Canadian Association of Gastroenterology Clinical Practice Guidelines: The Use of Infliximab in Crohn's Disease

Remo Panaccione MD (Co-Chair)1, Richard N Fedorak MD (Co-Chair)2, Guy Aumais MD3, Charles N Bernstein MD4, Alain Bitton MD5, Ken Croitoru MD6, Robert Enns MD7, Brian Feagan MD8, Marty Fishman MD7*, Gordon Greenberg MD9, Anne Griffiths MD9, John K Marshall MD6*, Imran Rasul MD10*, Daniel Sadowski MD2*, Ernest Seidman MD11, Hillary Steinhart MD9, Lloyd Sutherland MD1, Eric Walli MD12*, Gary Wild MD5, C Noel Williams MD2, Mary Zachos MD9


VALIDITY OF THE GUIDELINES
The present guidelines acknowledge the unique nature of each clinical encounter and practice setting, and allow practitioners and their patients to choose other options when appropriate.
An update through a consensus meeting is planned for the first half of 2006.It is assumed that the therapeutic use of anti-TNF agents will be influenced by continued large, randomized clinical studies.

QUALITY OF THE EVIDENCE
The guidelines were developed following the recommendations outlined by Marshall (4).The following categories were used to grade the statements in the guidelines (according to the guidelines of the Agency for Health Care Policy and Research): Ia Evidence obtained from the meta-analysis of randomized, controlled trials.
Ib Evidence obtained through one or more randomized, controlled trials.
IIa Evidence obtained through a well-designed, controlled study without randomization.
IIb Evidence obtained through another type of welldesigned, experimental study (eg, from multiple time series or from dramatic results in uncontrolled experiments).
III Evidence obtained through a well-designed, nonexperimental study (eg, descriptive studies which include comparative, correlation and case studies).
IV Evidence obtained from opinions of respected authorities, and based on clinical experience, descriptive studies, or reports of expert committees.

QUALITY OF THE GUIDELINES
Guidelines deduced from published evidence and/or from expert opinions were graded according to the recommendations of the Agency for Health Care Policy and Research.The following grading system was used: A Based on at least one randomized, controlled trial (evidence categories Ia or Ib).
B Based on clinical studies without randomization (evidence categories IIa, IIb or III).
C Based on expert committees, opinions or experiences (evidence category IV).The evidence is graded separately for the adult and pediatric population based on the best available evidence at the time of the consensus.

TARGET POPULATION
These clinical practice guidelines are directed at specialists who treat adult or pediatric patients with Crohn's disease.

B. Initial dosing
There is evidence to suggest that initial dosing with three infusions, at weeks 0, 2 and 6, results in higher remission and response (by approximately 15%) at 14 weeks than dosing at weeks 0 and 14 (33).Studies need to be conducted to determine if similar efficacy, but with improved cost effectiveness, could be achieved with infusions at week 0 and week 8.

F. Potential indications
Infliximab has also been shown to be beneficial in the following clinical situations associated with inflammatory bowel disease: 1. Hospitalized patients with moderately severe or fistulizing Crohn's disease where a rapid onset of action is desired (Adult and pediatric level of evidence C) (35).
2. As a bridge to immunosuppressants which may take eight to 24 weeks to be effective (Adult and pediatric level of evidence C) (35).

G. Use of infliximab in children and adolescents
In the management of pediatric Crohn's disease, efficacy of pharmacological therapies (eg, azathioprine/6-mercaptopurine) has generally been extrapolated from adult studies long before it has been specifically confirmed in younger patients (55).It is reasonable to apply the foregoing guidelines concerning indications for infliximab, dosing regimens, concomitant medications and precautions to the treatment of children and adolescents with Crohn's disease.Although Grade A evidence from specifically pediatric trials has hitherto been lacking, clinical experience with infliximab use in children and adolescents (8)(9)(10)(11)(12)19,21) is supportive of the now substantial adult clinical trial data.A pediatric randomized clinical trial comparing two maintenance dosing regimens is underway; until these data are available, it is reasonable to follow the above described dosing recommendations for pediatric patients.

H. Acute management of infusion reactions
Infusion reactions can occur during intravenous administration of infliximab.During the infusion the patients' vital signs should be monitored every 30 min.
If there is a prior history of an infusion-related reaction the vital signs should be monitored every 10 min during the first 30 min and then every 30 min thereafter.In this case, premedication could also be considered (diphenhydramine 25 mg to 50 mg orally and/or acetaminophen 500 mg to 650 mg orally and/or hydrocortisone 100 mg intravenously. If an infusion reaction should occur the infusion should be slowed or stopped depending on the severity.When stopped, the intravenous access should be maintained with 154 mM sodium chloride at 250 mL/h, and the following management strategies assessed ( April 27, 2004).Practice guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to investigation and management of the problem.While practice guidelines are intended to be useful to all physicians, it is recognized that specialists may rely less on practice guidelines than those in a more general practice.These guidelines are intended to give a practical approach to a problem based on the current literature, but are not intended to be state-of-theart reviews with extensive references.Practice guidelines are developed to be of assistance to practicing clinicians and are not intended to be the only approach to the management of clinical problems, nor are they intended to be considered as a 'standard of care'.The CAG Practice Affairs Committee recognizes that clinical circumstances may, at times, justify an approach different from that outlined in a practice guideline.It is also recognized that new developments in medical research and clinical practice may require subsequent changes to the practice guideline.

ACKNOWLEDGEMENTS:
The authors thank Lorie Ingram for assistance in preparation of the manuscript.They also acknowledge the significant contributions of Paul Sinclair and Sandra Daniels in assisting in the organization of the guidelines.
GRANT SUPPORT: In part by an 'arms-length' unrestricted educational grant to the University of Alberta and the University of Calgary from Schering Canada Inc.