Background & Aims: Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. Methods: We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. Results: The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent.# 
Crohn's disease (CD) is a lifelong illness with substantial morbidity and mortality. Studies have shown that up to one-third of patients require hospitalization within the first year after diagnosis and more than half within 5 years. 1 In addition to increased risk of mortality from digestive conditions, CD is also associated with a significantly increased risk of all-cause mortality compared with the general population (standardized mortality ratio, 1.45; 95% confidence interval , 1.34-1.58). 2 Furthermore, health-related quality of life (HRQoL) is significantly lower among patients with CD compared with normal populations because of the impact of CD on physical, emotional, and social well-being. 3 The cause of CD is not well-defined, which makes it challenging to develop specific targeted treatments, but a number of treatments have demonstrated efficacy in CD. In the last decade, treatment paradigms have changed, recognizing that certain clinical parameters carry an increased risk of progressive and disabling disease. In addition, as the association between mucosal healing and improved short-term and long-term outcomes has been increasingly recognized, 4,5 this is becoming an important treatment goal. 6 Evidence suggests that initiation of highly effective therapies can lead to symptomatic improvement and mucosal healing. For this reason the present consensus statements generally recommend that management strategies strive for complete remission, which is defined as both symptomatic and endoscopic remission. However, it is recognized that the outcome assessed in most randomized controlled trials (RCTs) has been either symptomatic remission or symptomatic response, with only more contemporary clinical trials including endoscopic outcomes. Therefore, in many cases the quality of evidence (QoE) according to Grading of Recommendation Assessment, Development and Evaluation (GRADE) methodology associated with the consensus statements had to be downgraded.
In addition, the consensus group recognized that because of the substantial impact of CD on patient daily life and HRQoL, it is imperative to consider the patient's perspective when making treatment decisions. In many instances, factors that influence patient decisions relating to therapy choice and goals of therapy are not the same as those of the treating clinician. 7,8 This is the reality of clinical practice, and it is important to keep this in mind when making therapeutic decisions.
At the time the literature searches were conducted for the present consensus (April 2016) and at the time the consensus group met (September 2016), the most recent clinical practice guideline on the treatment of CD was the second European evidence-based consensus from the European Crohn's and Colitis Organisation (ECCO), which incorporated data published until 2008. 9 Subsequently, the third European evidence-based consensus from the ECCO was published online in November Abbreviations used in this paper: CAG 10 However, there are differences between the present consensus guidelines and the ECCO consensus with respect to the methods for grading the level of evidence, the conclusions reached, the recommendations made, and the presentation of the discussions. As such, both guidelines are likely to be relevant to clinicians and their patients when managing CD. The purpose of these consensus statements is to review the literature relating to the medical management of luminal CD and to develop specific statements regarding the various therapies available for ambulatory patients with mild to severe active disease. Furthermore, we offer practical guidance for the practicing clinician given the evidence.

# METHODS

# Scope and Purpose
These consensus statements focused on specific questions, identified and discussed by the participants, regarding the management of luminal CD in adults. Statements on the management of fistulizing CD were also developed and were presented in a separate publication. The development of this clinical practice guideline began in September 2015, with the full consensus group participating in a face-to-face meeting in September 2016. The entire process spanned approximately 22 months, and the final manuscript was submitted for publication in July 2017 and revised after review.

# Sources and Searches
The Editorial Office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University performed a systematic literature search of MEDLINE (1946 on), EMBASE (1980 on), and CENTRAL (Cochrane Central Register of Controlled Trials) for trials published through February-April 2016. Key search terms included Crohn, antibiotic, 5-aminosalicylate, corticosteroid, anti-tumor necrosis factor, thiopurine, methotrexate, vedolizumab, ustekinumab, probiotics, omega-3 fatty acid, naltrexone, and enteral nutrition. Only human studies published in English were considered; further details regarding the search strategies used for preparing the initial consensus statements can be found in Supplementary Appendix 1. Additional focused (but non-systematic) searches were also performed up to the September 2016 consensus meeting.

# Review and Grading of Evidence
Two non-voting methodologists (G.L., P.M.) used the GRADE approach 11 to assess the risk of bias (of individual studies and overall across studies), indirectness, inconsistency, imprecision, as well as other considerations (including publication bias) to determine the overall quality of evidence for each statement. The quality of evidence for each statement was graded as high, moderate, low, or very low, as described in GRADE 11,12 and used in prior Canadian Association of Gastroenterology (CAG) consensus documents.  The evidence was derived mainly from published systematic reviews and meta-analyses of RCTs. When network meta-analyses (NMAs) were available, the evidence was derived mainly from direct comparison estimates, whereas the indirect and mixed comparisons provided supportive evidence (but could not override direct evidence in case of discrepancies). When needed, we conducted our own updated analyses or subgroup analyses. When no RCT data were available, we extracted evidence from observational studies. GRADE assessments were reviewed and agreed on by voting members of the consensus group at the meeting. The finalized GRADE assessments (risk of bias assessment of included studies and evidence profiles, with revisions done at the meeting) are shown in Supplementary Appendix 2.
One statement (statement 1) was determined to meet the criteria for a "good practice statement" 17 ; the consensus group believed the recommendation was clinically obvious, and therefore the collection and GRADE analysis of supporting evidence were deemed to be unnecessary. Although formal GRADE evaluation of the supporting evidence was not performed, information is provided in the text for this statement.
Approved product labeling from government regulatory agencies varies from country to country, and although not ignored, recommendations are based on evidence from the literature and consensus discussion and may not fully reflect the product labeling for a given country.

# Consensus Process
The consensus group was composed of 20 voting participants with expertise in the management of CD, including the chairs (R.P., A.H.S.), academic and community gastroenterologists, as well as a nurse practitioner specializing in inflammatory bowel disease (IBD). Nonvoting participants included a patient representative, non-voting observers, the GRADE experts (G.L., PM), and a moderator ( J.M.).
The CAG used a web-based platform (ECD Solutions, Atlanta, GA) to aid in the consensus process before the 2-day face-to-face consensus meeting held in Toronto, Ontario, Canada in September 2016. The steering committee (R.P., A.H.S., B.B., R.K., J.K.M., L.T.) and one of the nonvoting methodologists (G.L.) developed the initial statements. Using the consensus web-based 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. All participants then used the web-based platform and a modified Delphi process 18,19 to vote anonymously on their level of agreement with the statements, suggest revisions, and provide comments. The statements were revised through 2 separate iterations and finalized at the consensus meeting. All participants had access to all abstracts and electronic copies of the individual "tagged" references. The GRADE evaluations of the evidence for each statement were provided at the meeting.
At the consensus conference, participants presented data, reviewed GRADE evaluations of the evidence for the individual statements, and discussed the phrasing of specific statements before their subsequent finalization. Participants then indicated their level of agreement for each statement by voting. A statement was accepted if >75% of participants voted 4 (agree) or 5 (strongly agree) on a scale of 1-5 (with 1, 2, and 3 indicating disagree strongly, disagree, and uncertain, respectively). After acceptance of a statement, participants voted on the "strength" of the recommendation. 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 the recommendation considered risk-benefit balance, patients' values and preferences, cost and resource allocation, and the quality of the evidence. Therefore, it was possible for a recommendation to be classified as strong despite having low-quality evidence or conditional despite the existence of high-quality evidence. 20 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 that 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". 20 In many cases the outcomes of clinical trials were assessed symptomatically without endoscopy; therefore, the QoE was often downgraded for indirect outcomes, resulting in a low or very low QoE, making it difficult to approve strong recommendations in many cases.
At the meeting, the group was unable to reach consensus on 5 of the initial statements (No recommendation A-E); thus, these statements were rejected. In addition, because of the absence of evidence the group decided not to vote on 2 statements (No recommendation F and G) regarding strategies in patients who had failed non-tumor necrosis factor (TNF) targeted biologic therapies, electing to discuss this issue in the "Future Directions" section.
The manuscript was initially drafted by the co-chairs (R.P., A.H.S.), after which it was then reviewed and revised by steering committee members before being disseminated to the remaining members of the consensus group for review and approval. As per CAG policy for all clinical practice guidelines, the manuscript was made available to all CAG members for commenting before submission for publication. Members were notified that the manuscript was available on the members-only section of the CAG website and open for comment for a 2-week period.
In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants and made available to all group members.

# Role of the Funding Sources