PedsQoL Multidimensional Fatigue Scale) also improved significantly versus the control period. CONCLUSIONS: A 12-week lifestyle intervention improved bowel symptoms, quality of life, and fatigue in pediatric IBD patients.

Improved clinical outcomes with early anti-tumour necrosis factor alpha therapy in children with newly diagnosed Crohn's disease: real world data from the international prospective PIBD-SETQuality inception cohort study.

BACKGROUND & AIMS: Treatment guidelines for paediatric Crohn's disease (CD) suggest early use of anti-tumour necrosis factor alpha (anti-TNF) in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. METHODS: Children with newly-diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF (<90 days after diagnosis) and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission (SSFR) without treatment intensification (specified as SSFR*) and sustained steroid-free mild/inactive disease without treatment intensification (specified as SSFMI*). Penalised logistic regression model-based standardisation was applied to estimate the relative risks (RR) of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients based on presence of predictors of poor outcome (POPOs) and disease activity at diagnosis. RESULTS: In total, 331 children (median age 13.9 years [IQR 12.2 - 15.3]) were enrolled, with 135 (41%) receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* (30% vs. 14%, p<0.001) and SSFMI* (69% vs. 33%, p<0.001), with RRs of 2.95 (95%CI 1.63-5.36) and 4.67 (95%CI 2.46-8.87) respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared to mild/inactive disease at diagnosis (5.50 [95%CI 2.51-12.05]) vs. 2.91 [95%CI 0.92-9.11]), and those with any POPO compared to no POPO (5.05 [95%CI 2.45-10.43] vs. 3.41 [95%CI 0.54-21.7]). CONCLUSION: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.

Infant nutritional factors and functional constipation in childhood: the Generation R study.

OBJECTIVES: Food allergy and celiac disease may lead to childhood constipation. Early introduction of food allergens and gluten in the first year of life has been suggested to have a function in these food intolerances, but it is unclear whether this also holds true for development of childhood constipation. The aim of this study was to assess the association between the timing of introduction of food allergens and gluten early in life and functional constipation in childhood. METHODS: This study was embedded in the Generation R study, a population-based prospective cohort study from fetal life until young adulthood. Functional constipation at 24 months of age was defined in 4,651 children according to the Rome II criteria of defecation frequency <3 times a week or the presence of mainly hard feces for at least 2 weeks. RESULTS: At the age of 24 months, 12% of the children had functional constipation. Children with functional constipation got introduced to gluten more often before or at the age of 6 months than children without functional constipation (37% and 27%, respectively). After adjustment for birth weight, gestational age, gender, ethnicity, maternal education, and family history of atopy and chronic intestinal disorders, functional constipation was significantly associated with early gluten introduction (odds ratio (OR): 1.35; 95% confidence interval (CI): 1.10-1.65). No association was found between timing of introduction of cow's milk, hen's egg, soy, peanuts, and tree nuts with functional constipation. A history of cow's milk allergy in the first year of life was significantly associated with functional constipation in childhood (OR: 1.57; 95% CI: 1.04-2.36). CONCLUSIONS: These results suggest that early gluten introduction in the first year of life provide a trigger for functional constipation in a subset of children. In case of functional constipation, there also might be a role for cow's milk allergy initiated in the first year of life.

IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.

Breach of tolerance to gluten leads to the chronic small intestinal enteropathy celiac disease. A key event in celiac disease development is gluten-dependent infiltration of activated cytotoxic intraepithelial lymphocytes (IELs), which cytolyze epithelial cells causing crypt hyperplasia and villous atrophy. The mechanisms leading to gluten-dependent small intestinal IEL infiltration and activation remain elusive. We have demonstrated that under homeostatic conditions in mice, gluten drives the differentiation of anti-inflammatory T cells producing large amounts of the immunosuppressive cytokine interleukin-10 (IL-10). Here we addressed whether this dominant IL-10 axis prevents gluten-dependent infiltration of activated cytotoxic IEL and subsequent small intestinal enteropathy. We demonstrate that IL-10 regulation prevents gluten-induced cytotoxic inflammatory IEL infiltration. In particular, IL-10 suppresses gluten-induced accumulation of a specialized population of cytotoxic CD4+CD8αα+ IEL (CD4+ CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4+CD8α- IEL population expressing Il17a, Il21, and Il10. Concomitantly, IL-10 suppresses gluten-dependent small intestinal epithelial hyperproliferation and upregulation of stress-induced molecules on epithelial cells. Remarkably, frequencies of granzyme B+CD4+CD8α+ IEL are increased in pediatric celiac disease patient biopsies. These findings demonstrate that IL-10 is pivotal to prevent gluten-induced small intestinal inflammation and epithelial damage, and imply that CD4+ CTL are potential new players into these processes.

IL-10 signaling in dendritic cells controls IL-1ß-mediated IFNγ secretion by human CD4+ T cells: relevance to inflammatory bowel disease.

Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4+ T cells. Deficiency in IL-10 signaling dramatically increased IL-1ß release by moDCs. IL-1ß boosted IFNγ secretion by CD4+ T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1ß expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4+ T cells in humans and identifies IL-1ß as a potential classifier for a subgroup of IBD patients.

Early onset IBD: what's the difference?

In this paper we describe an array of differences between paediatric and adult inflammatory bowel diseases. Specifically, patient specifics such as genetics, disease location, immune responses and drug responsiveness are addressed. Given the distinct disease phenotype in children, it seems warranted that early onset inflammatory bowel diseases will be denoted as a specific disease entity.

Systematic review with meta-analysis: anxiety and depression in children and adolescents with inflammatory bowel disease.

BACKGROUND: The co-existence of psychological problems and paediatric inflammatory bowel disease (IBD) is receiving increasing attention. Most studies investigated anxiety and depression, with prevalence rates varying from 0% to 50%. A systematic review is necessary to provide clear insight into the prevalence of anxiety and depression in paediatric IBD. AIM: To systematically evaluate available data on the prevalence of anxiety and depressive symptoms and disorders in paediatric IBD (aged 6-18 years). METHODS: Comprehensive searches were performed in Embase, Medline Ovid, Web of Science, Cochrane, PubMed, PsychInfo Ovid, and Google scholar for studies published from 1994 to 2017. Pooled prevalence rates were calculated using inverse variance heterogeneity models. Meta-regression was used to study if disease type, disease activity and gender influence prevalence. RESULTS: Twenty-eight studies (N = 8107, mean age: 14.3) were identified. Pooled prevalence estimates were 16.4% (95% confidence interval [CI] 6.8%-27.3%) for anxiety symptoms and 4.2% (95% CI 3.6%-4.8%) for anxiety disorders. Pooled prevalence estimates were 15.0% (95% CI 6.4%-24.8%) for depressive symptoms and 3.4% (95% CI 0%-9.3%) for depressive disorders. Meta-regression showed no influence of disease type or gender on these prevalence rates, but studies with a higher percentage of active disease had a higher rate of depressive symptoms. CONCLUSIONS: The described pooled prevalence of anxiety and depressive symptoms is lower than in adult IBD. However, due to varying instruments/cut-offs for measuring symptoms and few studies investigating disorders, the results should be interpreted with caution. Cross-cultural use of the same instruments is needed to gain better insight into prevalence rates.

Clinical disease activity is associated with anxiety and depressive symptoms in adolescents and young adults with inflammatory bowel disease.

BACKGROUND: Youths with inflammatory bowel disease (IBD) are at risk for developing anxiety and depressive symptoms with a reported 20%-50% prevalence rate. AIMS: This prospective study aimed to: (1) describe the prevalence and severity of anxiety and depressive symptoms in a large Dutch cohort of young IBD patients, and (2) identify demographic and clinical risk factors for anxiety and depression. METHODS: IBD patients (n = 374; 10-25 years) were screened for anxiety, depression and quality of life using validated age-specific questionnaires. Patients with elevated scores for anxiety and/or depressive symptoms received a diagnostic interview assessing psychiatric disorders. Demographic and clinical characteristics were retrieved from medical charts. Multiple logistic regression analysis was performed to identify risk factors for anxiety and/or depression. RESULTS: Patients (mean age 18.9 years, 44.1% male, Crohn's disease 60.4%) had disease in remission (75.4%), or mild, moderate and severe clinical disease activity in, respectively, 19.8%, 2.7% and 2.1%. Mild anxiety/depressive symptoms were present in 35.2% and severe symptoms in 12.4% of patients. Elevated symptoms of either anxiety (28.3%), depression (2.9%) or both (15.8%) were found and did not differ between adolescents (10-17 years) and young adults (18-25 years). Active disease significantly predicted depressive symptoms (odds ratio (OR): 4.6 [95% confidence interval [CI]: 2.4-8.8], P < 0.001). Female gender (OR: 1.7 [95% CI: 1.1-2.7]), active disease (OR: 1.9 [95% CI: 1.1-3.2]) and a shorter disease duration (OR: 1.3 [95% CI: 0.6-1.0) (all P < 0.025) significantly predicted anxiety and/or depressive symptoms. CONCLUSIONS: Considering the high prevalence of anxiety and depressive symptoms, psychological screening is recommended in young IBD patients. Screening facilitates early recognition and psychological treatment. Female patients and patients with active disease are the most vulnerable.

Molecular basis of lactase levels in adult humans.

The molecular basis of adult human "lactase deficiency" has long been a subject of controversy. To address this issue, small intestinal biopsies from orienta, black, and white patients were analyzed. Adjacent samples were assayed for lactase and sucrase specific activities and the sucrase/lactase ratio (high ratio signifies lactase deficiency), and the results were compared to lactase steady-state mRNA levels detected in Northern blots probed with a human lactase mDNA. All oriental patients had high ratios and no detectable lactase mRNA. Four black patients had a similar pattern; two with low ratios had detectable mRNA. The group of white patients displayed a range of findings, from high ratio/no mRNA to low ratio/considerable mRNA. Elevated levels of lactase mRNA always correlated with the presence of elevated levels of lactase enzyme activity, suggesting that the difference in levels of adult human intestinal lactase activity among racial groups may be regulated at the level of gene transcription.

Pharmacogenetics of thiopurine therapy in paediatric IBD patients.

BACKGROUND: Azathioprine is widely used in the treatment of children with inflammatory bowel disease. The occurrence and type of adverse events to azathioprine may be related to thiopurine S-methyltransferase (TPMT) enzyme activity and to inosine triphophate pyrophosphatase (ITPase) deficiency. AIM: Investigate frequencies of functional TPMT polymorphisms and ITPA polymorphisms and their association with the occurrence of adverse events during azathioprine therapy in a paediatric inflammatory bowel disease population. METHODS: Seventy-two azathioprine treated paediatric inflammatory bowel disease patients, 47% girls, mean age 12.5 years (range 6.5-17.5), were assessed for TPMT and ITPA polymorphisms and for adverse events. The relation between polymorphisms and adverse events is evaluated. RESULTS: Of all azathioprine treated patients, 11 experienced an adverse event for which azathioprine was stopped: pancreatitis (n = 4), leucopenia (n = 2) and 'general malaise' (n = 5). Of the 11 patients who stopped azathioprine because of adverse events, 10 had wild-type alleles for all investigated genotypes. Genotyping of ITPA 94C>A polymorphisms showed that two patients were homozygous, both tolerated azathioprine well. CONCLUSIONS: No association of functional ITPA and TPMT polymorphisms and the occurrence of azathioprine related adverse events could be detected. Pharmacogenetic assessment prior to thiopurine therapy does not seem warranted.

Top-down Infliximab Study in Kids with Crohn's disease (TISKids): an international multicentre randomised controlled trial.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory disease predominantly affecting the gastrointestinal tract. CD usually requires lifelong medication and is accompanied by severe complications, such as fistulae and strictures, resulting in surgery. Infliximab (IFX) is very effective for treating paediatric patients with CD, but is currently only registered for therapy refractory patients-the so-called step-up strategy. We hypothesise that using IFX first-line, that is, top-down, will give more mucosal healing, fewer relapses, less complications, need for surgery and hospitalisation. METHODS AND ANALYSIS: This international multicentre open-label randomised controlled trial includes children, aged 3-17 years, with new-onset, untreated CD with moderate-to-severe disease activity (weighted Paediatric Crohn's Disease Activity Index (wPCDAI)>40). Eligible patients will be randomised to top-down or step-up treatment. Top-down treatment consists of 5 IFX infusions combined with azathioprine (AZA). After these 5 infusions, patients will continue AZA. Patients randomised to step-up will receive standard induction treatment, either oral prednisolone or exclusive enteral nutrition, combined with AZA as maintenance treatment. The primary outcome is clinical remission (wPCDAI<12.5) at 52 weeks without need for additional CD-related therapy or surgery. Total follow-up is 5 years. Secondary outcomes include clinical disease activity, mucosal healing by endoscopy (at week 10 and optionally week 52), faecal calprotectin, growth, quality of life, medication use and adverse events. ETHICS AND DISSEMINATION: Conducted according to the Declaration of Helsinki and Good Clinical Practice. Medical-ethical approval will be obtained for each site. TRIAL REGISTRATION NUMBER: NCT02517684; Pre-results.

[Transition from paediatric to adult care: management of adolescents with inflammatory bowel disease]. / Transitie van kinder- naar volwassenenzorg.

The transfer of adolescent patients with inflammatory bowel disease (IBD) to adult gastroenterology services is often troublesome. Failed transition can have adverse effects on the course of disease. We present two cases of adolescent IBD patients and their transition process. We identify requirements for successful transition and discuss potential barriers. We illustrate and emphasise that the medical teams on each side (paediatric and adult), as well as the patient and the parents should actively participate in the process of transition. The medical team should, preferably during a local transition clinic, regularly evaluate disease knowledge and self-management skills of the patient and make an individual transition plan to fill the gaps in knowledge and/or skills. Patients should be willing to learn to become more independent and parents should be stimulated to create an environment so that their child can actually try to become more independent. Lastly, we present the Rotterdam model for transition of IBD patients.

Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations.

There is a growing interest in the use of thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) for the management of inflammatory bowel disease. The genetically controlled thiopurine (S)-methyltransferase enzyme is involved in the metabolism of these agents and is hypothesised to determine the clinical response to thiopurines. Diminished activity of this enzyme decreases the methylation of thiopurines, theoretically resulting in potential overdosing, while high thiopurine (S)-methyltransferase status leads to overproduction of toxic metabolites and ineffectiveness of azathioprine and 6-mercaptopurine. In practice, controversies exist regarding the utility of standard thiopurine (S)-methyltransferase pheno- and genotyping. Current pharmacogenetic insights suggest that another enzyme system may participate in the efficacy and toxicity of thiopurines; inosine triphosphate pyrophosphatase. Other topics discussed in this review are the utilisation of therapeutic drug monitoring and the experimental use of 6-thioguanine in the treatment of inflammatory bowel disease. 6-Thioguanine has a less genetically controlled metabolism and skips genetically determined metabolic steps. On theoretical basis, 6-thioguanine might therefore have a more predictable profile than azathioprine and 6-mercaptopurine. However, the use of 6-thioguanine has been associated with an increased risk of nodular regenerative hyperplasia of the liver and veno-occlusive disease. Further research is warranted before 6-thioguanine can be considered as a treatment option for inflammatory bowel disease.

Pharmacokinetics of budesonide controlled ileal release capsules in children and adults with active Crohn's disease.

BACKGROUND: Systemic glucocorticosteroid therapy is effective in Crohn's disease, but is associated with side-effects. Budesonide has high topical anti-inflammatory activity, but considerably lower systemic activity than other oral glucocorticosteroids. AIM: To evaluate the systemic exposure to budesonide (controlled ileal release capsules) in children and adults with active Crohn's disease, and to assess the suppression of plasma cortisol. METHODS: In an open label study, patients (eight children and six adults) with active Crohn's disease received 9 mg budesonide (Entocort capsules) orally once daily for 7 days. Plasma concentrations were determined on the seventh day of administration, and pharmacokinetic parameters were calculated. For reference, 0.5 mg budesonide was given intravenously separately. Plasma cortisol levels were compared with the pre-treatment baseline values. RESULTS: Systemic exposure to budesonide (AUC0-24 h) after 1 week of oral administration was 41 +/- 21 nmol/L x h (mean +/- s.d.) in children and 35 +/- 20 nmol/L x h in adults. The estimated systemic availability in children was 9 +/- 5% and in adults 11 +/- 7%. The mean plasma cortisol (AUC0-24 h) decreased by 64 +/- 18% in children and by 50 +/- 27% in adults. CONCLUSIONS: The systemic exposure, systemic availability and cortisol suppression after oral administration of 9 mg budesonide were similar in children and adults with active Crohn's disease. Budesonide was well tolerated and no clinically important safety-related findings were identified.

[Infliximab therapy in children and adolescents with refractory Crohn's disease in the Netherlands; experience with 23 patients]. / Toepassing van infliximab bij kinderen en adolescenten met therapieresistente ziekte van Crohn in Nederland; ervaringen bij 23 patiënten.

OBJECTIVE: To describe the clinical experience of infliximab treatment in children and adolescents with refractory Crohn's disease in the Netherlands. DESIGN: Descriptive. METHOD: From November 1998 to February 2002, 23 patients (aged 7-18 years) with refractory Crohn's disease or steroid-dependent Crohn's disease (with or without severe fistulas) were treated with infliximab. Patients were treated with 1-11 infusions, with an average follow-up of 14.5 months after the start of infliximab therapy. RESULTS: Ten patients had refractory Crohn's disease. Four of these showed good long-term response on infliximab treatment (modified 'Paediatric Crohn's disease activity index' (PCDAI) < or = 10 points or growth acceleration after stunting). Twelve patients had Crohn's disease with severe fistulas. Five of these showed good long-term response (closure or non-productiveness of fistulas). One patient had metastatic Crohn's disease in the skin and showed good long-term response. CONCLUSION: Response rates were lower than observed in previous studies. Specifically, a decrease of response was demonstrated after repeated infusion. The treatment frequency should be determined by the increase in complaints rather than using a fixed interval of 8 weeks.

Treatment of inflammatory bowel disease in childhood.

Of all patients with Crohn disease and ulcerative colitis, the first presentation of inflammatory bowel disease (IBD) is at a paediatric or adolescent age in 20% to 30%, most children being prepubertal at diagnosis. It is essential to provide an accurate diagnosis in children suspected of IBD, as the initial treatment of Crohn disease and ulcerative colitis in children is not the same as it is in adults. While the role of enteral feeding in the treatment of Crohn disease in adults continues to be controversial, there is firm evidence to support the use of enteral feeding as primary therapy for Crohn disease in children. Nutrition is improved by enteral feeding, and growth and pubertal development are promoted, while the systemic toxicity of corticosteroid therapy is avoided. Supplementary nocturnal enteral nutrition (with daytime intake of normal diet) after primary therapy and remission induction may be associated with the prolongation of remission. Drug treatment in children with IBD is characterized by a lack of evidence from controlled trials.

Infant feeding and anti-tissue transglutaminase antibody concentrations in the Generation R Study.

BACKGROUND: Celiac disease (CD) has emerged as a common, but largely undiagnosed health problem. Numerous studies examined the influence of infant nutrition on the development of diagnosed CD. However, results are still inconsistent. In addition, the effect of infant feeding practices on the development of potential forms of CD might be different. OBJECTIVE: The objective was to examine whether the timing of gluten introduction and breastfeeding duration are associated with CD autoimmunity (CDA) in children at the age of 6 y. DESIGN: This study was embedded in the Generation R Study, a population-based prospective cohort study. Participants included 1679 Dutch children who were positive for human leukocyte antigen (HLA) DQ2/DQ8. Data on the timing of gluten introduction (<6 mo compared with ≥6 mo) and duration of breastfeeding (<6 mo compared with ≥6 mo) were obtained by questionnaire. Serum samples were analyzed for anti-tissue transglutaminase (anti-tTG) concentrations at age 6 y. Anti-tTG concentrations were categorized into negative (<7 U/mL) and positive (≥7 U/mL) values. Positive anti-tTG concentrations were further categorized based on ≥10 times the upper limit of normal (ULN) values of the test kit (≥7-70 and ≥70 U/mL). Multivariable logistic regression analyses were performed. RESULTS: Positive anti-tTG concentrations were found in 43 children, 26 of whom had concentrations ≥10 times the ULN (≥70 IU/mL). The introduction of gluten from the age of 6 mo onward and breastfeeding for ≥6 mo were not significantly associated with positive anti-tTG concentrations. In addition, the timing of gluten introduction and duration of breastfeeding were not significantly associated with positive anti-tTG concentrations below or above 10 times the ULN. CONCLUSIONS: Delayed introduction of gluten beyond the age of 6 mo does not increase the risk of CDA. In addition, breastfeeding for ≥6 mo does not decrease the risk of CDA in children at 6 y of age.

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease.

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.