TITLE: Managing Crohn s Disease in Adults: A Summary of the Guidelines

Transcription

1 TITLE: Managing Crohn s Disease in Adults: A Summary of the Guidelines DATE: 24 March 2009 CONTEXT AND POLICY ISSUES: Crohn s disease (CD) is one of two main disease categories of inflammatory bowel disease (IBD); the other being ulcerative colitis. 1 In Canada, approximately 200,000 men and women suffer from IBD and most are diagnosed by the age of CD is a chronic disorder of unknown etiology whereby the digestive or gastrointestinal (GI) tract is inflamed due to the inappropriate response of the patient s immune system. 1,3 The immune system attacks bacteria and other organisms normally found in the intestines resulting in chronic inflammation. 1 This leads to ulcerations and bowel injury causing the patient to experience the symptoms of IBD. 1 Symptoms might include fatigue, diarrhea, abdominal pain, and cramping (with or without gross bleeding) as well as symptoms outside of the GI tract including episcleritis (often confused with pink eye ) and arthritis. 1-3 In addition, symptoms of perianal disease (e.g., perirectal abscess and fistulae) and fistulae in areas adjacent to the diseased bowel segment (e.g., enteroenteric fistula, enterovaginal fistula) may occur. 3 CD can involve any area of the GI tract from the mouth to the anus. 1 It most commonly affects the end of the small intestine (i.e., ileum) and/or the beginning of the large intestine (i.e., the colon). 1 There is no cure for CD. 1 Patients go through intermittent exacerbations of symptoms followed by periods of remission. 3 The goal of treatment is to suppress the inflammatory response in order to allow the intestinal tissue to heal, and to relieve the symptoms. 1 Symptoms of CD are managed through pharmacological agents, surgery, or both. 2 There are various groups of drugs that can be used to treat CD, including aminosalicylates (5-ASA), corticosteroids, antibiotics, and biologic therapies. 1,4 Surgery is undertaken in two-thirds to three-quarters of patients with CD when medication no longer controls the symptoms, to repair a fistula or fissure, when there is an intestinal obstruction, or when there is another complication like an intestinal abscess. 1 Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information on available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 Patients with CD usually require continuous medication. 5 This report was requested because CD patients may not all have access to specialists and so they must rely on their family physician to manage their CD. Thus, it is important that family physicians are updated as to the most recent, evidence-based guidelines for treating CD in order to help patients achieve the best possible quality of life. RESEARCH QUESTIONS: 1. What are the evidence-based guidelines for pharmacologic management of adult patients with Crohn s disease? 2. What are the evidence-based guidelines for treating adult patients pharmacologically during an exacerbation of Crohn s disease? METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, The Cochrane Library (Issue 1, 2009), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. Results include articles published between 2004 and February 2009, and are limited to English language publications only. Filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, and guidelines. Only relevant articles that provided evidence-based guidelines from Canada, United Kingdom, Europe, and the United States were considered for inclusion. SUMMARY OF FINDINGS: Seven relevant evidence-based guidelines were identified. No Canadian guidelines were retrieved. Within some of these guidelines there is information on treating adult patients during an exacerbation of CD. Guidelines or recommendations for indications for surgery were omitted as this topic is outside of the scope of the current HTIS report. Additional articles that may be of interest are in Appendix 1. As the management of CD is complex, and the guidelines quite detailed, it is suggested that the full article(s) of interest are obtained for patient treatment. Guidelines and recommendations Lichtenstein et al. 6 published guidelines on managing CD in adults in The guidelines were developed in consultation with the American College of Gastroenterology and its Practice Parameters Committee. The committee reviewed the guidelines along with available evidence and clinical expert advice. The severity of CD was categorized according to the Crohn s Disease Activity Index (CDAI) score. CD in remission usually corresponds to a score of <150, mild to moderate disease activity corresponds to a score between 150 and 220, moderate to severe disease activity corresponds to a score between 220 and 450, and severe/fulminant disease corresponds to a score >450. Other patient symptoms can be indicative of disease severity. These are presented in the guideline with the intent to provide a more clinical working definition for practitioners. The authors of the report disclosed that they were involved with industry during the time the report was underway. Managing Crohn s Disease in Adults 2

3 Briefly, the recommendations for patients with mild to moderate disease activity stated that budesonide or conventional corticosteroids could be used in ileal, ileocolonic, or colonic disease and sulfasalazine could be effective for ileocolonic or colonic disease. For patients with moderate to severe CD, prednisone could be effective. The guidelines were also given a grading of A (at least one RCT of good quality was retrieved), B (non-randomized clinical studies), and C (expert opinion or clinical experience). Appendix 2, Table 1 provides a summary of the recommendations (and grade) for patients with active, inflammatory CD. The guidelines stated that once patients achieve medically-induced remission, maintenance therapy is required. The recommendation for patients with steroid-induced remission was that azathioprine (AZA)/6-mercaptopurine (6-MP) could be effective, and if the disease was steroid refractory or steroid-dependent, parenteral methotrexate (MTX) might be effective. In a patient who has not responded to a corticosteroid or an immunosuppressive agent, infliximab (IFX), adalimumab, or certoizumab pegol may be effective. In severe/fulminant disease, once the presence of an abscess has been excluded or if the patient has been receiving corticosteroids, parenteral corticosteroids equivalent to 40 to 50 milligrams (mg) of prednisone daily or its equivalent could be administered. Sulfasalazine and mesalamine were not found to have consistent benefits. Lichtenstein et al. 6 provided recommendations for treatment in patients with medically-induced remission. AZA, 6-MP, MTX, and IFX were all indicated as providing therapeutic benefits. Sulfasalazine, mesalamine, and conventional corticosteroids were not found to be an effective therapy. Budesonide was found to be effective, but only for six months. See Appendix 2, Table 2 for additional details. In 2007, Sandborn et al. 7 published an American study on evidence-based treatment algorithms for mild to moderate CD. While the authors reported that it was a systematic review, they did not report how study selection was performed, thus it remains unknown whether the review was indeed performed systematically (and therefore less prone to bias). Industry was involved in the editing of the article. For patients with mild to moderate CD, it was found that sulfasalazine, budesonide, prednisone, and IFX were all possible treatment options. For patients in remission, budesonide could be administered as induction therapy. For patients who received induction prednisone or prednisolone therapy, immunosuppressants may be the best choice. Each guideline was graded as A, B, or C depending on the evidence supporting the guideline. See Appendix 3, Table 1 for more details on treatment options and grading for active mild to moderate CD and Appendix 3, Table 2, for more details on treatment options and grading for remission of mild to moderate CD. Vader et al. published guidelines resulting from the Expert Panel on the Appropriateness of Crohn s Disease Therapy (EPACT) in 2007 on treatment for active CD. 5 The EPACT consisted of a panel of 15 specialists comprised of 10 gastroenterologists, 3 surgeons, and 2 internists/general practitioners from twelve European countries. 8 The panel developed criteria to assess the appropriateness of therapeutic options with the motive to assist clinicians in their decision-making. 8 This was done using the RAND Appropriateness Method (RAM) which is a multi-step process. 8 Briefly, the process included performing a systematic and critical review of the literature, grading the quality of the evidence according to preset criteria, preparing clinical situation/scenarios (with ongoing expert feedback) based on the literature, submitting the scenarios to the panel of experts who rated the appropriateness of the proposed clinical Managing Crohn s Disease in Adults 3

4 scenarios, and integrating these opinions along with final literature documents and clinical scenarios and forwarding them to a formal meeting of the experts, where the final appropriateness was rated. 8 The goal was to incorporate expert experience to bridge the gaps where high-level evidence was lacking. 5 Treatments that were currently under development or testing were not included. 5 The panel rated the therapeutic appropriateness of 569 clinical presentation scenarios (that each described patient, disease, and treatment characteristics). The focus of the panel was on medical, not surgical therapy. Industry provided funding. The authors concluded that for mild to moderate colonic disease, it was appropriate to consider sulfasalazine, mesalazine (if it has had prior success), and prednisone as they were all potentially effective therapy choices. Budesonide, AZA/6-MP, MTX, IFX, and natalizumab were considered inappropriate choices. The guidelines stated that it was uncertain whether antibiotics were appropriate. For mild to moderate ileocolonic disease, budesonide and prednisone were appropriate choices. The authors were uncertain whether 5-ASA could be used. The guidelines stated that it was inappropriate to consider antibiotics, AZA/6-MP, MTX, IFX, and natalizumab. For severe CD, systemic corticosteroids were an appropriate choice [especially intravenous (IV)], as well as prednisone, MTX, IFX with AZA/6-MP, as well as adding immunomodulating therapy to IFX. For more details on these therapies along with treatment appropriateness for when there are complications in CD like steroid-dependency, see Appendix 4, Table 1. The guidelines presented did not have an associated quality of evidence grading. For maintenance therapy, the guidelines indicated that patients with a low-frequency of relapse might be best to receive no therapy other than to advise patients who smoke to stop smoking. However, when there is a high-frequency of relapse, patients might consider taking AZA/6-MP (if not previously given or previously successful), MTX (if previous failure with AZA/6-MP, previous success with MTX, or never received MTX), or IFX (if previous failures with AZA/6-MP and MTX). It was uncertain whether natalizumab should be considered. 5-ASA was considered an inappropriate choice. Appendix 4, Table 1 contains more information on maintenance therapy. Froehlich et al. 9 published a report in 2007 on the maintenance of surgically induced remission in CD. This article is conducted by the same group and updates and replaces the work published by Vader et al. 5 and thus, that section of Vader s work was not summarized. As there was no methodology section, the evidence base used to generate the guidelines remains unclear. This may indicate a greater chance of bias in both the literature reviewed and conclusions made by the authors. Definitions for CD activity such as relapse and remission were not reported. The authors declared there was no conflict of interest. For maintaining remission, the authors concluded that best treatment option was sulfasalazine. They noted that mesalazine was usually the first-line therapy, even though it had questionable efficacy. 6-MP was considered more effective than mesalazine. It was stated that immunosuppressive therapy was often selected as second-line therapy although there was high risk of recurrence and little evidence of efficacy. Nitroimidazole antibiotics were considered effective as initial (post-operative), short-term prevention therapy. Budesonide did not appear to be effective and conventional steroids were deemed inappropriate treatment. For more details on the guidelines, see Appendix 5, Table 1. The guidelines were not graded for quality of evidence; however, the evidence used to make the decisions was often stated and is included in Table 1. Managing Crohn s Disease in Adults 4

5 Travis et al. 10 published guidelines on managing CD in These guidelines are part of the European Crohn s and Colitis Organization (ECCO) Consensus on the management of CD. The focus of the article is on the treatment of active disease and maintaining medically-induced remission. The authors provided guidelines based on site of disease, disease activity, and behaviour of the disease (e.g., response to previous medications). In addition, the authors supported the strategy that patients should have a voice in their treatment options. The treatment guidelines were based on varying rigor and amount of evidence and clinical expert opinion. Full details of the evidence-base can be found in the ECCO Statement guideline. Funding from several pharmaceuticals companies was received. There was a subsequent report published in 2006 by Strange et al. 11 that summarized the definitions and diagnoses used in the Travis 10 report. Crohn s disease severity of mild, moderate, and severe corresponded to the CDAI scores of 150 to 220, 220 to 450, and > 450, respectively. The summary of these treatment guidelines for active CD are provided in Table 1 (see Appendix 6, Table 1 for a more detailed summary). The evidence used to develop most of the guidelines was reported; however, guideline quality was not given a rating or grade. Table 1. Summary of Treatment Options of Active Crohn s Disease, by Disease Site and/or Activity 10 Disease Site, Guideline Activity localized ileocaecal, budesonide recommended mildly active no treatment for some patients with mild symptoms antibiotics not recommended mesalazine, limited benefit localized ileocaecal, budesonide or systemic corticosteroids recommended moderately active can add antibiotics if septic complications suspected localized ileocaecal, severely active colonic, active small bowel, extensive, active (>100 cm) initially treat with systemic corticosteroids in relapse, add AZA/ 6-MP(or MTX if intolerant) in addition, IFX if intolerant to or refractory to corticosteroid, immunomodulator or surgery is determined to be inappropriate, or if severe inflammatory activity antibiotics only if septic complication surgical options should be considered sulfasalazine or systematic corticosteroid (prednisolone or equivalent) recommended daily if mildly active; if relapsed, add AZA/6-MP; if intolerant to AZA/6-MP, consider adding MTX in addition, recommend IFX if intolerant to or refractory to corticosteroid or immunomodulator, surgery is determined to be inappropriate, or if current, severe inflammatory activity surgical options should be considered topical treatment can be considered for distal disease systemic corticosteroids recommended if moderate or severe if relapsed, add AZA/6-MP; if intolerant to AZA/6-MP, consider adding MTX adjunctive nutritional support (or primary treatment if disease is mild) is recommended consider adding IFX if treatment fails and if area is currently inflamed Managing Crohn s Disease in Adults 5

6 Disease Site, Activity esophageal and gastroduodenal, active Guideline surgical options should be considered topical treatment should be considered for distal disease proton pump inhibitors are recommended may add systemic corticosteroids and AZA/6-MP or, if intolerant, MTX if refractory disease, can use IFX if obstructive symptoms, dilatation or surgery are options 5-ASA=aminosalicylates; AZA=azathioprine; 6-MP=6-mercaptopurine; CD=Crohn s Disease; IFX=infliximab; MTX=methotrexate The authors concluded that when patients initially entered remission, options included mesalazine, AZA (if remission was achieved with systemic corticosteroids or IFX), 6-MP (if patients were intolerant to AZA or if remission was achieved with IFX), or MTX (if patients were intolerant of thiopurines). 5-ASA was not found to be an effective treatment. More details are provided in Appendix 6, Table 2. For patients who are in medically-induced remission, the best choices were AZA, 6-MP, MTX (at least in patients who achieved remission with MTX), or IFX (infusion every eight weeks). Appendix 6, Table 2 provides some more detail on patients in medically-induced remission. Additional guideline information from Travis et al. can be found in Appendix 6, Tables 3 through 5. Table 3 provides a summary of active CD by behaviour of the disease (i.e., early relapse, corticosteroid dependent and corticosteroid refractory). Table 4 provides a summary of treatment options of active CD by therapy (e.g., 5-ASA, antibiotics, and corticosteroids), and Table 5 provides a summary of treatment options for active CD by disease course. 10 Buning et al. published an article in 2006 providing guidelines for practitioners regarding conventional therapy for CD. 12 The methodology was not explicitly reported but there was mention that the evidence focus was on RCTs and meta-analyses and where evidence from controlled clinical trials was lacking, expert opinion was included. Thus, it is unknown how the literature search was conducted, which databases were used, and how expert consultation was performed. The authors did not explicitly state how they defined disease activity for the purpose of their report but did report that disease activity could be defined using CDAI values of 150 and below to indicate remission, values between 150 and 450 to indicate active disease, and a score of >450 to indicate extremely severe disease. The authors stated that other diagnostic tests (e.g., C-reactive protein, blood sedimentation rate) can provide input into disease activity. The authors also reported the definitions for clinical practice provided by the American College of Gastroenterology. For example, the definition for moderate to severe disease: is when patients have failed to respond to mild to moderate disease treatment or those with more prominent symptoms such as fever, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings). (p4795) 12 The summary statements of therapy were not graded and it was not clear what evidence supported the therapy recommendations. No conflict of interest or funding information was provided. For treating active CD, the first-line therapies mentioned were 5-ASA and budesonide. Other therapies that could be effective in more specific situations were systemic corticosteroids, AZA, IFX, IV cyclosporine, and tacrolimus. In addition, antibiotics may be used as additional therapy if Managing Crohn s Disease in Adults 6

7 an infectious complication was suspected. Appendix 7, Table 1 provides more detailed treatment information for active CD. For maintaining surgically-induced remission in CD, mesalamine and AZA/6-MP were both found to be effective. Mesalamine would not be appropriate, however, if it was the treatment used to induce the remission itself. For patients with medically-induced remission, preferable treatment options were AZA or 6-MP, budesonide, MTX, IFX, or no treatment. Appendix 7, Table 2 provides more detailed information. For patients with complications in CD like fistulizing CD, and chronically active CD, see Appendix 7, Table 3. In 2004, Carter et al. published guidelines for managing IBD in adults. 13 The guidelines were based on a literature search which was also circulated to the IBD section of the British Society of Gastroenterology (BSG) before submitting it to the Clinical Service Committee of the BSG. The guidelines were also given a grading of A, B, or C. The authors also stated that the guidelines should be revised within three years of publication to account for new evidence; thus, these guidelines are outdated. Conflict of interest was not stated, nor was whether there was industry involvement. Recommendations were provided for treating active CD. For active ileal, colonic, or ileocolonic disease, the overall recommendation stated was to initially treat with mesalazine, corticosteroids, nutritional therapy, or undergo surgery. Treatment was to be tailored to severity of disease and patient s opinion. For patients with chronically active and steroid-dependent disease (relapse within 6 weeks of stopping dose or reducing dose to <20 mg/day), the overall recommendation was to treat the patient with immunomodulators (AZA, 6-MP, or MTX if steroids could not be withdrawn without deterioration of disease activity). There was no recommendation for fistulating and perianal disease as there was a lack of controlled clinical trials. See Appendix 8, Table 1 for more detailed information on treating active CD. For patients with remission, the effective treatment strategies were to advocate cessation of smoking as well as to use immunomodulators (i.e., AZA, 6-MP or MTX, with conditions). Other options were stated as well. See Appendix 8, Table 2 for more information. Limitations No Canadian guidelines were retrieved. Thus, the treatment guidelines might not reflect what Canadian experts are advising. As clinical expert advice does play a significant role in the guidelines (to bridge the many evidence gaps), it is unclear how generalizable the guidelines are to the Canadian population. Due to the complexity of CD, a comprehensive summary of the guidelines is not plausible. One issue is that treatment suggestions are based in part on how the CD is classified and this can vary. While the CDAI is used in trials and is one way to classify disease severity and activity, some researchers attempted to use a more clinical approach to classifying disease severity (e.g., Varder et al. 5 and Froelich et al. 9 ). Some researchers also chose to provide specific recommendations based not only on disease activity and severity but also on location of disease (e.g., Travis et al. 10 ). In addition, course of treatment is based on each patient s history of treatment response, tolerance, and preference, which also varies. Furthermore, recommendations can be based on a variety of evidence rigour, from systematic review/metaanalyses to case series to expert opinion. Managing Crohn s Disease in Adults 7

8 Some of the guidelines retrieved had industry involvement. Industry involvement, either through funding or editing privileges, may increase the risk of bias. It was also uncertain what the typical patient was for the guidelines as age, gender, ethnicity, and co-morbidities were often not discussed. So, it is uncertain how treatment effectiveness can be generalized and utilized by various patients. No computer algorithms or computer-based information systems to help treat patients with CD were identified. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: Treating CD is a complex endeavor. Recent American and European guidelines provide insight into various treatment strategies that can be used. The guidelines contained within the appendices provide information on the evidence level with which recommendations are based, thus clarifying which treatment options are based on more or less rigorous evidence and which guidelines are based on expert opinions. However, the treatment guidelines may not be appropriate for all patients; for example, those in special circumstances, such as pregnant women. There are abundant pharmaceutical therapies that can be used for various stages, locations, and severities of CD. It is not plausible to indicate what the common first-line, second-line, and third-line treatments should be used for CD, as it is a complex disease and treatment depends on each patient s situation. Knowledge of the patient s history, as well as the patient s opinion and circumstances, should be considered by clinician s when deciding how to best manage active CD or maintain remission. The full guidelines contain abundant information and therefore, should be consulted when deciding on a course of action for patients with CD. PREPARED BY: Rhonda Boudreau, M.A, B.Ed, B.A, Research Officer Carolyn Spry, M.L.I.S, Information Specialist Health Technology Inquiry Service htis@cadth.ca Tel: Managing Crohn s Disease in Adults 8

9 REFERENCES: 1. About Crohn's Disease. In: Disease information. New York: Crohn's & Colitis Foundation of America (CCFA); Available: (accessed 2009 Feb 25). 2. What is inflammatory bowel disease (IBD)? In: Crohn's & colitis. Toronto: Crohn's & Colitis Foundation of Canada; Available: (accessed 2009 Feb 25). 3. Peppercorn MA. Clinical manifestations, diagnosis and natural history of Crohn's disease in adults. In: UpToDate [database online]. Version Waltham (MA): UpToDate; Farrel RJ, Peppercorn MA. Medical management of Crohn's disease in adults. In: UpToDate [database online]. Version Waltham (MA): UpToDate; Vader JP, Froehlich F, Juillerat P, Burnand B, Felley C, Gonvers JJ, et al. Appropriate treatment for Crohn's disease: methodology and summary results of a multidisciplinary international expert panel approach--epact. Digestion 2006;73(4): Lichtenstein GR, Hanauer SB, Sandborn WJ, Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol 2009;104(2): Sandborn WJ, Feagan BG, Lichtenstein GR. Medical management of mild to moderate Crohn's disease: evidence-based treatment algorithms for induction and maintenance of remission. Aliment Pharmacol Ther 2007;26(7): Caprilli R, Michetti P. The European Panel on the Appropriateness of Crohn's Disease Therapy. Digestion 2005;71(1): Froehlich F, Juillerat P, Pittet V, Felley C, Mottet C, Vader JP, et al. Maintenance of surgically induced remission of Crohn's disease. Digestion 2007;76(2): Travis SPL, Stange EF, Lémann M, Öresland T, Chowers Y, Forbes A, et al. European evidence based consensus on the diagnosis and management of Crohn's disease: current management. Gut 2006;55(Suppl 1):i16-i35. Available: (accessed 2009 Feb 25). 11. Stange EF, Travis SP, Vermeire S, Beglinger C, Kupcinkas L, Geboes K, et al. European evidence based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis. Gut 2006;55(Suppl 1):i1-i15. Available: (accessed 2009 Mar 10). 12. Buning C, Lochs H. Conventional therapy for Crohn's disease. World J Gastroenterol 2006;12(30): Available: (accessed 2009 Feb 25). Managing Crohn s Disease in Adults 9

10 13. Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004;53(Suppl 5):v1-v16. Available: (accessed 2009 Feb 25). Managing Crohn s Disease in Adults 10

11 APPENDIX 1: Additional References 1. Juillerat P, Pittet V, Felley C, Mottet C, Froehlich F, Vader JP, et al. Drug safety in Crohn's disease therapy. Digestion 2007;76(2): PM: This article is a review of the adverse events with 5-ASA compounds, antibiotics, corticosteroids, thiopurines, methotrexate, anti-tumour necrosis factor inhibitors, natalizumab, anticalcineurin inhibitors, and mycophenolate mofetil. This review updates and replaces a prior review done as preparatory work for the European Panel on the Appropriateness of Crohn s Disease Therapy (EPACT). (p161) 2. Adalimumab resubmission #3 (Humira - Abbott Laboratories Ltd.): CEDAC final recommendation and reasons for recommendation. Ottawa: Canadian Agency for Drugs and Technologies in Health (CADTH); Available: pdf (accessed 2009 Feb 25). The committee recommends that adalimumab be listed for moderate to severely active Crohn s disease in patients with refractory or with contraindications to an adequate course of 5-aminosalicylic acid and corticosteroids and other immunosuppressive therapy. (p1) 3. Cullen G, Keegan D, Mulcahy HE, O'Donoghue DP. A 5-year prospective observational study of the outcomes of international treatment guidelines for Crohn's disease. Clin Gastroenterol Hepatol 2009;7(3): PM: The authors concluded that, based on a case series of 102 newly diagnosed Crohn s Disease patients, when current American Gastroenterology Association Institute and European Crohn s and Colitis Organisation guidelines are strictly followed, patients with moderate to severe Crohn s disease can achieve high rates of remission and low rates of morbidity at five years. Managing Crohn s Disease in Adults 11

12 APPENDIX 2: Summary Tables for Lichtenstein, et al. 6 Table 1. Summary of Recommendations for Patients with Active, Inflammatory Crohn s Disease 6 Disease State Recommendation (evidence level) mild to moderate mesalamine minimally effective in ileal, ileocolonic or colonic disease (Grade A) mesalamine less effective than budesonide or conventional corticosteroids in ileal, ileocolonic or colonic disease (Grade A) metronidazole,10 to 20 mg/kg/day, used in patients not responding to sulfasalazine ileocolonic, or colonic disease (Grade C) controlled ileal release budesonide (9mg/day) effective when active disease is confined to the ileum and/or right colon (Grade A) sulfasalazine for ileocolonic or colonic disease, 3 to 6 mg/daily (Grade A) anti-tuberculosis therapy not effective(grade A) moderate to severe prednisone, 40 to 60 mg/day, until symptom resolution and weight gain (Grade A) antibiotic therapy or drainage for infection or abscess (Grade C) corticosteroids more effective than elemental diets but elemental diets avoid the toxicities associated with corticosteroids (Grade A) AZA/6-MP effective for maintaining steroid-induced remission (Grade A) parenteral MTX at 25 mg/week effective for steroid-dependent and steroid refractory disease (Grade B) IFX, adalimumab, and certolizumab pegol effective in patients who have not responded to corticosteroid or immunosuppressive agents (Grade A) IFX monotherapy and IFX with AZA are more effective than AZA in patients who have failed to respond to mesalamine and/or corticosteroids (Grade A) IFX, adalimumab, certolizumab pegol (anti-tnf monoclonal antibody therapy) alternatives to steroid therapy in patients with contraindications to corticosteroids (Grade B) natalizumab effect for patients with inadequate or tolerability issues with conventional therapies and anti-tnf monoclonal antibody therapy (Grade A) severe/fulminant once presence of abscess have been excluded or if the patient has been receiving corticosteroids, parenteral corticosteroids equivalent to 40 mg to 50 mg of prednisone daily or its equivalent (Grade C) perianal and fistulizing elemental feeding or parental hyperalimentation for 5 to 7 days in patients unable to maintain adequate nutritional requirements (Grade C) surgical drainage (with or without placement of non-cutting setons) is appropriate for acute suppuration (Grade C) antibiotics (Grade C), immunosuppressive (Grade C), or IFX (Grade A) for non-suppurative, chronic fistulization or perianal fissuring 5-ASA=aminosalicylates; AZA=azathioprine; 6-MP=6-mercaptopurine; IFX=infliximab; kg=kilograms; MTX=methotrexate; mg=milligram Grade A=RCTs or cohorts, homogenous evidence, adequate power; Grade B=at least one RCT or cohort or casecontrol, large and well designed meta-analysis; Grade C=descriptive, clinical experience or expert committee reports Managing Crohn s Disease in Adults 12

13 Table 2. Summary of Recommendations for Patients with Medically-Induced Remission of Crohn s Disease 6 Treatment Recommendation sulfasalazine and mesalamine, no consistent benefits (Grade A) long-term conventional corticosteroids not recommended to prevent relapse (Grade A) budesonide at 6 mg/day reduces time to relapse in ileal and/or right colonic disease but benefits disappear after six months (Grade A) AZA/6-MP and MTX beneficial after corticosteroid-induced remission (Grade B) AZA effective if IFX-induced remission in steroid-naïve patients (Grade B) IFX monotherapy and IFX combined with AZA are more effective than AZA alone in patients who have failed to respond to mesalamine and or corticosteroids (grade B) natalizumab is effective (Grade A) metronidazole (Grade B), mesalamine (Grade C), AZA-6-MP (Grade B), or IFX (Grade B) should be considered after ileocolonic resections conventional corticosteroids (Grade A) not effective budesonide at 6 mg/day (Grade B) not effective 5-ASA=aminosalicylates; AZA=azathioprine; 6-MP=6-mercaptopurine; IFX=infliximab; mg=milligram; MTX, methotrexate Grade A=RCTs or cohorts, homogenous evidence, adequate power; Grade B=at least one RCT or cohort or casecontrol, large and well designed meta-analysis; Grade C=descriptive, clinical experience or expert committee reports Managing Crohn s Disease in Adults 13

14 APPENDIX 3: Summary Tables for Sandborn et al. 7 Table 1. Summary of Maintenance Guidelines for Mild to Moderate Crohn s Disease 7 Treatment Guideline sulfasalazine 3 to 6 g/day in patients with disease in the left colon (Grade A) budesonide 9 g/day for disease involving the ileum and/or proximal colon (Grade A) prednisone when patients fail to respond to sulfasalazine or budesonide (Grade B) or have systemic systems (Grade A) IFX in patients who fail to respond to sulfasalazine or budesonide or in patients intolerant to prednisone (Grade B) g=grams; IFX=infliximab Grade A=RCTs or cohorts, homogenous evidence, adequate power; Grade B=at least one RCT or cohort or casecontrol, large and well designed meta-analysis; Grade C=descriptive, clinical experience or expert committee reports Table 2. Summary of Remission Guidelines for Mild to Moderate Crohn s Disease 7 Treatment Guideline budesonide 6 g/day for up to 3 to 6 months for patients receiving induction budesonide therapy (Grade A) immunosuppression for patients receiving induction prednisone or prednisolone therapy (Grade A) no evidence for patients receiving induction budesonide therapy or for patients receiving induction sulfasalazine therapy g=grams Grade A=RCTs or cohorts, homogenous evidence, adequate power; Grade B=at least one RCT or cohort or casecontrol, large and well designed meta-analysis; Grade C=descriptive, clinical experience or expert committee reports Managing Crohn s Disease in Adults 14

15 APPENDIX 4: Summary Table for Vader et al. 5 Table 1. Summary Statements on Appropriateness of Crohn s Disease Treatment 5 Disease Description Treatment Appropriateness mild to moderate luminal sulfasalazine and mesalazine, appropriate if mesalazine had shown prior success -colonic disease prednisone appropriate (regardless of prior success with 5-ASA or steroids) budesonide AZA/6-MP, MTX, IFX, natalizumab, inappropriate antibiotics uncertain appropriateness when 5-ASA has failed and no prior experience with steroids iieocolonic budesonide and prednisone appropriate 5-ASA, disagreement on appropriateness if budesonide previously successful, uncertain if budesonide had previously failed antibiotics, AZA/6-MP, MTX, IFX, natalizumab, inappropriate severe luminal systemic corticosteroids (1 mg/kg/day) appropriate (IV preferably) even if steroids had failed in the past adding immunomodulating therapy to IFX appropriate IFX associated with AZA/6-MP, MTX appropriate prednisone >20 mg/day appropriate Limited anatomical extension steroids are preferred option, even if history of failure IFX appropriate if prior history of success or failure of steroids IFX inappropriate if previously unsuccessful (regardless of past response to steroids or extent of disease) surgery when patients had prior failure of IFX and steroids, disagreement as to appropriateness surgery and repeated steroid therapy rated appropriate if prior failure of both steroids and IFX Extensive disease uncertain/disagreement as to appropriateness of cyclosporine, tacrolimus, natalizumab, and surgery after failure of both steroids and IFX mycophenolate not appropriate steroid dependent AZA/6-MP the most appropriate if MTX successful in past, AZA/6-MP or MTX MTX if AZA/6-MP failed IFX if AZA/6-MP and MTX failed if 20 mg prednisone/day then IFX did not require concurrent immunosuppressive agent surgery appropriate after AZA/6-MP and MTX failure in limited disease disagreement on use of MTX in AZA/6-MP naïve patients disagreement on IFX after AZA/6-MP failure in patients with previous MTX success Managing Crohn s Disease in Adults 15

16 Disease Description Treatment Appropriateness steroid refractory IFX plus immunosuppression the most appropriate regardless of history with AZA/6-MP or MTX IFX alone appropriate with previous failure of MTX, but disagreement AZA/6-MP and MTX alone, disagreement on appropriateness if patient s condition and time permitted, classical immunosuppressants should be favoured surgery appropriate when previous failure of AZA/6-MP, MTX, and IFX and for limited disease only fistulizing Simple fistula abscess drainage prerequisite to medical therapy AZA/6-MP appropriate if antibiotics and surgery were not controlling the lesions IFX appropriate if failure of antibiotics, surgery, and immunosuppressive therapy antibiotics, if never used before Complex fistula abscess drainage prerequisite to medical therapy antibiotics, if never used before AZA/6-MP are appropriate IFX if AZA/6-MP are not controlling the disease aggressive surgery (e.g., derivation) appropriate if IFX fails MTX, cyclosporine, tacrolimus inappropriate fibrostenotic AZA/6-MP, steroids, MTX, and IFX inappropriate for a stenosis >7 cm maintenance of medicallyinduced low-frequency of relapse remission smoking cessation the only appropriate intervention high frequency of relapse smoking cessation AZA/6-MP appropriate if not previously given or previously successful MTX appropriate with AZA/6-MP failure or never received MTX or previous success with MTX IFX appropriate with AZA/6-MP and MTX failure 5-ASA not appropriate natalizumab insufficient evidence to assign appropriateness 5-ASA=5 aminosalicyclic acid; 6-MP=6-mercaptopurine; AZA=azathioprine; IFX=infliximab; IV=intravenous; kg=kilogram; mg=milligram; MTX=methotrexate Managing Crohn s Disease in Adults 16

17 APPENDIX 5: Summary Table for Froehlich et al. 9 Table 1. Maintenance of Crohn s Disease After Surgically-Induced Remission 9 Treatment Option Effectiveness/Recommendation mesalazine uncertain whether it reduces post-operative recurrence ( 1 MA) 4 g/day has no advantage in recurrence over 2 g/day, correct dosage uncertain ( 1 MA) sulfasalazine is historically been effective (at 2 years) but is rarely used (no statement was to why) (NK) usually first-line of treatment (despite controversy in its efficacy) immunosuppressive 6-MP effective in preventing relapse at (2 years) ( 1 RCT) therapy 6-MP more effective than mesalazine ( 1 RCT) immunosuppressive therapy is used even with little evidence, high risk of recurrence ( 1 RCT) usually second-line treatment in patients at high risk of recurrence, with symptoms or with early endoscopic lesions in the neoterminal ileum (NK) nitroimidazole antibiotics (metronidazole, ornidazole) effective at controlling active CD in postoperative setting. Use as initial short-term prevention therapy, not long-term therapy given their known toxicity. (no major clinical trials) third-line treatment as initial short-term prevention therapy rather than long-term (NK) conventional steroids no role (NK) budesonide at one year, ineffective when 3 mg/day or 6 mg/day given within two weeks post surgery ( 1 RCT) interleukin-10 not effective 12 weeks post surgery ( 1RCT) 5-ASA=aminosalicylates; AZA=azathioprine; 6-MP=6-mercaptopurine; CD, Crohn s Disease; IFX=infliximab; MTX=methotrexate EO=expert opinion; 1 SR=at least one systematic review; 1 CS=at least one cohort study; 1 CaseS =at least one case series; 1 MA=at least one meta-analysis; NK=not known Managing Crohn s Disease in Adults 17

18 APPENDIX 6: Summary Tables for Travis et al. 10 Table 1. Summary of Treatment Options of Active Crohn s Disease, by Disease Site and/or Acitvity 10 Disease Site, Guideline Activity localized ileocaecal, budesonide 9 mg daily ( 1 SR) mildly active no treatment for some patients with mild symptoms (EO) antibiotics not recommended ( 1 CS) mesalazine, limited benefit ( 1 SR) localized ileocaecal, budesonide 9 mg daily or systemic corticosteroids ( 1 SR) moderately active can add antibiotics if septic complications suspected (EO) localized ileocaecal, severely active colonic, active small bowel, extensive, active (>100 cm) Esophageal and gastroduodenal, active initially treated with systemic corticosteroids ( 1 SR) in relapse, add AZA/ 6-MP(or MTX if intolerant) ( 1 SR) in addition, IFX if intolerant to or refractory to corticosteroid or immunomodulator or surgery is determined to be inappropriate or if severe inflammatory activity ( 1 CS) antibiotics only if septic complication (NK) surgical options should be considered (NK) sulfasalazine daily if mildly active ( 1 CS) or systematic corticosteroid (prednisolone or equivalent) (EO); if relapsed, add AZA/6-MP( 1 SR); if intolerant, consider adding MTX instead ( 1 SR) in addition, IFX if intolerant to or refractory to corticosteroid or immunomodulator or surgery is determined to be inappropriate or if current, severe inflammatory activity ( 1 CS) surgical options should be considered (EO) topical treatment considered for distal disease (EO) systemic corticosteroids, if moderate or severe ( 1 SR) if relapsed, add AZA/6-MP ( 1 CS); if intolerant, then consider adding MTX instead ( 1 CS) adjunctive nutritional support (or primary treatment if disease is mild) ( 1 CaseS) consider adding IFX if treatment fails and if area is currently inflamed ( 1 CS) surgical options should be considered (NK) topical treatment considered for distal disease (NK) proton pump inhibitor (EO) may add systemic corticosteroids and AZA/6-MP or, if intolerant, MTX ( 1 CaseS) if refractory disease, can use IFX (NK) if obstructive symptoms dilatation or surgery are options ( 1 CaseS) 5-ASA=aminosalicylates; AZA=azathioprine; 6-MP=6-mercaptopurine; IFX=infliximab; MTX=methotrexate EO=expert opinion; 1 SR=at least one systematic review; 1 CS=at least one cohort study; 1 CaseS =at least one case series; 1 MA =at least one meta-analysis; NK=not known Managing Crohn s Disease in Adults 18

19 Table 2. Summary of Treatment Options for Medically Induced Remission of Crohn s Disease 10 Treatment Guideline 5-ASA not effective for maintaining remission ( 1 MA) corticosteroids not effective for maintaining remission at 12 months ( 1 MA) antibiotics evidence is Iacking ( 1 RCT) thiopurines AZA mg/kg/day is effective ( 1 MA) 6-MPis considered equivalent to AZA (no studies) thioguanine is not recommended due to adverse events to the liver ( 1 MA) MTX effective in doses of 15 mg/week, at least in patients who achieved remission with MTX ( 1 RCT) other no guidance stated; evidence is lacking for cyclosporine, immunosuppressants mycophenolate mofetil, tacrolimus, and cyclophosphamide IFX adalimumab etanercept IFX effective at 5 or 10 mg/kg every eight weeks in non-fistulating CD ( 1 RCT) adalimumab, etanercept not yet evaluated for maintenance of remission 5-ASA, aminosalicylates; AZA=azathioprine; 6-MP=6-mercaptopurine; CD=Crohn s Disease; IFX=infliximab; MTX=methotrexate EO=expert opinion; 1 SR=at least one systematic review; 1 CS=at least one cohort study; 1 CaseS =at least one case series Managing Crohn s Disease in Adults 19

20 Table 3. Summary of Treatment Options for Medically Induced Remission of Crohn s Disease by Disease Course/Behaviour 10 Treatment Guideline first presentation maintenance with mesalazine, but no consistent evidence for its of remission efficacy ( 1 CS) consider AZA if remission was achieved with systemic corticosteroids, 6-MP 1.0 to 15 mg/kg/day can be tried in patients intolerant of AZA (except in cases of pancreatitis and cytopenia) ( 1 SR) 5-ASA not effective ( 1 MA) Relapse of localized ileocaecal disease relapse of extensive disease relapse while taking AZA Maintenance after induction of remission with IFX Duration of maintenance therapy MTX is an option for patients intolerant of thiopurines (NK) consider escalating maintenance treatment (EO) consider surgery ( 1 CaseS) do not use corticosteroids ( 1 SR) consider AZA if remission is induced with corticosteroids ( 1 SR) AZA is recommended ( 1 CS) if taking AZA, increase to >2.6 mg/kg/day ( 1 SR) if taking 6-mercaptopurine, increase to >15 mg/kg/day ( 1 SR) or can give MTX ( 1 CS) consider surgery in localized disease ( 1 CaseS) AZA, or 6-MPor MTX are appropriate ( 1 SR) if the above fails, consider regular IFX infusions ( 1 CS) consider surgery in localized disease ( 1 CaseS) patients on 5-ASA, consider cessation after two years of full remission (EO) patients on AZA, consider cessation after four years of full remission ( 1 CS) prolonged use, beyond one year, of IFX and MTX may be considered, however, no recommendation is given due to lack of evidence 5-ASA, aminosalicylates; AZA=azathioprine; 6-MP=6-mercaptopurine; IFX=infliximab; kg=kilogram; mg=milligram; MTX=methotrexate EO=expert opinion; 1 SR=at least one systematic review; 1 CS=at least one cohort study; 1 CaseS =at least one case series Managing Crohn s Disease in Adults 20

21 Table 4. Summary of Treatment Options of Active Crohn s Disease by Therapy 10 Therapy Guideline 5-ASA ( 1 MA) no more effective than placebo for active ileal or colonic CD intolerance in up to 15% antibiotics ( 1 MA) appropriate only when septic complications, symptoms attributable to bacterial overgrowth, or perineal disease corticosteroids ( 1 good at inducing remission but ineffective at maintaining remission RCT) IFX ( 1 RCT) 5 mg/kg (can increase to 10 mg/kg if no initial response at 5 mg/kg) is effective for active CD but use with care when patient has obstructive symptoms appropriate for corticosteroid dependence, intolerance, or refractoriness can be considered after failure of either AZA/6-MPor MTX but should be used in conjunction with these therapies if they can be tolerated as they reduce development of antibodies to IFX that may reduce efficacy and increase side effects contraindicated if sign of active chest infection or if a patient with perianal disease has an abscess not recommended as pre-treatment of refractory disease to facilitate surgery other biologics, adalimumab ( 1 RCT) likely to have a role for patients who initially newer and under respond to IFX but subsequently lose response development etanercept ( 1 RCT) was ineffective at doses prescribed for rheumatoid arthritis natalizumab ( 1 RCT) may be effective as maintenance therapy but development was suspended alicaforsen (NK), does not work for active CD at the doses given thiopurines AZA mg/kg or 6-MP mg/kg as adjunctive therapy for IBD in active CD and as a corticosteroid sparing agent ( 1 SR) unlicensed for this indication (NK) slow onset of action; not to be used as sole therapy (NK) used in patients with severe relapse (NK) require two or more corticosteroid courses in a calendar year (NK) if require corticosteroids dose of 15 mg or greater to prevent relapse (NK) relapse within three months of stopping corticosteroids (NK) postoperative prophylaxis of fistulating or extensive CD (NK) MTX 25mg/week( 1 SR) unlicensed therapy for IBD (NK) cyclosporine and tacrolimus used similarly to thiopurines (NK) oral cyclosporine not recommended for corticosteroid refractory or corticosteroid dependent( 1 RCT, 1 CS) intravenous cyclosporine still debated (NK) nutritional therapy enteral therapy as adjunctive treatment to support nutrition, not for primary therapy (NK) 5-ASA=aminosalicylates; AZA=azathioprine; 6-MP=6-mercaptopurine; CD=Crohn s Disease; kg=kilogram; mg=milligram; IFX=infliximab; MTX=methotrexate EO=expert opinion; 1 SR=at least one systematic review; 1 CS=at least one cohort study; 1 CaseS =at least one case series; 1 MA =at least one meta-analysis; NK=not known Managing Crohn s Disease in Adults 21