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Clinical Practice Guidelines for the Medical Management of Nonhospitalized Ulcerative Colitis: The Toronto Consensus

      Background & Aims

      The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC.

      Methods

      A systematic literature search identified studies on the management of UC. 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 working group of specialists.

      Results

      The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti–tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes.

      Conclusions

      Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.

      Keywords

      Abbreviations used in this paper:

      ADA (antidrug antibodies), CAG (Canadian Association of Gastroenterology), CI (confidence interval), FMT (fecal microbial transplant), GRADE (Grading of Recommendation Assessment, Development and Evaluation), IBD (inflammatory bowel disease), MMX (multi-matrix), NS (not significant), OR (odds ratio), RCT (randomized controlled trial), RR (relative risk), TNF (tumor necrosis factor), TPMT (thiopurine methyltransferase), UC (ulcerative colitis)
      See commentary on page 877.
      A substantial burden of illness is attributable to inflammatory bowel disease (IBD)—ulcerative colitis (UC) and Crohn’s disease—due to the high prevalence and high per-patient costs of these chronic disorders.
      • Rocchi A.
      • Benchimol E.I.
      • Bernstein C.N.
      • et al.
      Inflammatory bowel disease: a Canadian burden of illness review.
      The incidence and prevalence of IBD are highest in Western nations, including Canada, the United States, and Europe.
      • Molodecky N.A.
      • Soon I.S.
      • Rabi D.M.
      • et al.
      Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.
      There are approximately 104,000 Canadians living with UC and ∼10,200 incident cases each year (2012 estimates).
      • Rocchi A.
      • Benchimol E.I.
      • Bernstein C.N.
      • et al.
      Inflammatory bowel disease: a Canadian burden of illness review.
      In the United States, the prevalence of UC in adults was estimated at 593,000 cases (2009 estimates).
      • Kappelman M.D.
      • Moore K.R.
      • Allen J.K.
      • et al.
      Recent trends in the prevalence of Crohn's disease and ulcerative colitis in a commercially insured US population.
      In Canada, the total annual cost of IBD was C$2.8 billion (C$1.2 billion in direct costs and C$1.6 billion in indirect costs), corresponding to approximately C$12,000 per year for each patient with IBD (2008 estimates).
      • Rocchi A.
      • Benchimol E.I.
      • Bernstein C.N.
      • et al.
      Inflammatory bowel disease: a Canadian burden of illness review.
      In the United States, direct medical costs alone are more than $4 billion annually (2004 estimates).
      • Nguyen G.C.
      • Tuskey A.
      • Dassopoulos T.
      • et al.
      Rising hospitalization rates for inflammatory bowel disease in the United States between 1998 and 2004.
      • Kappelman M.D.
      • Rifas-Shiman S.L.
      • Porter C.Q.
      • et al.
      Direct health care costs of Crohn's disease and ulcerative colitis in US children and adults.
      Furthermore, the personal impact of these disorders includes painful and bothersome symptoms, anxiety regarding the future, and functional impairment.
      • Rocchi A.
      • Benchimol E.I.
      • Bernstein C.N.
      • et al.
      Inflammatory bowel disease: a Canadian burden of illness review.
      All of these factors are important determinants of health-related quality of life.
      In a 2011 survey of Canadian gastroenterologists, topics relevant to IBD were among the most desired educational areas.
      • Render C.
      • Daniels S.
      2011 Canadian Association of Gastroenterology educational needs assessment report.
      Four of the top 6 topics were linked to IBD, including difficult cases, therapeutics, pathogenesis and genetics, and nutrition. The management of IBD is complicated by an unpredictable and chronic course, inadequate or delayed access to drug therapies, and a lack of support for patients and caregivers.
      • Rocchi A.
      • Benchimol E.I.
      • Bernstein C.N.
      • et al.
      Inflammatory bowel disease: a Canadian burden of illness review.
      The most recent clinical practice guidelines for the medical treatment of ambulatory patients with UC are the second European evidence-based consensus, which incorporates data published until 2012.
      • Dignass A.
      • Lindsay J.O.
      • Sturm A.
      • et al.
      Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management.
      • Dignass A.
      • Eliakim R.
      • Magro F.
      • et al.
      Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis.
      Since that time, therapy has evolved with the approval of new agents (eg, budesonide multi-matrix [MMX], adalimumab, golimumab, and vedolizumab) and a better understanding of strategies to optimize anti–tumor necrosis factor (TNF) therapy (eg, measuring anti-TNF trough levels and antibodies). Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient.
      • Bitton A.
      • Buie D.
      • Enns R.
      • et al.
      Treatment of hospitalized adult patients with severe ulcerative colitis: Toronto consensus statements.
      The purpose of these consensus statements is to review the literature relating to the medical management of UC and to develop specific recommendations for ambulatory patients with mild to severe active UC.

      Methods

       Scope and Purpose

      Specific questions regarding therapy were identified and addressed by the participants, aided by evidence derived from review of the literature on UC. The process for guideline development is outlined in Figure 1. The process took approximately 1 year, with the first meeting of the steering committee in November 2013, the meeting of the full consensus group in June 2014, and submission of the manuscript for publication in November 2014.

       Sources and Searches

      The editorial office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University conducted a systematic literature search of MEDLINE (1946 on), EMBASE (1980 on), and CENTRAL (Cochrane Central Register of Controlled Trials) up to February 2014. Key search terms were ulcerative colitis, 5-aminosalicylate, corticosteroid, anti–tumor necrosis factor, thiopurine, methotrexate, vedolizumab, and probiotics. The search was limited to human studies and the English language. The MEDLINE, EMBASE, and CENTRAL search strategies used are detailed further in Supplementary Appendix 1. Supplemental manual searches of these databases were performed up to June 2014.

       Review and Grading of Evidence

      The quality of evidence was assessed according to the GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      and determined by 2 methodologists (Dr Grigorios Leontiadis and Dr Francis Tse) who did not vote on the statements. The methodologists determined the risk of bias within individual studies, the risk of bias across studies, and the overall quality of evidence across the identified studies for each statement. The voting members of the consensus group then reviewed and agreed on the GRADE assessments at the meeting.
      The quality of evidence for each consensus statement was classified as high, moderate, low, or very low. Evidence from randomized controlled trials (RCTs) was initially classified as high quality but could be downgraded for the following reasons: heterogeneity among outcomes of individual studies, ambiguity in results, indirect study findings, reporting bias, or if it was determined a high risk of bias existed across studies supporting the statement. Data from cohort studies or case-control findings were initially categorized as low-quality evidence; however, the rating could be lowered as a result of the same criteria applied to RCTs, or raised if a very large treatment effect or a dose-response relationship was identified or if all plausible biases would tend to change the magnitude of effect toward the opposite direction.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      Approved product labeling from government regulatory agencies varies from country to country, and while 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 included 23 voting participants, including academic and community gastroenterologists with expertise in various aspects of UC management, a pharmacist, and a nonvoting facilitator (Dr Paul Moayyedi).
      Working subgroups and the meeting cochairs (Dr Brian Bressler and Dr John K. Marshall) developed initial statements. A web-based consensus platform (ECD Marketing Solutions, Atlanta, GA) supported by the Canadian Association of Gastroenterology (CAG) was used to facilitate most aspects of the consensus process before the final face-to-face meeting. Via the consensus platform, the working groups (1) reviewed the results of initial literature searches and identified relevant references that were then “tagged” (selected and linked) to each statement, (2) used a modified Delphi process
      • Dalkey N.
      An experimental study of group opinion: the Delphi method.
      • Cook D.J.
      • Greengold N.L.
      • Ellrodt A.G.
      • et al.
      The relation between systematic reviews and practice guidelines.
      to vote anonymously on their level of agreement with the statements, (3) suggested revisions to statements, and (4) provided comments on specific references and background data. 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.
      The group held a 2-day consensus conference in Toronto, Ontario, Canada, in June 2014, at which data were presented, the wording of the statements was discussed and finalized, and participants voted on their level of agreement with each statement. A statement was accepted if >75% of participants voted 4 (agree) or 5 (strongly agree) on a scale of 1 to 5 (with 1, 2, and 3 indicating disagree strongly, disagree, and uncertain, respectively). The strength of each recommendation was assigned by the consensus group, per the GRADE system, as strong (“we recommend…”) or weak (“we suggest…”). The strength of recommendations is composed of 4 components (risk/benefit balance, patients’ values and preferences, cost and resource allocation, and quality of evidence). Therefore, it is possible for a recommendation to be classified as strong despite having low-quality evidence to support it or as weak despite the existence of high-quality evidence to support it.
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      Going from evidence to recommendations.
      Based on the GRADE approach, a strong recommendation indicates the statement should be applied in most cases, whereas a weak recommendation signifies 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.”
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      Going from evidence to recommendations.
      The manuscript was initially drafted by Drs Bressler and Marshall and then reviewed and revised by members of the steering committee before being circulated to all participants for review and approval. Written disclosures of potential conflicts of interest for the 24-month period preceding the consensus meeting were completed and submitted in accordance with CAG policies and were subsequently available to all members of the consensus group.

       Role of the Funding Sources

      The consensus meeting was funded by unrestricted grants to the CAG from AbbVie Canada, Actavis Specialty Pharmaceuticals, Janssen Inc, Shire Pharma Canada ULC, Takeda Canada, and the Canadian Institutes of Health Research. The CAG administered all aspects of the meeting, and the funding sources had no role in drafting or approving these guidelines.

      Definitions of UC

      Before finalizing the individual statements for the management of UC, the consensus group first discussed and agreed on definitions of terminology that were then used throughout the consensus process. Definitions were presented by a member of the steering committee (C.N.B.), discussed and revised, and then agreed on by the group without a formal vote.

       Disease Extent

      The extent of endoscopic disease was categorized as (1) proctitis (distal to the rectosigmoid junction or within 18 cm of the anal verge), (2) left-sided colitis (extending anywhere from the sigmoid to the splenic flexure), or (3) extensive colitis (extending beyond the splenic flexure).
      • Satsangi J.
      • Silverberg M.S.
      • Vermeire S.
      • et al.
      The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications.

       Disease Activity

      Although the participants concluded that disease activity is best determined by clinical symptoms and an objective assessment of disease activity through endoscopy, they also recognized that, for pragmatic reasons, it is often necessary to make clinical decisions based on symptoms alone. For the purposes of these guidelines, disease activity reflects symptomatic assessment unless otherwise stated. Specific categories of disease activity were defined as mild, moderate, and severe active disease.
      The consensus group recommended that, ideally, a formal scoring tool such as the Mayo score or a similar disease activity score should be used to determine disease activity in patients with UC. The Mayo score includes 4 measures: stool frequency, rectal bleeding, endoscopic findings, and the physician’s global assessment (Supplementary Appendix 2).
      • Schroeder K.W.
      • Tremaine W.J.
      • Ilstrup D.M.
      Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.
      Unless otherwise specified, references to mild, moderate, and severe disease activity in this document refer to those disease strata as defined by Mayo score. Although such a scoring system is desirable for accurate and consistent assessment of disease activity, it is often necessary to make management decisions in the absence of endoscopic information while considering the subjective aspects of disease presentation not captured by the full Mayo score. In such circumstances, the partial Mayo score (which omits the endoscopic subscore) can be informative.

       Remission and Response

      Terminology and definitions used in this guideline are shown in Table 1. Complete remission, including both symptomatic and endoscopic remission, is the preferred outcome. Complete remission requires endoscopy to document mucosal healing. Although this cannot be conducted at every assessment, the consensus group recommended performance of endoscopy when making important management decisions, such as assessing efficacy at the end of induction therapy or considering a change in therapy due to loss of response. Mucosal healing is an important predictor of long-term outcomes of treatment for UC. Patients who achieve mucosal healing (generally defined as a Mayo endoscopic subscore of 0 or 1) have lower rates of hospitalization, decreased need for corticosteroids, and lower rates of colectomy.
      • Ardizzone S.
      • Cassinotti A.
      • Duca P.
      • et al.
      Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis.
      • Laharie D.
      • Filippi J.
      • Roblin X.
      • et al.
      Impact of mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab: a multicenter experience.
      • Colombel J.F.
      • Rutgeerts P.
      • Reinisch W.
      • et al.
      Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.
      Table 1Defining Remission and Response in Patients With UC
      Complete remissionBoth symptomatic remission and endoscopic healing as defined below
      Endoscopic healingNormal mucosa, vascular blurring, or chronic changes (eg, inflammatory polyps, scarring) without friability
      Symptomatic remissionNormal stool frequency (≤3/day) and no blood in the stool
      Symptomatic responseMeaningful improvement in symptoms as judged by both the patient and physician in the absence of remission; response should not be considered a desirable final outcome but is useful to assess early response to treatment
      However, it should be recognized that escalation of therapy to treat patients who are asymptomatic but have endoscopically active disease remains controversial. Similarly, the management of histological disease activity with macroscopic endoscopic remission is also unclear.
      • D'Haens G.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.
      In lieu of full endoscopic assessment, objective measures of inflammation may be useful when evaluating disease activity. Fecal calprotectin levels have been shown to correlate with endoscopic disease activity better than either symptoms or systemic inflammatory markers such as C-reactive protein.
      • Schoepfer A.M.
      • Beglinger C.
      • Straumann A.
      • et al.
      Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes.

       Risk Profile

      Individual patients may present with similar disease activity but differ in their risk profile for adverse outcomes; this concept should be considered when making therapeutic decisions. Risk factors for colectomy include more extensive colitis,
      • Solberg I.C.
      • Lygren I.
      • Jahnsen J.
      • et al.
      Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study).
      flares requiring hospitalization,
      • Ananthakrishnan A.N.
      • Issa M.
      • Beaulieu D.B.
      • et al.
      History of medical hospitalization predicts future need for colectomy in patients with ulcerative colitis.
      • Langholz E.
      • Munkholm P.
      • Davidsen M.
      • et al.
      Changes in extent of ulcerative colitis: a study on the course and prognostic factors.
      and elevated levels of acute phase reactants, such as a high erythrocyte sedimentation rate
      • Solberg I.C.
      • Lygren I.
      • Jahnsen J.
      • et al.
      Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study).
      or high concentration of C-reactive protein.
      • Henriksen M.
      • Jahnsen J.
      • Lygren I.
      • et al.
      C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study.
      • Turner D.
      • Walsh C.M.
      • Steinhart A.H.
      • et al.
      Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression.
      Older age has been associated with a lower risk of relapse or disease progression
      • Langholz E.
      • Munkholm P.
      • Davidsen M.
      • et al.
      Changes in extent of ulcerative colitis: a study on the course and prognostic factors.
      • Hoie O.
      • Wolters F.
      • Riis L.
      • et al.
      Ulcerative colitis: patient characteristics may predict 10-yr disease recurrence in a European-wide population-based cohort.
      and colectomy.
      • Solberg I.C.
      • Lygren I.
      • Jahnsen J.
      • et al.
      Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study).
      Patients who require corticosteroid therapy are at higher risk for both relapse
      • Ardizzone S.
      • Petrillo M.
      • Molteni P.
      • et al.
      Coated oral 5-aminosalicylic acid (Claversal) is equivalent to sulfasalazine for remission maintenance in ulcerative colitis. A double-blind study.
      • Fockens P.
      • Mulder C.J.
      • Tytgat G.N.
      • et al.
      Comparison of the efficacy and safety of 1.5 compared with 3.0 g oral slow-release mesalazine (Pentasa) in the maintenance treatment of ulcerative colitis. Dutch Pentasa Study Group.
      and colectomy.
      • Faubion Jr., W.A.
      • Loftus Jr., E.V.
      • Harmsen W.S.
      • et al.
      The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.

       Disease Impact

      The overall impact of disease (“severity”) has not typically been defined or captured in clinical trials. The consensus group believed it is important for clinicians to consider more than symptoms when managing UC and proposed a more holistic approach to assessing the impact of UC on patients’ lives (Table 2). Disease impact can help inform a physician’s global assessment, which is a component of the Mayo score and other disease activity scoring tools.
      Table 2Factors to Consider in a Comprehensive Assessment of Disease Impact
      High disease activity (in acute setting)
      Frequency of hospitalization
      Need for surgery
      Inability to work or participate in leisure activities
      Failure to respond to medication

       Use of Corticosteroids

      Based on clinical experience and various definitions used in clinical trials of UC, the consensus group defined “corticosteroid resistance” as a lack of a symptomatic response despite a course of oral prednisone of 40 to 60 mg/day (or equivalent)
      • Turner D.
      • Walsh C.M.
      • Steinhart A.H.
      • et al.
      Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression.
      for a minimum of 14 days. “Corticosteroid dependence” was defined as the inability to withdraw (within 3 months of initiation) oral corticosteroid therapy without recurrence of symptoms, a symptomatic relapse within 3 months of stopping corticosteroid therapy, or the need for 2 or more courses of corticosteroid therapy within 1 year.

       Treatment Failure

      Definitions of treatment failure are shown in Table 3. Before determining treatment failure, clinicians should rule out other causes of symptoms, such as malignancy, irritable bowel syndrome, bleeding hemorrhoids, dietary intolerance, drug toxicity, or enteric infection (eg, Clostridium difficile or cytomegalovirus), as the circumstances warrant.
      • Dignass A.
      • Lindsay J.O.
      • Sturm A.
      • et al.
      Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management.
      Table 3Definitions of Treatment Failure
      5-ASA failureInability of the patient to achieve and maintain complete corticosteroid-free remission despite optimal treatment with oral, rectal, or combination 5-ASA therapy
      Thiopurine failureInability of the patient to maintain corticosteroid-free complete remission despite dose optimization
      Biologic failurePrimary failure: Inability of the patient to achieve corticosteroid-free complete remission despite dose optimization

      Secondary failure: Inability of the patient to maintain corticosteroid-free complete remission after achieving a symptomatic response

      Recommendation Statements

      The individual recommendation statements are provided and include the “GRADE” of supporting evidence and the voting results, after which a discussion of the evidence considered for the specific statement is presented. A summary of the recommendation statements is provided in Table 4.
      Table 4Summary of Consensus Recommendations for the Medical Management of UC
      Statements regarding 5-ASA
      • 1. In patients with mild to moderate active ulcerative proctitis, we recommend rectal 5-ASA, at a dosage of 1 g daily, as first-line therapy to induce symptomatic remission. GRADE: Strong recommendation, high-quality evidence.
      • 2. In patients with mild to moderate active left-sided UC, we recommend 5-ASA enemas, at a dosage of at least 1 g daily, as an alternative first-line therapy to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence.
      • 3. In patients with mild to moderate active UC of any disease extent beyond proctitis, we recommend an oral 5-ASA preparation, at dosages between 2.0 and 4.8 g/day, as an alternative first-line therapy to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence.
      • 4. In patients with mild to moderate active UC of any disease extent beyond proctitis, we suggest the combination of a rectal and an oral 5-ASA preparation over oral 5-ASA alone as an alternative first-line therapy to induce complete remission. GRADE: Weak recommendation, low-quality evidence.
      • 5. We recommend that patients with UC be evaluated for lack of symptomatic response to oral/rectal 5-ASA induction therapy in 4 to 8 weeks to determine the need to modify therapy. GRADE: Strong recommendation, very low-quality evidence.
      • 6. In patients with oral or rectal 5-ASA–induced complete remission of mild to moderate active left-sided UC or proctitis, we recommend the same therapy be continued to maintain complete remission. GRADE: Strong recommendation, moderate-quality evidence.
      • 7. In patients with oral 5-ASA–induced complete remission of mild to moderate active UC of any disease extent, we recommend continued oral therapy of at least 2 g/day to maintain complete remission. GRADE: Strong recommendation, moderate-quality evidence.
      • 8. In selected 5-ASA–naive patients with UC who have achieved symptomatic remission on oral corticosteroids, we suggest an oral 5-ASA preparation of at least 2 g/day while being assessed for corticosteroid-free complete remission. GRADE: Weak recommendation, very low-quality evidence.
      • 9. In patients with UC who have failed to respond to oral 5-ASA, we recommend against switching to another oral 5-ASA formulation to induce remission. GRADE: Strong recommendation, low-quality evidence.
      • 10. When using oral 5-ASA to induce or maintain complete remission of UC, we suggest once-daily over more frequent dosing. GRADE: Weak recommendation, moderate-quality evidence.
      Statements regarding corticosteroids
      • 11. In patients with moderate to severe active UC, we recommend oral corticosteroids as first-line therapy to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence.
      • 12. In patients with mild to moderate active UC who fail to respond to 5-ASA therapy, we recommend oral corticosteroids as second-line therapy to induce complete remission. GRADE: Strong recommendation, low-quality evidence.
      • 13. In patients with mild to moderate active left-sided UC or proctitis who fail to respond to rectal 5-ASA therapy, we suggest rectal corticosteroids as second-line therapy to induce complete remission. GRADE: Weak recommendation, overall very low-quality evidence.
      • 14. In patients with UC, we recommend against the use of oral corticosteroids to maintain complete remission because they are ineffective for this indication and their prolonged use is associated with significant adverse effects. GRADE: Strong recommendation, moderate-quality evidence.
      • 15. In patients with mild to moderate UC of any disease extent, we suggest oral budesonide MMX as an alternative first-line therapy to induce complete remission. GRADE: Weak recommendation, high-quality evidence.
      • 16. We recommend that patients with UC be evaluated for lack of symptomatic response to corticosteroid induction therapy within 2 weeks to determine the need to modify therapy. GRADE: Strong recommendation, very low-quality evidence.
      Statements regarding immunosuppressants
      • 17. In patients with UC, we recommend against the use of thiopurine monotherapy to induce complete remission. GRADE: Strong recommendation, low-quality evidence.
      • 18. In selected patients with UC who have achieved symptomatic remission on oral corticosteroids, we suggest thiopurine monotherapy as an option to maintain complete corticosteroid-free remission. GRADE: Weak recommendation, low-quality evidence.
      • 19. In patients with UC, we recommend against the use of methotrexate monotherapy to induce or maintain complete remission. GRADE: Strong recommendation, low-quality evidence for induction and very low-quality evidence for maintenance.
      Statements regarding anti-TNF therapy
      • 20. In patients with UC who fail to respond to thiopurines or corticosteroids, we recommend anti-TNF therapy to induce complete corticosteroid-free remission. GRADE: Strong recommendation, high-quality evidence.
      • 21. When starting anti-TNF therapy, we recommend it be combined with a thiopurine or methotrexate rather than used as monotherapy to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence for azathioprine and very low-quality evidence for methotrexate.
      • 22. In patients with UC who are corticosteroid dependent, we recommend anti-TNF therapy to induce and maintain complete corticosteroid-free remission. GRADE: Strong recommendation, very low-quality evidence.
      • 23. We recommend that patients with UC be evaluated for lack of symptomatic response to anti-TNF induction therapy in 8 to 12 weeks to determine the need to modify therapy. GRADE: Strong recommendation, low-quality evidence.
      • 24. In patients with UC who respond to anti-TNF induction therapy, we recommend continued anti-TNF therapy to maintain complete remission. GRADE: Strong recommendation, very low-quality evidence for infliximab and adalimumab and high-quality evidence for golimumab.
      • 25. In patients with UC who have a suboptimal response to anti-TNF induction therapy, we recommend dose intensification to achieve complete remission. GRADE: Strong recommendation, very low-quality evidence.
      • 26. In patients with UC who lose response to anti-TNF maintenance therapy, we recommend optimizing dose to recapture complete remission. GRADE: Strong recommendation, very low-quality evidence.
      • 27. We recommend that dose optimization for patients with UC be informed by therapeutic drug monitoring. GRADE: Strong recommendation, low-quality evidence.
      Statements regarding other agents
      • 28. In patients with primary failure to an anti-TNF therapy, we recommend switching to vedolizumab over switching to another anti-TNF therapy to induce complete corticosteroid-free remission. GRADE: Strong recommendation, very low-quality evidence.
      • 29. In patients with secondary failure to an anti-TNF therapy, we recommend switching to another anti-TNF therapy or vedolizumab based on therapeutic drug monitoring results to induce complete corticosteroid-free remission. GRADE: Strong recommendation, very low-quality evidence.
      • 30. In patients with moderate to severe active UC who fail to respond to corticosteroids, thiopurines, or anti-TNF therapies, we recommend vedolizumab to induce complete corticosteroid-free remission. GRADE: Strong recommendation, moderate-quality evidence.
      • 31. We recommend that patients with UC be evaluated for lack of symptomatic response to vedolizumab induction therapy in 8 to 14 weeks to determine the need to modify therapy. GRADE: Strong recommendation, very low-quality evidence.
      • 32. In patients with UC who respond to vedolizumab, we recommend continued vedolizumab therapy to maintain complete corticosteroid-free remission. GRADE: Strong recommendation, moderate-quality evidence.
      • 33. In patients with UC, we recommend against fecal microbial transplant to induce or maintain complete remission outside the setting of a clinical trial. GRADE: Strong recommendation, low-quality evidence.
      • 34. In patients with UC, we recommend against probiotics to induce or maintain complete remission outside the setting of a clinical trial. GRADE: Strong recommendation, very low-quality evidence.
      NOTE. The strength of each recommendation was assigned by the consensus group, per the GRADE system, as strong (“we recommend…”) or weak (“we suggest…”). A recommendation could be classified as strong despite low-quality evidence to support it or as weak despite the existence of high-quality evidence due to the 4 components that are considered in each recommendation (risk/benefit balance, patients’ values and preferences, cost and resource allocation, and quality of evidence).

       Statements Regarding 5-Aminosalicylates

       Statement 1. In patients with mild to moderate active ulcerative proctitis, we recommend rectal 5-aminosalicylate (5-ASA), at a dosage of 1 g daily, as first-line therapy to induce symptomatic remission

      GRADE: Strong recommendation, high-quality evidence. Vote: strongly agree, 57%; agree, 30%; uncertain, 9%; disagree, 4%.

       Statement 2. In patients with mild to moderate active left-sided UC, we recommend 5-ASA enemas, at a dosage of at least 1 g daily, as an alternative first-line therapy to induce complete remission

      GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 52%; agree, 48%.
      Meta-analyses have shown the efficacy of rectally administered 5-ASA as induction therapy in patients with mild to moderate active ulcerative proctitis or left-sided UC.
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      • Ford A.C.
      • Khan K.J.
      • Achkar J.P.
      • et al.
      Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis.
      • Marshall J.K.
      • Irvine E.J.
      Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis.
      • Marshall J.K.
      • Irvine E.J.
      Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative colitis.
      • Bergman R.
      • Parkes M.
      Systematic review: the use of mesalazine in inflammatory bowel disease.
      • Cohen R.D.
      • Woseth D.M.
      • Thisted R.A.
      • et al.
      A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis.
      • Manguso F.
      • Balzano A.
      Meta-analysis: the efficacy of rectal beclomethasone dipropionate vs. 5-aminosalicylic acid in mild to moderate distal ulcerative colitis.
      A meta-analysis of 38 studies in patients with mild to moderate active UC included 10 studies of rectal 5-ASA versus placebo.
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      Rectal 5-ASA was superior to placebo, with a pooled odds ratio (OR) for symptomatic remission of 8.30 (8 trials; 95% confidence interval [CI], 4.28–16.12; P < .00001) and for endoscopic remission of 5.31 (7 trials; 95% CI, 3.15–8.92; P < .00001). Rectal 5-ASA was also superior to rectal corticosteroids for inducing symptomatic remission, with a pooled OR of 1.65 (6 trials; 95% CI, 1.11–2.45; P = .01). In these RCTs, 5-ASA was delivered as liquid, gel, or foam enemas or suppositories in doses ranging from 1 to 4 g, with no difference in treatment response according to dose or formulation. Meta-analyses of 4 studies of rectal 5-ASA compared with oral 5-ASA have not shown superiority for symptomatic improvement (pooled OR, 2.25; 95% CI, 0.53–9.54; P = .27)
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      or relative risk (RR) of no remission (0.82; 95% CI, 0.52–1.28).
      • Ford A.C.
      • Khan K.J.
      • Achkar J.P.
      • et al.
      Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis.
      Three trials included in the meta-analysis by Marshall et al (2010) enrolled only patients with proctitis, but rectal 5-ASA appeared to be effective in both proctitis and left-sided disease.
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      One trial reported that rectal 5-ASA was more effective than oral 5-ASA alone for proctitis.
      • Gionchetti P.
      • Rizzello F.
      • Venturi A.
      • et al.
      Comparison of oral with rectal mesalazine in the treatment of ulcerative proctitis.
      One additional RCT published after the meta-analysis evaluated 5-ASA suppositories according to disease extent.
      • Watanabe M.
      • Nishino H.
      • Sameshima Y.
      • et al.
      Randomised clinical trial: evaluation of the efficacy of mesalazine (mesalamine) suppositories in patients with ulcerative colitis and active rectal inflammation—a placebo-controlled study.
      For proctitis, the endoscopic remission rates after 4 weeks were 83.8% and 36.1% in the 5-ASA and placebo suppository groups, respectively, and for all other types of UC were 78.6% and 21.4%, respectively (P < .0001 for both subgroups). The consensus group concluded that rectal 5-ASA (any formulation) is an effective therapy for both proctitis and proctosigmoiditis.
      Complete remission should be the goal of therapy in most patients. However, because the natural history of proctitis includes a low risk of colectomy
      • Langholz E.
      • Munkholm P.
      • Davidsen M.
      • et al.
      Changes in extent of ulcerative colitis: a study on the course and prognostic factors.
      and cancer,
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Ulcerative colitis and colorectal cancer. A population-based study.
      it may be less important to confirm mucosal healing in these patients, and symptomatic assessments may be adequate.
      For proctitis, no dose response has been shown for total daily doses greater than 1 g. Suppositories may be more appropriate than enemas in patients with proctitis, because their distribution mirrors disease extent.
      • van Bodegraven A.A.
      • Boer R.O.
      • Lourens J.
      • et al.
      Distribution of mesalazine enemas in active and quiescent ulcerative colitis.
      For active left-sided UC, 5-ASA enemas at a dosage of at least 1 g daily are preferred over 5-ASA suppository therapy because they are more likely to deliver medication to the splenic flexure.
      • Brown J.
      • Haines S.
      • Wilding I.R.
      Colonic spread of three rectally administered mesalazine (Pentasa) dosage forms in healthy volunteers as assessed by gamma scintigraphy.
      An RCT found that low-volume 5-ASA enemas were as effective as high-volume 5-ASA enemas but were better tolerated in patients with distal UC.
      • Eliakim R.
      • Tulassay Z.
      • Kupcinskas L.
      • et al.
      Clinical trial: randomized-controlled clinical study comparing the efficacy and safety of a low-volume vs. a high-volume mesalazine foam in active distal ulcerative colitis.

       Statement 3. In patients with mild to moderate active UC of any disease extent beyond proctitis, we recommend an oral 5-ASA preparation, at dosages between 2.0 and 4.8 g/day, as an alternative first-line therapy to induce complete remission

      GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 52%; agree, 43%; uncertain, 4%.
      Meta-analyses support the efficacy of oral 5-ASA for induction therapy for patients with mild to moderate active UC.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      • Ford A.C.
      • Achkar J.P.
      • Khan K.J.
      • et al.
      Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
      Results were similar in these meta-analyses, reported as the RR of no remission; one meta-analysis of 8 trials found an RR of 0.86 (95% CI, 0.81–0.91),
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      and another analysis of 11 trials found an RR of 0.79 (95% CI, 0.73–0.85).
      • Ford A.C.
      • Achkar J.P.
      • Khan K.J.
      • et al.
      Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
      Overall, in the meta-analyses, a dose response was reported,
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      with dosages ≥2.0 g/day shown to be more effective than dosages <2.0 g/day for remission (RR, 0.91; 95% CI, 0.85–0.98).
      • Ford A.C.
      • Achkar J.P.
      • Khan K.J.
      • et al.
      Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
      However, data are conflicting for dosages >2 g/day; a pooled analysis of the ASCEND trials (n = 1459 patients) found no statistically significant difference in clinical improvement between mesalamine (Asacol, Procter & Gamble Pharmaceuticals, Inc, Mason, OH) 4.8 g/day and 2.4 g/day,
      • Sandborn W.J.
      • Regula J.
      • Feagan B.G.
      • et al.
      Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis.
      • Hanauer S.B.
      • Sandborn W.J.
      • Dallaire C.
      • et al.
      Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial.
      • Hanauer S.B.
      • Sandborn W.J.
      • Kornbluth A.
      • et al.
      Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial.
      although subgroup analysis indicated that patients with moderate disease may benefit from the higher dosage.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      In contrast, studies with mesalamine (Pentasa, Shire US Inc, Wayne, PA) and MMX mesalamine (Lialda, Shire US Inc or Mezavant, Shire Pharma Canada ULC, Saint-Laurent, QC, Canada) have reported no statistically significant differences in efficacy with 4.0 to 4.8 g/day versus 2.25 to 2.4 g/day.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      The consensus group recommended a dosage of 2.0 to 2.4 g/day for patients with mild UC, whereas patients with moderate disease may benefit from higher doses. The consensus group agreed that sulfasalazine has efficacy similar to that of 5-ASA but that higher total doses of sulfasalazine are required to deliver equivalent doses of 5-ASA.
      Intolerance of 5-ASA occurs in up to 15% of patients; the most common adverse events are flatulence, abdominal pain, nausea, diarrhea, headache, worsening UC, rash, and thrombocytopenia.
      • Dignass A.
      • Lindsay J.O.
      • Sturm A.
      • et al.
      Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      Meta-analyses report no significant differences in the incidence of adverse events between 5-ASA and placebo.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      • Loftus Jr., E.V.
      • Kane S.V.
      • Bjorkman D.
      Systematic review: short-term adverse effects of 5-aminosalicylic acid agents in the treatment of ulcerative colitis.
      However, sulfasalazine is not as well tolerated as 5-ASA.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      There have been rare, idiosyncratic reports of renal impairment,
      • Gisbert J.P.
      • Gonzalez-Lama Y.
      • Mate J.
      5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
      and the product labeling recommends that all patients have an evaluation of renal function before initiation of therapy and periodically thereafter while on 5-ASA therapy. The consensus group believed there was no evidence that patients with a history of allergy to acetylsalicylic acid could not safely take 5-ASA preparations. The majority of patients who are intolerant or hypersensitive to sulfasalazine can take 5-ASA preparations without risk of similar reactions, but caution should be exercised.

       Statement 4. In patients with mild to moderate active UC of any disease extent beyond proctitis, we suggest the combination of a rectal and an oral 5-ASA preparation over oral 5-ASA alone as an alternative first-line therapy to induce complete remission

      GRADE: Weak recommendation, low-quality evidence. Vote: strongly agree, 43%; agree, 57%.
      A meta-analysis of 4 RCTs in patients with active UC reported that combination rectal and oral therapy was superior to oral 5-ASA alone for induction of remission (RR of no remission, 0.65; 95% CI, 0.47–0.91).
      • Ford A.C.
      • Khan K.J.
      • Achkar J.P.
      • et al.
      Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis.
      There are few data comparing the efficacy of combination therapy with rectal 5-ASA alone.
      In the meta-analysis, there was no significant difference in the rate of adverse events between patients receiving combination (22.3%) and oral 5-ASAs (26.9%) (RR, 0.77; 95% CI, 0.55–1.09).
      • Ford A.C.
      • Khan K.J.
      • Achkar J.P.
      • et al.
      Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis.
      Given the limited evidence showing the superiority of this strategy, patient preference and cost should be considered when choosing combination therapy over oral 5-ASA monotherapy; however, the consensus group concluded that combination therapy is the optimal first-line option given a potentially favorable risk/benefit trade-off.

       Statement 5. We recommend that patients with UC be evaluated for lack of symptomatic response to oral/rectal 5-ASA induction therapy in 4 to 8 weeks to determine the need to modify therapy

      GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree, 35%; agree, 57%; uncertain, 4%; disagree, 4%.
      The RCTs of 5-ASA therapy report that approximately 10% to 30% of patients were in symptomatic remission at week 2, 30% to 45% at week 4, and 45% to 50% at week 8.
      • Pruitt R.
      • Hanson J.
      • Safdi M.
      • et al.
      Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis.
      • Levine D.S.
      • Riff D.S.
      • Pruitt R.
      • et al.
      A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis.
      The median time to symptomatic remission was 10 to 37 days with oral 5-ASA.
      • Pruitt R.
      • Hanson J.
      • Safdi M.
      • et al.
      Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis.
      • Levine D.S.
      • Riff D.S.
      • Pruitt R.
      • et al.
      A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis.
      Generally, 5-ASA therapy is associated with improvements in symptom scores over the first 2 to 4 weeks, although additional improvement can occur up to week 16.
      • Pruitt R.
      • Hanson J.
      • Safdi M.
      • et al.
      Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis.
      • Cortot A.
      • Maetz D.
      • Degoutte E.
      • et al.
      Mesalamine foam enema versus mesalamine liquid enema in active left-sided ulcerative colitis.
      • Farup P.G.
      • Hovde O.
      • Halvorsen F.A.
      • et al.
      Mesalazine suppositories versus hydrocortisone foam in patients with distal ulcerative colitis. A comparison of the efficacy and practicality of two topical treatment regimens.
      • Hartmann F.
      • Stein J.
      Clinical trial: controlled, open, randomized multicentre study comparing the effects of treatment on quality of life, safety and efficacy of budesonide or mesalazine enemas in active left-sided ulcerative colitis.
      • Lemann M.
      • Galian A.
      • Rutgeerts P.
      • et al.
      Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis.
      • Safdi M.
      • DeMicco M.
      • Sninsky C.
      • et al.
      A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis.
      • Kamm M.A.
      • Lichtenstein G.R.
      • Sandborn W.J.
      • et al.
      Effect of extended MMX mesalamine therapy for acute, mild-to-moderate ulcerative colitis.
      The consensus group considered that symptomatic improvement should be evident by week 4 and symptomatic remission achieved by week 12. Although it is important not to delay assessment of therapeutic response and risk poor outcomes from the continuation of ineffective treatment, it is also important not to evaluate and change therapies before the completion of an adequate trial. However, definite and progressive worsening before the full 4- to 8-week trial may require intervention.

       Statement 6. In patients with oral or rectal 5-ASA–induced complete remission of mild to moderate active left-sided UC or proctitis, we recommend the same therapy be continued to maintain complete remission

      GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 48%; agree, 52%.
      Almost three-fourths of patients with left-sided UC or proctitis will experience a relapse within 1 year, underscoring the importance of maintenance therapy.
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Efficacy of topical 5-aminosalicylates in preventing relapse of quiescent ulcerative colitis: a meta-analysis.
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      Meta-analyses have shown the efficacy of maintenance 5-ASA therapy in these patients.
      • Marshall J.K.
      • Irvine E.J.
      Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis.
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Efficacy of topical 5-aminosalicylates in preventing relapse of quiescent ulcerative colitis: a meta-analysis.
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      In an analysis of 7 RCTs in patients treated with 5-ASA for a mean of 6 to 24 months, maintenance rectal 5-ASA therapy was associated with an RR of relapse of 0.60 (95% CI, 0.49–0.73; number needed to treat, 3) compared with placebo.
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Efficacy of topical 5-aminosalicylates in preventing relapse of quiescent ulcerative colitis: a meta-analysis.
      A second meta-analysis, using different definitions of remission, included only 4 RCTs.
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      In these studies, 12-month symptomatic remission rates were 62% with rectal 5-ASA and 30% with placebo (RR, 2.22; 95% CI, 1.26–3.90; P < .01). A meta-analysis of 2 RCTs found no statistically significant differences between rectal and oral 5-ASA for either symptomatic or endoscopic remission over a 6-month follow-up period.
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      In the meta-analysis by Ford et al (2012), a subgroup analysis of continuous (daily) and intermittent (first 7 days of the month, twice weekly, every third day) dosing schedules found a trend toward better results with the continuous dosing schedule, but this was not significant.
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Efficacy of topical 5-aminosalicylates in preventing relapse of quiescent ulcerative colitis: a meta-analysis.
      Therefore, rectal 5-ASA therapy can be used at a similar or reduced dosing frequency as the induction therapy to maintain complete remission. The consensus group agreed that not all patients with proctitis require maintenance therapy. In addition, patient preference should be considered.
      Meta-analyses of maintenance studies have reported no significant differences in rates of adverse events between 5-ASA and placebo groups.
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Efficacy of topical 5-aminosalicylates in preventing relapse of quiescent ulcerative colitis: a meta-analysis.
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.

       Statement 7. In patients with oral 5-ASA–induced complete remission of mild to moderate active UC of any disease extent, we recommend continued oral therapy of at least 2 g/day to maintain complete remission

      GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 57%; agree, 43%.
      Relapse rates among patients with UC of any extent were approximately 60% in the placebo arms of RCTs; thus, maintenance therapy is recommended.
      • Ford A.C.
      • Achkar J.P.
      • Khan K.J.
      • et al.
      Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      A meta-analysis of 11 RCTs in patients with quiescent UC found an RR of relapse with 5-ASA of 0.65 (95% CI, 0.55–0.76; number needed to treat, 4) compared with placebo.
      • Ford A.C.
      • Achkar J.P.
      • Khan K.J.
      • et al.
      Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
      An analysis of 6 RCTs that assessed complete remission (clinical and endoscopic) showed an RR of 0.59 (95% CI, 0.52–0.68). A meta-analysis of 7 trials (excluding sulfasalazine) reported relapse rates of 41% with 5-ASA compared with 58% with placebo (RR, 0.69; 95% CI, 0.62–0.77).
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      Sulfasalazine was statistically significantly superior to 5-ASA, with relapse rates of 48% and 43%, respectively (12 studies; RR, 1.14; 95% CI, 1.03–1.27).
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      Dosages of 5-ASA of ≥2.0 g/day appear to be more effective than <2.0 g/day for preventing relapse (RR, 0.79; 95% CI, 0.64–0.97).
      • Ford A.C.
      • Achkar J.P.
      • Khan K.J.
      • et al.
      Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      High-dose therapy appears to be as safe as low-dose therapy and is not associated with a higher incidence of adverse events.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      The consensus group concluded that patients with more active UC, extensive colitis, or frequent relapses may benefit in particular from a higher maintenance dosage up to 4.8 g/day.
      No significant differences in rates of adverse events between oral 5-ASA and placebo have been reported.
      • Ford A.C.
      • Achkar J.P.
      • Khan K.J.
      • et al.
      Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.

       Statement 8. In selected 5-ASA–naive patients with UC who have achieved symptomatic remission on oral corticosteroids, we suggest an oral 5-ASA preparation of at least 2 g/day while being assessed for corticosteroid-free complete remission

      GRADE: Weak recommendation, very low-quality evidence. Vote: strongly agree, 9%; agree, 78%; uncertain, 13%.
      Meta-analyses have confirmed the benefits of 5-ASA maintenance therapy (as described in statements 5 and 7); however, in most studies, patients were not stratified according to the treatment used to induce remission.
      • Ford A.C.
      • Achkar J.P.
      • Khan K.J.
      • et al.
      Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      A subgroup analysis of one RCT found no differences in the efficacy of 5-ASA for maintenance of remission between patients who had or had not received prior oral corticosteroid therapy.
      • Miner P.
      • Hanauer S.
      • Robinson M.
      • et al.
      Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Pentasa UC Maintenance Study Group.
      Data suggest that the need for corticosteroid treatment is a marker of poor prognosis.
      • Ardizzone S.
      • Petrillo M.
      • Molteni P.
      • et al.
      Coated oral 5-aminosalicylic acid (Claversal) is equivalent to sulfasalazine for remission maintenance in ulcerative colitis. A double-blind study.
      • Fockens P.
      • Mulder C.J.
      • Tytgat G.N.
      • et al.
      Comparison of the efficacy and safety of 1.5 compared with 3.0 g oral slow-release mesalazine (Pentasa) in the maintenance treatment of ulcerative colitis. Dutch Pentasa Study Group.
      • Faubion Jr., W.A.
      • Loftus Jr., E.V.
      • Harmsen W.S.
      • et al.
      The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.
      Therefore, the consensus group considered that 5-ASA maintenance therapy after corticosteroid induction therapy is a reasonable option for select patients, such as those with newly diagnosed lower-risk UC not previously treated with 5-ASA. For patients at higher risk for relapse or colectomy (see Definitions), immunosuppressants may be preferred (see statement 16). Other factors to consider include patient preference, cost, and the appropriateness of the corticosteroid induction therapy.

       Statement 9. In patients with UC who have failed to respond to oral 5-ASA, we recommend against switching to another oral 5-ASA formulation to induce complete remission

      GRADE: Strong recommendation, low-quality evidence. Vote: strongly agree, 39%; agree, 57%; uncertain, 4%.
      Meta-analyses have reported no clinically important differences in efficacy or safety among the various 5-ASA formulations for induction or maintenance therapy.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      • Feagan B.G.
      • Chande N.
      • MacDonald J.K.
      Are there any differences in the efficacy and safety of different formulations of Oral 5-ASA used for induction and maintenance of remission in ulcerative colitis? evidence from cochrane reviews.
      The consensus group believed that for patients who fail to achieve remission with 5-ASA therapy, there appears to be little or no benefit to changing among 5-ASA formulations before moving on to other therapeutic options. However, this recommendation does not preclude switching 5-ASA formulations for other reasons, such as adherence, tablet size, perceived intolerance, or cost.

       Statement 10. When using oral 5-ASA to induce or maintain complete remission of UC, we suggest once-daily over more frequent dosing

      GRADE: Weak recommendation, moderate-quality evidence. Vote: strongly agree, 52%; agree, 43%; uncertain, 4%.
      A meta-analysis of 3 trials found no statistically significant differences in efficacy or adherence between once-daily and conventionally dosed 5-ASA for induction of remission (nonremission RR, 0.95; 95% CI, 0.82–1.10).
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      • Feagan B.G.
      • MacDonald J.K.
      Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis.
      One additional RCT also found no differences in rates of remission or safety between once- and twice-daily oral 5-ASA (with once-daily enema).
      • Flourie B.
      • Hagege H.
      • Tucat G.
      • et al.
      Randomised clinical trial: once- vs. twice-daily prolonged-release mesalazine for active ulcerative colitis.
      For maintenance of remission, meta-analyses of 7 RCTs
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      • Feagan B.G.
      • MacDonald J.K.
      Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis.
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis.
      showed no significant difference in relapse rates with once-daily compared with conventional 5-ASA dosing (RR, 0.94; 95% CI, 0.82–1.08).
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis.
      In one RCT, which showed superior maintenance of remission with oral 5-ASA dosed once versus twice daily, it was speculated that higher absolute topical drug concentrations may have resulted in better pharmacological control of inflammation; however, there are no data to support this.
      • Dignass A.U.
      • Bokemeyer B.
      • Adamek H.
      • et al.
      Mesalamine once daily is more effective than twice daily in patients with quiescent ulcerative colitis.
      Once-daily dosing was not associated with a significant increase in the rate of adverse events compared with conventional dosing.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      • Feagan B.G.
      • MacDonald J.K.
      Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis.
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis.
      There were no significant differences in rates of medication adherence between once-daily and conventional dosing.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      • Feagan B.G.
      • Macdonald J.K.
      Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
      • Feagan B.G.
      • MacDonald J.K.
      Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis.
      • Ford A.C.
      • Khan K.J.
      • Sandborn W.J.
      • et al.
      Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis.
      However, adherence in the clinical trial environment is considerably higher (90%)
      • Feagan B.G.
      • MacDonald J.K.
      Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis.
      than in community-based studies (40%).
      • Kane S.V.
      • Cohen R.D.
      • Aikens J.E.
      • et al.
      Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis.
      Nonadherence with maintenance therapy is associated with a greater risk of recurrence and higher health care costs.
      • Kane S.
      • Huo D.
      • Aikens J.
      • et al.
      Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis.
      • Higgins P.D.
      • Rubin D.T.
      • Kaulback K.
      • et al.
      Systematic review: impact of non-adherence to 5-aminosalicylic acid products on the frequency and cost of ulcerative colitis flares.
      • Kane S.V.
      Strategies to improve adherence and outcomes in patients with ulcerative colitis.
      In addition, data suggest that most patients prefer once-daily over conventional dosing.
      • Kruis W.
      • Kiudelis G.
      • Racz I.
      • et al.
      Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial.
      • Sandborn W.J.
      • Korzenik J.
      • Lashner B.
      • et al.
      Once-daily dosing of delayed-release oral mesalamine (400-mg tablet) is as effective as twice-daily dosing for maintenance of remission of ulcerative colitis.
      The consensus group suggested once-daily dosing of 5-ASA therapy, which may enhance adherence in clinical practice, particularly during maintenance therapy.

       Statements Regarding Corticosteroids

       Statement 11. In patients with moderate to severe active UC, we recommend oral corticosteroids as first-line therapy to induce complete remission

      GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 70%; agree, 30%.

       Statement 12. In patients with mild to moderate active UC who fail to respond to 5-ASA therapy, we recommend oral corticosteroids as second-line therapy to induce complete remission

      GRADE: Strong recommendation, low-quality evidence. Vote: strongly agree, 57%; agree, 43%.
      A meta-analysis of 5 RCTs showed that corticosteroids were superior to placebo for induction of remission (RR of no remission, 0.65; 95% CI, 0.45–0.93).
      • Ford A.C.
      • Bernstein C.N.
      • Khan K.J.
      • et al.
      Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis.
      The analysis did not specify whether the patients were treatment naive or previously treated (ie, first- or second-line oral corticosteroid therapy). The optimal dose and dosing regimen for systemic corticosteroids in UC is uncertain, but based on a meta-analysis reporting no evidence of benefit with dosages higher than 60 mg/day, the consensus group agreed with the commonly used regimen of oral prednisone 40 to 60 mg/day (or equivalent).
      • Turner D.
      • Walsh C.M.
      • Steinhart A.H.
      • et al.
      Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression.
      Oral corticosteroid preparations with low systemic bioavailability, such as beclomethasone dipropionate or budesonide (MMX), have also shown efficacy for induction of remission with fewer systemic corticosteroid adverse effects.
      • Campieri M.
      • Adamo S.
      • Valpiani D.
      • et al.
      Oral beclometasone dipropionate in the treatment of extensive and left-sided active ulcerative colitis: a multicentre randomised study.
      • Travis S.P.
      • Danese S.
      • Kupcinskas L.
      • et al.
      Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study.
      Approximately 50% of patients experience short-term corticosteroid-related adverse events such as acne, edema, sleep and mood disturbance, glucose intolerance, and dyspepsia.
      • Lichtenstein G.R.
      • Abreu M.T.
      • Cohen R.
      • et al.
      American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease.
      • Dignass A.
      • Van Assche G.
      • Lindsay J.O.
      • et al.
      The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management.
      The consensus group agreed that selected patients, such as those with contraindications to corticosteroids, can be considered for anti-TNF or vedolizumab therapy (see statements 20 and 30). Because oral corticosteroids are not recommended for maintenance therapy (see statement 14), appropriate assessments for maintenance therapy should be considered when corticosteroid therapy is initiated (eg, thiopurine methyltransferase [TPMT] testing if thiopurines are being considered, hepatitis B and tuberculosis testing if anti-TNF therapy is being considered; see statements 18 and 22).

       Statement 13. In patients with mild to moderate active left-sided UC or proctitis who fail to respond to rectal 5-ASA therapy, we suggest rectal corticosteroids as second-line therapy to induce complete remission

      GRADE: Weak recommendation, overall very low-quality evidence. Vote: strongly agree, 26%; agree, 61%; uncertain, 13%.
      A meta-analysis that included studies of both conventional corticosteroids (2 RCTs) and budesonide (2 RCTs) showed that rectal corticosteroid therapy was superior to placebo in inducing remission.
      • Marshall J.K.
      • Irvine E.J.
      Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis.
      In a meta-analysis of 6 RCTs, rectal 5-ASA was superior to rectal corticosteroids for inducing symptomatic remission with an OR of 1.65 (95% CI, 1.11–2.45; P = .01).
      • Marshall J.K.
      • Thabane M.
      • Steinhart A.H.
      • et al.
      Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.
      An analysis performed for this consensus included only the 3 trials using conventional corticosteroids
      • Farup P.G.
      • Hovde O.
      • Halvorsen F.A.
      • et al.
      Mesalazine suppositories versus hydrocortisone foam in patients with distal ulcerative colitis. A comparison of the efficacy and practicality of two topical treatment regimens.
      Topical 5-aminosalicylic acid versus prednisolone in ulcerative proctosigmoiditis. A randomized, double-blind multicenter trial. Danish 5-ASA Group.
      • Lee F.I.
      • Jewell D.P.
      • Mani V.
      • et al.
      A randomised trial comparing mesalazine and prednisolone foam enemas in patients with acute distal ulcerative colitis.
      and found 2-fold higher odds of remission with 5-ASA (OR, 2.01; 95% CI, 1.41–2.88; P = .0001) (Figure 2). The nonsystemic corticosteroid budesonide has also been shown to be inferior to 5-ASA for induction of remission.
      • Hartmann F.
      • Stein J.
      Clinical trial: controlled, open, randomized multicentre study comparing the effects of treatment on quality of life, safety and efficacy of budesonide or mesalazine enemas in active left-sided ulcerative colitis.
      • Lemann M.
      • Galian A.
      • Rutgeerts P.
      • et al.
      Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis.
      • Marshall J.K.
      • Irvine E.J.
      Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis.
      A meta-analysis of 4 RCTs with rectal beclomethasone dipropionate showed no significant difference in improvement/remission compared with 5-ASA (OR, 1.23; 95% CI, 0.82–1.85; P = not significant [NS]).
      • Manguso F.
      • Balzano A.
      Meta-analysis: the efficacy of rectal beclomethasone dipropionate vs. 5-aminosalicylic acid in mild to moderate distal ulcerative colitis.
      Figure thumbnail gr2
      Figure 2Meta-analysis of rectal corticosteroids versus 5-ASA controls for induction of symptomatic remission.
      Despite evidence showing the superiority of rectal 5-ASA over rectal corticosteroids, the consensus group agreed that there is a role for rectal corticosteroids as second-line therapy given their superiority over placebo. Furthermore, hydrocortisone and budesonide are available as foam preparations,
      • Bar-Meir S.
      • Fidder H.H.
      • Faszczyk M.
      • et al.
      Budesonide foam vs. hydrocortisone acetate foam in the treatment of active ulcerative proctosigmoiditis.
      • Sandborn W.
      • Bosworth B.
      • Zakko S.
      • et al.
      Efficacy and safety of budesonide foam for inducing remission in mildly to moderately active ulcerative proctitis or ulcerative proctosigmoiditis (abstr P-149).
      which can have an advantage over liquid formulations when proctitis is quite active.
      Rectal corticosteroids are associated with similar short-term adverse events as seen with oral corticosteroids, although generally at lower frequency and severity.
      • Marshall J.K.
      • Irvine E.J.
      Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis.
      Although the consensus group suggested rectal corticosteroid therapy, they also believed there may be a role for adding oral 5-ASA in patients who fail to respond to rectal 5-ASA (particularly for patients with moderate left-sided UC) (see statement 4).

       Statement 14. In patients with UC, we recommend against the use of oral corticosteroids to maintain complete remission because they are ineffective for this indication and their prolonged use is associated with significant adverse effects

      GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 96%; uncertain, 4%.
      Few RCTs have assessed the efficacy of corticosteroids for maintenance therapy,
      • Lichtenstein G.R.
      • Abreu M.T.
      • Cohen R.
      • et al.
      American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease.
      • Powell-Tuck J.
      • Bown R.L.
      • Chambers T.J.
      • et al.
      A controlled trial of alternate day prednisolone as a maintenance treatment for ulcerative colitis in remission.
      • Lennard-Jones J.E.
      • Misiewicz J.J.
      • Connell A.M.
      • et al.
      Prednisone as maintenance treatment for ulcerative colitis in remission.
      • Truelove S.C.
      • Witts L.J.
      Cortisone and corticotrophin in ulcerative colitis.
      although 2 small RCTs have found this strategy to be ineffective.
      • Lennard-Jones J.E.
      • Misiewicz J.J.
      • Connell A.M.
      • et al.
      Prednisone as maintenance treatment for ulcerative colitis in remission.
      • Truelove S.C.
      • Witts L.J.
      Cortisone and corticotrophin in ulcerative colitis.
      Adverse effects associated with long-term use of corticosteroids include cataracts, osteoporosis, myopathy, and susceptibility to infections.
      • Lichtenstein G.R.
      • Abreu M.T.
      • Cohen R.
      • et al.
      American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease.
      • Dignass A.
      • Van Assche G.
      • Lindsay J.O.
      • et al.
      The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management.
      • Bjarnason I.
      • Macpherson A.
      • Mackintosh C.
      • et al.
      Reduced bone density in patients with inflammatory bowel disease.
      In the TREAT registry of patients with Crohn’s disease, prednisone therapy was associated with an increased risk of serious infections (hazard ratio, 1.57; 95% CI, 1.17–2.10; P = .002) and increased mortality (hazard ratio, 2.14; 95% CI, 1.55–2.95; P < .001).
      • Lichtenstein G.R.
      • Feagan B.G.
      • Cohen R.D.
      • et al.
      Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry.
      The consensus group recommended against the use of oral corticosteroids for maintenance therapy because evidence suggests that the risks of long-term therapy outweigh the benefits.

       Statement 15. In patients with mild to moderate UC of any disease extent, we suggest oral budesonide MMX as an alternative first-line therapy to induce complete remission

      GRADE: Weak recommendation, high-quality evidence. Vote: strongly agree, 35%; agree, 61%; uncertain, 4%.
      In RCTs, budesonide in the oral MMX formulation was significantly more effective than placebo
      • Travis S.P.
      • Danese S.
      • Kupcinskas L.
      • et al.
      Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study.
      • Sandborn W.J.
      • Travis S.
      • Moro L.
      • et al.
      Once-daily budesonide MMX(R) extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study.
      • D'Haens G.R.
      • Kovacs A.
      • Vergauwe P.
      • et al.
      Clinical trial: Preliminary efficacy and safety study of a new Budesonide-MMX(R) 9 mg extended-release tablets in patients with active left-sided ulcerative colitis.
      and as effective as 5-ASA in inducing remission.
      • Sandborn W.J.
      • Travis S.
      • Moro L.
      • et al.
      Once-daily budesonide MMX(R) extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study.
      However, this may not be true of other budesonide formulations; the ileal-release preparations of budesonide, Entocort (AstraZeneca, Lund Sweden) and Budenofalk (Dr Falk Pharma GmbH, Freiburg, Germany), were inferior to placebo
      • Lofberg R.
      • Danielsson A.
      • Suhr O.
      • et al.
      Oral budesonide versus prednisolone in patients with active extensive and left-sided ulcerative colitis.
      and 5-ASA,
      • Gross V.
      • Bunganic I.
      • Belousova E.A.
      • et al.
      3g mesalazine granules are superior to 9mg budesonide for achieving remission in active ulcerative colitis: a double-blind, double-dummy, randomised trial.
      respectively.
      • Sherlock M.E.
      • Seow C.H.
      • Steinhart A.H.
      • et al.
      Oral budesonide for induction of remission in ulcerative colitis.
      Budesonide has been associated with a lower rate of systemic adverse effects than conventional corticosteroids (33% vs 55%).
      • Dignass A.
      • Van Assche G.
      • Lindsay J.O.
      • et al.
      The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management.
      Budesonide has not been associated with suppression of plasma cortisol
      • Lofberg R.
      • Danielsson A.
      • Suhr O.
      • et al.
      Oral budesonide versus prednisolone in patients with active extensive and left-sided ulcerative colitis.
      or a significant decrease in bone mineral density.
      • Schoon E.J.
      • Bollani S.
      • Mills P.R.
      • et al.
      Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn's disease.
      Although budesonide MMX is not approved in Canada, it is available in other jurisdictions. The consensus group agreed that budesonide MMX might be appropriate both as an alternative to 5-ASA as first-line therapy and as second-line therapy in patients with mild to moderate UC who fail to respond to or do not tolerate 5-ASA.

       Statement 16. We recommend that patients with UC be evaluated for lack of symptomatic response to corticosteroid induction therapy within 2 weeks to determine the need to modify therapy

      GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree, 65%; agree, 35%.
      Patients undergoing a course of oral corticosteroid induction therapy should be assessed within 2 weeks. In trials, significant improvements in clinical and endoscopic measures with corticosteroid therapy are seen at the earliest assessment (week 2) compared with baseline.
      • Lemann M.
      • Galian A.
      • Rutgeerts P.
      • et al.
      Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis.
      • Campieri M.
      • Adamo S.
      • Valpiani D.
      • et al.
      Oral beclometasone dipropionate in the treatment of extensive and left-sided active ulcerative colitis: a multicentre randomised study.
      Early clinical assessment to identify nonresponders can help avoid delays in initiating other effective therapy. In addition, the short-term and long-term adverse event profiles associated with corticosteroid use suggest minimizing exposure whenever possible.
      • Lichtenstein G.R.
      • Abreu M.T.
      • Cohen R.
      • et al.
      American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease.
      • Dignass A.
      • Van Assche G.
      • Lindsay J.O.
      • et al.
      The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management.
      The consensus group agreed that if there is no response within 2 weeks, therapy should be modified; however, if there is a partial response, a short extension of full-dose corticosteroid induction therapy may be warranted based on a patient’s individual situation.

       Statements Regarding Immunosuppressants

       Statement 17. In patients with UC, we recommend against the use of thiopurine monotherapy to induce complete remission

      GRADE: Strong recommendation, low-quality evidence. Vote: strongly agree, 52%; agree, 43%; uncertain, 4%.
      A meta-analysis of 4 controlled trials concluded that the thiopurines, azathioprine and 6-mercaptopurine, were not effective for the induction of remission in patients with UC (OR, 1.59; 95% CI, 0.59–4.29; P = NS) compared with placebo or 5-ASA therapy.
      • Gisbert J.P.
      • Linares P.M.
      • McNicholl A.G.
      • et al.
      Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis.
      Analysis of the 2 placebo-controlled RCTs
      • Jewell D.P.
      • Truelove S.C.
      Azathioprine in ulcerative colitis: final report on controlled therapeutic trial.
      • Sood A.
      • Midha V.
      • Sood N.
      • et al.
      Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial.
      found no significant benefit of azathioprine/6-mercaptopurine for the outcome of endoscopic remission (RR, 0.85; 95% CI, 0.71–1.01)
      • Khan K.J.
      • Dubinsky M.C.
      • Ford A.C.
      • et al.
      Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis.
      or clinical remission (OR, 1.44; 95% CI, 0.68–3.03; P = NS).
      • Gisbert J.P.
      • Linares P.M.
      • McNicholl A.G.
      • et al.
      Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis.
      One RCT showed that azathioprine was significantly more effective than 5-ASA in inducing complete, corticosteroid-free remission in patients with corticosteroid-dependent UC (OR, 4.78; 95% CI, 1.57–14.5; P = .006).
      • Ardizzone S.
      • Maconi G.
      • Russo A.
      • et al.
      Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis.
      Given the safety and tolerability issues (see statement 18) and delayed onset of action (up to 2–6 months for therapeutic effect),
      • Gisbert J.P.
      • Linares P.M.
      • McNicholl A.G.
      • et al.
      Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis.
      the consensus group recommended against the routine use of these agents for induction therapy. However, thiopurines could be considered in select patients with mild UC who are uncontrolled on 5-ASA but refuse anti-TNF therapy when the prolonged time to therapeutic effect is unlikely to result in significant deterioration in disease severity. It is also important to recognize that thiopurines can be combined with anti-TNF therapies to augment their efficacy as both induction and maintenance agents (see statement 21).

       Statement 18. In selected patients with UC who have achieved symptomatic remission on oral corticosteroids, we suggest thiopurine monotherapy as an option to maintain complete corticosteroid-free remission

      GRADE: Weak recommendation, low-quality evidence. Vote: strongly agree, 22%; agree, 78%.
      Meta-analyses support the benefit of azathioprine for maintenance of remission
      • Gisbert J.P.
      • Linares P.M.
      • McNicholl A.G.
      • et al.
      Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis.
      • Khan K.J.
      • Dubinsky M.C.
      • Ford A.C.
      • et al.
      Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis.
      • Timmer A.
      • McDonald J.W.
      • Tsoulis D.J.
      • et al.
      Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.
      in patients with UC. A meta-analysis of 4 RCTs,
      • Jewell D.P.
      • Truelove S.C.
      Azathioprine in ulcerative colitis: final report on controlled therapeutic trial.
      • Sood A.
      • Midha V.
      • Sood N.
      • et al.
      Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial.
      • Sood A.
      • Kaushal V.
      • Midha V.
      • et al.
      The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis.
      • Hawthorne A.B.
      • Logan R.F.
      • Hawkey C.J.
      • et al.
      Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.
      found that 44% of azathioprine-treated patients failed to maintain remission compared with 65% of patients receiving placebo (RR, 0.68; 95% CI, 0.54–0.86).
      • Timmer A.
      • McDonald J.W.
      • Tsoulis D.J.
      • et al.
      Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.
      Similar results were found in a meta-analysis of 3 studies (RR, 0.60; 95% CI, 0.37–0.95),
      • Khan K.J.
      • Dubinsky M.C.
      • Ford A.C.
      • et al.
      Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis.
      which did not include the withdrawal study by Hawthorne et al (1992).
      • Hawthorne A.B.
      • Logan R.F.
      • Hawkey C.J.
      • et al.
      Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.
      Two of these studies included patients in remission after corticosteroid therapy,
      • Jewell D.P.
      • Truelove S.C.
      Azathioprine in ulcerative colitis: final report on controlled therapeutic trial.
      • Sood A.
      • Kaushal V.
      • Midha V.
      • et al.
      The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis.
      while one included corticosteroid-dependent patients.
      • Sood A.
      • Midha V.
      • Sood N.
      • et al.
      Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial.
      The withdrawal study included patients in remission on azathioprine and found 1-year relapse rates of 36% with continued azathioprine and 59% with placebo (hazard ratio, 0.5; 95% CI, 0.25–1.0; P = .039).
      • Hawthorne A.B.
      • Logan R.F.
      • Hawkey C.J.
      • et al.
      Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.
      The quality of the individual studies used in these meta-analyses was insufficient due to heterogeneous trial designs, small patient numbers, and variability of outcome measures; therefore, the consensus group suggested, rather than recommended, this approach.
      Although rare, thiopurine therapy is associated with an increased risk of lymphoma (including hepatosplenic T-cell lymphoma)
      • Kornbluth A.
      • Sachar D.B.
      Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee.
      • Smith M.A.
      • Irving P.M.
      • Marinaki A.M.
      • et al.
      Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel disease.
      • Kotlyar D.S.
      • Osterman M.T.
      • Diamond R.H.
      • et al.
      A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease.
      and nonmelanoma skin cancer.
      • Ariyaratnam J.
      • Subramanian V.
      Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis.
      In 2014, Health Canada issued an alert warning of the risk of hepatosplenic T-cell lymphoma with azathioprine/6-mercaptopurine.

      Health Canada. Imuran (azathioprine) or Purinethol (mercaptopurine) - association with a type of blood cancer - hepatosplenic T-cell lymphoma - for health professionals. Last Update 2014. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/38691a-eng.php. Accessed January 17, 2015.

      Thiopurines have also been associated with bone marrow suppression, pancreatitis, hepatotoxicity, allergic reactions, and opportunistic infections, especially when used in combination with corticosteroids or infliximab.
      • Dignass A.
      • Lindsay J.O.
      • Sturm A.
      • et al.
      Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management.
      • Kornbluth A.
      • Sachar D.B.
      Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee.
      A position statement from the CAG recommended that continuation of thiopurine therapy balance the evidence for risk and efficacy against an individual patient’s response to therapy, preferences, and risk tolerance.
      • Marshall J.K.
      • Otley A.R.
      • Afif W.
      • et al.
      Canadian Association of Gastroenterology position statement regarding the use of thiopurines for the treatment of inflammatory bowel disease.
      Because thiopurines are metabolized by TPMT, which may be absent or present in low levels in some patients, a TPMT assay is necessary before initiation of treatment to identify patients at risk for severe dose-dependent myelosuppression.
      • Kornbluth A.
      • Sachar D.B.
      Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee.
      In addition, higher levels of the thiopurine metabolite 6-thioguanine nucleotide have been correlated with clinical remission rates; therefore, thiopurine metabolite levels may be helpful to guide therapy.
      • Kornbluth A.
      • Sachar D.B.
      Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee.
      Note that TPMT testing does not replace the need for mandatory monitoring of complete blood cell count.
      Given the safety and tolerability issues, the consensus group suggested thiopurine maintenance therapy for selected patients, including patients with a low risk of disease progression who responded to their first course of corticosteroids and those who cannot afford or are unable to tolerate anti-TNF therapy. The consensus group believed that for patients who are corticosteroid dependent and thus at higher risk of poorer outcomes, more effective, safer options were preferred over thiopurine therapy (see statement 22). Response to a thiopurine for corticosteroid-sparing maintenance therapy should be evaluated as early as 10 to 12 weeks.
      • Sood A.
      • Midha V.
      • Sood N.
      • et al.
      Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial.
      • Sood A.
      • Kaushal V.
      • Midha V.
      • et al.
      The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis.

       Statement 19. In patients with UC, we recommend against the use of methotrexate monotherapy to induce or maintain complete remission

      GRADE: Strong recommendation, low-quality evidence for induction and very low-quality evidence for maintenance. Vote: strongly agree, 65%; agree, 26%; uncertain, 9%.
      Meta-analyses of methotrexate for induction
      • Khan K.J.
      • Dubinsky M.C.
      • Ford A.C.
      • et al.
      Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis.
      • Chande N.
      • MacDonald J.K.
      • McDonald J.W.
      Methotrexate for induction of remission in ulcerative colitis.
      or maintenance therapy
      • Khan K.J.
      • Dubinsky M.C.
      • Ford A.C.
      • et al.
      Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis.
      • El-Matary W.
      • Vandermeer B.
      • Griffiths A.M.
      Methotrexate for maintenance of remission in ulcerative colitis.
      reveal the paucity of data with this agent for the treatment of UC. The only placebo-controlled RCT for induction therapy reported no statistically significant benefit of methotrexate (RR, 1.29; 95% CI, 0.95–1.75) over placebo in patients with corticosteroid-dependent UC.
      • Oren R.
      • Arber N.
      • Odes S.
      • et al.
      Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial.
      A meta-analysis of 2 RCTs
      • Oren R.
      • Arber N.
      • Odes S.
      • et al.
      Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial.
      • Onuk M.
      • Kaymakoglu S.
      • Demir K.
      • et al.
      Low-dose weekly methotrexate therapy in remission maintenance in ulcerative colitis (abstr).
      found no statistically significant benefit of adjunctive methotrexate over placebo for maintenance of remission (RR, 0.59; 95% CI, 0.04–7.90).
      • Khan K.J.
      • Dubinsky M.C.
      • Ford A.C.
      • et al.
      Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis.
      In corticosteroid-dependent patients, 2 small RCTs with active comparator arms
      • Mate-Jimenez J.
      • Hermida C.
      • Cantero-Perona J.
      • et al.
      6-mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease.
      • Egan L.J.
      • Sandborn W.J.
      • Tremaine W.J.
      • et al.
      A randomized dose-response and pharmacokinetic study of methotrexate for refractory inflammatory Crohn's disease and ulcerative colitis.
      and 2 cohort studies
      • Manosa M.
      • Garcia V.
      • Castro L.
      • et al.
      Methotrexate in ulcerative colitis: a Spanish multicentric study on clinical use and efficacy.
      • Khan N.
      • Abbas A.M.
      • Moehlen M.
      • et al.
      Methotrexate in ulcerative colitis: a nationwide retrospective cohort from the Veterans Affairs Health Care System.
      found that approximately 20% to 60% of patients achieved corticosteroid-free remission, which was not significantly different from that seen with 5-ASA.
      • Mate-Jimenez J.
      • Hermida C.
      • Cantero-Perona J.
      • et al.
      6-mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease.
      Two multicenter randomized trials, METEOR (European) and MERIT (US), comparing methotrexate and placebo are under way. These trials should help determine if methotrexate is a valuable therapeutic option in UC.
      Based on current data, the consensus group recommended against the routine use of methotrexate for induction or maintenance therapy.

       Statements Regarding Anti-TNF Therapy

       Statement 20. In patients with UC who fail to respond to thiopurines or corticosteroids, we recommend anti-TNF therapy to induce complete corticosteroid-free remission

      GRADE: Strong recommendation, high-quality evidence. Vote: strongly agree, 70%; agree, 30%.
      The anti-TNF therapies, infliximab, adalimumab, and golimumab, have shown efficacy for the induction and maintenance of remission in patients with moderate to severe active UC. The efficacy of infliximab was shown in meta-analyses of RCTs in patients who failed to respond to or were receiving corticosteroids.
      • Ford A.C.
      • Sandborn W.J.
      • Khan K.J.
      • et al.
      Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis.
      • Lawson M.M.
      • Thomas A.G.
      • Akobeng A.K.
      Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis.
      • Lv R.
      • Qiao W.
      • Wu Z.
      • et al.
      Tumor necrosis factor alpha blocking agents as treatment for ulcerative colitis intolerant or refractory to conventional medical therapy: a meta-analysis.
      A meta-analysis of 5 trials found that infliximab was superior to placebo in inducing endoscopic remission (RR for no remission, 0.72; 95% CI, 0.57–0.91; P = .006) (Figure 3).
      • Ford A.C.
      • Sandborn W.J.
      • Khan K.J.
      • et al.
      Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis.
      Analysis of the 2 largest trials, the ACT 1 (n = 364) and ACT 2 (n = 364) trials,
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      found that infliximab was more effective than placebo in inducing clinical (RR, 3.22; 95% CI, 2.18–4.76) and endoscopic remission (RR, 1.88; 95% CI, 1.54–2.28).
      • Lawson M.M.
      • Thomas A.G.
      • Akobeng A.K.
      Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis.
      Figure thumbnail gr3
      Figure 3Meta-analysis of infliximab for induction of endoscopic remission (RR for no remission).
      From Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2011;106:644–659.
      • Ford A.C.
      • Sandborn W.J.
      • Khan K.J.
      • et al.
      Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis.
      Copyright ©2011 Massachusetts Medical Society.
      Two large RCTs, ULTRA 1 (n = 390)
      • Reinisch W.
      • Sandborn W.J.
      • Hommes D.W.
      • et al.
      Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.
      and ULTRA 2 (n = 494),
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
      have assessed the efficacy of adalimumab in patients with moderate to severe active UC failing to respond to treatment with corticosteroids or immunosuppressants. A meta-analysis of these 2 trials conducted for this consensus showed that adalimumab was effective in inducing complete remission (OR for no remission, 0.60; 95% CI, 0.42–0.86; P = .006) (Figure 4).
      Figure thumbnail gr4
      Figure 4Meta-analysis of adalimumab for induction of complete remission.
      The efficacy of golimumab was shown in the PURSUIT-SC trial (n = 774), with rates of complete remission of 18% with golimumab compared with 6% with placebo (P < .0001).
      • Sandborn W.J.
      • Feagan B.G.
      • Marano C.
      • et al.
      Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.
      The consensus group concluded that no data exist to guide the choice of a particular anti-TNF therapy. Comparison of data from different studies is not appropriate, and head-to-head comparative studies are not available.
      In induction trials, the rates of adverse events with anti-TNF therapy, including infusion/injection reactions, headache, rash, and arthralgia, were not significantly different from placebo.
      • Ford A.C.
      • Sandborn W.J.
      • Khan K.J.
      • et al.
      Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis.
      However, adverse events related to sensitization may be more common with prolonged use. Anti-TNF therapy is associated with a small increased absolute risk of opportunistic infections
      • Ford A.C.
      • Peyrin-Biroulet L.
      Opportunistic infections with anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials.
      and serious infections,
      • Targownik L.E.
      • Bernstein C.N.
      Infectious and malignant complications of TNF inhibitor therapy in IBD.
      which is discussed in more detail in statement 24.

       Statement 21. When starting anti-TNF therapy, we recommend it be combined with a thiopurine or methotrexate rather than used as monotherapy to induce complete remission

      GRADE: Strong recommendation, moderate-quality evidence for azathioprine and very low-quality evidence for methotrexate. Vote: strongly agree, 26%; agree, 65%; uncertain, 9%.
      The use of combination therapy is based on the rationale that immunosuppressants optimize induction and may reduce the likelihood of secondary loss of response to anti-TNF therapies. Across therapeutic areas in which anti-TNF therapies have been used, the development of anti-drug antibodies (ADA) has been associated with poorer clinical outcomes, and the use of immunosuppressants with thiopurines or methotrexate has been shown to reduce their formation.
      • Krieckaert C.L.
      • Bartelds G.M.
      • Lems W.F.
      • et al.
      The effect of immunomodulators on the immunogenicity of TNF-blocking therapeutic monoclonal antibodies: a review.
      Furthermore, adalimumab levels were found to be significantly higher in patients with rheumatoid arthritis receiving concomitant methotrexate.
      • Pouw M.F.
      • Krieckaert C.L.
      • Nurmohamed M.T.
      • et al.
      Key findings towards optimising adalimumab treatment: the concentration-effect curve.
      The data from RCTs regarding the use of anti-TNF therapies and azathioprine in combination are sparse, and no such data exist for combination therapy with methotrexate. The efficacy of anti-TNF therapy in combination with azathioprine is supported by the results of the UC SUCCESS trial
      • Panaccione R.
      • Ghosh S.
      • Middleton S.
      • et al.
      Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.
      and observational data.
      • Reinisch W.
      • Sandborn W.J.
      • Hommes D.W.
      • et al.
      Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
      • Adedokun O.
      • Xu Z.
      • Marano C.
      • et al.
      Effects of immunomodulators on the pharmacokinetics and efficacy of golimumab in patients with moderately to severely active ulcerative colitis: Results from phase 2/3 PURSUIT-SC induction and maintenance studies (abstr).
      Among anti-TNF–naive patients with moderate to severe UC included in the UC SUCCESS trial, corticosteroid-free remission rates at 16 weeks were significantly higher with the combination of infliximab plus azathioprine (39.7%) compared with either infliximab (22.1%, P = .017) or azathioprine monotherapy (23.7%; P = .032).
      • Panaccione R.
      • Ghosh S.
      • Middleton S.
      • et al.
      Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.
      Combination therapy also led to significantly better mucosal healing than azathioprine monotherapy. However, the UC-SUCCESS trial was only of 16 weeks’ duration, and other end points, including mucosal healing and improvements in partial or total Mayo scores, were similar between the infliximab monotherapy and combination groups.
      In addition, a systematic review of subgroup data from 4 RCTs concluded that concomitant use of immunosuppressants did not improve efficacy or pharmacokinetics in patients with IBD receiving maintenance infliximab.
      • Lichtenstein G.R.
      • Diamond R.H.
      • Wagner C.L.
      • et al.
      Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials.
      Nonetheless, these data should be interpreted with caution and in the context of the recent experience in Crohn’s disease, where a similar conclusion based on subgroup analyses was later discredited by the results of SONIC.
      • Colombel J.F.
      • Sandborn W.J.
      • Reinisch W.
      • et al.
      Infliximab, azathioprine, or combination therapy for Crohn's disease.
      Analysis of patients receiving immunosuppressants in the adalimumab study, ULTRA 1, showed a more pronounced treatment effect in patients treated with immunosuppressants without corticosteroids at baseline.
      • Reinisch W.
      • Sandborn W.J.
      • Hommes D.W.
      • et al.
      Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.
      In ULTRA 2, there was a lower rate of development of adalimumab ADAs in patients receiving combination therapy compared with adalimumab monotherapy.
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
      In the PURSUIT studies, concomitant immunosuppressant use was associated with a decreased incidence of antibodies to golimumab but did not substantially affect golimumab serum levels or improve efficacy.
      • Adedokun O.
      • Xu Z.
      • Marano C.
      • et al.
      Effects of immunomodulators on the pharmacokinetics and efficacy of golimumab in patients with moderately to severely active ulcerative colitis: Results from phase 2/3 PURSUIT-SC induction and maintenance studies (abstr).
      Although the absolute baseline rates of serious infections and malignancy are low among patients with IBD, they may be increased with anti-TNF therapies and thiopurines, particularly when these agents are used in combination (see statements 18 and 24).
      • Targownik L.E.
      • Bernstein C.N.
      Infectious and malignant complications of TNF inhibitor therapy in IBD.
      • Lichtenstein G.R.
      • Diamond R.H.
      • Wagner C.L.
      • et al.
      Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials.
      An analysis of patients with Crohn’s disease found an increased risk of nonmelanoma skin cancer or other cancers in patients receiving combination therapy but not in those receiving anti-TNF monotherapy, suggesting that the increased rate of malignancy compared with the general population is likely due to the immunosuppressant rather than the anti-TNF therapy.
      • Osterman M.T.
      • Sandborn W.J.
      • Colombel J.F.
      • et al.
      Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn's disease.
      However, the magnitude of the increased risk remains controversial.
      Although controversial, and based on somewhat limited evidence, the consensus group concluded that combination therapy is preferred in thiopurine-naive patients starting anti-TNF therapy. The decision as to what to do in patients who fail to respond to thiopurine therapy is less clear. Available data for combination therapy in patients with UC is primarily based on the use of azathioprine and infliximab.
      • Panaccione R.
      • Ghosh S.
      • Middleton S.
      • et al.
      Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.
      However, the observational data suggesting a decreased risk of developing anti-TNF antibodies to adalimumab and golimumab provide support for the relevance of this strategy for all 3 of the anti-TNF therapies. In addition, data extrapolated from studies in patients with rheumatoid arthritis
      • Pouw M.F.
      • Krieckaert C.L.
      • Nurmohamed M.T.
      • et al.
      Key findings towards optimising adalimumab treatment: the concentration-effect curve.
      led the consensus group to believe that methotrexate may also be a useful alternative to azathioprine in some patients at higher risk for nonmelanoma skin cancer or lymphoma, such as elderly patients.

       Statement 22. In patients with UC who are corticosteroid dependent, we recommend anti-TNF therapy to induce and maintain complete corticosteroid-free remission

      GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree, 52%; agree, 48%.
      Patients who require corticosteroid therapy are at higher risk for relapse
      • Ardizzone S.
      • Petrillo M.
      • Molteni P.
      • et al.
      Coated oral 5-aminosalicylic acid (Claversal) is equivalent to sulfasalazine for remission maintenance in ulcerative colitis. A double-blind study.
      • Fockens P.
      • Mulder C.J.
      • Tytgat G.N.
      • et al.
      Comparison of the efficacy and safety of 1.5 compared with 3.0 g oral slow-release mesalazine (Pentasa) in the maintenance treatment of ulcerative colitis. Dutch Pentasa Study Group.
      and colectomy.
      • Faubion Jr., W.A.
      • Loftus Jr., E.V.
      • Harmsen W.S.
      • et al.
      The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.
      Given the adverse effects associated with long-term corticosteroid use,
      • Lichtenstein G.R.
      • Abreu M.T.
      • Cohen R.
      • et al.
      American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease.
      • Dignass A.
      • Van Assche G.
      • Lindsay J.O.
      • et al.
      The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management.
      • Bjarnason I.
      • Macpherson A.
      • Mackintosh C.
      • et al.
      Reduced bone density in patients with inflammatory bowel disease.
      one of the most important goals of therapy in UC is to maintain corticosteroid-free remission.
      A majority of patients in RCTs of anti-TNF therapies in UC had failed to respond to or were receiving corticosteroid therapy.
      • Ford A.C.
      • Sandborn W.J.
      • Khan K.J.
      • et al.
      Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis.
      • Reinisch W.
      • Sandborn W.J.
      • Hommes D.W.
      • et al.
      Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Marano C.
      • et al.
      Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.
      Anti-TNF therapy showed corticosteroid-sparing effects in these trials. In the ACT 1 and 2 trials with infliximab, approximately 60% of patients were receiving corticosteroids at baseline, and approximately 30% had corticosteroid-resistant disease.
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      Significantly more patients had corticosteroid-free complete remission in the infliximab groups compared with placebo (20%–30% vs 3%–10% at week 30). In addition, complete remission rates were similar in patients who were and were not corticosteroid resistant.
      In the ULTRA 2 study, approximately 31% of patients in the adalimumab group and 18% in the placebo group discontinued corticosteroid therapy by week 16, and this was maintained through week 52.
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
      In the PURSUIT maintenance study, 54% of patients were receiving corticosteroids at baseline; of these, approximately one-fourth achieved corticosteroid-free complete remission at week 54 with golimumab compared with 18% with placebo (not statistically significant).
      • Sandborn W.J.
      • Feagan B.G.
      • Marano C.
      • et al.
      Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis.
      Although azathioprine is also recommended as an option in patients who have achieved symptomatic remission on oral corticosteroids (see statement 18), the consensus group believed that anti-TNF combination therapy is the preferred choice for corticosteroid-dependent patients because of the more robust evidence for efficacy and the suggestion of potentially better short-term mucosal healing rates with infliximab compared with azathioprine in the UC SUCCESS trial.
      • Panaccione R.
      • Ghosh S.
      • Middleton S.
      • et al.
      Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.

       Statement 23. We recommend that patients with UC be evaluated for lack of symptomatic response to anti-TNF induction therapy in 8 to 12 weeks to determine the need to modify therapy

      GRADE: Strong recommendation, low-quality evidence. Vote: strongly agree, 43%; agree, 57%.
      Most RCTs assessed patients every 2 weeks and reported significant improvements in symptom scores as early as week 2 to 4 with anti-TNF therapies compared with placebo.
      • Reinisch W.
      • Sandborn W.J.
      • Hommes D.W.
      • et al.
      Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Marano C.
      • et al.
      Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.
      In the anti-TNF induction therapy trials, significantly greater remission rates with anti-TNF therapy compared with placebo were seen at week 8.
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      • Reinisch W.
      • Sandborn W.J.
      • Hommes D.W.
      • et al.
      Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Marano C.
      • et al.
      Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.
      In addition, in ULTRA 2, the proportion of patients achieving symptomatic remission with adalimumab reached a maximum at week 16 and declined thereafter.
      • Sandborn W.J.
      • van Assche G.
      • Reinisch W.
      • et al.
      Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
      Therefore, the consensus group agreed that clinical assessment at 8 to 12 weeks after initiation of therapy is important to identify patients who have failed to respond and modify their therapy. If a response occurs, subsequent assessments should include endoscopy to confirm complete remission, but the optimal timing of endoscopy is currently uncertain. Patients with more severe disease may require earlier assessments.

       Statement 24. In patients with UC who respond to anti-TNF induction therapy, we recommend continued anti-TNF therapy to maintain complete remission

      GRADE: Strong recommendation, very low-quality evidence for infliximab and adalimumab and high-quality evidence for golimumab. Vote: strongly agree, 65%; agree, 35%.
      The efficacy of infliximab therapy after 1 year was shown in the ACT 1 trial, with 35% of patients achieving complete remission compared with 16% receiving placebo (P = .001).
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      Longer-term open-label follow-up of infliximab-treated patients showed that approximately 90% of patients maintained symptomatic remission with up to 3 years of therapy.
      • Reinisch W.
      • Sandborn W.J.
      • Rutgeerts P.
      • et al.
      Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies.
      Similarly, adalimumab was effective in the 1-year ULTRA 2 trial, with 31% of the patients who had a clinical response at week 8 achieving complete remission by week 52.
      • Sandborn W.J.
      • Colombel J.F.
      • D'Haens G.
      • et al.
      One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2.
      In the open-label follow-up of patients in the ULTRA 1 study, 30% were in complete remission at 1 year, including almost 40% of patients who had responded at week 8.
      • Reinisch W.
      • Sandborn W.J.
      • Panaccione R.
      • et al.
      52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants.
      In the 1-year PURSUIT maintenance study, patients who had responded to golimumab induction therapy were randomized to maintenance therapy with golimumab or placebo.
      • Sandborn W.J.
      • Feagan B.G.
      • Marano C.
      • et al.
      Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis.
      At week 54, patients who received golimumab were more likely to be in complete remission (23%–28%) than patients assigned to placebo (15.6%; P = .004).
      Anti-TNF therapies have been associated with a small increased risk of opportunistic infections, particularly when used in combination with corticosteroids or immunosuppressants
      • Ford A.C.
      • Peyrin-Biroulet L.
      Opportunistic infections with anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials.
      • Targownik L.E.
      • Bernstein C.N.
      Infectious and malignant complications of TNF inhibitor therapy in IBD.
      • Williams C.J.
      • Peyrin-Biroulet L.
      • Ford A.C.
      Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor-alpha therapy in inflammatory bowel disease.
      ; however, the absolute risk remains low. A meta-analysis of 22 RCTs in patients with UC and Crohn’s disease reported opportunistic infections in 0.9% (39/4135) of patients receiving anti-TNF therapies compared with 0.3% (9/2919) of patients receiving placebo (RR, 2.05; 95% CI, 1.10–3.85).
      • Ford A.C.
      • Peyrin-Biroulet L.
      Opportunistic infections with anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials.
      In the anti-TNF therapy group, infections included Mycobacterium tuberculosis (n = 8), herpes simplex infection (n = 8), oral or esophageal candidiasis (n = 6), herpes zoster infection (n = 6), varicella-zoster virus infection (n = 2), cytomegalovirus or Epstein–Barr virus infection (n = 2), and Nocardia infection (n = 1). Anti-TNF therapy was associated with a 2.5-fold increased risk of tuberculosis infection.
      A meta-analysis of 22 RCTs in patients with UC and Crohn’s disease reported malignancies in 0.39% (16/4135) of patients receiving anti-TNF therapies compared with 0.45% (13/2919) of patients receiving placebo (RR, 0.77; 95% CI, 0.37–1.59).
      • Williams C.J.
      • Peyrin-Biroulet L.
      • Ford A.C.
      Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor-alpha therapy in inflammatory bowel disease.
      There were no cases of lymphoma with anti-TNF therapy compared with 3 (0.1%) with placebo. Anti-TNF therapy did not appear to be associated with an increased risk of malignancy in trials of up to 1 year.
      The evidence grading is higher for golimumab,
      • Sandborn W.J.
      • Feagan B.G.
      • Marano C.
      • et al.
      Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis.
      which used a rerandomization design for maintenance, compared with adalimumab and infliximab,
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      • Reinisch W.
      • Sandborn W.J.
      • Rutgeerts P.
      • et al.
      Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies.
      • Sandborn W.J.
      • Colombel J.F.
      • D'Haens G.
      • et al.
      One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2.
      • Reinisch W.
      • Sandborn W.J.
      • Panaccione R.
      • et al.
      52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants.
      which used continuous treatment designs and thus were not true assessments of maintenance therapy contingent on successful induction. However, although the level of evidence may differ, the consensus group determined that there was no evidence to suggest clinical differences among the agents, and therapy should continue with the agent used to induce remission. There are few data beyond 1 year for most agents; therefore, the consensus group recommended that anti-TNF therapy be continued until loss of response. Patients should be informed of the potential safety issues, particularly when anti-TNF therapies are used in combination with corticosteroids or immunosuppressants.

       Statement 25. In patients with UC who have a suboptimal response to anti-TNF induction therapy, we recommend dose intensification to achieve complete remission

      GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree, 39%; agree, 61%.

       Statement 26. In patients with UC who lose response to anti-TNF maintenance therapy, we recommend optimizing dose to recapture complete remission

      GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree, 61%; agree, 39%.
      In patients with an inadequate response to initial anti-TNF therapy, it is important to consider dose intensification before deciding this to be a primary biologic failure. In RCTs, patients with higher serum anti-TNF concentrations have a higher probability of induction and maintenance of complete remission.
      • Adedokun O.
      • Xu Z.
      • Marano C.
      • et al.
      Effects of immunomodulators on the pharmacokinetics and efficacy of golimumab in patients with moderately to severely active ulcerative colitis: Results from phase 2/3 PURSUIT-SC induction and maintenance studies (abstr).
      • Bewernitz M.
      • Garnett C.
      • Gottlieb K.
      • et al.
      Assessment of adalimumab dose selection for adult ulcerative colitis using exposure-response analyses (abstr).
      • Reinisch W.
      • Feagan B.
      • Rutgeerts P.
      • et al.
      Infliximab concentration and clinical outcome in patients with ulcerative colitis (abstr).
      Higher trough levels have been associated with higher rates of mucosal healing.
      • Roblin X.
      • Marotte H.
      • Rinaudo M.
      • et al.
      Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases.
      • Hibi T.
      • Sakuraba A.
      • Watanabe M.
      • et al.
      Retrieval of serum infliximab level by shortening the maintenance infusion interval is correlated with clinical efficacy in Crohn's disease.
      During induction therapy, dose intensification can include increasing the dose or shortening the interval between doses.
      During maintenance therapy, a secondary loss of response may be the result of inadequate drug levels, which may, in some cases, reflect the development of ADAs.
      • Reinisch W.
      • Sandborn W.J.
      • Rutgeerts P.
      • et al.
      Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies.
      • Vande Casteele N.
      • Gils A.
      • Singh S.
      • et al.
      Antibody response to infliximab and its impact on pharmacokinetics can be transient.
      A retrospective analysis found that among 110 patients undergoing serum concentration testing because of loss of response or partial response, subtherapeutic concentrations were seen in 45% and ADAs in 17%.
      • Afif W.
      • Loftus Jr., E.V.
      • Faubion W.A.
      • et al.
      Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.
      In patients with subtherapeutic anti-TNF therapy concentrations, dose escalation was associated with a response in 86% of patients, whereas in antibody-positive patients, dose escalation had a response of only 17%. Similarly, in a prospective study of consecutive patients with IBD having a disease flare while on adalimumab maintenance therapy, dose optimization led to symptomatic response in 67% of patients with low adalimumab trough levels without ADAs but therapeutic failure in those with both low adalimumab levels and ADAs.
      • Roblin X.
      • Rinaudo M.
      • Del Tedesco E.
      • et al.
      Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases.
      In an open-label study of patients with Crohn’s disease with loss of response to infliximab, shortening the treatment interval from 8 to 4 weeks resulted in symptomatic responses in 83% of patients at week 54. A correlation between clinical efficacy and serum trough level was found (P < 0.01, overall).
      • Hibi T.
      • Sakuraba A.
      • Watanabe M.
      • et al.
      Retrieval of serum infliximab level by shortening the maintenance infusion interval is correlated with clinical efficacy in Crohn's disease.
      The consensus group concluded that doses of anti-TNF therapy should be optimized before considering anti-TNF therapy to be a failure. Ideally, this should be informed by therapeutic drug monitoring, but this is not universally available (see statement 27).

       Statement 27. We recommend that dose optimization for patients with UC be informed by therapeutic drug monitoring

      GRADE: Strong recommendation, low-quality evidence. Vote: strongly agree, 61%; agree, 35%; uncertain, 4%.
      The negative impact of low serum trough levels
      • Adedokun O.
      • Xu Z.
      • Marano C.
      • et al.
      Effects of immunomodulators on the pharmacokinetics and efficacy of golimumab in patients with moderately to severely active ulcerative colitis: Results from phase 2/3 PURSUIT-SC induction and maintenance studies (abstr).
      • Bewernitz M.
      • Garnett C.
      • Gottlieb K.
      • et al.
      Assessment of adalimumab dose selection for adult ulcerative colitis using exposure-response analyses (abstr).
      • Reinisch W.
      • Feagan B.
      • Rutgeerts P.
      • et al.
      Infliximab concentration and clinical outcome in patients with ulcerative colitis (abstr).
      • Roblin X.
      • Marotte H.
      • Rinaudo M.
      • et al.
      Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases.
      • Hibi T.
      • Sakuraba A.
      • Watanabe M.
      • et al.
      Retrieval of serum infliximab level by shortening the maintenance infusion interval is correlated with clinical efficacy in Crohn's disease.
      and ADAs on outcomes
      • Vande Casteele N.
      • Gils A.
      • Singh S.
      • et al.
      Antibody response to infliximab and its impact on pharmacokinetics can be transient.
      • Roblin X.
      • Rinaudo M.
      • Del Tedesco E.
      • et al.
      Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases.
      suggests the value of therapeutic drug monitoring in guiding management decisions. Therapeutic drug monitoring should include measurement of both the trough level of anti-TNF therapy and the titer of ADAs.
      In RCTs of anti-TNF maintenance therapy, approximately 3% of patients developed anti-golimumab antibodies during 1-year follow-up,
      • Sandborn W.J.
      • Feagan B.G.
      • Marano C.
      • et al.
      Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis.
      and approximately 15% of patients tested positive for antibodies to infliximab during up to 3 years of therapy.
      • Reinisch W.
      • Sandborn W.J.
      • Rutgeerts P.
      • et al.
      Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies.
      Among patients with secondary loss of response to anti-TNF therapy, approximately 20% will test positive for ADAs.
      • Afif W.
      • Loftus Jr., E.V.
      • Faubion W.A.
      • et al.
      Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.
      • Roblin X.
      • Rinaudo M.
      • Del Tedesco E.
      • et al.
      Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases.
      Although ADAs may be transient and may not always lead to a worse clinical outcome, sustained high-titer ADA levels lead to permanent loss of response.
      • Vande Casteele N.
      • Gils A.
      • Singh S.
      • et al.
      Antibody response to infliximab and its impact on pharmacokinetics can be transient.
      A study of consecutive patients with IBD and secondary failure to infliximab maintenance therapy used therapeutic drug monitoring to show that an increase in infliximab trough level after dose intensification strongly predicted the likelihood of achieving mucosal healing.
      • Paul S.
      • Del Tedesco E.
      • Marotte H.
      • et al.
      Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study.
      A retrospective analysis of therapeutic drug monitoring in patients with partial response or loss of response showed that a dose increase was more effective than switching anti-TNF therapies when trough levels were low, but changing to another anti-TNF therapy was more effective when antibodies were detected.
      • Afif W.
      • Loftus Jr., E.V.
      • Faubion W.A.
      • et al.
      Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.
      Conversely, in a prospective cohort study of patients with secondary biologic failure, the presence of high trough levels was associated with failure of 2 anti-TNF therapies in 90% of patients.
      • Roblin X.
      • Rinaudo M.
      • Del Tedesco E.
      • et al.
      Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases.
      The consensus group considered that therapeutic drug monitoring should be used (when available) to guide treatment decisions, particularly for secondary loss of response.

       Statements Regarding Other Agents

       Statement 28. In patients with primary failure to an anti-TNF therapy, we recommend switching to vedolizumab over switching to another anti-TNF therapy to induce complete corticosteroid-free remission

      GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree, 48%; agree, 43%; uncertain, 9%.

       Statement 29. In patients with secondary failure to an anti-TNF therapy, we recommend switching to another anti-TNF therapy or vedolizumab based on therapeutic drug monitoring results to induce complete corticosteroid-free remission

      GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree, 43%; agree, 57%.

       Statement 30. In patients with moderate to severe active UC who fail to respond to corticosteroids, thiopurines, or anti-TNF therapies, we recommend vedolizumab to induce complete corticosteroid-free remission

      GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 70%; agree, 26%; disagree, 4%.
      For patients with an inadequate response to anti-TNF therapy, dose intensification should first be considered (see statements 25 and 26). Ideally, this should be informed by therapeutic drug monitoring (see statement 25).
      In patients with biologic failure despite dose intensification, no studies have directly compared switching to vedolizumab and switching to an alternate anti-TNF therapy. The available observational data suggest that switching to a different anti-TNF therapy may be more effective in patients who develop ADAs and less effective in primary failure (see statements 25, 26, and 27).
      • Roblin X.
      • Marotte H.
      • Rinaudo M.
      • et al.
      Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases.
      • Afif W.
      • Loftus Jr., E.V.
      • Faubion W.A.
      • et al.
      Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.
      • Roblin X.
      • Rinaudo M.
      • Del Tedesco E.
      • et al.
      Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases.
      Because vedolizumab acts via a different mechanism than anti-TNF therapies, it is possible that switching to this class of agents may be effective in patients with either primary or secondary anti-TNF therapy failure.
      In the induction component of the GEMINI I trial, 374 randomized patients who had previously received therapy with corticosteroids, immunosuppressants, or anti-TNF therapies were randomized to vedolizumab or placebo.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      At week 6, vedolizumab showed significantly higher rates of complete remission compared with placebo in patients overall (16.9% vs 5.4%; P = .001) and numerically higher rates in patients with prior anti-TNF therapy (9.8% vs 3.2%), corticosteroid (21.4% vs 0%), or immunosuppressant failure (21.9% vs 10.9%).
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      • Parikh A.
      Efficacy of vedolizumab in ulcerative colitis by prior treatment failure in GEMINI I, a randomized, placebo-controlled, double-blind, multicenter trial (abstr P-29).
      Rates of symptomatic response were significantly higher in the overall patient population (47.1% vs 25.5%; P < .001) and those with prior anti-TNF therapy (39.0% vs 20.6%) or corticosteroid failure (59.5% vs 20.0%).
      • Parikh A.
      Efficacy of vedolizumab in ulcerative colitis by prior treatment failure in GEMINI I, a randomized, placebo-controlled, double-blind, multicenter trial (abstr P-29).
      In patients with prior corticosteroid failure, mucosal healing rates were dramatically improved with vedolizumab therapy compared with placebo (59.5% vs 24.0%). An earlier, small phase 2 dose-finding RCT found that symptomatic response rates with vedolizumab were approximately twice those of placebo (>50% vs 22%–33%).
      • Parikh A.
      • Leach T.
      • Wyant T.
      • et al.
      Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study.
      During the induction phase, the proportion of patients experiencing one or more adverse events was similar between the active treatment and placebo groups (40% vs 46%), and the rate of serious adverse events was lower with vedolizumab (2% vs 7%).
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      The most common adverse events reported with vedolizumab were headache, worsening disease activity, and infection.
      The consensus group concluded that vedolizumab is a useful option in patients who have failed to respond to corticosteroid, immunosuppressant, or anti-TNF therapy. No data are currently available regarding treatment strategies following failure of vedolizumab; however, a trial of anti-TNF therapy can be considered. The GEMINI I trial showed no significant differences in efficacy between 4-week and 8-week maintenance dosing but did show an exposure-response relationship.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      Patients assigned to 4-week dosing did not experience more adverse events than those who received treatment every 8 weeks. However in the absence of controlled data, dose intensification to 4-week dosing is not advocated. For patients who are unresponsive to induction with all medical therapies, or those with prolonged corticosteroid dependence, colectomy remains an option.
      • Dignass A.
      • Lindsay J.O.
      • Sturm A.
      • et al.
      Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management.
      • Bitton A.
      • Buie D.
      • Enns R.
      • et al.
      Treatment of hospitalized adult patients with severe ulcerative colitis: Toronto consensus statements.

       Statement 31. We recommend that patients with UC be evaluated for lack of symptomatic response to vedolizumab induction therapy in 8 to 14 weeks to determine the need to modify therapy

      GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree, 35%; agree, 65%.
      In the GEMINI I trial, vedolizumab showed significantly greater symptomatic response compared with placebo at week 6 (47.1% vs 25.5%; 95% CI, 11.6–31.7; P < .001).
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      Improvements in mean partial Mayo scores seemed to reach a maximum at week 6 and were maintained throughout the maintenance phase of the trial with little further improvement.
      The consensus group believed that in clinical practice, initial follow-up should occur before the first maintenance dose and thus recommended that symptomatic response be assessed at 8 to 14 weeks. This recommendation does not preclude earlier assessments, particularly for tolerability, if clinically indicated.

       Statement 32. In patients with UC who respond to vedolizumab, we recommend continued vedolizumab therapy to maintain complete corticosteroid-free remission

      GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 87%; agree, 13%.
      In the maintenance phase of the GEMINI I trial, patients who responded to blinded or open-label vedolizumab therapy (n = 373) were randomized to continued vedolizumab every 4 or every 8 weeks or placebo. At week 52, vedolizumab showed significantly higher rates of complete remission compared with placebo in patients in the overall group (44.8% and 41.8% vs 15.9%; P < .001). In patients who had failed to respond to corticosteroids, long-term mucosal healing rates were significantly higher with vedolizumab compared with placebo (60.0% and 68.4% vs 26.9%).
      • Parikh A.
      Efficacy of vedolizumab in ulcerative colitis by prior treatment failure in GEMINI I, a randomized, placebo-controlled, double-blind, multicenter trial (abstr P-29).
      No difference in efficacy was observed between dosing every 4 and every 8 weeks.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      In another small trial, vedolizumab was effective in maintaining complete remission in approximately 60% of patients treated with 8-week doses for up to 78 weeks. No new safety signals were observed during longer-term therapy.
      • Parikh A.
      • Fox I.
      • Leach T.
      • et al.
      Long-term clinical experience with vedolizumab in patients with inflammatory bowel disease.
      Analysis of safety findings from 9 clinical trials that included both patients with IBD and healthy controls (n = 579) showed vedolizumab to be well tolerated.
      • Feagan B.
      • Leach T.
      • Milch C.
      • et al.
      Emerging safety profile of vedolizumab: A novel, selective integrin inhibitor for the treatment of IBD (abstr P-0025).
      The proportion of patients experiencing one or more adverse events was similar between the active treatment and placebo groups (84% vs 87%), as was the rate of serious adverse events (12% vs 14%). The most common adverse events reported with vedolizumab were headache, nausea, abdominal pain, fatigue, and nasopharyngitis.
      • Feagan B.
      • Leach T.
      • Milch C.
      • et al.
      Emerging safety profile of vedolizumab: A novel, selective integrin inhibitor for the treatment of IBD (abstr P-0025).
      As of February 2013, no cases of progressive multifocal leukoencephalopathy had been reported in approximately 3000 patients exposed to vedolizumab for a median of 18.8 months.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      In the GEMINI I trial, serious infections were not more common with vedolizumab than with placebo.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      Among 620 patients, 3.7% of patients had at least one blood sample that was positive for anti-vedolizumab antibodies, and 1% had persistent anti-vedolizumab antibodies through week 52. Anti-vedolizumab antibodies were detected in 10% of patients when measured at week 66 (after the drug was no longer in the patient’s system).
      • Rosario M.
      • Wyant T.
      • Milch C.
      • et al.
      Pharmacokinetic and pharmacodynamic relationship and immunogenicity of vedolizumab in adults with inflammatory bowel disease: Additional results from the GEMINI 1 and 2 studies (abstr DOP058).
      The use of concomitant immunosuppressant therapy was associated with decreased immunogenicity. Based on these data and experience with other monoclonal antibodies, the consensus group believed that combination immunosuppressant therapy should be considered when using vedolizumab.
      Based on favorable 1-year efficacy and safety data, the consensus group recommended ongoing maintenance therapy in patients who respond to induction with vedolizumab.

       Statement 33. In patients with UC, we recommend against fecal microbial transplant to induce or maintain complete remission outside the setting of a clinical trial

      GRADE: Strong recommendation, low-quality evidence. Vote: strongly agree, 70%; agree, 30%.
      Data are insufficient to support the use of fecal microbial transplant (FMT) in patients with UC. Although case reports have suggested benefits,
      • Moayyedi P.
      • Marshall J.K.
      • Yuan Y.
      • et al.
      Canadian Association of Gastroenterology position statement: fecal microbiota transplant therapy.
      interim analysis of the first RCT of FMT in 63 patients with active UC found no significant benefits of FMT at week 7.
      • Moayyedi P.
      • Surette M.
      • Wolfe M.
      • et al.
      A randomized, placebo controlled trial of fecal microbiota therapy in active ulcerative colitis (abstr 929c).