Background & Aims: We aim to provide guidance for medical treatment of luminal Crohn's disease in children. Methods: We performed a systematic search of publication databases to identify studies of medical management of pediatric Crohn's disease. Quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. We developed statements through an iterative online platform and then finalized and voted on them. Results: The consensus includes 25 statements focused on medical treatment options. Consensus was not reached, and no recommendations were made, for 14 additional statements, largely due to lack of evidence. The group suggested corticosteroid therapies (including budesonide for mild to moderate disease). The group suggested exclusive enteral nutrition for induction therapy and biologic tumor necrosis factor antagonists for induction and maintenance therapy at diagnosis or at early stages of severe disease, and for patients failed by steroid and immunosuppressant induction therapies. The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy, corticosteroids for maintenance therapy, and cannabis in any role. The group was unable to clearly define the role of concomitant immunosuppressants during initiation therapy with a biologic agent, although thiopurine combinations are not recommended for male patients. No consensus was reached on the# 
While inflammatory bowel disease (IBD) has become a global disease, the incidence and prevalence of both pediatric-and adult-onset IBD in Canada remain among the highest worldwide. 1,2 Canadian data suggest that the incidence may have stabilized among adults, but continues to increase in children, reaching 9.68 (95% confidence interval , 9.11-10.25) per 100,000 children under age 16 years for the period 1999-2010. 2 Although the highest percentage increases in incidence were among children aged younger than 5 years at time of diagnosis, pediatric-onset IBD still develops most commonly in adolescence. 2 Crohn's disease (CD) predominates over ulcerative colitis, accounting for 65.6% of pediatric IBD based on national administrative data up until 2010, 2 and occurring in 62% of 1146 children in the Canadian Children IBD Network inception cohort study. 3 Pediatric CD encompasses a heterogeneous spectrum of phenotypic features (as recognized by the Paris modification of the Montreal classification 4 ), disease severity, and treatment responsiveness. Intestinal healing, rather than symptom control alone, has become an important therapeutic goal. 5 This may be especially important in young patients, given the potential for growth impairment as a direct effect of persistent chronic inflammation 6,7 and their long lives ahead, during which disease complications may occur. Mucosal healing became a realistic goal for patients with the advent of monoclonal antibodies directed against tumor necrosis factor (TNF)-. As alternate pathway biologic agents and new small molecule therapies emerge, it behooves clinicians to recommend treatment of pediatric CD based on critical evaluation of efficacy and safety.
Choice of treatment for active pediatric CD must always be made with a maintenance strategy in mind.
When the pediatric consensus group met in October 2017, the most recent consensus guidelines for the treatment of CD in pediatric patients were those from the European Society of Pediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organization published in April 2014, which incorporated data published until June 2013. 8 The Canadian Association of Gastroenterology (CAG) has established infrastructure for the development of consensus clinical practice guidelines, 9 but to date has focused on adult patients, including consensus guidelines for both luminal and fistulizing CD. Given the increasing prevalence of pediatric CD, the challenges specific to young patients, and the uncertainties around treatment choices, the Canadian Children IBD Network partnered with CAG to systematically review the literature relating to the medical management of luminal CD and to develop specific recommendations for pediatric patients.

# Methods

# Scope and Purpose
This guideline focuses on the medical management of luminal CD in pediatric patients, and does not specifically address the diagnostic evaluation of luminal CD, the role of surgical management, growth monitoring, social and psychological interventions, and preventative health measures, such as vaccinations. Specific questions pertaining to the medical management of luminal CD in pediatric patients Abbreviations used in this paper: were developed by the steering committee (DM, AG, EIB, JC, JD, and JM) and GRADE (Grading of Recommendation Assessment, Development, and Evaluation) experts (PM, FT).
Recommendations were developed by all members of the group at a face-to-face meeting in October 2017.

# Definitions Used in Framing Questions

# Disease activity
The categories of disease activity discussed in this guideline (mild to moderate and moderate to severe active CD) were defined in many clinical trials according to the Crohn's Disease Activity Index in studies involving adult patients or the Pediatric Crohn's Disease Activity Index in studies involving children. Therefore, in general, descriptions of activity in this document reflect Crohn's Disease Activity Index or Pediatric Crohn's Disease Activity Index scores, as described in the evidence.

# Outcomes
Clinical remission was consistently chosen as the primary outcome in the statements because of knowledge that until recently "clinical remission" (usually defined by a multi-item measure of disease activity) has been the primary end point in clinical trials assessing treatment efficacy. Evidence of efficacy of specific treatments in achieving mucosal healing is limited, therefore, "complete" or "deep" remission (clinical remission plus mucosal healing) was not the chosen primary outcome in this guideline. Mucosal healing, however, is increasingly replacing "clinical remission" as a treatment target for adults and children with IBD. 5 Such healing has been associated with sustained clinical remission and a reduced need for hospitalization and surgery.  Statements regarding the importance of evaluating mucosal healing in pediatric patients achieving clinical remission were therefore discussed, despite the limitations of existing data precluding its choice as a primary outcome.
Clinical response was defined as reduction in symptoms determined by clinically meaningful changes in a multi-item measure of disease activity, in the absence of complete resolution of symptoms.

# Sources and Searches
A systematic search of the literature relevant to the selected questions from January 2000 to June 2017 was conducted by the Editorial Office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University using MEDLINE, EMBASE, Cochrane Central, and Cochrane database of systematic reviews. Key search terms included pediatric, Crohn's, antibiotic, 5-aminosalicylate, corticosteroid, anti-tumour necrosis factor, thiopurine, methotrexate, vedolizumab, ustekinumab, and enteral nutrition. The search was limited to human studies and English publications; additional details of the search strategies utilized are provided in the Supplementary Material Appendix 1.
The consensus process was facilitated by the CAG via a web-based consensus platform (ECD Solutions, Atlanta, GA). Using this platform, the steering committee reviewed the results of initial literature searches and identified relevant references that were then "tagged" (selected and linked) to each statement. Copies of the tagged references were available to all members of the consensus group. The full consensus group voted anonymously on their level of agreement with the individual statements, using a modified Delphi process. 13,14 Participants suggested revisions and commented on the statements, after which, the specific statements were revised through 2 iterations.

# Assessment of the Quality of Evidence
Two non-voting methodologists (PM, FT) used the GRADE approach 15 to assess the strength of the evidence for each statement. The quality of evidence for each consensus statement was classified as high, moderate, low, or very low, as described in GRADE 15,16 and used in previous CAG consensus guidelines.  Randomized controlled trials (RCTs) began as high-quality evidence but could be downgraded because of heterogeneity or inconsistency of results, imprecision, indirect study findings, reporting bias, or if it was determined that a high risk of bias existed across studies supporting the statement. Data from observational studies began as low-quality evidence, but could be lowered because of the same factors, or raised if a very large treatment effect or a dose-response relationship was identified, or if all plausible biases would change the magnitude of effect toward the opposite direction. 15,16 Using the GRADE approach, it is rare to have high-quality evidence unless it fulfills all domains in terms of risk of bias, inconsistency, imprecision, indirectness, and no other bias (eg, publication bias). The evidence is always reviewed in relation to the PICO (patient population, intervention, comparator, and outcome) question. So, the trials may be high methodological quality, but if they do not address the PICO question directly in terms of populations, interventions, and outcomes, the evidence will be downgraded. In addition to an updated review of the literature, new meta-analyses were performed for this consensus.
Much of the evidence for the efficacy and safety of CD treatments was available from RCTs conducted in adult populations. In some cases, the quality of evidence was downgraded for indirectness with respect to the populations when no studies were found that evaluated the drug in children, and as such both safety and effectiveness data had to be extrapolated from adult studies. Considering the course of disease, responses to treatments and dose-response relationships may differ between pediatric and adult populations with CD and, as such, the evidence was less certain in children than in adults when only adult data were available. However, if there were studies done in children (even observational in nature) that supported the findings in adults, the evidence was not downgraded for indirectness. In some cases, when confronted by very-low-quality evidence in the absence of a compelling benefit to risk ratio, the consensus group agreed not to make a recommendation for or against a particular strategy.
Approved product labeling from government regulatory agencies varies from country to country, and although it was not ignored, recommendations were based on evidence from the literature and consensus discussion, and may not fully reflect the product labeling for a given country.

# Consensus Process
The 2-day, face-to-face consensus meeting was held in Toronto, Ontario, Canada, in October 2017. The consensus group was composed of 15 voting pediatric gastroenterologists, from Canada and the United States with expertise in multiple areas, including nutrition (SL, WE, HH, AO), growth impairment in IBD (TW, AG), microbiome (DM), clinical epidemiology, health services research and quality improvement (EB, PJ, AO, MS, MDK, WE), and patient-reported measures or patient engagement (AO, MDK). Non-voting participants included the co-chairs (AG, DM), GRADE experts (PM, FT), a representative from the adult CD CAG consensus group ( JM), nonvoting observers, and the co-moderators (PM, DS). At the consensus conference, data and the GRADE evaluations of the evidence were presented, and each individual statement was discussed and the wording finalized. Participants voted on their level of agreement for each statement. If 75% of participants voted 4 (agree) or 5 (strongly agree) on a 1-5 scale (1, 2, and 3 being disagree strongly, disagree, and uncertain, respectively), then the statement was accepted. If a statement was accepted, a second vote on the strength of the recommendation was conducted. A level of agreement of 75% of participants was needed to classify a statement as "strong" (we recommend); if this threshold was not met, the statement defaulted to "conditional" (we suggest). The strength of a recommendation considers the benefit-to-risk balance, patients' values and preferences, cost and resource allocation, and the quality of the evidence. Consequently, a recommendation could be classified as strong despite low-quality evidence, or conditional despite high-quality evidence. 22 As per the GRADE method, a strong recommendation is indicative of a more broadly applicable statement ("most patients should receive the recommended course of action"), whereas a conditional recommendation suggests clinicians should ". . . recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences. " 22 During the consensus meeting, voting members were unable to reach consensus on 14 statements (No recommendation A-N) and these statements were rejected. The evidence that was reviewed for these statements and the discussion has been summarized in the text, but the consensus group did not make a recommendation for or against these treatment strategies.
The manuscript was initially drafted by the co-chairs (DM, AG), and then reviewed and revised by the GRADE experts and members of the steering committee before being sent to the full consensus group for review. Upon approval from the group, the manuscript was made available to all CAG members for comment during a 2-week period before submission for publication.
In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months preceding the consensus meeting were provided by all participants, and made available to all group members, and CAG members reviewing the manuscript.

# Role of the Funding Sources