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CCFA Quality Indicator Project
Proposed Quality Indicators
and Literature Reviews
The Crohn’s and Colitis Foundation of America (CCFA) is committed to the
improvement of the quality of care for those suffering from inflammatory bowel disease
(IBD). The Professional Education Committee of the CCFA has defined a mission
statement toward achieving this objective, which begins with Defining Quality of Care.
This project represents the initial step toward achieving this goal, through the
Development of Quality Indicators for IBD whereby basic measures of quality are
defined.
This initiative has followed methodology developed at RAND/UCLA, which has been
previously used to develop quality indicators for a host of medical conditions including
rheumatoid arthritis, cirrhosis, and the elderly. The methodology incorporates both
expert opinion and an evidence basis for the identification of quality indicators through
an iterative process.
CCFA Professional Education,
Clinical Advisory Panel
Quality Subcommittee
(December, 2009)
Thomas Ullman, M.D. (Chair, Prof Ed)
Corey Siegel, M.D. (Co-Chair, Prof Ed)
Brennan Spiegel, M.D. (Moderator)
Gil Melmed, M.D. (QI Subcommittee)
David Rubin, M.D.
John Allen, M.D.
Themos Dassipoules, M.D.
Stephen Hanauer, M.D.
Ted Denson, M.D.
Michael Kappelman, M.D.
Doug Wolf, M.D.
Robert Cima, M.D.
Russell Cohen, M.D.
Multi-Disciplinary Advisory Panel
(December, 2010)
Brennan Spiegel, M.D. (Moderator)
Balfour Sartor, M.D.
James Lewis, M.D.
David Rubin, M.D.
John Allen, M.D.
Stephen Hanauer, M.D.
Michael Kappelman, M.D.
Doug Wolf, M.D.
Russell Cohen, M.D.
Jean-Fred Colombel, M.D.
Ronald Schwartz, M.D.
Amy Moynihan, R.N.
Authors:
Bincy Abraham, M.D. ............................................................................................. Baylor School of Medicine
Nikhil Agarwal, M.D. ................................................................................ Cedars-Sinai Medical Center/UCLA
Garrett Cullen, M.D ............................................................................ Beth Israel Deaconess Medical Center
Shani DeSilva, M.D ............................................................................... Dartmouth-Hitchcock Medical Center
Shane Devlin, M.D. ....................................................................................................... University of Calgary
Sharyle Fowler, M.D. .................................................................................. Massachusetts General Hospital
Gauree Gupta, M.D. ............................................................................... Cedars-Sinai Medical Center/UCLA
Gilaad Kaplan, M.D. ...................................................................................................... University of Calgary
David Klibansky, M.D., ......................................................................... Dartmouth-Hitchcock Medical Center
Garrett Lawlor, M.D ......................................................................... .Beth Israel Deaconesss Medical Center
Campbell Levy, M.D ............................................................................ ..Dartmouth-Hitchcock Medical Center
Burr Loew, M.D\ .................................................................................... Dartmouth-Hitchcock Medical Center
Millie Long, M.D. ..................................................................................................University of North Carolina
Nimisha Parekh, M.D ....................................................................................... .University of California, Irvine
Keely Parisian, M.D ............................................................................................................... Cleveland Clinic
Atsushi Sakuraba, M.D ..................................................................................................University of Chicago
Justin Sewell, M.D ............................................................................ University of California, San Franscisco
Shamita Shah, M.D .......................................................................................................... .Stanford University
Brijen Shah, M.D .......................................................................................... Mount Sinai Medical Center, NY
Andrew Tinsely, M.D. ................................................................................... Mount Sinai Medical Center, NY
Chad Williams, M.D ...........................................................................................Cedars-Sinai Medical Center
Project personnel
Thomas Ullman, M.D. ........................................................................................................................... Editor
Corey Siegel, M.D. ................................................................................................................................ Editor
Gil Melmed, M.D. ...................................................................................................... Project Manager, Editor
Cathy MacLean, M.D, PhD. ................................................................................................................Advisor
Thomas Mead . ................................................................................................................. Research Librarian
Kimberly Isaacs ...................................................................................................................................... CCFA
Laura Wingate ........................................................................................................................................ CCFA
Jennifer Talley ................................................................................................ Center for Outcomes Research
Review does not imply endorsement of the findings, which remain the sole responsibility of the authors and the review team.
Table of Contents
Methods ............................................................................................................. 6
Diagnosis ........................................................................................................... 9
Q.I. #1: Determine disease phenotype ............................................................................................... 9
Q.I. #2: Patient Support..................................................................................................................... 15
Q.I. #3: Re-Evaluation Within 6 Weeks ............................................................................................ 17
Q.I. #4 and #5: Crohn’s Disease and Smoking ............................................................................... 20
Q.I. #6 C. Difficile testing during disease flare ................................................................................ 25
Q.I. #7: Testing for non-C. Difficile enteric infections ...................................................................... 28
Q.I. #8: Counselling against NSAIDs .............................................................................................. 31
Drug Safety and Monitoring ............................................................................ 34
Q.I. #9: Tuberculosis testing before anti-TNF therapy .................................................................... 34
Q.I. #10: Laboratory Monitoring on anti-TNF Therapy .................................................................... 40
Q.I. #11: Assessment of Viral Hepatitis prior to anti-TNF Therapy ................................................ 42
Q.I. #12: Renal function on 5-ASA ................................................................................................... 45
Q.I. #13: TPMT Testing before 6MP/AZA ........................................................................................ 50
IBD Treatment .................................................................................................. 54
Q.I. #14: Topical and Oral 5-ASA for distal ulcerative colitis .......................................................... 54
Q.I. #15: Oral Aminosalicylate therapy for mild to moderate extensive ulcerative colitis .............. 60
Q.I. #16: Oral therapy for ulcerative proctitis refractory to topical agents ...................................... 70
Q.I. #17: Steroid-Sparing Therapy for UC........................................................................................ 72
Q.I. #18: Oral cyclosporine after IV induction .................................................................................. 77
Q.I. #19: Check CMV in hospitalized UC ......................................................................................... 80
IBD Health-Care Maintenance ......................................................................... 83
Q.I. #20: Annual Review ................................................................................................................... 83
Q.I. #21: Influenza vaccine ............................................................................................................... 86
Q.I. #22: Avoid live virus vaccines if immunosuppressed ............................................................... 88
IBD and Colon Cancer ..................................................................................... 92
Q.I. #23 Surveillance Colonoscopy ................................................................................................. 92
Q.I. #24: Biopsy of colonic strictures ................................................................................................ 96
Q.I. #25: Discuss implications of surveillance.................................................................................. 99
Q.I. #26: Surveillence in Crohn’s colitis.......................................................................................... 101
Q.I.#27: Biopsy Adjacent Mucosa of Polypoid Lesions ................................................................. 104
Q.I. #28: Surveillence colonoscopy in P.S.C. ................................................................................ 107
Q.I. #29: Flat Low Grade Dysplasia ............................................................................................... 110
IBD Surgical Issues ....................................................................................... 116
Q.I. #30: Surgical drainage ............................................................................................................. 116
Q.I. #31: Discuss options for UC surgery ....................................................................................... 119
Q.I. #32: Surgery for colonic perforation ........................................................................................ 122
Miscellaneous ................................................................................................ 123
Q.I. #33: Inquire about CAM ........................................................................................................... 123
Q.I. #34: Ophthalmology referral .................................................................................................... 127
Q.I. #35: Weight and Nutrition ........................................................................................................ 129
5
Methods
In this monograph, we present a set of candidate quality indicators for Crohn’s disease and
ulcerative colitis, along with a synthesis of the available evidence supporting a link between the
indicator and an outcome of interest. We developed potential quality indicators from two
sources: Review of existing guidelines, and expert opinion based on an Advisory Panel Meeting
in December, 2009.
We constructed potential quality indicators in an “if-then-because” format. “If” refers to the
clinical characteristics that describe persons eligible for the quality indicator (For example: If a
patient has ulcerative colitis for 8 years, then such-and-such should be done). The “then”
portion refers to the actual process that should or should not be performed. The “because”
section refers to the expected health impact if the indicator is (or is not) performed. We focused
exclusively on quality indicators that measured processes, rather than outcomes, of care
because process measures are a more efficient means of assessing quality. Processes are
thought to be completely under the control of the health care system and, therefore, are
amenable to change. Futhermore, true outcome measures in IBD are difficult to define.
We included potential quality indicators for consideration for two reasons: Either they were
believed to have a significant impact on outcomes, or they were widely recommended. To be a
valid measure of quality, a proposed process must be linked to an impact on outcome;
consequently, we performed a comprehensive search of the literature to assess the available
evidence linking the proposed process quality indicators to their impacts on outcome. In some
instances, the available evidence did not support some of the widely recommended potential
quality indicators; those quality indicators and a summary of the evidence pertaining to them are
also included in this monograph. Thus, inclusion of an indicator in this monograph does
not necessarily imply that either the authors or the project team believe it to be a valid
measure of quality.
Guidelines from which Quality Indicators were extracted
Guidelines published after 2002 were searched for potential quality indicators. Guidelines were
obtained that were published by or under the auspices of various specialty organizations
including:
American Gastroenterology Association (AGA)
American College of Gastroenterology (ACG)
American Society of Gastroenterology Endoscopy (ASGE)
American Society of Colorectal Surgeons (ASCRS)
British Society of Gastroenterology (BSG)
European Crohn’s and Colitis Organization (ECCO)
Crohn’s and Colitis Foundation of America (CCFA)
Development of this “Candidate Set” of 35 Quality Indicators
All guidelines were read in duplicate, from which over 500 potential quality indicators were
extracted by members of the Quality of Care Subcommittee. From this initial set, we developed
a set of approximately 100 potential quality indicators. In developing these indicators, we
addressed processes that pertained to diagnosis, treatment, and health care maintenance of
patients with IBD. Most measures were applicable to both Crohn’s disease (CD) and ulcerative
colitis (UC) unless specifically relevant to one disease. We then circulated a preliminary set of
process indicators to our Advisory Committee for review. Reviewers electronically rated these
‘top 100’ for validity, and then met in-person for a moderated session (December, 2009) to
discuss discrepancies and confidentially re-rate for both validity and feasibility.
On the basis of the re-rating, we subsequently narrowed down the initial set to the 35 highest
rated indicators that met approval by the Advisory Committee for both validity and feasibility. We
then searched MEDLINE via the National Library of Medicine’s PubMed to identify evidence
linking the potential indicators to the outcomes of interest. All searches were limited to English
language and human subjects. We performed separate MEDLINE searches for each quality
indicator (exact search strategies available from authors on request) and searched the
references of key articles to identify over 2,000 titles. Together with a team of literature
reviewers, we sequentially reviewed the titles, abstracts, and articles from these searches for
relevance to this report. Studies were included if they provided evidence on the potential
relationship between the process in question and better outcomes in humans.
7
Purpose of this Monograph:
This monograph is intended to inform the panelists who will be participating in the
Multidisciplinary Advisory Panel on December 9, 2010. Panelists will be asked to confidentially
rate the validity of each QI twice – once via internet prior to the December meeting, and once at
the meeting itself. The literature summaries provided in this compendium are intended to serve
as a reference; the decision to rate an item as valid should be based on the expert interpretation
and experience of the individual panelists.
IBD CANDIDATE QUALITY INDICATORS
Diagnosis
Q.I. #1: Determine disease phenotype
Q.I. #1
IF a patient is newly diagnosed with inflammatory bowel disease
THEN the type and extent of disease should be determined
BECAUSE this evaluation is necessary to guide treatment strategies.
Summary: Disease location and severity can influence the management of IBD with
respect to choice of medications, type of surgery, and counseling for colorectal cancer
surveillance.
Details
The diagnosis of ulcerative colitis and Crohn’s disease is made using clinical history,
endoscopic findings, histology, and radiologic imaging. As part of the diagnostic workup, other
etiologies of colitis/enteritis should be excluded including infections, ischemic, medication
induced, radiation induced, neoplastic and other inflammatory conditions.1-5
Ulcerative Colitis
Endoscopy is used to confirm diagnosis of ulcerative colitis, assess extent of disease, and
disease severity. The recommended endoscopic procedure is colonoscopy and ileoscopy with
segmental biopsies to evaluate for IBD and to help differentiate between ulcerative colitis and
Crohn’s disease.6 However, colonoscopy should be avoided in severe ulcerative colitis and
flexible sigmoidoscopy with biopsy should be done to confirm diagnosis and exclude infections.
The extent of disease in ulcerative colitis is determined by endoscopic evaluation and
characterized in the Montreal classification as: E1 proctitis, E2 Left sided colitis, E3
9
Pancolitis.10,11 If disease extent cannot be assessed on initial evaluation, it should be assessed
once a patient’s condition permits. It is important to delineate disease inflammation as distal
(limited to below the descending colon and within reach of topical therapy) or proximal, with
extension to the transverse and ascending colon thus requiring systemic medication.3
In ulcerative colitis, disease severity is generally classified by clinical parameters originally
described by Truelove and Witts13 describing disease as mild, moderate and severe. ECCO
and ACG recommend the use of clinical parameters to describe severity of disease.14, 15 The
Montreal Classification characterizes ulcerative colitis by similar criteria as seen in Table 1.10, 11
Population data suggest that most patients present initially with “moderate to higher” disease
activity.12
Table 110, 11: Montreal Classification for Ulcerative Colitis
Disease Severity
Disease Extent
Remission (S0) No more than 3 bowel
movements daily, no blood in stools, and
no urgency
Mild (S1) Up to 4 bowel movements daily,
E1
Proctitis
E2
Left sided colitis
E3
Pancolitis
trace amounts of blood, normal pulse,
temperature, hemoglobin and ESR
Moderate (S2) 4 to 6 bloody bowel
movements daily, no signs of systemic
involvement
Severe (S3) more than 6 bloody bowel
movements daily, temperature >37.5 C,
heart rate >90, hemoglobin below 10.5g/dl,
ESR >30mm/h
The initial approach to therapy for UC is determined by severity and anatomic extent of disease,
with the oral or topical 5-aminosalicylate (5-ASA) agents first-line therapy for mild to moderate
distal disease.3, 16 In addition, the extent of disease determines the start and frequency of
surveillance program for colorectal cancer screening, as pancolitis carries higher risk of
colorectal cancer than left sided disease.
Crohn’s Disease
Crohn’s disease has several different phenotypic presentations. Diagnostic testing in Crohn’s
disease is guided by presenting symptoms, physical findings, and laboratory parameters.
Endoscopy is also the recommended to confirm diagnosis of Crohn’s disease, document
location of disease, and for tissue sampling.17 While colonoscopy and ileoscopy with segmental
biopsies is the procedure of choice, patients with severe disease should only have a
sigmoidoscopy until clinical symptoms improve.
Esophagogastroduodenoscopy is recommended in patients with upper GI symptoms. In
children, the European Society of Pediatric Gastroenterology Hepatology and Nutrition
(ESPGHAN) developed the “Porto Criteria” and recommend that all children suspected with
Crohn’s disease should have a complete examination at time of diagnosis to establish
diagnosis, assess disease severity and extent before treatment is started.19 Complete
examination includes colonoscopy and ileoscopy with biopsy, esophagogastroduodenoscopy
with biopsy, and small bowel imaging (small bowel follow through or enteroclysis). The
European Crohn’s and Colitis Organisation (ECCO) also supports this recommendation in
children.20 To date there are no recommendations for routine upper endoscopy for adult
patients with Crohn’s disease.
Crohn’s disease can affect the small bowel that is not in the reach of colonoscope. Several
techniques are available to image the small intestine including: small bowel follow through,
ultrasound, CT enterography, MR enterography, enteroclysis, CT enteroclysis, MR enteroclysis,
and video capsule endoscopy. CT and MR enterography offer the possible ability to
differentiate between inflammation and noninflammation.17 Due to risks of radiation, MRI may
be preferred over CT.21 Video capsule endoscopy can be considered in patients in whom a
stricture/stenosis have been excluded.
11
Perianal disease should be assessed with exam under anesthesia, pelvic MRI, and or anorectal
endoscopic ultrasound.22
The Montreal Classification of Crohn’s disease takes into account the age at time of diagnosis,
location of disease and development of complications such as strictures, fistulas and
abscesses.10, 11 (see Table 2)
Montreal Classification of Crohn’s Disease10, 11
A1: < 16years at diagnosis
L1: Terminal ileum
B1: Without stricture,
nonpenetrating
A2: 17 to 40 years at
L2: Colon
B2: With stricture formation
L3: Ileocolon
B3: Internally penetrating
L4: Upper GI tract
B3p: Perianally penetrating
diagnosis
A3: > 40 years at diagnosis
L4 +: Lower GI tract and
distal disease
Crohn’s disease activity is also classified by clinical parameters and described as mild,
moderate, or severe as described by ECCO and ACG guidelines as follows:4, 23
Mild: Patient able to walk, tolerate oral nutrition, no signs of dehydration, no systemic
involvement, no abdominal pain or mass, no ileus, or loss of no more than 10% of body weight,
CRP is elevated.
Moderate: Intermittent vomiting, loss of more than 10% of body weight, lack of response to drug
therapy for mild Crohn’s disease, no ileus, and elevated CRP
Severe: Cachectic with BMI under 18, ileus, abscess, persistent symptoms despite intensive
therapy, and elevated CRP.
By combining disease location, severity and presence of complications describes the phenotype
of patient with Crohn’s disease and guides management decisions in terms of medication
choice and surgery.24
References:
1. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and
evolving therapies. Lancet 2007;369(9573):1641-57.
2. Thielman NM, Guerrant RL. Clinical practice. Acute infectious diarrhea. The New England journal of
medicine 2004;350(1):38-47.
3. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of
Gastroenterology, Practice Parameters Committee. The American journal of gastroenterology;105(3):50123; quiz 24.
4. Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults. The
American journal of gastroenterology 2009;104(2):465-83; quiz 4, 84.
5. Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal
inflammation. Gastroenterology 2004;126(6):1518-32.
6. Leighton JA, Shen B, Baron TH, et al. ASGE guideline: endoscopy in the diagnosis and treatment of
inflammatory bowel disease. Gastrointestinal endoscopy 2006;63(4):558-65.
7. Simpson P, Papadakis KA. Endoscopic evaluation of patients with inflammatory bowel disease.
Inflammatory bowel diseases 2008;14(9):1287-97.
8. Fefferman DS, Farrell RJ. Endoscopy in inflammatory bowel disease: indications, surveillance, and
use in clinical practice. Clin Gastroenterol Hepatol 2005;3(1):11-24.
9. Ladefoged K, Munck LK, Jorgensen F, Engel P. Skip inflammation of the appendiceal orifice: a
prospective endoscopic study. Scandinavian journal of gastroenterology 2005;40(10):1192-6.
10. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory
bowel disease: controversies, consensus, and implications. Gut 2006;55(6):749-53.
11. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological
classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World
Congress of Gastroenterology. Canadian journal of gastroenterology = Journal canadien de
gastroenterologie 2005;19 Suppl A:5-36.
12. Langholz E, Munkholm P, Nielsen OH, Kreiner S, Binder V. Incidence and prevalence of ulcerative
colitis in Copenhagen county from 1962 to 1987. Scandinavian journal of gastroenterology
1991;26(12):1247-56.
13. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. British medical
journal 1955;2(4947):1041-8.
14. Stange EF, Travis SP. The European consensus on ulcerative colitis: new horizons? Gut
2008;57(8):1029-31.
13
15. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of
Gastroenterology, Practice Parameters Committee. The American journal of gastroenterology
2004;99(7):1371-85.
16. 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. The American journal of
gastroenterology 1997;92(10):1867-71.
17. Stange EF, Travis SP, Vermeire S, et al. European evidence based consensus on the diagnosis and
management of Crohn's disease: definitions and diagnosis. Gut 2006;55 Suppl 1:i1-15.
18. Nahon S, Bouhnik Y, Lavergne-Slove A, et al. Colonoscopy accurately predicts the anatomical
severity of colonic Crohn's disease attacks: correlation with findings from colectomy specimens. The
American journal of gastroenterology 2002;97(12):3102-7.
19. Escher JC, Aml Dias, J, Bochenek, K. Inflammatory Bowel Disease in children and adolescents.
Recommendations for Diagnosis: The Porto Criteria. Medical Position Paper. J Pediatri Gastroenterology
Nutrition 2005;41:1-7.
20. Caprilli R, Gassull MA, Escher JC, et al. European evidence based consensus on the diagnosis and
management of Crohn's disease: special situations. Gut 2006;55 Suppl 1:i36-58.
21. Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. The New
England journal of medicine 2007;357(22):2277-84.
22. Schwartz DA, Loftus EV, Jr., Tremaine WJ, et al. The natural history of fistulizing Crohn's disease in
Olmsted County, Minnesota. Gastroenterology 2002;122(4):875-80.
23. Travis SP, Stange EF, Lemann M, et al. European evidence based consensus on the diagnosis and
management of Crohn's disease: current management. Gut 2006;55 Suppl 1:i16-35.
24. Walfish A, Sachar D. Phenotype classification in IBD: Is there an impact on therapy? Inflammatory
bowel diseases 2007;13(12):1573-5.
Q.I. #2: Patient Support
QI#2
IF a patient is newly diagnosed with IBD
THEN information about patient support groups and sources of help
should be made available
BECAUSE IBD patients who feel well supported and well informed are
more likely to positively cope with and manage their illness.
SUMMARY
Despite the lack of studies on this issue, expert opinion advocates that IBD patients
should receive information about support groups and other sources of help. According to
expert opinion, patients who are educated about their disease and have adequate social
support experience a better quality of life and may also be more likely to adhere to
medical therapy resulting in management of disease.
DETAILS
Our search revealed one study that assessed the effect of patient support in patients with
IBD(1). This study was prospective but neither randomized nor controlled. Investigations
prospectively assessed 61 children and adolescents with IBD before and after a one week long
support-group camp. Questionnaires were administered pre and post camp to assess quality of
life variables, the IMPACT II (a tool to assess health-related quality of life) and the State-Trait
Anxiety Inventory for Children. Significant improvements in quality of life and bowel symptoms
were noted at the completion of the support camp. There was no significant change in the level
of anxiety. There may also be an association between patient support and adherence to
medication. Patients who do not feel well supported, particularly by the medical team, are less
likely to adhere to medical therapy for their IBD(2). This may translate into poorer disease
control.
Expert opinion advocates for providing patients with adequate resources and support. The
British Society of Gastroenterology guidelines for the management of IBD and The IBD
15
Standards Group both recommend that providers give educational information about IBD and
support to patients and their families(3, 4). They cite that such measures are important to allow
patients better manage their IBD, have a better quality of life and to be more involved in their
own care. Recent World Gastroenterology Organization (WGO) guidelines, based on expert
opinion, also state that patients should be educated about their disease at the time of
diagnosis(5).
References:
1. Shepanski MA, Hurd LB, Culton K, et al. Health-related quality of life improves in children and
adolescents with inflammatory bowel disease after attending a camp sponsored by the Crohn's and
Colitis Foundation of America. Inflamm Bowel Dis 2005;11:164-70.
2. Robinson A. Review article: improving adherence to medication in patients with inflammatory bowel
disease. Aliment Pharmacol Ther 2008;27 Suppl 1:9-14.
3. Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in
adults. Gut 2004;53 Suppl 5:V1-16.
4. IBD Standards Group. Quality Care Service standard for the healthcare of people who have
Inflammatory Bowel Disease (IBD). 2009.
5. Bernstein CN, Fried M, Krabshuis JH, et al. World Gastroenterology Organization Practice Guidelines
for the diagnosis and management of IBD in 2010. Inflamm Bowel Dis;16:112-24.
Q.I. #3: RE-EVALUATION WITHIN 6 WEEKS
QI #3 IF a patient with CD is started on therapy
THEN he or she should be re-evaluated within 6 weeks
BECAUSE evaluation is necessary to assess symptoms, physical signs,
laboratory and other investigations that may indicate treatment response, failure
or adverse events
Summary: There has been no prospective study evaluating the impact of review 6 weeks
after starting a new therapy on outcomes in CD. However, based on the pharmacology of
commonly used therapies, 6 weeks seems to be an appropriate interval for assessment of
both tolerability and efficacy of treatment relevant to many commonly used therapies.
Details
A variety of therapies are used in Crohn’s disease (CD) with the aim of inducing and maintaining
remissionRecent data have suggested that early introduction of immunosuppressant therapy
may alter the natural history of Crohn’s disease1. While this has not been widely adopted at this
time, many practitioners are aware of the need to be aggressive early in the disease course,
particularly in those with complicated disease (extensive, stricturing or penetrating). In light of
this, early assessment of response to therapy is important so that patients are quickly
transitioned to effective treatment.
Aminosalicylates are a mainstay of therapy for UC and (despite a strong evidence base) are
frequently used in CD. Typically, patients with UC treated with 5-ASAs have a response within
2 weeks of starting the drug.
Corticosteroids are effective agents for induction of remission4, but they are not suitable for
maintenance therapy and should be tapered following response. If there has been no response
to by 7-10 days, the patient should change therapy (or be admitted to hospital for intravenous
therapy in certain circumstances). Budesonide is a topically active glucocorticoid that is effective
for the induction of remission in ileal or ileocolonic CD5. Its efficacy in the induction of remission
is comparable to prednisone and it has an onset of action of approximately 2 weeks6.
17
The thiopurines (azathioprine and 6-mercaptopurine) can take up to 3 (and even 6) months to
reach maximum efficacy7. However, 20% can have a response by 2 weeks and this can be
assessed at 6-week follow-up8. The main short-term concern with these agents is related to
adverse events and patients should have a white blood count and liver tests checked early in
the course of therapy.
Methotrexate is typically started at 25mg subcutaneously weekly for the first 16 weeks before
being reduced to 15mg weekly. The onset of action is thought to be similar to that of the
thiopurines although it has been suggested that it may even be slightly earlier9. Review at 6
weeks allows for assessment of tolerability and early response.
Anti-TNF agents (infliximab, adalimumab and certolizumab pegol) are frequently assessed for
symptomatic benefit at 6 weeks. In the case of all 3 agents, the induction regimen is for 4
(adalimumab and certolizumab pegol) to 6 (infliximab) weeks and a complete lack of any
response at this point suggests a primary non-response.. The AGA Institute suggest that a
complete lack of response after 2 doses of infliximab should be an indication for
discontinuation10. Those who have had an attenuated response may benefit from a reduction
in dosing interval or an increase in dose10.
The monoclonal antibody against alpha-4 integrin, natalizumab, is licensed for Crohn’s disease
under the TOUCH program whereby clinicians are obliged to discontinue it if there has been no
response after 12 weeks of therapy (because of the risk of progressive multifocal
leukoencephalopathy). The drug is given at 4 week intervals and so a 6 week interval is a good
time to evaluate tolerability and possible early response to the first 2 doses,
Data from large randomized controlled trials in CD have shown that endoscopically-visualised
mucosal healing is possible with certain therapies11, 12. Furthermore, there are data to suggest
improved outcomes in those with mucosal healing offering an additional therapeutic goal to that
of symptomatic improvement13, 14. Although this is currently an important focus of research and
is increasingly used as an endpoint in clinical trials it not typically assessed as early as 6 weeks
and is more likely to be checked at 3, 6 or 12 months in those who have symptomatic response.
References
1. D'Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or
conventional management in patients with newly diagnosed Crohn's disease: an open
randomised trial. Lancet 2008;371:660-7.
2. Pinczowski D, Ekbom A, Baron J, Yuen J, Adami HO. Risk factors for colorectal cancer in
patients with ulcerative colitis: a case-control study. Gastroenterology 1994;107:117-20.
3. Jess T, Gamborg M, Matzen P, Munkholm P, Sorensen TI. Increased risk of intestinal
cancer in Crohn's disease: a meta-analysis of population-based cohort studies. The American
journal of gastroenterology 2005;100:2724-9.
4. Faubion WA, Jr., Loftus EV, Jr., Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural
history of corticosteroid therapy for inflammatory bowel disease: a population-based study.
Gastroenterology 2001;121:255-60.
5. Greenberg GR, Feagan BG, Martin F, et al. Oral budesonide for active Crohn's disease.
Canadian Inflammatory Bowel Disease Study Group. The New England journal of medicine
1994;331:836-41.
6. Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG. Oral budesonide is as effective as
oral prednisolone in active Crohn's disease. The Global Budesonide Study Group. Gut
1997;41:209-14.
7. Su C, Lichtenstein GR. Treatment of inflammatory bowel disease with azathioprine and 6mercaptopurine. Gastroenterol Clin North Am 2004;33:209-34, viii.
8. Sandborn WJ, Tremaine WJ, Wolf DC, et al. Lack of effect of intravenous administration on
time to respond to azathioprine for steroid-treated Crohn's disease. North American
Azathioprine Study Group. Gastroenterology 1999;117:527-35.
9. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's
disease. The North American Crohn's Study Group Investigators. The New England journal of
medicine 1995;332:292-7.
10. Clark M, Colombel JF, Feagan BC, et al. American gastroenterological association
consensus development conference on the use of biologics in the treatment of inflammatory
bowel disease, June 21-23, 2006. Gastroenterology 2007;133:312-39.
11. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's
disease: the ACCENT I randomised trial. Lancet 2002;359:1541-9.
12. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab
is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's
disease. Gastrointestinal endoscopy 2006;63:433-42; quiz 64.
13. Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical
remission in patients with early-stage Crohn's disease. Gastroenterology;138:463-8; quiz e10-1.
14. Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of
maintenance therapy with infliximab in Crohn's disease. Inflammatory bowel diseases
2009;15:1295-301.
19
Q.I. #4 and #5: Crohn’s Disease and Smoking
Q.I. #4
IF a patient who is newly diagnosed with Crohn’s disease (CD)
THEN he or she should be educated about the risks of disease exacerbation
from cigarette smoking
BECAUSE cigarette smoking has been associated with CD exacerbation,
recurrence after surgery, and resistance to anti-TNF therapy.
Q.I. #5
IF you have a patient with Crohn’s disease who is an active smoker
THEN smoking cessation should be recommended, including referral for
counseling or nicotine substitutes
BECAUSE smoking cessation lowers the risk of disease flares and lowers
the need for corticosteroids, immunomodulators, and dose increase in
immunomodulators
Summary: Smoking has a negative effect on patients with CD. Several studies have reported
that smokers have a more severe disease course and are more likely to develop a more
complicated form of CD. A large meta-analysis of observational studies indicates a significantly
increased risk of surgical recurrence and clinical exacerbation in CD patients who are smokers.
Published literature is mixed in terms of whether smoking affects the efficacy of anti-TNF
therapy. Three studies reported a negative association whereas most others showed no
difference or reported mixed results.
Furthermore, ex-smokers have a more favorable disease course that resembles that of nonsmokers. The risk of endoscopic and clinical recurrence in former smokers who have not
smoked for at least 1 year is similar to that of non-smokers1, and the benefit of smoking
cessation may be seen within the year following cessation. Thus, data suggests that smoking
cessation should be recommended for active smokers with Crohn’s disease. There is only one
prospective intervention study that supports these recommendations in CD patients.
Details
Cigarette Smoking and Crohn’s exacerbation including risk of complicated CD:
We have identified five studies, which report current cigarette smokers experience higher risk of
relapses and more severe disease. Four of these studies are prospective cohort studies. In
1992 Wright et al observed 239 patients and found cigarette smokers were more likely to have
ileocolitis that nonsmokers (47% vs 32% p=0.028), and ileocolitis was linked to an increased
number of inflammatory attacks (47% for ileocolitis vs. 35% for ileitis and 14% for colitis;
p=.001). In another prospective cohort of 74 patients Duffy et al reported that current smoking
increases the risk of relapse for Crohn’s patients. The risk increased by 1.6 times that of
nonsmokers (p<0.01)2. The largest published cohort of 622 patients found that current smoking,
and particularly heavy smoking, markedly increases the risk of flare-up in CD. Interestingly,
former smokers had similar risk to that of nonsmokers3. A prospective cohort of 152 pts in a
multicenter trial from Canada also reports that relapses of CD were associated with smoking
status (current smokers 53%, former smoker 35%, nonsmokers 30%, p=0.02)4. One
retrospective series of 400 CD patients revealed that those who smoke, particularly women and
heavy smokers run higher risk of developing severe disease. In this series, immunosuppressive
therapy neutralized the influence of smoking on surgical rates5.
However, other studies do not show the same harmful effects of smoking on the course of CD.
Studies in patients from Israel and Hungary have not found differences in the need for surgery
or for immunosuppressants between smokers and nonsmokers. 6, 7, 8
Smoking tobacco may have an effect on the development of a more complicated form of CD.
There were two retrospective studies suggesting that this may be related to smoking load9,10. A
study by Louis et al. used a multivariate analysis to study the relationship between smoking and
disease behavior and found that active smoking is associated with a penetrating pattern of
disease compared with a non-stricturing, non-penetrating pattern (P=0.02)11. Rocca et al found
that current smoking was related to fistulizing CD (p=0.008) and obstruction (p=0.01) in
women12. In another retrospective study by Picco et al smoking was associated with
progression of CD. They found that nonsmokers reported lower proportional rate of stricturing
and penetrating-type disease than did smokers. Also, those who smoked more than 1 packyear reported a higher frequency of severe (stricturing and penetrating) disease than did
nonsmokers and CD patients who smoked less than 1 pack-year (p=0.002). In another
retrospective study published in 1996 involving 287 CD patients, smokers were more likely to
have one (odds ratio [OR]: 3.9) or more (OR: 10.8) surgeries than nonsmokers13.
Cigarette smoking and recurrence of CD after surgery:
Reese et al performed a meta-analysis of observational studies quantifying the risk of
postoperative recurrence associated with cigarette smoking in CD in 200815. Sixteen studies
21
were included in the analysis of which three were prospective non-randomized studies (Table
1). There were a total of 2,962 patients, which included 1,425 non-smokers (48.1%), 1,393
smokers (47.0%) and 137 ex-smokers (4.6%). Smokers had significantly higher clinical postoperative recurrence than non-smokers (OR = 2.15; 95% CI = 1.42-3.27; p < 0.001). Smokers
were also more likely to experience recurrence requiring surgery by 5 years (OR = 1.06; 95% CI
= 0.32-3.53; p = 0.92) and 10 years of follow-up (OR = 2.56; 95% CI = 1.79-3.67; p < 0.001)
compared to non-smokers, although the crude re-operation rate was not statistically significant.
When matched for the type of operation and disease site, smokers had significantly higher reoperation rates compared to non-smokers (OR = 2.3; 95% CI = 1.29-4.08; p = 0.005). There
was no significant difference between ex-smokers and non-smokers in re-operation rate at 10
years (OR = 0.30; 95%CI = 0.09-1.07; p = 0.10) or in post-operative acute relapses (OR = 1.54;
95%CI = 0.78, 3.02; p = 0.21).
Cigarette smoking and resistance to anti-TNF therapy:
The current data regarding the influence of smoking status on the response to infliximab (IFX)
are conflicting. In 2009, Narula et al performed a systematic review on this topic. This review
included 10 studies, both retrospective cohort studies and randomized controlled trials16. Two of
these studies found that smoking had a significant negative impact on response to IFX
17, 18
.
One additional study found that nonsmokers who received adalimumab (ADA) had a better
response rate than smokers25. Other studies did not confirm smoking to be a predictor of poor
response to IFX 19, 20, 21, 22, 23, 24 and ADA26. These studies are summarized in Table 2.
Smoking cessation intervention:
A large prospective intervention study by Cosnes et al followed 59 patients who stopped
smoking following a smoking cessation intervention. They examined the disease course from 1
year following smoking cessation onwards. The flare-up rate, therapeutic needs, and disease
severity were similar in patients who had never smoked and in those who stopped smoking, and
both had a better course than current smokers. Those who quit smoking had a 65% lower risk
of disease flares compared with continuing smokers. The need for corticosteroids,
immunosuppressive therapy, or a dose increase of immunosuppressant’s was also lower2.
Smokers with CD should be informed of the adverse association between smoking and their
disease, and an individually based smoking cessation strategy should be defined. In the general
population, various strategies to promote smoking cessation have been described. These may
include early nicotine substitution in heavy smokers, group therapy, and pharmacologic
treatment, such as serotonergic agents and buproprion.
Table 2: Overview of interventional studies examining the efficacy of anti-TNF therapy in CD
smokers vs. non-smokers
Author
Year
Design
n
Interventions
Outcomes
Measured
Decreased efficacy of
anti-TNF agents in
smokers vs.
non-smokers
Vermeire
2002
P
240
Clinical response
No
Parsi
2002
R
100
Clinical response and
duration of response
Yes
Arnott
2003
P
74
P
200
Short-term response
at four weeks and remission
at one year
Clinical response and
duration of response
Yes
Fefferman
2004
LunaChadid
2004
Parsi
2004
Orlando
2005
P
108
IFX
refractory luminal CD(57%)
fistulizing (43%) CD
IFX
luminal CD (59%)
fistulizing (41%) CD
IFX
refractory luminal (81%)
fistulizing (19%) CD
IFX
Luminal CD (61%)
fistulizing CD (39%)
IFX
fistulizing CD
Cessation of drainage
from fistula
No
R
60
573
Cessation of drainage
from fistula
Clinical response and
clinical remission
No
P
Laharie
2005
R
44
IFX
fistulizing CD
IFX in refractory luminal CD
(54%), fistulizing CD (33%) or
both (13%)
IFX in luminal CD
No
Hlavaty
2005
P
287
Kevans
2006
P
93
Triantifillidis
2010
P
30
Response to IFX (CDAI
decline by >100) and longterm remission (CDAI<150)
Decline in CDAI to <150 or by
>70 for luminal CD; cessation
of drainage for fistulizing CD
Complete resolution of CD
symptoms or closure of all
fistulae
Ability to tolerate ADA and
clinical remission (CDAI score
<150); clinical response
(decrease in CDAI >70)
Nichita
2010
R
55
Disease severity scored using
HBI; remission (HBI of ≤4)
and response (reduction in
HBI of >3 at evaluation
compared to the baseline
No
IFX in refractory luminal CD (71%)
and
fistulizing CD (29%)
IFX in refractory luminal (78%)
and fistulizing (22%) CD
ADA
Mod active CD
Naïve to biologic-19 pts
Loss of response or intolerant to
IFX-11pts
Mod to severe CD
No
No
No
No
Yes
PNR prospective non-randomized, R retrospective; IFX=infliximab; ADA=adalimumab; CDAI- Crohn’s disease activity index
HBI-Harvey Bradshaw index
23
1. Cottone M, Rosselli M, Orlando A, et al. Smoking habits and recurrence in Crohn's disease.
Gastroenterology 1994; 106: 643-648
2. Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease:
An Intervention Study
3. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a
nicotine patch, or both for smoking cessation. N Engl J Med. 1999;340:685– 691.
Q.I. #6 C. Difficile testing during disease flare
Q.I. #6:
IF you have a patient in whom a severe or refractory flare of IBD is
suspected with increased stool frequency
THEN the patient should undergo C difficile testing,
BECAUSE patients with symptoms of disease exacerbation may have
C difficile infection. C difficile infection increases risk of adverse
outcomes among hospitalized IBD patients, including mortality, and
this risk increases when patients are treated concomitantly with
antibiotics and immunosuppressive agents.
Summary: Several studies of large national datasets identified higher and more
rapidly increasing prevalence of C difficile infection among hospitalized IBD
inpatients compared with other inpatients. Hospitalized IBD patients with C
difficile infection have elevated mortality rates; among C difficile-infected UC
patients the in-hospital mortality risk is four percent. The use of combination
antibiotics and immunosuppressive agents among such patients also increases
mortality risk. More than 10% of ambulatory IBD patients are C difficile carriers,
and 8-20% percent of ambulatory flares may be associated with C difficile
infection.
Details
The majority of studies investigating C difficile infection among IBD patients were
performed in hospitalized patients. The incidence of C difficile infection continues to
rise among all hospitalized patients, but temporal increases are more marked among
patients with IBD.1 In a study using Nationwide Inpatient Sample data, the prevalence
of C difficile infection among hospitalized patients with UC nearly doubled from 26.6 per
1,000 discharges in 1998 to 51.2 per 1,000 in 2004 (P<.0001); rises for Crohn’s disease
were less marked but were also statistically significant. Because the study included
patients with any diagnosis of IBD (rather than only those with a primary diagnosis of
IBD), prevalence rates may actually have been underestimated. This is because
patients with a primary discharge diagnosis of IBD were probably more likely to be
admitted for a disease exacerbation versus patients with a secondary or tertiary
diagnosis, and those admitted with a disease exacerbation were probably more likely to
have C difficile infection. C difficile infection is more prevalent among hospitalized
25
patients with IBD compared with non-IBD hospitalizations. In the above study, the
prevalence of C difficile infection was nearly eight times greater among UC patients
(37.3 per 1,000 discharges) than patients admitted for non-IBD gastrointestinal
indications (4.8 per 1,000) or patients admitted for non-gastrointestinal indications (4.5
per 1,000); rates for Crohn’s disease patients (10.9 per 1,000) were double those of
non-IBD groups (P<.0001 comparing UC and Crohn’s patients to other groups).1 In a
single-center study of 3,397 hospitalized IBD patients and 353,845 hospitalized non-IBD
controls, UC patients were three times more likely than non-IBD patients to have C
difficile infection (39.4 per 1,000 admissions versus 12.3 per 1,000 admissions, P<.001);
Crohn’s disease patients had incidence (15.9 per 1,000) similar to non-IBD patients.2
Several studies document poor outcomes among hospitalized IBD patients with C
difficile infection. In the above study using Nationwide Inpatient Sample data, four
percent of UC patients with C difficile infection died while hospitalized; this risk was four
times greater than UC patients without C difficile infection in extensively adjusted
analysis. 1 Similar risk was not seen among Crohn’s disease patients. In a different
analysis of Nationwide Inpatient Sample data from 2003, hospitalized IBD patients with
C difficile infection had a nearly 5-times increased odds of mortality in adjusted analysis
compared with IBD patients lacking C difficile infection (4.2% versus 0.5%, P<.05).3 C
difficile-infected IBD patients also experienced poorer secondary outcomes, including
longer and more costly hospitalizations and increased use of total parenteral nutrition.
In a study of 155 hospitalized C difficile-infected IBD patients, the use of combination
therapy with antibiotics and immunosuppressive agents increased risk of adverse
outcomes (including mortality, need for colectomy, colonic perforation, megacolon,
shock, and need for mechanical ventilation) compared with antibiotics alone in adjusted
analysis (likelihood ratio 11.9, 0.9-157, P=.06).4 The use of two or three
immunosuppressive agents was associated with a 17-fold increased odds of adverse
outcomes compared with a single immunosuppressive agent (OR 17.1, 3.2-91, P<.01).
Three studies evaluated C difficile infection among ambulatory IBD patients. A singlecenter British study studied 120 ambulatory IBD patients with apparent disease
exacerbation.5 Ten (8.3%) outpatient flares were associated with C difficile infection.
Another single-center study found that eleven (20%) of 54 IBD patients with flare
symptoms had C difficile infection.6 A final single-center study performed stool studies
on 122 asymptomatic IBD patients and found that 13 (10.7%) were C difficile carriers;
this was evenly split between patients with UC and Crohn’s disease and was
significantly greater than non-IBD controls, in which only 2% were carriers.7
The above studies provide strong evidence that, among apparently flaring IBD patients,
C difficile infection is common, morbid, and, in the inpatient setting, sometimes fatal.
These findings support C difficile testing in the setting of IBD flare as an important
quality indicator.
References
1. Nguyen GC, Kaplan GG, Harris ML, et al. A national survey of the prevalence and impact of
Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J
Gastroenterol. 2008;103: 1443-1450.
2. Rodemann JF, Dubberke ER, Reske KA, et al. Incidence of Clostridium difficile infection in
inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5: 339-344.
3. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with
Clostridium difficile in patients with inflammatory bowel disease. Gut. 2008;57: 205-210.
4. Ben-Horin S, Margalit M, Bossuyt P, et al. Combination immunomodulator and antibiotic
treatment in patients with inflammatory bowel disease and clostridium difficile infection. Clin
Gastroenterol Hepatol. 2009;7: 981-987.
5. Mylonaki M, Langmead L, Pantes A, et al. Enteric infection in relapse of inflammatory bowel
disease: importance of microbiological examination of stool. Eur J Gastroenterol Hepatol.
2004;16: 775-778.
6. Meyer AM, Ramzan NN, Loftus EV,Jr, et al. The diagnostic yield of stool pathogen studies
during relapses of inflammatory bowel disease. J Clin Gastroenterol. 2004;38: 772-775.
7. Clayton EM, Rea MC, Shanahan F, et al. The vexed relationship between Clostridium difficile
and inflammatory bowel disease: an assessment of carriage in an outpatient setting among
patients in remission. Am J Gastroenterol. 2009;104: 1162-1169.
27
Q.I. #7: Testing for non-C. difficile enteric infections
IBD QI #7:
IF a patient with colonic IBD in remission develops unexpected
exacerbation
THEN stool examination for bacterial and parasitic infection, and
serologic testing for amoebiasis should be performed
BECAUSE enteric infections can coexist with IBD flares
Summary: Data support testing for bacterial and amoebic colitis in the setting of colonic IBD
flare. Testing for other parasitic infections is clinically reasonable, but strong data do not
exist to support this is as a quality indicator.
Details
Enteric infections other than C. Difficile
Case reports of IBD flares associated with enteric infections other than C difficile exist, but few
studies document incidence or prevalence. Table 1 summarizes the five studies identified;
these include either outpatients alone or outpatients and inpatients combined. Studies that
exclusively evaluated C difficile infection are excluded, as they are discussed elswhere.
Table 1. Studies of enteric infections and IBD exacerbation, excluding studies that exclusively
studied C difficile infection.
Study and
Number and
Frequency of infection by
Different prevalence in
geographic location
type of flaring
organism, No. (%)
colonic IBD versus non-
IBD patients
colonic IBD?
studied
Meyer, United
UC: 24
C. difficile: 11 (20.0%)
States5
CD: 21
Campylobacter: 1 (1.9%)
IC: 9
P. shigelloides: 1 (1.9%)
Total: 54
Parasitic infection: 0 (0.0%)
Total: 13 (24.1%)
Total non-C difficile: 2 (3.7%)
Not reported
Mylonaki, United
UC: 89
C. difficile: 13 (9.5%)
Kingdom4
CD: 45
Campylobacter: 5 (3.6%)
IC: 3
E. histolytica: 3 (2.2%)
Total: 137
Salmonella: 1 (0.7%)
No
P. shigelloides: 1 (0.7%)
S. stercoralis: 1 (0.7%)
B. hominis: 1(0.7%)
Total: 25 (18.2%)
Total non-C difficile: 12 (8.8%)
Ozin, Turkey6
UC: 111
E. histolytica: 35 (31.5%)
N/A, UC patients only
Total: 35 (31.5%)
Navarro-Llavat,
UC: 49
Campylobacter: 5 (5.0%)
5 (71.4%) infections
Spain7
CD: 47
C. difficile: 1 (1.0%)
were in UC patients, 2
IC: 4
B. hominis: 1 (1.0%)
(28.6%) of 7 in CD
Total: 100
Total: 7 (7.0%)
patients
UC: 25
C. difficile: 6 (24.0%)
N/A, UC patients only
Kochhar, India
8
E. histolytica: 3 (12.0%)
Salmonella: 1 (4.0%)
Total: 8 (40.0%)
CD, Crohn’s disease; IC, indeterminate colitis; N/A, not applicable; UC, ulcerative colitis
Based on these studies, the bacterial enteric infection rate among flaring IBD patients ranges
from 7-40% and pathogens vary based on geographic location. The available data do not
permit comparison of colonic versus non-colonic IBD, but, based extrapolation of the C difficile
data could suggest that patients with colonic IBD may be more frequently and severely affected.
These data support evaluation for bacterial pathogens and E. histolytica among flaring IBD
patients as a reasonable quality indicator. While testing for other parasites is clinically
reasonable, sufficient data to support its use as a quality indicator are not available.
References
1. Nguyen GC, Kaplan GG, Harris ML, et al. A national survey of the prevalence and impact of
Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J
Gastroenterol. 2008;103: 1443-1450.
29
2. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with
Clostridium difficile in patients with inflammatory bowel disease. Gut. 2008;57: 205-210.
3. Rodemann JF, Dubberke ER, Reske KA, et al. Incidence of Clostridium difficile infection in
inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5: 339-344.
4. Mylonaki M, Langmead L, Pantes A, et al. Enteric infection in relapse of inflammatory bowel
disease: importance of microbiological examination of stool. Eur J Gastroenterol Hepatol.
2004;16: 775-778.
5. Meyer AM, Ramzan NN, Loftus EV,Jr, et al. The diagnostic yield of stool pathogen studies
during relapses of inflammatory bowel disease. J Clin Gastroenterol. 2004;38: 772-775.
6. Ozin Y, Kilic MZ, Nadir I, et al. Presence and diagnosis of amebic infestation in Turkish
patients with active ulcerative colitis. Eur J Intern Med. 2009;20: 545-547.
7. Navarro-Llavat M, Domenech E, Bernal I, et al. Prospective, observational, cross-sectional
study of intestinal infections among acutely active inflammatory bowel disease patients.
Digestion. 2009;80: 25-29.
8. Kochhar R, Ayyagari A, Goenka MK, et al. Role of infectious agents in exacerbations of
ulcerative colitis in India. A study of Clostridium difficile. J Clin Gastroenterol. 1993;16: 26-30.
9. Forrest K, Symmons D, Foster P. Systematic review: is ingestion of paracetamol or nonsteroidal anti-inflammatory drugs associated with exacerbations of inflammatory bowel disease?
Aliment Pharmacol Ther. 2004;20: 1035-1043.
10. Dominitz JA, Koepsell TD, Boyko EJ. Association between analgesic use and inflammatory
bowel disease (IBD) flares: a retrospective cohort study. Gastroenterology. 2000;118: A581.
11. Aalykke E, Hallas J, Lauritsen JM, et al. Role of NSAID use in inflammatory bowel disease.
Gastroenterology. 2000;118: A869.
12. Bonner GF, Walczak M, Kitchen L, et al. Tolerance of nonsteroidal antiinflammatory drugs in
patients with inflammatory bowel disease. Am J Gastroenterol. 2000;95: 1946-1948.
13. Bonner GF, Fakhri A, Vennamaneni SR. A long-term cohort study of nonsteroidal antiinflammatory drug use and disease activity in outpatients with inflammatory bowel disease.
Inflamm Bowel Dis. 2004;10: 751-757.
14. Jowett SL, Seal CJ, Barton JR, et al. Factors predictive of relapse in ulcerative colitis.
Gastroenterology. 2002;122: A605.
15. Meyer AM, Ramzan NN, Heigh RI, et al. Relapse of inflammatory bowel disease associated
with use of nonsteroidal anti-inflammatory drugs. Dig Dis Sci. 2006;51: 168-172.
16. Rampton DS, McNeil NI, Sarner M. Analgesic ingestion and other factors preceding relapse
in ulcerative colitis. Gut. 1983;24: 187-189.
17. Riley SA, Mani V, Goodman MJ, et al. Why do patients with ulcerative colitis relapse? Gut.
1990;31: 179-183.
Q.I. #8: Counselling against NSAIDs
Q.I. #8:
IF a patient is newly diagnosed with Crohn’s disease,
THEN he or she should be educated about the risks of disease
exacerbation from nonsteroidal anti-inflammatory drugs (NSAIDs),
BECAUSE NSAIDs may be associated with exacerbations of Crohn’s
disease.
Summary: NSAIDs may be associated with exacerbations of Crohn’s disease, but
evidence supporting a causal relationship is limited.
Details
Although NSAID use is widely believed to increase risk of Crohn’s disease exacerbation, the
evidence for such association is limited. A systematic review of studies evaluating risk for
exacerbation of inflammatory bowel disease (IBD) with NSAID use was published in 2004;1 no
additional relevant studies were identified through further literature review. Seventeen original
studies investigated links between IBD and NSAID use; five presented sufficient data to
evaluate associations between NSAID use and Crohn’s exacerbation. Three of five studies
identified significant associations between active Crohn’s disease and analgesic use; in one of
these the association was with acetaminophen rather than traditional NSAIDs. Reported odds
ratios included both Crohn’s disease and ulcerative colitis patients combined, reducing their
applicability to Crohn’s patients specifically. The largest two studies failed to identify significant
associations. The studies are summarized in table 1.
Table 1. Studies documenting association between NSAID use and Crohn’s disease
exacerbations.
Study
Publication
Design
type
Number
Association between NSAID
of CD
use and active CD?
patients
Aalykke,
Abstract
Retrospective 270
20002
onlya
cohort
31
Yes, OR = 1.95 (1.15,3.29)b
Bonner,
Original
20003
article
Bonner,
Original
4
c
2004
article
Dominitz,
Abstract
20005
onlya
Case-control
40
No, OR = 0.34 (0.07,1.39)
Prospective
426
No
881
Yes,
cohort
Case-control
NSAIDs: OR = 0.93
(0.68,1.27)b
Acetaminophen: OR = 1.57
(1.21,2.03)b
Meyer, 20066
Original
Case-control
41
Yes, OR = 6.31 (1.16,34.38)b
articlec
CD, Crohn’s disease; OR, odds ratio
a Abstract
reported in systematic review not identified on search of Gastroenterology website; full original
article not identified in literature search
b OR
is for all IBD; not reported separately for CD
c Cited
as an abstract in systematic review; subsequent original article identified through literature search
The design of these studies was suboptimal; all were single-center studies, and four of five were
retrospective. None employed a randomized, double-blinded, placebo-controlled design that
would be necessary to definitively identify or exclude a link between Crohn’s disease
exacerbation and NSAID use. That two studies were apparently never published in a peerreviewed journal is notable, especially given their large sample sizes. Based on the available
data, assessment of NSAID use in newly diagnosed Crohn’s disease may be clinically
appropriate, but is evidence is limited and conflicting.
References
1. Forrest K, Symmons D, Foster P. Systematic review: is ingestion of paracetamol or nonsteroidal anti-inflammatory drugs associated with exacerbations of inflammatory bowel disease?
Aliment Pharmacol Ther. 2004;20: 1035-1043.
2. Aalykke E, Hallas J, Lauritsen JM, et al. Role of NSAID use in inflammatory bowel disease.
Gastroenterology. 2000;118: A869.
3. Bonner GF, Walczak M, Kitchen L, et al. Tolerance of nonsteroidal antiinflammatory drugs in
patients with inflammatory bowel disease. Am J Gastroenterol. 2000;95: 1946-1948.
4. Bonner GF, Fakhri A, Vennamaneni SR. A long-term cohort study of nonsteroidal antiinflammatory drug use and disease activity in outpatients with inflammatory bowel disease.
Inflamm Bowel Dis. 2004;10: 751-757.
5. Dominitz JA, Koepsell TD, Boyko EJ. Association between analgesic use and inflammatory
bowel disease (IBD) flares: a retrospective cohort study. Gastroenterology. 2000;118: A581.
6. Meyer AM, Ramzan NN, Heigh RI, et al. Relapse of inflammatory bowel disease associated
with use of nonsteroidal anti-inflammatory drugs. Dig Dis Sci. 2006;51: 168-172.
33
Drug Safety and Monitoring
Q.I. #9: Tuberculosis testing before anti-TNF therapy
QI #9:
IF a patient with IBD is initiating anti-tumor necrosis factor (antiTNF) therapy
THEN Tuberculosis (TB) risk assessment should be documented, and tuberculin
skin testing (TST) or interferon gamma release assay (IGRA) should be
performed
BECAUSE anti-TNF therapy increases the risk of developing active TB and
therapy for latent TB infection (LTBI) reduces this risk.
Summary: Although studies on the risk of reactivation of latent TB infection (LTBI) with antiTNF therapy do not exist specifically for the IBD population, these risks have been studied in the
rheumatology population. The risk of serious infection is doubled with anti_TNF therapy,1
including a risk of 95/ 100,000 person-years for development of active TB.2 The risk of active
TB is much higher than the risk of other opportunistic infections associated with anti-TNF
therapy.3 Effective screening tools for LTBI are available, although the specificity of these tools
may be limited in the setting of immunosuppression.4 Treatment of LTBI prior to initiation of
anti-TNF therapy dramatically decreases the incidence of active TB by > 80%5 and has been
shown to be effective in the IBD population.6
DETAILS:
Risk of active and latent TB
Globally, nine million people develop active M. tuberculosis infection each year, and 2 billion
people are thought to be latently infected (LTBI) with M. tuberculosis.7, 8 People with LTBI are
at increased risk for developing active disease. A tuberculin skin test (TST) survey in 2000
indicated that approximately 11,213,000 U.S. residents (4.2% of the U.S. population aged >1
year) had LTBI.9 Rates of LTBI and active TB vary based on the presence of risk factors. U.S.
residents with no risk factors are considered to be at low risk for infection from M. tuberculosis,
with a prevalence of infection of ≤1%.
Those with LTBI are at increased risk of developing active TB after treatment with anti-TNF
therapy. Animal studies have shown that TNF-α can prevent the reactivation of LTBI.10 TNF-α
is a necessary component of host defense against mycobacterial infection by regulating
macrophage activation, cell recruitment, and granuloma formation.11-13 Blocking TNF-α in
patients with LTBI can therefore disrupt the granuloma and disseminate M. tuberculosis
infection.
The prevalence of LTBI within IBD populations varies by country, prior vaccination with Bacille
Calmette-Guérin (BCG) and risk factor status. No specific per country estimates of the rate of
LTBI within the IBD population exist. However, the majority of cases of active TB after anti-TNF
therapy have been reported in countries with a low overall incidence of TB,3 thereby
demonstrating that risk is present regardless of a country’s background rate of LTBI or active
TB. In the British rheumatology population, the risk of development of active TB in those treated
with anti-TNF therapy has been reported to be 95/100,000 person-years.2
Screening modalities
Several options exist to screen for LTBI, including risk assessment (Table 1), TST with or
without control, and IGRA. There is not a consensus as to which test or combination of tests is
most effective in patients with IBD. There has been one study of TST in the IBD population
prior to or during treatment with anti_TNF therapy. None of the patients had a positive TST
result. A total of 71% of these patients were anergic to control skin testing as well (Candida,
tetanus, and/or mumps).14 Because of this high rate of anergy, the use of TB risk assessment
in addition to TST has been recommended in the IBD population. A meta-analysis of 58 studies
on the sensitivity, specificity and reproducibility of IGRAs in healthy and immunosuppressed
patients was performed in 2007. Sensitivity of TST and IGRAs were found to be similar,
although IGRAs were found to be more specific in those with previous vaccination. The studies
included in the meta-analysis were all limited, as there is no gold standard for diagnosis of LTBI.
There was insufficient evidence on IGRA performance in children, the elderly and those on
immunosuppression in this meta-analysis.4 . Since this meta-analysis, 4 further studies on
screening for LTBI specifically in the IBD population have been published. Schoepfer et al
compared IGRA to TST in a population of IBD patients and controls. The agreement between
the two types of testing was poor among IBD patients, and TST positivity was reduced in those
on immunosuppression and with previous vaccination.15 Soborg et al also found that agreement
between the two types of testing was low with a kappa of 0.2 (95% CI 0.02-0.3). In this study, a
positive IGRA result was more closely associated with risk factors for TB.11 Qumseya et al
found only moderate concordance between the TST and IGRA (κ = 0.4152, p = 0.0041).16
35
Papay et al found fair concordance between TST and IGRA (84.9%, κ = 0.21), This study also
found IGRA to be negatively influenced by immunosuppression (OR 0.3, 95% CI 0.1-0.9).17 The
CDC has released updated guidelines in 2010 on the use of IGRAs for detection of LTBI in the
United States. The expert panel concluded that TSTs and IGRAs may be used as aids in
diagnosing TB. They may be used for surveillance purposes and to identify persons likely to
benefit from treatment. They also concluded that additional research is needed on the value and
limitations of IGRAs.7
Table 1. Risk factors for Mycobacterium tuberculosis infection
Persons at increased risk* for M. tuberculosis infection







close contacts of persons known or suspected to have active tuberculosis;
foreign-born persons from areas that have a high incidence of active tuberculosis (e.g.,
Africa, Asia, Eastern Europe, Latin America, and Russia);
persons who visit areas with a high prevalence of active tuberculosis, especially if visits
are frequent or prolonged;
residents and employees of congregate settings whose clients are at increased risk for
active tuberculosis (e.g., correctional facilities, long-term care facilities, and homeless
shelters);
health-care workers who serve clients who are at increased risk for active tuberculosis;
populations defined locally as having an increased incidence of latent M. tuberculosis
infection or active tuberculosis, possibly including medically underserved, low-income
populations, or persons who abuse drugs or alcohol; and
infants, children, and adolescents exposed to adults who are at increased risk for latent
M. tuberculosis infection or active tuberculosis.
(Source: CDC Updated Guidelines for Using Interferon Gamma Release Assays to
Detect Mycobacterium tuberculosis Infection --- United States, 2010. MMWR 2010;
59(No. RR-5);1-25.7)
* Persons with these characteristics have an increased risk for M. tuberculosis infection
compared with persons without these characteristics.
Treatment of latent TB prior to anti-TNF therapy
One cohort study on the treatment of LTBI in the IBD population prior to anti-TNF therapy was
found. In a European population, a total of 12.5% (63/497) of those evaluated for anti-TNF
therapy were diagnosed with LTBI via TST, the majority of whom were on immunomodulators at
the time of testing. Approximately 14% of those with LTBI were diagnosed via a second TST
after the first was negative. Treatment was with isoniazid (INH) alone for 6-9 months. Only
1/63 required discontinuation of INH related to hepatotoxicity. Therefore, treatment of LTBI was
found to be safe in IBD patients on other forms of immunosuppression.6 Similar studies in the
rheumatology population have found no increased risks of hospitalization or death with therapy
for LTBI.5 The optimal timing of anti-TNF therapy after initiation of treatment for LTBI is
unknown.18
Reduction of TB risk associated with implementation of screening recommendations
No studies on the risk reduction associated with the implementation of screening
recommendations for LTBI prior to anti-TNF therapy exist specifically for the IBD population.
One study in the rheumatology population has demonstrated that implementation of screening
recommendations for LTBI prior to anti-TNF therapy has reduced the risk of active TB by 83%.
The rate of active TB in the anti-TNF treated rheumatology population is now reported to be
similar to the background rate in the rheumatology population not on anti-TNF therapy (RR 1.0
95% CI 0.02-8.2).5
Guidelines
Guidelines for testing for LTBI in patients with IBD prior to initiation of anti-TNF therapy were
released in 2009 in the United States. These guidelines state that all patients should have a
careful risk assessment and TST prior to initiation of ant-TNF therapy.19 Additionally, the
American Gastroenterological Association also recommends TST and comprehensive risk factor
assessment for all IBD patients prior to initiation of anti-TNF therapy.18 Additional guidelines for
TB screening prior to anti-TNF therapy were established by the British Society for
Rheumatology (BSR) and the British Thoracic Society (BTS), with an update in 2005. 20, 21
These guidelines recommend that all patients should have a clinical examination, a chest
radiograph within three months of starting anti-TNF therapy, their history of prior TB checked
and, if appropriate, a TST performed.
References
1.
Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF
antibody therapy in rheumatoid arthritis and the risk of serious infections and
malignancies: systematic review and meta-analysis of rare harmful effects in randomized
controlled trials. JAMA 2006;295:2275-85.
2.
Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, Symmons DP.
Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with antiTNF therapy: results from the British Society for Rheumatology Biologics Register
(BSRBR). Ann Rheum Dis 2010;69:522-8.
3.
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD,
Siegel JN, Braun MM. Tuberculosis associated with infliximab, a tumor necrosis factor
alpha-neutralizing agent. N Engl J Med 2001;345:1098-104.
37
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent
tuberculosis infection: areas of uncertainty and recommendations for research. Ann
Intern Med 2007;146:340-54.
Carmona L, Gomez-Reino JJ, Rodriguez-Valverde V, Montero D, Pascual-Gomez E,
Mola EM, Carreno L, Figueroa M. Effectiveness of recommendations to prevent
reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor
antagonists. Arthritis Rheum 2005;52:1766-72.
Zabana Y, Domenech E, San Roman AL, Beltran B, Cabriada JL, Saro C, Aramendiz R,
Ginard D, Hinojosa J, Gisbert JP, Manosa M, Cabre E, Gassull MA. Tuberculous
chemoprophylaxis requirements and safety in inflammatory bowel disease patients prior
to anti-TNF therapy. Inflamm Bowel Dis 2008;14:1387-91.
Mazurek M, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for
using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection
- United States, 2010. MMWR Recomm Rep 2010;59:1-25.
World Health Organization. Global tuberculosis control: epidemiology s, financing: WHO
report 2009. Geneva, Switzerland: World Health Organization; 2009. Available at
http://www.who.int/tb/publications/global_report/2009/pdf/report_without_annexes.pdf .
Accessed September 16, 2010. .
Bennett DE, Courval JM, Onorato I, Agerton T, Gibson JD, Lambert L, McQuillan GM,
Lewis B, Navin TR, Castro KG. Prevalence of tuberculosis infection in the United States
population: the national health and nutrition examination survey, 1999-2000. Am J
Respir Crit Care Med 2008;177:348-55.
Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, Vinh DC. Antitumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical
management. Lancet Infect Dis 2003;3:148-55.
Soborg B, Ruhwald M, Hetland ML, Jacobsen S, Andersen AB, Milman N, Thomsen VO,
Jensen DV, Koch A, Wohlfahrt J, Ravn P. Comparison of screening procedures for
Mycobacterium tuberculosis infection among patients with inflammatory diseases. J
Rheumatol 2009;36:1876-84.
Chakravarty SD, Zhu G, Tsai MC, Mohan VP, Marino S, Kirschner DE, Huang L, Flynn
J, Chan J. Tumor necrosis factor blockade in chronic murine tuberculosis enhances
granulomatous inflammation and disorganizes granulomas in the lungs. Infect Immun
2008;76:916-26.
Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates
chemokine induction essential for cell recruitment, granuloma formation, and clearance
of mycobacterial infection. J Immunol 2002;168:4620-7.
Mow WS, Abreu-Martin MT, Papadakis KA, Pitchon HE, Targan SR, Vasiliauskas EA.
High incidence of anergy in inflammatory bowel disease patients limits the usefulness of
PPD screening before infliximab therapy. Clin Gastroenterol Hepatol 2004;2:309-13.
Schoepfer AM, Flogerzi B, Fallegger S, Schaffer T, Mueller S, Nicod L, Seibold F.
Comparison of interferon-gamma release assay versus tuberculin skin test for
tuberculosis screening in inflammatory bowel disease. Am J Gastroenterol
2008;103:2799-806.
Qumseya BJ, Ananthakrishnan AN, Skaros S, Bonner M, Issa M, Zadvornova Y, Naik A,
Perera L, Binion DG. QuantiFERON TB gold testing for tuberculosis screening in an
inflammatory bowel disease cohort in the United States. Inflamm Bowel Dis 2010.
Papay P, Eser A, Winkler S, Frantal S, Primas C, Miehsler W, Novacek G, Vogelsang H,
Dejaco C, Reinisch W. Factors impacting the results of interferon-gamma release assay
and tuberculin skin test in routine screening for latent tuberculosis in patients with
inflammatory bowel diseases. Inflamm Bowel Dis 2010.
18.
19.
20.
21.
Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological
Association Institute technical review on corticosteroids, immunomodulators, and
infliximab in inflammatory bowel disease. Gastroenterology 2006;130:940-87.
Moscandrew M, Mahadevan U, Kane S. General health maintenance in IBD. Inflamm
Bowel Dis 2009;15:1399-409.
BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis
infection and disease in patients due to start anti-TNF-alpha treatment. Thorax
2005;60:800-5.
Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for
prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous
guidelines of April 2001). Rheumatology (Oxford) 2005;44:157-63.
39
Q.I. #10: Laboratory Monitoring on anti-TNF Therapy
QI # 10
IF a patient with IBD is maintained on anti-tumor necrosis factor
(anti-TNF) therapy
THEN CBC and liver enzymes should be checked every 3-6 months
BECAUSE anti-TNF therapy has rarely been associated with bone marrow
suppression and liver function test (LFT) abnormalities
Summary: Small increased risks of neutropenia and LFT abnormalities have been
demonstrated in patients with rheumatic disorders on anti-TNF therapy.1, 2 Because of this
increased risk, recommendations for monitoring exist. There have been no randomized
controlled trials or cost-effectiveness analyses evaluating this intervention. In the major
trials of anti-TNF therapy in the treatment of Crohn’s disease, neither neutropenia nor LFT
abnormalities were among the reported serious adverse events.
DETAILS:
Risk of bone marrow suppression:
No cohort studies have been published on bone marrow suppression in patients with IBD on
anti-TNF therapy, although there are case reports of these findings in the literature. No
randomized controlled trials of monitoring CBC in patients with IBD on anti-TNF therapy have
been performed. Neutropenia was not among the serious adverse events reported in the major
anti-TNF treatment trials for Crohn’s disease. In a single retrospective cohort study of
rheumatology patients on anti-TNF therapy, approximately 19% experienced at least one
episode of neutropenia, although many had previously or were currently on therapy with
methotrexate. Risk factors for neutropenia in this population included prior neutropenia with a
disease modifying agent (DMARD) and a low neutrophil count prior to initiation of anti-TNF
therapy.2
Risk of abnormal LFTs:
No cohort studies have been published on abnormal LFTs in patients with IBD on anti-TNF
therapy, although there are case reports of these findings in the literature. No randomized
controlled trials of monitoring LFTs in patients with IBD on anti-TNF therapy have been
performed. LFT abnormalities were not among the serious adverse events reported in the
major anti-TNF treatment trials for Crohn’s disease. A small increased risk of LFT abnormalities
has been described in a single cohort study of rheumatology patients on anti-TNF therapy (5.9%
with elevations >1 x the upper limit of normal (ULN), and 0.77% with elevations >2 x ULN).1
The authors were unable to completely rule out underlying hepatic disease or the contribution of
polypharmacy to these mild elevations of LFTs. Additionally, there is unclear clinical
significance to elevated LFTs in the range of 1-2 x ULN.
Guidelines:
Guidelines on general health maintenance in the IBD population were published in 2009. These
guidelines recommend CBC and liver function tests every 3-6 months for those on maintenance
therapy with anti-TNF therapy.3 Current British guidelines recommend periodic monitoring of
CBC while on anti-TNF therapy, whereas there is no recommendation for monitoring LFTs.4
References
1.
2.
3.
4.
Sokolove J, Strand V, Greenberg JD, Curtis JR, Kavanaugh A, Kremer JM, Anofrei A, Reed G,
Calabrese L, Hooper M, Baumgartner S, Furst DE. Risk of elevated liver enzymes associated
with TNF inhibitor utilisation in patients with rheumatoid arthritis. Ann Rheum Dis 2010;69:1612-7.
Hastings R, Ding T, Butt S, Gadsby K, Zhang W, Moots RJ, Deighton C. Neutropenia in patients
receiving anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken) 2010;62:764-9.
Moscandrew M, Mahadevan U, Kane S. General health maintenance in IBD. Inflamm Bowel Dis
2009;15:1399-409.
Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for
prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of
April 2001). Rheumatology (Oxford) 2005;44:157-63.
41
Q.I. #11: Assessment of Viral Hepatitis prior to anti-TNF Therapy
Q.I. #11
IF a patient with IBD is about to initiate therapy with anti-TNF
THEN antibodies to HAV and HBV should be checked and those without
antibodies to HAV or HBV should be vaccinated
BECAUSE immunosuppressed IBD patients are at risk of complications of
viral hepatitides.
SUMMARY
Three articles were identified that directly address the QI (1-3). Current management
guidelines based on case reports and case series recommend screening patients with
IBD for HAV and HBV prior to initiation of immunosuppressant therapies such as antiTNF(1, 2). These guidelines also recommend vaccinating individuals with no apparent
prior exposure to either HAV or HBV. There are currently no guidelines advocating
screening for HCV.
DETAILS
Concomitant IBD and viral hepatitis infection can complicate medical management. In particular,
many of the agents used to manage IBD, including anti-TNF agents can adversely affect viral
hepatitis infection – especially if the viral infection is unrecognized and not treated prior to
initiation of the anti-TNF agent. Vaccination against HAV and HBV prior to initiation of anti-TNF
therapy is recommended to prevent these infections in patients with IBD.
HAV
HAV is a common virus and most individuals are exposed to it at some point in their lifetime. In
immune-competent individuals it usually presents as transcient, mild flu-like symptoms but it can
rarely present as a fulminant hepatitis. Immunosuppressed individuals may be at increased risk
of fulminant hepatitis. IBD patients should be tested for anti-HAV IgG antibody, which confers
immunity, prior to initiating anti-TNF therapy. Individuals who are not immune should be
vaccinated prior to initiating anti-TNF therapy(1, 2). The vaccination is an inactivated, live virus
administered on a two-dose schedule.
HBV
Immune-competent individuals exposed to HBV may go on to become chronic carriers. The
chronic disease is categorized as active, inactive or resolved. Individuals with active disease
should be treated with anti-viral therapy. Those with inactive or resolved infection are at risk of
reactivation especially in the setting of immunosuppression(2, 3). Infliximab is an anti-TNF agent
that has been associated with an increased risk of reactivation of HBV. This has been
documented in case reports of individuals on infliximab therapy in combination with either
corticosteroid therapy or azathioprine(4, 5). While there are no case reports of HBV reactivation
of the other two anti-TNF agents, adalimumab and certolizumab pegol, it is considered to be a
class effect(2). All patients with IBD should be checked for HBV preferably at the time of
diagnosis of IBD but definitely prior to initiating anti-TNF therapy. The recommended screening
tests are HBsAg (hepatitis B surface antigen) and HBsAb (hepatitis B core antibody)(1). Hou et
al also recommend HBcAb (hepatitis B core antibody)(2). Non-immune individuals require
vaccination prior to initiation of anti-TNF. The vaccine consists of a recombinant DNA vaccine
and is administered as three injections over a 6-month period (1, 2).
HCV
Hepatitis C infection usually results in chronic disease. The currently is no vaccine against the
virus. Studies have not shown that anti-TNF therapy adversely affects patients infected with
HCV(2). Furthermore studies assessing the effect of anti-HCV therapy on IBD are
contradictory(6, 7). The disparity may be due to differences in drug dosing. There are no
guidelines recommending testing for HCV in IBD patients and there is currently no vaccine
against this virus.
References
1. Moscandrew M, Mahadevan U, Kane S. General health maintenance in IBD. Inflamm Bowel
Dis 2009;15:1399-409.
43
2. Hou JK, Velayos F, Terrault N, et al. Viral hepatitis and inflammatory bowel disease.
Inflamm Bowel Dis;16:925-32.
3. Ferkolj I. How to improve the safety of biologic therapy in Crohn's disease. J Physiol
Pharmacol 2009;60 Suppl 7:67-70.
4. Esteve M, Saro C, Gonzalez-Huix F, et al. Chronic hepatitis B reactivation following
infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut 2004;53:13635.
5. Ojiro K, Naganuma M, Ebinuma H, et al. Reactivation of hepatitis B in a patient with Crohn's
disease treated using infliximab. J Gastroenterol 2008;43:397-401.
6. Seow CH, Benchimol EI, Griffiths AM, et al. Type I interferons for induction of remission in
ulcerative colitis. Cochrane Database Syst Rev 2008:CD006790.
7. Watanabe T, Inoue M, Harada K, et al. A case of exacerbation of ulcerative colitis induced
by combination therapy with PEG-interferon alpha-2b and ribavirin. Gut 2006;55:1682-3.
Q.I. #12: Renal function on 5-ASA
Q.I. #12:
IF a patient with IBD is on 5-ASA therapy
THEN a creatinine should be checked prior to initiation, and then yearly
thereafter
BECAUSE there is a risk of nephrotoxicity associated with 5-ASA use, and
early withdrawal of the medication increases the chance of renal recovery.
SUMMARY
The incidence of 5-ASA induced nephrotoxicity in patients with IBD is low, and most
occur within the first year of therapy. The direct benefit of screening for nephrotoxicity in
asymptomatic individuals has not been demonstrated in studies. However, evidence
suggests that patients diagnosed early in treatment show better renal recovery. Also,
testing for renal impairment (serum creatinine) may be a far cheaper alternative than
long term renal replacement therapy in affected individuals.
DETAILS
Introduction
The occurrence of renal impairment induced by 5-ASA therapy in IBD is well reported in
numerous case reports/series. Interstitial nephritis (IN) has been shown to occur at a higher
frequency in patients taking mesalamine, but not sulfasalazine, where an idiosyncratic,
hypersensitivity reaction is more commonly reported1. Determining the actual incidence of renal
impairment directly related to 5-ASA use in patients with IBD is difficult because (1) the
incidence is rare, (2) disorders of chronic inflammation including IBD are associated with an
increased risk of renal impairment and (2) there is an age-related physiological decline in renal
function which is occasionally reported as being associated with drug therapy. Also, the most
commonly employed test to identify renal impairment, serum creatinine, is an imperfect tool as
significant renal damage may predate rises in creatinine. No urinary markers have to date
proved useful in the setting of identifying drug-related renal impairment.
Incidence of 5-ASA associated renal impairment, and is it related to dose or duration?
45
The incidence of clinically significant renal impairment in patients with IBD on 5-ASA is reported
to range from 1:500 to 1:40002, 3(Table 1). Determing how much of this is related to the therapy
and not the underlying disease process is difficult. Van Staa et al4 reported 0.17 cases of renal
impairment per 100 patients per year; however, in patients with IBD not on 5-ASA, the incident
rates of renal impairment were the similar, namely 0.25 cases per 100 patients per year. In this
study, adjusted odds ratio of renal disease among 5-ASA users was .86. Walker et al5 reported
an incidence of 0.2 per 100 patient years based on a single case of renal impairment. Similarly,
Elseviers et al6 reported 34 cases of renal impairment in patients on 5-ASA in a cohort of 1529,
and were able to attribute up to 5 of these to 5-ASA therapy suggesting a frequency of 1.3-3.3
per 1000 patients.
It is also difficult to determine if dose (daily or cumulative) has an impact on renal function.
Animal studies suggest a clear dose-dependent effect on renal function, though doses used
were higher than those used in humans. Conflicting results from human studies fail to determine
any effect of higher doses that is not related to the underlying disease process. The relative risk
with different agents is too small to draw a conclusion and influence choice of agent.
Why screen?
There is no evidence to suggest that screening improves morbidity in this arena. However,
pattern of recovery of those diagnosed early in therapy are favorable; if the diagnosis of renal
impairment is made within 12 months of onset of 5-ASA therapy, 40-85% of patients
demonstrate restoration of renal function2, 7. When the diagnosis is made >18moths after
therapy is instituted, only a third show even partial recovery.
Most cases occur within the first 12 months, but delayed presentation can occur after years2, 8.
How to screen, and why this pattern?
Serum creatinine pre-therapy, and every three months for one year, and then yearly for the
duration of the therapy.
Approximately 50% of cases of renal impairment occur within the first 12 months of beginning
therapy. Early withdrawal of therapy has been shown to improve chances of resolution of
disease2, 8. Monitoring should continue for the duration of therapy as reports of 5-ASA induced
nephrotoxicity have been reported many years after institution of therapy7.
Study
Type
9
Riley
Point
(1992)
prevalence
Schreiber
10
(1997)
Point
prevalence
Walker5
Retrospective
(1997)
Fraser11
Prospective (1
(2001)
year)
Ransford
1
(2002)
Retrospective
12
Cunliffe
(2002)
Dehmer13
(2003)
Number
Mode of
of IBD pts
discovery
62 pts
223 pts
2894 UC
Renal disease with 5-ASA?
Conclusion
urinary
No correlation of renal function and
Mesalamine and sulfasalazine
markers
cumulative dose/treatment duration.
carry same nephrotoxic risk
creatinine,
Rising incidence of tubular
urinary
proteinuria with increased 5-ASA
markers
doses
documented
0.2 per 100 person-years (1pt) in
report
high doses, 0 in low doses
Creatinine,
21 pts
urinary
No change in renal function
markers
5-ASA effect from IBD effect.
Nephrotoxicity is rare.
intestinal manifestation of IBD
irresepective of 5-ASA use.
IN reports formed 31%(29/93) of
11.1 reports of IN per million
7.5 million
documented
renal adverse events for mesal. vs
mesalamine prescriptions, none
Rxs.
report
0%(0/27) for SSZ renal events.
for sulfasalazine.
718 pts
documented
trials
(sulfa)
report
Review of 18
1638 pts
documented
1 case of IN associated (prevalence
trials
(mesala)
report
.06%)
weeks)
associated with proximal tubular
dysfunction - could not differentiate
Tubular proteinuria is an extra-
Review of 10
Prospective (6
Increasing doses of 5-ASA
47 pts
No change in renal function
urinary
No change in markers
markers
Nephrotoxicity is rare
IN is rare
5-ASA therapy does not impart a
dose-dependent tubulotoxicity.
Nephrotoxicity for IBD on 5-ASA:
Retrospective
19,025 pts
4
Van Staa
documented
report
(2004)
Elseviers6
(2004)
De Jong14
(2005)
Muller3
(2005)
incident rate 0.17 cases per 100
The incident rate of renal disease
patients per year; for IBD not on 5-
in those on 5-ASA is similar to
ASA: 0.25. Adjusted odds ratio for
those not on 5-ASA.
5-ASA induced renal disease - 0.86.
Prospective (1
year)
Retrospective
questionnaire
1529 pts
153 pts
5 episodes of renal impairment
serum
attributable to 5-ASA - 1.3-3.3 per
creatinine
1000 patients.
Low risk of nephrotoxicity with 5ASA
serum
Decline in renal function similar to
No association of 5-ASA and renal
creatinine
that of physiological aging decline.
function.
Serum
Estimated nephrotoxicity 1 in 4000
Nephrotoxicity is rare. Recovery
creatinine
patients/year
was better for those treated with 5-
47
ASA for less than 12 months.
Poulou15
Prospective
(2006)
(28.8mths)
Gisbert16
Prospective (4
(2008)
years)
Patel17
Retrospective
277 pts
150 pts
171 pts
(2009)
Sandborn
18
(2010)
Prospective (1
year)
1029 pts
Urinary
markers
serum
creatinine
serum
creatinine
No change in renal function
No effect on renal function
No change in renal function
No effect on renal function
Mean creatinine increase of
Significant dose-dependent and
12umol/L over 8.4 years. One case
duration dependent effect of 5-
of IN reported.
ASA on renal function.
documented
report
2 pts of acute renal failure
ARF is rare in IBD patients treated
with 5-ASA
IN - interstitial nephritis
sulfa – sulfasalazine
mesala – Mesalamine
References
(1) Ransford RA, Langman MJ. Sulphasalazine and mesalazine: serious adverse reactions reevaluated on the basis of suspected adverse reaction reports to the Committee on Safety of
Medicines. Gut 2002;51(4):536-539.
(2) World MJ, Stevens PE, Ashton MA, Rainford DJ. Mesalazine-associated interstitial nephritis.
Nephrol Dial Transplant 1996;11(4):614-621.
(3) Muller AF, Stevens PE, McIntyre AS, Ellison H, Logan RF. Experience of 5-aminosalicylate
nephrotoxicity in the United Kingdom. Aliment Pharmacol Ther 2005;21(10):1217-1224.
(4) Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-aminosalicylic acids and the risk of renal
disease: a large British epidemiologic study. Gastroenterology 2004;126(7):1733-1739.
(5) Walker AM, Szneke P, Bianchi LA, Field LG, Sutherland LR, Dreyer NA. 5-Aminosalicylates,
sulfasalazine, steroid use, and complications in patients with ulcerative colitis. Am J Gastroenterol
1997;92(5):816-820.
(6) Elseviers MM, D'Haens G, Lerebours E et al. Renal impairment in patients with inflammatory
bowel disease: association with aminosalicylate therapy? Clin Nephrol 2004;61(2):83-89.
(7) Gisbert JP, Gonzalez-Lama Y, Mate J. 5-Aminosalicylates and renal function in inflammatory
bowel disease: a systematic review. Inflamm Bowel Dis 2007;13(5):629-638.
(8) Corrigan G, Stevens PE. Review article: interstitial nephritis associated with the use of
mesalazine in inflammatory bowel disease. Aliment Pharmacol Ther 2000;14(1):1-6.
(9) Riley SA, Lloyd DR, Mani V. Tests of renal function in patients with quiescent colitis: effects of
drug treatment. Gut 1992;33(10):1348-1352.
(10) Schreiber S, Hamling J, Zehnter E et al. Renal tubular dysfunction in patients with inflammatory
bowel disease treated with aminosalicylate. Gut 1997;40(6):761-766.
(11) Fraser JS, Muller AF, Smith DJ, Newman DJ, Lamb EJ. Renal tubular injury is present in acute
inflammatory bowel disease prior to the introduction of drug therapy. Aliment Pharmacol Ther
2001;15(8):1131-1137.
(12) Cunliffe RN, Scott BB. Review article: monitoring for drug side-effects in inflammatory bowel
disease. Aliment Pharmacol Ther 2002;16(4):647-662.
(13) Dehmer C, Greinwald R, Loffler J et al. No dose-dependent tubulotoxicity of 5-aminosalicylic acid:
a prospective study in patients with inflammatory bowel diseases. Int J Colorectal Dis
2003;18(5):406-412.
(14) de Jong DJ, Tielen J, Habraken CM, Wetzels JF, Naber AH. 5-Aminosalicylates and effects on
renal function in patients with Crohn's disease. Inflamm Bowel Dis 2005;11(11):972-976.
(15) Poulou AC, Goumas KE, Dandakis DC et al. Microproteinuria in patients with inflammatory bowel
disease: is it associated with the disease activity or the treatment with 5-aminosalicylic acid?
World J Gastroenterol 2006;12(5):739-746.
(16) Gisbert JP, Luna M, Gonzalez-Lama Y et al. Effect of 5-aminosalicylates on renal function in
patients with inflammatory bowel disease: 4-year follow-up study. Gastroenterol Hepatol
2008;31(8):477-484.
(17) Patel H, Barr A, Jeejeebhoy KN. Renal effects of long-term treatment with 5-aminosalicylic acid.
Can J Gastroenterol 2009;23(3):170-176.
(18) Sandborn WJ, 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. Gastroenterology 2010;138(4):1286-96, 1296.
49
Q.I. #13: TPMT Testing before 6MP/AZA
Q.I. #13
IF a patient with IBD is initiating 6MP/AZA
THEN TPMT testing should be performed before starting therapy
BECAUSE testing can identify patients with high risk for toxicity and patients with
reduced chance for response, thereby allowing physicians to improve treatment
strategies.
Summary: The use of TPMT testing in IBD patients who are to initialize treatment with
6MP/AZA has been studied in multiple retrospective and prospective cohort studies. Most,
but not all of these studies have recommended that TPMT testing be performed before
initiation of treatment with 6MP/AZA in order to identify patients who are at high risk for side
effects and patients who have a reduced chance of response.
Details
We identified thirteen studies that investigated the use of TPMT testing in IBD patients who were to begin
treatment with 6MP/AZA. (1-13) Of these thirteen studies, nine showed a benefit of TPMT testing, as it
may help predict patients who are at high risk for adverse reactions, and also patients who may be low or
non-responders to therapy. (2, 3-6, 8-10, 12)
A closer look at the identified studies reveals five studies that were prospective, observational cohort
studies. (5, 6, 8, 9, 11). Of these five studies, four demonstrated benefit in performing TPMT testing
before initiation of 6MP/AZA therapy as it identified patients who were more likely to develop severe
adverse reactions, in particular myelosuppression. (5, 6, 8, 9)
Ansari and colleagues(5) looked prospectively at 215 patients with IBD. TPMT genotype testing
performed before AZA therapy was begun revealed 188 patients with the wild type TPMT allele and 19
patients with a heterozygous TPMT allele. Of the wild type patients, 35% experienced an adverse effect
compared to 79% of the heterozygotes. In addition, only 0.5% of the wild type patients experienced
myelotoxicity compared to 26% of heterozygotes. This prospective evaluation clearly demonstrated utility
in TPMT testing before initation of therapy with AZA in that it identified heterozygotes for the wild type
allele. Heterozygotes experienced a much higher incidence of adverse reactions including myelotoxicity
compared to wild types and therefore identification of this susceptible population before initiation of AZA
therapy may help the clinician prevent these toxicities from occurring in the patient.
Gisbert and colleagues(6) prospectively measured TPMT phenotype before initiation of AZA. TPMT
enzyme activity was measured in 394 patients with IBD. 366 patients were identified as having high
TPMT activity and 28 patients were identified as having intermediate TPMT activity. Of the high TPMT
activity patients, 18% experienced adverse reactions compared to 32% of the intermediate activity group.
In addition, only 4% of the high TPMT activity patients experience myelotoxicity compared to 14% of the
intermediate activity group. This study demonstrated the benefit of measuring TPMT activity before
initiation of AZA therapy in that it helps to minimize the risk of adverse affects from therapy including
serious adverse reactions like myelotoxicity.
Hindorf and colleagues (8) evaluated the pharmacogenetics of TMPT testing to determine clinical
outcome and occurrence of adverse effects in IBD patients initiated on thiopurine treatment. TPMT
genotype along with TPMT activity and gene expression was measured in patients initiated on thiopurine
therapy. No difference was found in the incidence of common adverse reactions among the wild type and
heterozygous alleles. However, genotype testing was useful in identifying patients at risk for developing
myelotoxicity.
Von Ahsen and colleagues (9) measured TPMT genotypes and enzyme activity before initiation of AZA
therapy in IBD patients. TPMT mutations and low TPMT enzyme activity was associated with a higher
rate of study drop out secondary to adverse reactions from AZA therapy. This study recommended TPMT
genotype and phenotype testing before initiation of AZA therapy in IBD patients as TPMT mutations and
low TPMT activity could alert the physician that certain patients may be at higher risk for intolerance due
to side effects and may require closer follow up and monitoring.
The only prospective analysis which did not show a clear benefit in TPMT testing before initiation of 6
MP/AZA therapy was performed by Sayani and colleagues (11). In this study, IBD patients were
randomized to: 1) in which no TPMT assay was performed before initiation of AZA therapy or 2) TPMT
activity was measured before initiation of AZA therapy. Both groups were observed for adverse reactions
as well as direct health costs (cost of TPMT assay, lab tests, physician visits, etc.). There was no
difference in adverse reactions or study drop outs between the two groups. When comparing health care
costs between the two groups, group 2 had higher direct costs than group 1 ($348.87 per person
compared to $300.11 per person). This study concluded that prospective assessment of TPMT activity
did not predict AZA induced toxicity and incurred higher costs.
One review article was found that recommended performing TPMT testing before initiation of therapy with
6MP/AZA is initiated so that the clinician may tailor their treatments based on a patients specific
51
genotype. (3) A cost-effectiveness analysis showed that testing for TPMT prior to starting 6MP/AZA was
cost-effective.
Based on FDA recommendations, the package insert for Imuran ® suggests "consideration for TPMT
testing" prior to initiation of therapy, but notes that TPMT testing does not replace the need for lab
monitoring.
References
1: Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, Maki S, Beppu T, Takaki Y,
Hirai F, Yao K. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase
genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2009
Jul;24(7):1258-64. PubMed PMID: 19682195.
2: Uchiyama K, Nakamura M, Kubota T, Yamane T, Fujise K, Tajiri H. Thiopurine S-methyltransferase
and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel
disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment. J
Gastroenterol. 2009;44(3):197-203. Epub 2009 Feb 13. PubMed PMID: 19214663.
3: Zhou S. Clinical pharmacogenomics of thiopurine S-methyltransferase. Curr Clin Pharmacol. 2006
Jan;1(1):119-28. Review. PubMed PMID: 18666383.
4: Andoh A, Tsujikawa T, Ban H, Hashimoto T, Bamba S, Ogawa A, Sasaki M, Saito Y, Fujiyama Y.
Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel
disease. J Gastroenterol Hepatol. 2008 Sep;23(9):1373-7. Epub 2008 Jul 23. PubMed PMID: 18662197.
5: Ansari A, Arenas M, Greenfield SM, Morris D, Lindsay J, Gilshenan K, Smith M, Lewis C, Marinaki A,
Duley J, Sanderson J. Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of
inflammatory bowel disease. Aliment Pharmacol Ther. 2008 Oct 15;28(8):973-83. PubMed PMID:
18616518.
6: Gisbert JP, Niño P, Rodrigo L, Cara C, Guijarro LG. Thiopurine methyltransferase (TPMT) activity and
adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients.
Am J Gastroenterol. 2006 Dec;101(12):2769-76. Epub 2006 Oct 6..
7: De Ridder L, Van Dieren JM, Van Deventer HJ, Stokkers PC, Van der Woude JC, Van Vuuren AJ,
Benninga MA, Escher JC, Hommes DW. Pharmacogenetics of thiopurine therapy in paediatric IBD
patients. Aliment Pharmacol Ther. 2006 Apr 15;23(8):1137-41..
8: Hindorf U, Lindqvist M, Peterson C, Söderkvist P, Ström M, Hjortswang H, Pousette A, Almer S.
Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease.
Gut. 2006 Oct;55(10):1423-31. Epub 2006 Mar 16. PubMed PMID: 16543290; PubMed Central PMCID:
9: von Ahsen N, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, Herfarth H, Stein J, Bias P, Adler
G, Shipkova M, Oellerich M, Kruis W, Reinshagen M, Schütz E. Association of inosine triphosphatase
94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under
azathioprine therapy in a prospective Crohn disease study. Clin Chem. 2005 Dec;51(12):2282-8. Epub
2005 Oct 7. Erratum in: Clin Chem. 2006 Aug;52(8):1628. Schütz, Ekkehard [added].
10: Gearry RB, Barclay ML, Roberts RL, Harraway J, Zhang M, Pike LS, George PM, Florkowski CM.
Thiopurine methyltransferase and 6-thioguanine nucleotide measurement: early experience of use in
clinical practice. Intern Med J. 2005 Oct;35(10):580-5.
11: Sayani FA, Prosser C, Bailey RJ, Jacobs P, Fedorak RN. Thiopurine methyltransferase enzyme
activity determination before treatment of inflammatory bowel disease with azathioprine: effect on cost
and adverse events. Can J Gastroenterol. 2005 Mar;19(3):147-51.
12: Winter J, Walker A, Shapiro D, Gaffney D, Spooner RJ, Mills PR. Cost-effectiveness of thiopurine
methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment
of inflammatory bowel disease. Aliment Pharmacol Ther. 2004 Sep 15;20(6):593-9.
13: Gearry RB, Barclay ML, Burt MJ, Collett JA, Chapman BA, Roberts RL, Kennedy
MA. Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug
reactions to thiopurine drugs in patients with inflammatory bowel disease.
Aliment Pharmacol Ther. 2003 Aug 15;18(4):395-400. PubMed PMID: 12940924.
14. Dubinsky MC, Reyes E, Ofman J, Chiou CF, Wade S, Sandborn WJ. A cost-effectiveness analysis of
alternative disease management strategies in patients with Crohn's disease treated with azathioprine or
6-mercaptopurine. Am J Gastroenterol. 2005 Oct;100(10):2239-47
15. Imuran ® Package insert.
53
IBD Treatment
Q.I. #14: Topical and Oral 5-ASA for distal ulcerative colitis
Q.I. #14
IF a patient has mild to moderate distal UC
THEN treatment with oral and/or topical aminosalicylates should be
recommended
BECAUSE, either alone or in combination, topical and oral aminosalicylates
increase the odds of achieving and maintaining remission.
Summary: Multiple trials and recent meta-analyses have found both topical and oral
aminosalicylates to be effective for inducing remission of mild to moderate UC. There is
somewhat less evidence for the maintenance of remission. A single small randomized
controlled trial has shown combination therapy for distal UC to be more effective than
either topical or oral 5-ASA alone.
Details
Topical therapies
Four studies have systematically reviewed the efficacy of topical mesalamine (5-ASA) for the
treatment of distal ulcerative colitis. Distal ulcerative colitis in all studies was defined as colitis
with a margin within the most distal 60 cm of the colon or more distal to the splenic flexure.
The largest and most recent analysis was published in 2010 by the Cochrane collaborative.(1)
Thirty-eight studies met inclusion criteria. Endpoints for clinical remission and for clinical
improvement among the included trials were varied. Eight of the eligible trials included data for
the induction of symptomatic remission using topical 5-ASA as compared to placebo with a
pooled odds ratio (POR) of 8.3, 95% CI 4.28-16.12. There were data from seven trials for
endoscopic remission (POR 5.3, 95% CI 3.15-8.92) and from five trials for histologic remission
(POR 6.28, 95% CI 2.74-14.4). It should be noted that a previous meta-analysis from 2000
yielded similar results (see table) and that all seven trials included in that study were also
included in the Cochrane analysis.(2) A third meta-analysis (which is not shown in the Table)
included only two studies. There was also a statistically significant pooled advantage for topical
5-ASA over placebo for induction of remission after both 2 weeks and 4 weeks of therapy.(3)
For maintenance of remission with topical mesalamine, studies were fewer in number and
smaller in size. The same publication by Cohen et al also included a systematic review that
identified three trials of 4-g mesalamine enemas with a combined maintenance rate of 78%
among 65 patients. Rates decreased to 72% with every other night dosing and 65% with every
third night dosing.(3)
Six trials were analyzed in the Cochrane review to compare topical aminosalicylates to rectal
corticosteroids for remission of distal colitis. The POR favored topical 5-ASA for inducing
symptomatic improvement and remission with PORs of 1.56 (6 trials, 95% CI 1.15-2.11; P =
0.004) and 1.65 (6 trials, 95% CI 1.11-2.45; P = 0.01) respectively.(1) The older analysis by
Marshall et al had three of the same studies among the seven used in the 2010 analysis. The
older study also found an advantage of 5-ASA over rectal steroids for inducing remission based
on symptoms, endoscopic findings, and histologic findings with a POR of 2.42 (95% CI 1.723.41), 1.89 (95% CI 1.29-2.76), and 2.03 (95% CI 1.28-3.20) respectively.(4)
The Cochrane analysis did not find any superiority of rectal therapy over oral therapy in
achieving symptomatic improvement (4 trials, POR 2.25; 95% CI 0.53 to 9.54; P = 0.27). The
four trials in the analysis were randomized controlled trials (see Table). One of these trials,
which showed a statistical advantage for topical 5-ASA, included only patients with ulcerative
procititis (mean DAI 1.48 for suppository vs 3.48 for oral 5-ASA, P<0.001).(5)
Oral therapies
Oral 5-ASA agents have been used for mild to moderate UC for decades, and many studies
have evaluated their efficacy. The Cochrane analyses of 2006 (over 2100 patients and 21
studies (9 placebo-controlled)) showed superiority for 5-ASA over placebo for induction of
remission (odds ratio for failing to induce clinical improvement or remission was 0.40, 95% CI
0.30-0.53) and for maintenance (odds ratio for failing to maintain clinical or endoscopic
remission was 0.47, 95% CI 0.36-0.42).(6, 7) The analysis does not specifically address distal
colitis; it should be noted that many of the earlier trials included in the analysis screened
patients based only on proctosigmoidoscopy.
55
A three arm trial by Schroeder et al (87 patients) that evaluated 4.8 g 5-ASA, 1.6 g 5-ASA, and
placebo did stratify by disease extent with L-sided disease (defined as disease distal the midtransverse colon).(8) Results showed 24% complete and 50% partial responses in those
receiving 4.8 g of 5-ASA per day as compared with 5% complete and 13% partial responses in
those receiving placebo (P<0.0001). Extent of disease did not affect clinical outcome, and,
among 55 patients with L-sided colitis, there was more benefit from 4.8 g of 5-ASA (24%
complete response and 50% partial response) than from placebo (4% complete and 9% partial
response, P<0.01).
Another three arm double-blinded, placebo controlled trial of mesalamine (2 g vs 4 g vs
placebo) stratified patients by extent of disease to left-sided disease or pancolitis.(9) The trial of
374 patients with mild-to-moderate ulcerative colitis showed statistically significant superiority of
mesalamine over placebo. Patients on a 2-g and 4-g dose of mesalamine received treatment
benefit based on the physician global assessment (79% and 84% respectively vs. 54% on
placebo, p < or = 0.0002), and both doses produced a statistically significant endoscopic
improvement as compared to placebo (p < 0.004). Similar to the trial previously described trial,
the benefit was observed regardless of disease extent.
Combination of oral and topical therapies
There has been only one trial for distal colitis that has compared a combined 5-ASA therapy
with either orally or rectally administered 5-ASA.(10) The randomized double-blind trial enrolled
60 patients. Patients receiving combination oral and rectal 5-ASA had a non-significant greater
improvement in their DAI (-5.2) compared with those treated with either monotherapy
(mesalamine enema -4.4, mesalamine tablet -3.9). However, differences in a secondary
endpoint, cessation of rectal bleeding, were significantly better for those treated with
combination therapy (89%) compared with rectal (69%) and with oral (46%) monotherapies.
Additionally, there are data favoring combination therapy from a larger trial (127 patients)
though it was for patients with extensive ulcerative colitis.(11)
Society and Consensus Recommendations
The European evidence-based Consensus (ECCO) recommends treatment of mild to moderate
distal UC initially with a combination of topical and oral 5-ASA.(12) The Crohn’s and Colitis
Foundation of America clinical guideline recommends initial treatment with a topical
aminosalicylates and, if there is an inadequate response, then adding an oral 5-ASA.(13) The
British Society of Gastroenterology guidelines advocate treatment with a combination of topical
and oral 5-ASA or corticosteroid.(14)
Author
Marshall et al,
Study Design
Meta-analysis
2010(1)
Intervention
Topical vs.
placebo
Endpoint
Trials (#)
Result
P value
8
OR 8.3 (4.28-16.12)
<0.00001
7
OR 5.31 (3.15-8.92)
<0.00001
5
OR 6.28 (2.74-14.4)
<0.0001
7
OR 7.71 (4.84-12.30)
7
OR 6.55 (4.15-10.36)
7
OR 6.91 (3.82-12.50)
Symptomatic remission
6
OR 1.65 (1.11-2.45)
Symptomatic remission
7
OR 2.42 (1.72-3.41)
7
OR 1.89 (1.29-2.76)
7
OR 2.03 (1.28-3.20)
4
OR 2.25 (0.53-9.54)
0.27
NA
Topical 94% “very much
0.02
Symptomatic remission
Endoscopic remission
Histologic remission
Marshall et al,
Meta-analysis
2000(2)
Topical vs.
placebo
Symptomatic remission
Endoscopic remission
Histologic remission
Marshall et al,
Meta-analysis
2010(1)
Topical vs. rectal
0.01
steroids
Marshall et al,
Meta-analysis
1997(4)
Topical vs. rectal
steroids
Endoscopic remission
Histologic remission
Marshall et al,
Meta-analysis
2010(1)
Kam et al,
RCT
1996(15)
Topical vs. oral 5-
Symptomatic
ASA
improvement
Topical 5-ASA vs.
Clinical global
oral SSZ
improvement
improved” or “much
improved” vs. 77% oral
SSZ
Safdi et al,
RCT
1997(10)
Topical 5-ASA vs.
oral 5-ASA vs.
combination*
Gionchetti et al,
RCT
1998(5)**
NA
Cessation rectal
RCT
Oral MMx 5-ASA
Topical -4.4; Oral -3.9
NS
Topical 68.8%; Oral
bleeding
45.5%
NS
Global assessment
NA
Topical 82.7%; Oral
<0.01
DAI
NA
Topical 1.48; Oral 3.48
Clinical remission
NA
Topical 50%
oral 5-ASA
Prantera et al,
2005(16)
Topical 5-ASA vs.
Improvement in DAI
34.5%
vs. Topical 5-ASA
Oral 60%
95% CI for difference (-12
- +32)
* Combination data not shown
** Included only patients with ulcerative proctitis
57
<0.001
References:
1. Marshall JK, Thabane M, Steinhart AH, Newman JR, Anand A, Irvine EJ. Rectal 5-aminosalicylic acid
for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2010(1):CD004115.
2. Marshall JK, Irvine EJ. Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative
colitis. Am J Gastroenterol. 2000 Jul;95(7):1628-36.
3. Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis and overview of the literature on
treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol. 2000
May;95(5):1263-76.
4. Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: a
meta-analysis. Gut. 1997 Jun;40(6):775-81.
5. Gionchetti P, Rizzello F, Venturi A, Ferretti M, Brignola C, Miglioli M, et al. Comparison of oral with
rectal mesalazine in the treatment of ulcerative proctitis. Dis Colon Rectum. 1998 Jan;41(1):93-7.
6. Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative
colitis. Cochrane Database Syst Rev. 2006(2):CD000544.
7. Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
Cochrane Database Syst Rev. 2006(2):CD000543.
8. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to
moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987 Dec 24;317(26):1625-9.
9. Hanauer SB. Dose-ranging study of mesalamine (PENTASA) enemas in the treatment of acute
ulcerative proctosigmoiditis: results of a multicentered placebo-controlled trial. The U.S. PENTASA
Enema Study Group. Inflamm Bowel Dis. 1998 May;4(2):79-83.
10. Safdi M, DeMicco M, Sninsky C, Banks P, Wruble L, Deren J, et al. A double-blind comparison of oral
versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am J
Gastroenterol. 1997 Oct;92(10):1867-71.
11. Marteau P, Probert CS, Lindgren S, Gassul M, Tan TG, Dignass A, et al. Combined oral and enema
treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive
mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study. Gut. 2005
Jul;54(7):960-5.
12. Travis SP, Stange EF, Lemann M, Oresland T, Bemelman WA, Chowers Y, et al. European
evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohn's &
Colitis. 2008;2:24-62.
13. Regueiro M, Loftus EV, Jr., Steinhart AH, Cohen RD. Clinical guidelines for the medical management
of left-sided ulcerative colitis and ulcerative proctitis: summary statement. Inflamm Bowel Dis. 2006
Oct;12(10):972-8.
14. Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in
adults. Gut. 2004 Sep;53 Suppl 5:V1-16.
15. Kam L, Cohen H, Dooley C, Rubin P, Orchard J. A comparison of mesalamine suspension enema
and oral sulfasalazine for treatment of active distal ulcerative colitis in adults. Am J Gastroenterol. 1996
Jul;91(7):1338-42.
16. Prantera C, Viscido A, Biancone L, Francavilla A, Giglio L, Campieri M. A new oral delivery system for
5-ASA: preliminary clinical findings for MMx. Inflamm Bowel Dis. 2005 May;11(5):421-7.
59
Q.I. #15: Oral Aminosalicylate therapy for mild to moderate extensive
ulcerative colitis
Q.I. #15
IF a patient has an established diagnosis of mild to moderate
extensive ulcerative colitis
THEN treatment with oral aminosalicylates, with or without
topical aminosalicylates, should be recommended
BECAUSE there are numerous randomized controlled trials
demonstrating the efficacy of oral aminosalicylates for the
induction and maintenance of remission in patients with mild to
moderate extensive ulcerative colitis
Summary: There have been numerous studies demonstrating the efficacy
of oral aminosalicylates, with or without topical therapy, for the induction and
maintenance of remission in patients with mild to moderate extensive
ulcerative colitis. Meta-analysis of published studies demonstrates that both
sulfasalazine and newer 5-ASA agents are superior to placebo for the
induction of remission. Efficacy is generally equivalent between both
groups with an improved side effect profile for the newer 5-ASA agents, but
lower cost of sulfasalazine. Similarly, both sulfasalazine and newer 5-ASA
agents are effective for the maintenance of remission in mild to moderate
extensive ulcerative colitis. Individual trials have demonstrated potential
benefit of adding topical therapy to oral aminosalicylate therapy, as well as
equivalent efficacy of newer once daily high-dose aminosalicylates relative
to original formulations.
Details
The Cochrane review group systematically reviewed the efficacy of oral aminosalicylate therapy
for both the induction1 and maintenance2 of remission of mild to moderate extensive ulcerative
colitis.
Induction of remission:
Twenty one prospective, randomized, double-blind, controlled trials, representing 2,124
patients were selected for review in order to evaluate the efficacy of oral aminosalicylates for the
induction of remission in mild to moderate extensive ulcerative colitis. Nine of these studies
evaluated aminosalicylate therapy relative to placebo control and twelve studies compared
aminosalicylate therapy to sulfasalazine. Of the nine placebo controlled studies, four reported
treatment outcomes in terms of the failure to induce complete global or clinical remission
3,4,5,6
.
The pooled odds ratio for all trials was 0.53 (95% CI, 0.36 to 0.79). 5-ASA was superior to
placebo in all dosage subgroups (<1g/d, 1-1.9 g/d, > or = 2g/d) with a trend towards a dosedependent relationship, although this did not meet statistical significance (p = 0.08). Eight trials,
representing 995 patients, reported treatment outcomes in terms of the failure to induce global
or clinical improvement (including remission) 3,5,6,7,8,10,11. For all treatment arms the pooled odds
ratio was 0.40 (95% CI, 0.30 or 0.53). 5-ASA therapy was superior to placebo at all doses with
a dose-dependent effect for clinical improvement (p = 0.002). Only two studies reported data on
failure to induce complete endoscopic remission 3,4. In these studies, therapy with 5-ASA
therapy was superior to placebo with a pooled odds ratio of 0.67 (95% CI, 0.47 to 0.95).
Of the twelve trials comparing 5-ASA therapy to sulfasalazine, seven studies evaluated
treatment effect in terms of failure to induce complete global or clinical remission
12,13,14,15,16,17,18,19
. No difference in efficacy between 5-ASA compounds and sulfasalazine was
observed with a pooled odds ratio of 0.77 (95% CI, 0.53 to 1.11). Eight trials, comprised of 687
patients, reported treatment efficacy as failure to induce global or clinical improvement
14,16,18,19,20,21,22,23
. These studies similarly demonstrated no difference in treatment efficacy
between 5-ASA compounds and sulfasalazine (Pooled odds ratio 0.83, 95% CI, 0.60 to 1.13).
Seven studies reporting safety data comparing 5-ASA to sulfasalazine therapy demonstrated a
pooled odds ratio of 0.38 (95% CI 0.25 to 0.57) for the number of patients who experienced any
adverse event 13,15,16,17,19,21,22. Seven studies reported data on the proportion of patients
withdrawing due to any adverse event 13,15,16,18,19,22,23, with a pooled odds ratio of 0.34 (95% CI
0.19 to 0.63) for those treated with 5-ASA compared to sulfasalazine. Collectively these studies
demonstrate an excess number of adverse events with sulfasalazine therapy relative to newer
5-ASA agents. Notably, all but one study incorporated as inclusion criteria of known tolerance
to sulfasalazine therapy prior to enrollment. Given this, these studies may actually
underestimate the number of adverse events related to sulfasalazine therapy.
Maintenance of remission:
For evaluation of the efficacy of oral aminosalicylates for the maintenance of remission in mild to
moderate extensive ulcerative colitis, sixteen prospective, randomized, double-blind, controlled
61
trials were selected for review. Of these sixteen studies, representing 2,479 patients, five
evaluated the efficacy of 5-ASA compounds relative to placebo and eleven compared the
efficacy of 5-ASA compounds to sulfasalazine. Data from the five placebo-controlled studies
24,25,26,27,28
, representing 881 patients, yielded a peto odds ratio of 0.47 (95% CI, 0.36 to 0.62) for
the failure to maintain endoscopic or clinical remission. 5-ASA was found to be more effective
than placebo in all dose ranges evaluated (<1 g/d, 1-1.9 g/d, >or=2g/d) although no dose
dependent relationship in effect was identified (p = 0.49). Amongst the eleven studies
comparing 5-ASA to sulfasalazine 12,18,29,30,31,32,33,34,35,36,37 , data from 1,598 patients was used to
evaluate for a treatment outcome of failure to maintain endoscopic or clinical remission. An odds
ratio of 1.29 (95% CI, 1.05 to 1.57) was identified suggesting possible superiority of
sulfasalazine to 5-ASA therapy. Statistical significance was lost when including only those
studies with a clinical endpoint up to 12 months with resultant odds ratio of 1.15 (95% CI, 0.89
to 1.50). Data from seven studies 12,30,32,33,34,35,37 revealed no difference in the proportion of
patients experiencing adverse effects between 5-ASA and sulfasalazine therapy. Of note, these
studies again only included patients in the sulfasalazine arm who were known to tolerate
sulfasalazine therapy previously, resulting in possible bias in favor of sulfasalazine therapy in an
intention to treat analysis.
Topical mesalamine in addition to oral mesalamine therapy:
Whether distal topical mesalamine therapy adds any additional benefit to oral mesalamine
therapy has been evaluated in variable fashion by a number of studies. Only one study was
identified which specifically evaluated the addition of topical mesalamine therapy to oral
mesalamine for patients with mild to moderate extensive ulcerative colitis. Marteau et al 38
evaluated 127 patients with mild to moderate extensive colitis in a randomized double-blind
placebo-controlled trial. The addition of 5-ASA enemas for the initial 4 weeks of an 8 week
course of 4g/d oral mesalamine therapy resulted in improved remission rates as determined by
UCDAI score at 8 weeks (64% vs. 43%, p = 0.03) but not at 4 weeks (44% vs. 34%, p = 0.31) .
Clinical improvement was observed at both the 4 week (89% vs. 62%, p = 0.0008) and 8 week
(86% vs. 68%, p = 0.026) time points. A one year randomized multicenter trial conducted by
Paoluzi et al 39 compared the efficacy of adding a 2g/day 5-ASA enema to 2.4g/day oral
mesalamine for the first 4 vs. 8 weeks of induction therapy followed by 1.2g/day oral
mesalamine maintenance therapy from week 8 to one year. No comparison to placebo control
was made in this study. In this trial of 149 patients with mild to moderate ulcerative colitis, only
40% had extensive colitis. No difference in clinical, endoscopic, or histologic remission was
identified between those treated with 4-week topical therapy vs. 8-week topical therapy (55% vs.
64%, p not provided but reported as non-significant). At 12 months, relapse rates were similar
between groups with rates of 50% in the 4-week regimen and 51% in the 8-week regimen
(p=0.89). Finally, Frieri et al 40 collected data for 18 patients (12 with extensive colitis) in clinical
remission on continuous oral 5-ASA treatment (2.4-3.2 g/day) who had experienced at least four
moderate to severe relapses in the preceding 2 years. With an increase in oral mesalamine
therapy to 3.2 - 4.8g/day as well as addition of 4g/day mesalazine enema, a reduction in the
total number of flares was observed relative to the reference period prior to intervention (8 vs.
80, p < .0001). Interpretation of these findings is limited by the non-controlled fashion of the
study, the use of historic data for comparison, and concomitant increase in oral mesalamine
therapy during the same time period.
High-concentration oral mesalamine therapy:
Since the time of the above Cochrane reviews, additional data has emerged on newer
formulations of mesalamine. The ASCEND I 41 trial was a multicentre randomized double-blind
controlled trial comparing the efficacy of 4.8 g/d mesalamine (using 800mg tablet formulation) to
2.4g/d (400mg tablets) for the management of mild to moderate ulcerative colitis. 301 adults (73
with extensive colitis) received therapy with a primary endpoint of either complete remission or a
clinical response to therapy (decrease in PGA score by at least one point plus improvement in
one other parameter such as stool frequency, rectal bleeding, PFA or endoscopic findings). At
week 6, there was no statistical difference between treatment groups for the primary endpoint
(56% vs. 51%, P = 0.44) although subgroup analysis suggested potential benefit amongst those
with moderate disease with a higher frequency of response with 4.8g/day therapy than 2.4g/d
(72% vs. 57%, p = 0.038). Results from ASCEND II
42
, which prospectively evaluated the same
treatment arms in patients specifically with moderately active ulcerative colitis, appeared to
support this result. In this trial of 386 patients with moderately ulcerative colitis (55 with
extensive colitis), 72% of patients treated with 4.8g/d Mesalamine achieved the primary
endpoint compared to 50% of those receiving 2.4g/d (p = 0.036). Finally ASCEND III 43,
established the non-inferiority of delayed-release oral mesalamine with treatment success in
70% of patients receiving 4.8g/day mesalamine (800mg tablet) compared to 66% in those
receiving 2.4g/d (400mg) (95% CI, 2.4g/d minus 4.8g/d, -11.2 to 1.9). Higher dose formulations,
utilizing MMX technology, have additionally been evaluated with a proposed clinical benefit of
63
improving treatment compliance because of decreased pill requirement. A multicenter, doubleblind, placebo and treatment controlled trial 44 compared once daily MMX mesalamine at 4.8g/d
or 2.4g/d compared to 2.4g/d split dose Asacol (400mg tablets) as well as placebo control. In
this study involving 343 patients, MMX mesalamine at both doses was found to result in clinical
and endoscopic remission with greater frequency compared to placebo (41.2% vs. 22.5%, p =
.007 for 4.8g/d ; 40.5% vs. 22.5%, p =.01 for 2.4g/d). No difference in efficacy was identified
between the two doses studied. A subsequent study, directly comparing once daily MMX
mesalamine to split dosing Asacol 45, demonstrated equivalent efficacy for the maintenance of
remission of left-sided ulcerative colitis. The potential benefits of these newer formulations in
improving patient compliance must be weighed against their increased cost.
The management of mild to moderate extensive colitis was recently reviewed by the 2010 ACG
ulcerative colitis practice guidelines 46 with recommendation that patients should received as
first line therapy sulfasalazine or an alternate oral aminosalicylate agent for both the induction
and maintenance of remission.
References
1. Sutherland LR and MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative
colitis (Review). Cochrane Database Syst Rev. 2006 Apr 19;(2):CD000543.
2. Sutherland LR and MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in
ulcerative colitis (Review). Cochrane Database Syst Rev. 2006 Apr 19;(2):CD000544.
3. Hanauer et al. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled
trial. Pentasa Study Group. Am J Gastroenterol. 1993;88(8):1188-97.
4. Hanauer et al. A multi-centre, double-blind, placebo-controlled, dose-ranging trial of olsalazine for
mild-moderately active ulcerative colitis. Gastroenterology 1996; 110: A921. (Abstract)
5. Schroeder et al. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative
colitis. A randomized study.
N Engl J Med. 1987;317(26):1625-9.
6. Sninsky et al. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. A multicenter
study. Ann Intern Med. 1991;115(5):350-5.
7. Feurle et al. Olsalazine versus placebo in the treatment of mild to moderate ulcerative colitis: a
randomized double blind trial. Gut. 1989;10:1354-61.
8. Hetzel et al. Azodisalicylate (Olsalazine) in the treatment of active ulcerative colitis. A placebo
controlled clinical trial and assessment of drug disposition. J Gastroent Hepatol 1986;1:257-66.
9. Robinson et al. Olsalazine in the treatment of mild to moderate ulcerative colitis [abstract].
Gastroenterology 1988;84:A381.
10. Sutherland et al. A double-blind, placebo-controlled, multicentre study of the efficacy and safety of 5aminosalicylic acid tablets in the treatment of ulcerative colitis. Can J Gastroenterol 1990;4:463-7.
11. Zinberg et al. Double-blind placebo-controlled study of olsalazine in the treatment of ulcerative colitis.
Am J Gastroenterol 1990;85:562-6.
12. Andreoli et al. 5-aminosalicylic acid versus salazopirin (SASP) in the oral treatment of active
ulcerative colitis (UC) and in remission [abstract]. Clinical controversies in Inflammatory Bowel Disease
1987:170.
13. Green et al. A double-blind comparison of balsalazide, 6.75g daily, and sulfasaline, 3g daily, in
patients with newly diagnosed or relapsed ulcerative colitis. Aliment Pharmacol Ther 2002;16(1):61-8.
14. Jiang et al. Different therapy for different types of ulcerative colitis. World J Gastroenterol
2004;10(10):1513-20.
15. Mansfield et al. A double-blind comparison of balsalazide, 6.75g, and sulfasalazine, 3g, as sole
therapy in the management of ulcerative colitis. Aliment Pharmacol Ther 2002;16(1):69-77.
16. Rachmilewitz et al. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment
of active ulcerative colitis: a randomisdd trial. Br Med J 1989;298:82-6.
17 Rijk et al. The efficacy and safety of sulphasalazine and olsalazine in patients with active ulcerative
colitis [abstract]. Gastroenterology 1991;100:A243.
18. Riley et al. Comparison of delayed released 5-aminosalicylic acid (mesalazine) and sulphasalazine in
the treatment of mild to moderate ulcerative colitis relapse. Gut 1988;29:669-74.
19. Fleig et al. Prospective, randomized, double-blind comparison of benzalazine and sulfasalazine in
the treatment of active ulcerative colitis. Digestion 1988;40:173-80.
20. Good et al. A double-blind comparison of controlled release mesalamine tablets and sulfasalzine in
the treatment of ulcerative coliis [abstract]. Gastroenterology 1992;102:A630.
21. Munakata et al. Double-blind comparative study of sulfasalazine and controlled-release mesalazine
tablets in the treatment of active ulcerative colitis. J Gastroenterol 1995;30(Suppl 8):108-111.
22. Rao et al. Olsalazine or sulphasalazine in first attacks of ulcerative colitis? A double-blind study. Gut
1989;30:675-9.
23. Willoughby et al. Double-blind comparison of olsalazine and sulfasalazine in active ulcerative colitis.
Scand J Gastroenterol 1988;148:40-4.
24. Hanauer et al. An oral preparation of mesalamine as long-term maintenance therapy for ulcerative
colitis. A randomized, placebo-controlled trial. Ann Intern Med 196;124:204-211.
25. Hawkey et al. A trial of zileuton versus mesalazine or placebo in the maintenance of remission of
ulcerative colitis. Gastroenterology 1997;112:718-24.
26. Miner et al. Safety and efficacy of controlled-release mesalamine for maintenance of remission in
ulcerative colitis. Dig Dis Sci 1995;40:296-304.
27. Sandberg-Gertzen et al. Azodisal sodium in the treatment of ulcerative colitis: a study of tolerance
and relapse prevention. Gastroenterolgy 1986;90:1024-30.
65
28. Wright et al. Olsalazine in maintenance of clinical remission in patients with ulcerative colitis. Dig Dis
Sci 1993;38:1837-42.
29. Ardizzone et al. Coated oral 50 aminosalicylic acid (Claversal) is equivalent to sulfasalazine for
remission maintenance in ulcerative colitis. J Clin Gastroenterol 1995;21:287-9.
30. Ireland et al. Controlled trial comparing olsalazine and sulphasalazine for the maintenance treatment
of ulcerative colitis. Gut 1988;29:835-7.
31. Kiilerich et al. Prophylactic effects of olsalzine versus sulphasalazine during 12 months maintenance
treatment of ulcerative colitis. Danish Olsalazine Study Group. Gut 1992;33:252-5.
32. Kruis et al. Double-blind dose-finding study of olsalazine versus sulphasalazine as maintenance
therapy for ulcerative colitis. Eur J Gastroenterol Hepatol 1995;7:391-6.
33. McIntyre et al. Balsalzine in the maintenance treatment of patients with ulcerative colitis, a doubleblind comparison with sulphasalazine. Aliment Pharmacol Ther 1988;2:237-43.
34. Mulder et al. Double-blind comparison of slow-release 5-aminosalicylate and sulfasalazine in
remission maintenance in ulcerative colitis. Gastroenterology 1988:95:1449-53.
35. Nilsson et al. Olsalazine versus sulphasalazine for relapse prevention in ulcerative colitis: a
multicenter study. Am J Gasroenterol 195;90:381-7.
36. Rijk et al. Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with
ulcerative colitis in remission: prospective, double-blind, randomized multicenter study. Am J
Gastroenterol 1992;87:438-42.
37. Rutgeerts P. Comparative efficacy of coated, oral 5-aminosalicylic acid (Claversal) and
sulphasalazine for maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1989;3:183-91.
38. Marteau et al. Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral
therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomized, double
blind, placebo controlled study. Gut 205;54:96-965.
39. Paoluzi et al. Oral and topical 5-aminosalicylic acid (mesalazine) in inducing and maintaining
remission in mild-moderate relapse of ulcerative colitis: one-year randomized multicentre trial. Diges Liver
Dis 2002;34:787-93.
40. Frieri et al. Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis. Diges
Liver Dis 2005;37:92–96.
41. Hanauer et al. Delayed-Release oral mesalamine 4.8g/d (800mg tablets) compared with 2.4g/day
(400mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial. Can
J Gastroenterol. 2007;21(12):827-834.
42. Hanauer et al. Delayed-Release Oral Mesalamine at 4.8g/day (800mg tablet) for the treatment of
moderately active ulcerative colitis: The ASCEND II trial. Am J Gastroenterol 2005;100:2478-2485.
43. Sandborn et al. Delayed-Release Oral Mesalamine 4.8g/day (800-mg tablet) is effective for patients
with moderately active ulcerative colitis. Gastroenterology 2009;137:1934-1943.
44. Kamm et al. Once-daily, High-concentration MMX mesalamine in active ulcerative colitis.
Gastroenterology 2007;132:66-75.
45. Prantera et al. Clinical trial: ulcerative colitis maintenance treatment with 5-ASA: a 1-year,
randomized multicentre study comparing MMX with Asacol. Alimen Pharmacol Ther 30, 908-918.
46. Kornbluth et al. Ulcerative Colitis Practice Guidelines in Adults: American College of
Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010 Mar;105(3):500.
67
Odds Ratio for the failure to induce remission with aminosalicylates (Sutherland et al 1)
Number of
Studies
n
Control Group
Endpoint
OR/ (95% CI)
Complete global or clinical remission
Clinical improvement (including
remission)
0.53 (0.36, 0.79)
Complete global or clinical remission
0.77 (0.53, 1.11)
4
892
Placebo
8
995
Placebo
7
496
Sulfasalazine
0.40 (0.3, 0.53)
Clinical improvement (including
remission)
8
687
Sulfasalazine
0.83 (0.60, 1.13)
Odds Ratio for the failure to maintain remission with aminosalicylates (Sutherland et al 2)
Number of Studies
n
5
881
11
1,598
Control Group
Placebo
Sulfasalazine
Endpoint
OR/RR (95% CI)
Endoscopic or clinical remission
0.47 (0.36, 0.62)
Endoscopic or clinical remission
1.29 (1.05, 1.57)
Comparison of aminosalicylate doses and formulations for induction of remission
Author
Study
Design
n
Hanauer et al. 41
Randomized
controlled trial
301
Hanauer et al. 42
Randomized
controlled trial
(moderate colitis)
386
Sandborn et al. 43
Randomized
controlled trial
(moderate colitis)
772
Control Group
Endpoint
4.8g/day
mesalamine
(800mg tab) vs.
2.4 g/day
(400mg tab)
4.8g/day
mesalamine
(800mg tab) vs.
2.4 g/day
(400mg tab)
4.8g/day
mesalamine
(800mg tab) vs.
2.4 g/day
(400mg tab)
Complete remission or
clinical response
Complete remission or
clinical response
Clinical improvement
P
P = 0.44 (56% vs.
51%)
P = 0.04 (72% vs.
57%)
(non-inferior)
P = 0.01 (40.5% vs.
22.1%) 2.4g/day vs.
placebo
Kamm et al.
44
Prantera et al. 45
Randomized
controlled trial
Randomized
controlled trial
343
331
2.4g/day vs.
4.8g/day
mesalamine
(1.2g/tablet)
vs. placebo
Clinical and Endoscopic
remission
2.4g/day
mesalamine
1.2g/tablets once
daily vs.
800mg/tablet
twice daily
Clinical and endoscopic
remission
69
P = .007 (41.2% vs.
22.1%) 4.8g/day vs.
placebo
P = .12 (40.5% vs.
41.2%) 2.4g/day vs.
4.8g/day
P = 0.69 (68.0% vs.
65.9%)
Q.I. #16: Oral therapy for ulcerative proctitis refractory to topical
agents
Q.I. #16:
IF a UC patient has active proctitis unrelieved by rectal therapies
THEN the patient should be treated with oral mesalazine or oral
corticosteroids
BECAUSE expert guidelines and reviews suggest that these will be effective
despite a lack of randomized controlled data.
Summary:
No studies have directly assessed the effect of oral 5-aminosalicylates (5-ASA) or oral
prednisone for patients with ulcerative proctitis refractory to rectal agents. Though data
are limited, expert guidelines advocate the addition of oral 5-ASA and/or maximizing
rectal therapy with combined corticosteroids and 5-ASA as initial approaches. For
patients with continued refractory disease, oral prednisone can be considered.
Details:
Rectally-delivered 5-aminosalicylates (5-ASA) or corticosteroids are the recommended first-line
agents for mild-moderate ulcerative proctitis (UP) and left-sided ulcerative colitis (UC) because
this modality offers the advantage of delivering high local concentrations of active medication to
the site of maximal inflammation with a low risk of systemic side effects. There are three
randomized double-blinded studies demonstrating increased remission rates and symptomatic
improvement in pooled analysis of rectal 5-ASA agents over oral 5-ASA in UP and left-sided
UC;1 one study indicated that patients treated with rectal 5-ASA agents even had an earlier
response than those receiving oral 5-ASA.2 In another investigation the combination of oral and
rectal 5-ASA achieved an earlier resolution of rectal bleeding compared to either agent alone in
this population of patients.3 Given that there does not seem to be a dose-dependent response
to rectal 5-ASA in pooled analysis, the benefit of combination therapy is likely derived from dual
modalities of therapy as opposed to a drug-dosing effect.1
Conventional rectal steroids have consistently been proven to be inferior to rectal 5-ASA though
some data indicates that topically-active corticosteroids may exert similar efficacy to rectal 5ASA. In one study combined rectal beclomethasone enema and 5-ASA enema were more
effective at inducing remission than either agent as monotherapy.4
Randomized trials have shown a benefit of orally administered 5-ASA for active left-sided UC at
doses of 2 and 4 grams compared to placebo.5 There are no studies demonstrating efficacy of
oral 5-ASA monotherapy in UP. Surprisingly, studies showing benefits of oral corticosteroids in
UC were reported over 50 years ago and restricted to ulcerative pancolitis; there are no studies
of oral corticosteroids for left-sided UC or UP.
Expert guidelines and reviews recommend that oral 5-ASA should be added to patients with UP
refractory to rectal therapies especially those failing dual rectal agents. Combination rectal
therapy with 5-ASA and steroids can be considered for patients failing rectal monotherapy with
or without the addition of oral 5-ASA. Patients with refractory UP despite these measures,
though in our clinical experience rare, should be considered for oral corticosteroids.6-9
References:
1. Marshall J, Irvine J. Putting rectal 5-aminosalicylic acid in its place: the role in distal
ulcerative colitis. Am J Gastroenterol 2000;95:1628-36.
2. Kam L, Cohen H, Dooley C, et al. A comparison of mesalamine suspension enema and
oral sulfasalazine for treatment of active distal ulcerative ulcerative colitis in adults. Am J
Gastroenterol 1996;91:1138-42.
3. 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. Am J
Gastroenterol 1997;92:1867-71.
4. Mulder CJJ, Fockens P, Meijer LWR, et al. Beclomethasone dipropionate (3mg) versus
5-aminosalicylic acid (2g) versus the combination (3mg/2g) as retention enemas in
active ulcerative proctitis. Eur J Gastroenterol Hepatol 1996;8:549-53.
5. Cohen R, Woseth D, Thisted R, et al. A meta-analysis and overview of the literature on
treatment options for left-sided ulcerative colitis and ulcerative proctitis. Amer J
Gastroenterol 2000;95;1263-76.
6. Bitton A. Medical management of ulcerative proctitis, proctosigmoiditis, and left-sided
colitis. Semin Gastrointest Dis 2001;12:263-74.
7. Regueiro M. Diagnosis and treatment of ulcerative proctitis. J Clin Gastroenterol
2004;38:733-740.
8. Regueiro M, Loftus E, Steinhart A, et al. Clinical guidelines for the medical management
of left-sided ulcerative colitis and ulcerative proctitis: Summary statement. Inflamm
Bowel Dis 2006;12:972-78.
9. Regueiro M, Loftus E, Steinhart A, et al. Medical management of left-sided ulcerative
colitis and ulcerative proctitis: Critical evaluation of therapeutic trials. Inflamm Bowel Dis
2006;12:979-94.
71
Q.I. #17: Steroid-Sparing Therapy for UC
QI #17
IF a patient with UC is unable to taper below 10 mg prednisone (or equivalent)
without recurrent symptoms
THEN AZA at 1.5-2.5 mg/kg/day or 6MP 0.75-1.5 mg/kg/day, OR IFX should be
administered
BECAUSE AZA/6MP and IFX are effective at maintaining remission in UC with
steroid-sparing effects
Summary: Several RCTs have demonstrated the efficacy of AZA/6MP and IFX in
maintaining remission in steroid-dependent UC. Guidelines from the British Society of
Gastroenterology, the American Gastroenterological Association, and the American College
of Gastroenterology recommend the use of these medications in steroid-dependent UC.
Details
Corticosteroids are highly effective in the control of symptoms in UC. Although most patients
initially respond to corticosteroids, after 1 year approximately 25% become steroid-dependent
(1). As well, steroid use should be limited due to a long list of potential side-effects. Treatment
options for steroid-dependent UC include steroid-sparing medical therapy with an
immunomodulator or biologic therapy, or colectomy. In UC, the standard medical treatment
options include AZA/6MP or IFX.
AZA/6MP
Despite the clear steroid-sparing effect of AZA/6MP in active and quiescent Crohn’s disease,
the benefit of AZA/6MP in UC has been more controversial. There have been relatively few
randomized controlled trials assessing the efficacy of thiopurines for the treatment of steroiddependent UC. Initial studies performed decades ago were limited by small samples sizes,
mixed patient populations with both steroid-dependent and steroid-refractory disease,
inadequate dosing of AZA/6-MP, short follow up, and ambiguous endpoints (2-5).
Since 2000, several randomized controlled trials have assessed the use of AZA and 6MP in
steroid-dependent UC. In 2000, Sood et al performed a randomized, placebo-controlled,
patient-blinded trial of AZA in patients with severe UC (defined clinically and endoscopically)
who relapsed within 2 months of corticosteroid withdrawal (6). All patients received oral
prednisolone 1 mg/kg/day (tapered over 12-16 weeks) and oral sulfasalazine 6-8 g/day.
Patients were randomized to AZA 2 mg/kg/day (n=25) or placebo (n=25). The primary outcome
was the response at 1 year. Both groups had similar response rates (68 vs 64%, NS), but the
AZA group had a lower relapse rate over 1 year (12 vs 24%, p<0.05).
In 2006, Ardizzone et al published the largest trial to date (7). This was a randomized,
investigator-blinded trial comparing AZA and mesalamine in a single center in Italy. Eligible
patients had clinically and endoscopically active disease despite taking at least 10 mg of
prednisolone daily and had failed at least 2 attempts to taper steroids within the preceding 6
months. Patients were randomized to AZA 2 mg/kg/day (n=36) or 5-ASA 3.2 g/day (n=36) for 6
months. All patients received prednisolone 40 mg at study entry and were subsequently
tapered according to a standardized protocol. The primary outcome was treatment success,
defined as induction of clinical and endoscopic remission and steroid discontinuation at 6
months. Significantly more patients in the AZA group, 19/36 (53%), than the 5-ASA group, 7/36
(19%), achieved treatment success (P = 0.006, OR 4.78 (95% CI 1.57-14.5)).
In a slightly different design, Mantzaris et al performed a randomized, observer-blinded, twoyear study in a single center in Greece (8). Patients with steroid-dependent UC in endoscopic
and clinic remission who relapsed when steroids were tapered to ≤ 15 mg/day were randomized
to AZA 2.2 mg/kg/day (n=34) or AZA 2.2 mg/kg/day with olsalazine 0.5 g TID (n=36) for 2 years.
The primary endpoint was relapse rate at 2 years. Relapse rates were 19% and 18% in the
AZA and combination groups respectively (p=NS), suggesting that there is no additional benefit
to the addition of 5-ASA to AZA in maintaining remission in steroid-dependent UC.
The only randomized trial of 6MP in steroid-dependent UC was performed by Mate-Jiminez et al
in 2000 (9). Patients were eligible if they were not able to lower to less than 20 mg of
prednisone. Patients were randomized to 6MP 1.5 mg/kg/day (n=14), MTX 15 mg/kg/week
(n=12), or 5-ASA 3 g/day (n=8). Primary endpoints were induction of remission at 30 weeks
and maintenance of remission at 76 weeks. Significantly more patients in the 6MP group
73
achieved induction of remission, 11/14 (78.6%), compared to patients in the 5-ASA group, 2/8
(25%), p<0.05. As well, significantly more patients were able to maintain remission off of
corticosteroids at 76 weeks in the 6MP group, 7/11 (63.6%), compared to patients in the 5-ASA
group, 0/2 (0%), p<0.01.
Although the above studies use doses of AZA and 6MP in the range of 1.5-2.5 mg/kg/day and
0.75-1.5 mg/kg/day, respectively, this is based on dose-finding studies in Crohn’s disease. The
optimal dose of AZA and 6MP in UC is unclear as there has been no formal dose-ranging study
reported in the literature.
The above studies have led to recommendations by the British Society of Gastroenterology, the
American Gastroenterological Association, and the American College of Gastroenterology for
the use of AZA and 6MP is steroid-dependent UC (Grade A) (10, 11, 12).
Randomized controlled studies of AZA and 6MP in steroid-dependent UC
Reference
n
Dose
Duratio
Endpoint
Treatment
Control
Response
Response
53%
19%
0.006
18%
19%
NS
Outcome
Remission
Remission
Remission
at 1 year
17/25
16/25 (64%);
NS; Relapse
25
(68%);
Relapse 6/25
<0.05
placeb
Relapse
(24%)
o)
3/25 (12%)
n
Ardizzone
72 (36
AZA 2
et al, 2006
AZA,
mg/kg/day;
and
36 5-
mesalamin
endoscopi
ASA)
e 3.2
c
g/day
remission
Mantzaris
70 (34
AZA 2.2
et al, 2004
AZA,
mg/kg/day;
36
olsalazine
AZA +
0.5 g TID
6 mo
24 mo
Clinical
Relapse
P
rate
5ASA)
Sood et al,
50 (25
AZA 2
2000
AZA,
mg/kg/day
Mate-
34 (14
6-MP 1.5
Jimenez et
6MP,
mg/kg/day
12 mo
76 wk
Clinical
Induction
Induction 2/8
Induction
and
11/14
(25%),
p<0.05;
al, 2000
12
endoscopi
(78.6%);
Maintenance
Maintenance
MTX,
c
Maintenanc
0/2 (0%)
p<0.01
8 5-
remission
e 7/11
ASA
(63.6%)
Infliximab
A systematic review of steroid withdrawal in anti-TNF treated patients with IBD was recently
published in Aug 2010 in Alimentary Pharmacology and Therapeutics (13). This identified 5
studies where the effect of IFX on steroid usage could be assessed, 3 in CD and 2 in UC. The
two studies in UC are ACT 1 and ACT 2 (14). At baseline, 61% of patients (222/364) were
receiving corticosteroids in ACT1, as were 51% in ACT2 (186/364). The baseline median daily
corticosteroid dose was 20 mg/day in both studies. Overall, in both studies, 22% (60/269) of
patients treated with IFX had discontinued corticosteroids by week 30 compared to only 7%
(10/139) of patients treated with placebo. In ACT 1, at week 54, 21% (30/143) of patients
treated with IFX and 8.9% (7/79) of patient treated with placebo had discontinued
corticosteroids respectively. In patients who remained on corticosteroids, those who received
IFX had greater decreases in their dose than those in the placebo group.
Based on these results, guidelines from the American Gastroenterological Association and the
American College of Gastroenterology both recommend the use of infliximab for the treatment
of steroid-dependent UC (grade A) (11, 12).
References:
1) Faubion WA Jr, Loftus EV Jr, Harmsen WS, Sinsmeister AR, Sandborn WJ. The natural history of
corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology
2001;121:255-60.
2) Jewel DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial.
BML 1974;4:627-30.
3) Rosenberg JL, Wall AJ, Levin B, Binder HJ, Kirsner JB. A controlled trial of azathioprine in the
management of chronic ulcerative colitis. Gastroenterology 1975;69:96-99.
4) Kirk AP, Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. BML
1982;284:1291-2.
75
5) Adler DJ, Korelitz BI. The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis. Am J
Gastroenterol 1990;85:717-22.
6) Sood A, Midha V, Sood N, Kaushal V. Role of azathioprine in severe ulcerative colitis: one-year,
placebo-controlled, randomized trial. Indian J Gastroenterol 2000;19:14-16.
7) Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi Porro G. Randomised controlled trial
of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut
2006;55:47-53.
8) Mantzaris GJ, Sfakianakis M, Archavlis E, Petraki K, Christidou A, Karagiannidis A, Triadaphyllou G. A
prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and
olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol
2004;99:112-8.
9) Mate-Jimenez J, Hermida C, Cantero-Perona J, Moreno-Otero R. 6-mercaptopurine or methotrexate
added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease.
Eur J Gastroenterol Hepatol 2000;12:1227-33.
10) Carter MJ, Lobo AJ, Travis SPL. Guidelines for the management of inflammatory bowel disease in
adults. Gut 2004;53(Suppl V):v1-v16.
11) Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association
Institute Technical Review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel
disease. Gastroenterology 2006;130:940-987.
12) Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College of
Gastroenterology, practice parameters committee. Am J Gastroenterol 2010; 105:501-523.
13) Bultman E, Kuipers EJ, van der Woude CJ. Systematic review: steroid withdrawal in anti-TNF-treated
patients with inflammatory bowel disease. Aliment Pharmacol Ther 2010;32:313-323.
14) Rutgeerts P, Sandborn WJ, Geagan BG, et al. Infliximab for induction and maintenance therapy for
ulcerative colitis. N Engl J Med 2005;353:2462-76.
Q.I. #18: Oral cyclosporine after IV induction
Q.I. #18
IF a hospitalized ulcerative colitis patient responds to intravenous
cyclosporine
THEN oral cyclosporine should be administered for 3-6 months
BECAUSE once remission is achieved with intravenous cyclosporine, oral
therapy will allow time for other immunomodulator therapy to be established.
Summary: The use of intravenous cyclosporine to induce remission in acute severe
ulcerative colitis, followed by a period of oral cyclosporine therapy, has been shown to
be effective but only in the short to medium term.
Details
We identified 8 studies that investigated the role of intravenous cyclosporine followed by oral
cyclosporine in the treatment of acute severe ulcerative colitis
1-8
. The largest set of data
published by the Leuven group was a retrospective cohort study involving 142 patients, with 118
(83%) responding to intravenous cyclosporine and following 3 months of oral cyclosporine the
colectomy rate was 33% after one year, however this rose to 88% at seven years
(1)
. The rate of
colectomy in those already on azathioprine compared to those starting concurrently with
cyclosporine was 59% vs 31% respectively, thus suggesting that azathioprine naïve patients
had better outcomes
(1)
. Similar colectomy rates where demonstrated in an Italian open label
study involving 61 patients, 39 (63%) who initially responded to intravenous therapy, and
following 3-6 months of oral cyclosporine 61% remained colectomy free at 1 year which dropped
to 35% at 7 years
(2)
. In the subset of patients receiving azathioprine 80% remained colectomy
free at one year, with 60% at 7 years (2).
Earlier studies did show a more promising long term response to intravenous cyclosporine
followed by oral cyclosporine for a mean of 8 months, with an initial 76% response to
intravenous therapy (21/16), with remission maintained in 10/16 (62%) at an eight year
retrospective review
(3)
, however in this study one fatality was reported due to an opportunistic
infection. Another retrospective review carried out looked at the use of oral cyclosporine for 20
weeks following intravenous therapy, and of the 36 initial responders (86%), 10 had colectomies
at a mean of 6 months with a non-colectomy survival of 70% at 5.5 years (4).
77
These high figures have not since been replicated, with one smaller prospective study involving
18 patients showing colectomy free rates of 56% at 24 months, with at least one relapse
(5)
.A
retrospective review in another smaller study involving 16 patients showed a colectomy free rate
of 56% at 3 year follow up in those treated initially with oral cyclosporine then maintained on
azathioprine (6).
Studies with shorter follow up included a retrospective study of 46 patients, 32 of which (69%)
responded to intravenous therapy followed by 3 months of oral cyclosporine, with only a minority
(26%) remaining in sustained remission at 22 months
(7)
, but there were two serious infective
complications possibly related to therapy with cyclosporine. A further study involving 26 patients
found an initial response rate of 76% to intravenous cyclosporine therapy and following oral
cyclosporine for 3.5 months and concomitant azathioprine, the colectomy rate at 12 months was
46% (8).
References
(1) Moskovitz DN, Van Assche G, Maenhour b, Arts J, Ferrante M, Vermeire S, et al. Incidence of
colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis.
Clin Gastroenterol Hepatol 2006;4(12):1551.
(2) Actis GC, Fadda M, David E, Sapino A. Colectomy rate in steroid-refractory colitis initially responsive
to cyclosporin: a long-term retrospective cohort study. BMC Gastroenterol. 2007 Mar 27;7:13.
(3) Santos J:,S., Casellas F, Guarner L, Vilaseca J, Malagelada J. Efficacy of intravenous cyclosporine for
steroid refractory attacks of ulcerative colitis. J Clin Gastroenterol 1995;20(4):285-9.
(4) Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience.
Am.J.Gastroenterol. 1999 Jun;94(6):1587-1592.
(5) Holme O, Thiis-Evensen E, Vatn MH. Treatment of fulminant ulcerative colitis with cyclosporine A.
Scand.J.Gastroenterol. 2009;44(11):1310-1314.
(6) Campbell S, Ghosh S. Combination immunomodulatory therapy with cyclosporine and azathioprine in
corticosteroid-resistant severe ulcerative colitis: the Edinburgh experience of outcome. Dig.Liver Dis.
2003 Aug;35(8):546-551.
(7) McCormack G, McCormick PA, Hyland JM, O'Donoghue DP. Cyclosporin therapy in severe ulcerative
colitis: is it worth the effort? Dis.Colon Rectum 2002 Sep;45(9):1200-1205.
(8) Message L, Bourreille A, Laharie D, Quinton A, Galmiche JP, Lamouliatte H, et al. Efficacy of
intravenous cyclosporin in moderately severe ulcerative colitis refractory to steroids.
Gastroenterol.Clin.Biol. 2005 Mar;29(3):231-235.
79
Q.I. #19: Check CMV in hospitalized UC
IF a hospitalized patient with severe colitis is not improving on IV steroids
Q.I. #19
within three days
THEN sigmoidoscopy with biopsy should be performed to exclude CMV,
AND surgical consultation should be obtained
BECAUSE CMV infection is associated with steroid refractory disease and
lack of early response to intravenous steroids is a predictor of colectomy
on that admission.
Summary: Following three days of intravenous steroid therapy if there is no
response, then a flexible sigmoidoscopy is indicated to rule out the possibility of CMV
infection contributing to the flare. There is also evidence to suggest that if a patient
has not responded by then, the risk of having a colectomy on that admission is
raised, hence the need for a surgical consultation.
Details
Following three days of intravenous steroid therapy for acute ulcerative colitis if there is no
clinical improvement there is some evidence to suggest the possibility of CMV infection
complicating the course of the illness and contributing to the flare. One study examined surgical
specimens taken from patients who had colectomies for a severe flare, refractory disease or
dysplasia. They found 25% of 32 patients who had a severe flare were positive for CMV
compared with 8.3% of 72 patients in the refractory group and none of the 22 patients in the
dysplasia group
(1)
, thus suggesting that CMV is found more frequently in patients with severe
UC. A further study involving 77 consecutive UC patients who underwent colectomy found CMV
in the specimen of 15/55 steroid refractory patients (27.3%) and 2/22 non-refractory patients
(9.1%), however only 6 patients had positive staining for CMV in pre-operative endoscopic
biopsy specimens (2).
An Italian study evaluated 55 consecutive patients admitted with severe UC, 7 with Crohn’s
colitis. In 7 (5 with UC, 2 with CD) patients out of 19 (36%) with refractory disease CMV was
identified by biopsy, suggesting that CMV could be a cause for those with refractory disease
and should be identified (3). In this study 5 patients who were initially refractory to steroid therapy
went into remission with antiviral therapy. A larger prospective observational study carried out in
Spain looked at 114 patients with active UC, steroid refractory UC, inactive UC on mesalamine
and inactive UC on azathioprine and healthy controls
(4)
. They identified CMV disease by
carrying out colonic biopsies in 6 steroid refractory, CMV-IgG positive patients, but not amongst
controls, inactive UC or steroid responding UC patients.
A retrospective review of biopsies was carried out 40 patients with refractory UC who underwent
colectomy, 40 patients with severe but non-refractory UC and a control group of 40 patients who
underwent colectomies for other reasons. They detected CMV inclusions by haematoxylin and
eosin (H&E) in 2 of 40 patients with refractory UC but not in other groups, and 10/40 (25%) with
refractory disease had CMV detected by immunohistochemistry, concluding that CMV infection
was significantly associated with steroid-refractory UC
(5)
. Smaller studies have also that for
patients with severe UC, severity of CMV infection tended to correlate with older age and more
rapid deterioration (6).
Several studies have also shown that if a patient has not responded to intravenous steroids by
day 3, their chances of needing a colectomy on that admission are increased, thus the need to
involve the surgical team at this stage. The Oxford data showed that after three days of
intravenous steroids if a patient was still having >8 bowel movements per day, then their
chances of needing a colectomy during that admission was 85%
(7)
. An earlier study showed
that on day 2 of steroid therapy if there was >12 bowel movements per day then the chances of
colectomy were 55%
(8)
. Similar results were shown in the Swedish study with a colectomy risk
of 75% if on day three of intravenous steroid therapy there were >4 bowel movements/ day and
a CRP >25 mg/L (9).
References
(1) Kojima T, Watanabe T, Hata K, Shinozaki M, Yokoyama T, Nagawa H. Cytomegalovirus infection in
ulcerative colitis. Scand.J.Gastroenterol. 2006 Jun;41(6):706-711.
(2) Maconi G, Colombo E, Zerbi P, Sampietro GM, Fociani P, Bosani M, et al. Prevalence, detection rate
and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection.
Dig.Liver Dis. 2005 Jun;37(6):418-423.
(3) Cottone M, Pietrosi G, Martorana G, Casa A, Pecoraro G, Oliva L, et al. Prevalence of
cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis. Am.J.Gastroenterol. 2001
Mar;96(3):773-775.
(4) Domenech E, Vega R, Ojanguren I, Hernandez A, Garcia-Planella E, Bernal I, et al. Cytomegalovirus
infection in ulcerative colitis: a prospective, comparative study on prevalence and diagnostic strategy.
Inflamm.Bowel Dis. 2008 Oct;14(10):1373-1379.
81
(5) Kambham N, Vij R, Cartwright CA, Longacre T. Cytomegalovirus infection in steroid-refractory
ulcerative colitis: a case-control study. Am.J.Surg.Pathol. 2004 Mar;28(3):365-373.
(6) Kuwabara A, Okamoto H, Suda T, Ajioka Y, Hatakeyama K. Clinicopathologic characteristics of
clinically relevant cytomegalovirus infection in inflammatory bowel disease. J.Gastroenterol. 2007
Oct;42(10):823-829.
(7) Travis SP, Farrant J, Rickets C, Nolan D, Mortensen N, kettlewell N, et al. Predicting outcome in
severe ulcerative colitis. Gut 1996;38:905-10.
(8) Lennard J, Ritchie J, Hilder W, Spicer C. Assessment of severity in colitis: a preliminary study. Gut
1975;16:579-84.
(9) Lindgren S., Flood L, Kilander A, et al. Early predictors of glucocorticoid treatment failure in severe
and moderately severe attacks of ulcerative colitis. Eur J Gastroenterol Hepatol 1998;10:831-5.
IBD Health-Care Maintenance
QI #20: Annual Review
Q.I. #20:
IF a patient has IBD
THEN he or she should have an annual review (in person or by
telephone)
BECAUSE patients with IBD require health care maintenance even when
in clinical remission. These include therapeutic monitoring (both for
efficacy and adverse events), bone health, immunizations, smoking
cessation, and colorectal cancer surveillance.
Summary: There are no specific data to support the practice of annual review for all
patients with IBD. However, patients with IBD may rely on their gastroenterologist for
general health maintenance. Whether this should be addressed by improving knowledge
of the issues surrounding IBD at primary care level or whether the gastroenterologist
should take on these additional responsibilities is not clear.
Details
There is evidence that IBD patients get less primary care than non-IBD patients of the same
age1. There are also data to suggest that primary care providers are not comfortable providing
care to patients with IBD2. This is important as there are a number of primary care issues that
are of specific relevance to IBD. These include but are not limited to cancer surveillance
(colorectal, cervical and skin), osteoporosis screening, vaccination, pre-pregnancy counselling
and smoking cessation advice and support. IBD patients are frequently a young and mobile
group who have a single illness and are likely to want to spend their healthcare consultation
time with their specialist (the gastroenterologist) rather than their primary care physician. While
this seems self-evident, there are no data to show improved outcomes associated with regular
visits when in remission.
The following are some of the issues that can be reviewed during annual review.
Laboratory testing: there are no data to support the practice of regular laboratory monitoring in
patients with mild disease in prolonged remission off medication. Some have recommended
annual complete blood count, liver blood tests and renal function in addition to inflammatory
markers3. Anemia is common in Crohn’s disease4 as is vitamin B12 deficiency in those with
ileal disease or previous ileal resection. Recent evidence suggests lower vitamin D in Crohn’s
disease,5 in addition to data suggesting a role for vitamin D in the inflammatory process.6
83
Monitoring of therapy: Annual BUN, creatinine and urinalysis for those on aminosalicyclates (ref
QI #12). The American Gastroenterology Association recommends 3 monthly white blood count
and liver blood tests in those on stable doses on thiopurines and anti-TNF therapy and 3
monthly liver blood tests for methotrexate7 (ref QI #). Annual PPD for patients on anti-TNF
therapy performed by some following recommendation by certain societies 8 but overall, the
evidence for this approach is lacking. As mentioned above this group should also be targeted
for annual review of vaccination status.
Smoking has a deleterious effect on the clinical course of Crohn’s disease, being associated
with disease relapse, complications and the need for resection surgery or immunosuppressive
therapy9. Although it makes sense that reinforcement of this information is important, here are
no data on the effectiveness of smoking cessation interventions in IBD.
Supervision of medical therapy. A recent review of oral drug compliance in IBD suggests 3045% of patients are non-adherent with their medications. This is important as non-compliance is
associated with an increased risk of disease relapse10 and, in the case of 5-ASAa may reduce
the risk of colorectal cancer in those with colitis11.
Number of PCP visits and time since last office visit are not associated with non-adherence
although number of office visits did have an association is some studies (but not in others) 12-15.
Vaccination status: the need for vaccination against common preventable illnesses is increased
in IBD and yet the rates of vaccination in IBD patients is low. A study of 169 IBD patients (86%
of whom had current or prior immunosuppressant use) 28% received regular influenza
vaccination, 9% had pneumococcal vaccine and 28% had been vaccinated against hepatitis B16
(QI #21).
Other important issues for IBD patients include colorectal cancer surveillance which can be
reviewed at annual review to ensure compliance (QI #s)
References
1. Selby L, Kane S, Wilson J, et al. Receipt of preventive health services by IBD patients is significantly
lower than by primary care patients. Inflammatory bowel diseases 2008;14:253-8.
2. Selby L, Hoellein A, Wilson JF. Are Primary Care Providers Uncomfortable Providing Routine
Preventive Care for Inflammatory Bowel Disease Patients? Digestive diseases and sciences.
3. Moscandrew M, Mahadevan U, Kane S. General health maintenance in IBD. Inflammatory bowel
diseases 2009;15:1399-409.
4. Gisbert JP, Gomollon F. Common misconceptions in the diagnosis and management of anemia in
inflammatory bowel disease. The American journal of gastroenterology 2008;103:1299-307.
5. McCarthy D, Duggan P, O'Brien M, et al. Seasonality of vitamin D status and bone turnover in
patients with Crohn's disease. Alimentary pharmacology & therapeutics 2005;21:1073-83.
6. Wang TT, Dabbas B, Laperriere D, et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of
the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. The Journal of
biological chemistry;285:2227-31.
7. Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association
Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory
bowel disease. Gastroenterology 2006;130:935-9.
8. Perlmutter A, Mittal A, Menter A. Tuberculosis and tumour necrosis factor-alpha inhibitor therapy: a
report of three cases in patients with psoriasis. Comprehensive screening and therapeutic guidelines for
clinicians. Br J Dermatol 2009;160:8-15.
9. Sutherland LR, Ramcharan S, Bryant H, Fick G. Effect of cigarette smoking on recurrence of Crohn's
disease. Gastroenterology 1990;98:1123-8.
10. Higgins PD, Rubin DT, Kaulback K, Schoenfield PS, Kane SV. Systematic review: impact of nonadherence to 5-aminosalicylic acid products on the frequency and cost of ulcerative colitis flares.
Alimentary pharmacology & therapeutics 2009;29:247-57.
11. Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and
management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology;138:746-74, 74 e14; quiz e12-3.
12. Horne R, Parham R, Driscoll R, Robinson A. Patients' attitudes to medicines and adherence to
maintenance treatment in inflammatory bowel disease. Inflammatory bowel diseases 2009;15:837-44.
13. Kane S, Huo D, Magnanti K. A pilot feasibility study of once daily versus conventional dosing
mesalamine for maintenance of ulcerative colitis. Clin Gastroenterol Hepatol 2003;1:170-3.
14. Shale MJ, Riley SA. Studies of compliance with delayed-release mesalazine therapy in patients with
inflammatory bowel disease. Alimentary pharmacology & therapeutics 2003;18:191-8.
15. Waters BM, Jensen L, Fedorak RN. Effects of formal education for patients with inflammatory bowel
disease: a randomized controlled trial. Canadian journal of gastroenterology = Journal canadien de
gastroenterologie 2005;19:235-44.
16. Melmed GY, Ippoliti AF, Papadakis KA, et al. Patients with inflammatory bowel disease are at risk for
vaccine-preventable illnesses. The American journal of gastroenterology 2006;101:1834-40.
85
Q.I. #21: Influenza vaccine
Q.I. #21
IF a patient with IBD is on immunosuppressive therapy,
THEN the injectable seasonal inactivated influenza vaccine should
be administered annually
BECAUSE patients on immunosuppressive therapy are at
increased risk of infection with influenza.
Summary: Killed intramuscular influenza vaccine should be administered yearly
in immunocompromised patients with IBD.
Details
The injectable inactivated trivalent influenza vaccine and inactivated H1N1 vaccine are safe in
immunosuppressed recipients, whereas the live attenuated intranasal influenza and H1N1
vaccines are contraindicated [1]. Influenza vaccination is effective in inducing immune
responses in children with IBD, but may be less effective among those on anti-TNF therapies [24]. The majority of IBD patients develop protective antibody titers following influenza
vaccination, regardless of immunosuppressive medication use. To date, there are no studies of
H1N1 vaccination in IBD patients. However, as demonstrated with seasonal influenza vaccines,
antibody response to H1N1 vaccination may be diminished among IBD patients on
immunosuppressive medications. Annual administration appears to be efficacious, as no studies
to date have evaluated whether more frequent administration would improve immunogenicity.
References
1.
Fiore, A.E., et al., Prevention and control of influenza with vaccines: recommendations of the
Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 59(RR-8):
p. 1-62.
2.
Lu, Y., et al., Immune response to influenza vaccine in children with inflammatory bowel disease.
Am J Gastroenterol, 2009. 104(2): p. 444-53.
3.
Gelinck, L.B., et al., The effect of anti-tumour necrosis factor alpha treatment on the antibody
response to influenza vaccination. Ann Rheum Dis, 2008. 67(5): p. 713-6.
4.
Mamula, P., et al., Immune response to influenza vaccine in pediatric patients with inflammatory
bowel disease. Clin Gastroenterol Hepatol, 2007. 5(7): p. 851-6.
87
Q.I. #22: Avoid live virus vaccines if immunosuppressed
Q.I. #22
IF a patient with IBD is on immunosuppressive therapy,
THEN live virus vaccines (inhaled influenza, varicella, zoster,
measles/mumps/rubella, oral polio, Bacillus Calmette-Guerin and
yellow fever) should not be administered
BECAUSE patients on immunosuppressive therapy are at risk for
contracting active disease from these vaccines
Summary: Live virus vaccines should not be administered in immunocompromised
individuals with IBD.
Details
Patients with inflammatory bowel disease (IBD), are at increased risk of acquiring a vaccinepreventable infection, due to immunosuppressive therapy used to treat the disease and
underutilization of vaccines [1, 2]. These immunosuppressant medications include
corticosteroids, azathioprine/6-mercaptopurine, methotrexate, and anti-TNF alpha therapies.
While IBD patients should receive standard recommended immunizations as outlined by the
Advisory Committee on Immunization Practices (ACIP) of the Center for Disease Control and
Prevention (CDC), and the European Crohn’s and Colitis Organization (ECCO), live virus
vaccines should be avoided in IBD patients on chronic immunosuppression because of the
potential for virus replication and spread [3-4]. Live virus vaccines include inhaled influenza,
varicella, zoster, measles/mumps/rubella (MMR), oral polio, Bacillus Calmette-Guerin (BCG)
and yellow fever. Chronic immunosuppression in children and adults with IBD is defined as
treatment with glucocorticoids (prednisone 20mg/d or equivalent), 6mercaptopurine/azathioprine, methotrexate, or biologics, including within 3-6 months of
discontinuing any of these medications [5].
Recently, data has been published on vaccinations in patients with autoimmune disorders,
including those requiring corticosteroids and other immunosuppressive medications [6]. It states
that live virus vaccines can be given to patients receiving systemic corticosteroids for less than
two weeks (regardless of dose, although controversial at higher doses) or at daily doses not
exceeding 10mg per day of prednisone equivalent [6]. Likewise, to avoid the risk of systemic
infection from live virus vaccination, it would be conservative to wait 6 weeks prior to restarting
immunosuppressive therapy, although there is very limited data assessing this approach.
Ideally, patients either newly diagnosed with IBD or at their initial IBD consultation should be
queried regarding vaccination status, travel history, and risk factors for various infections [1, 4].
Where possible, all indicated vaccines (see Table) should be administered to patients before
starting immunosuppressive therapy, in order to maximize the chance of an adequate immune
response and allow for administration of live vaccines if needed. However, in cases where
patients need to initiate immunosuppressive treatment immediately, these immunizations may
need to be postponed.
Evidence Table
Select Immunization Recommendations for Adult Patients (>18 years of age) with Inflammatory
Bowel Disease
Immunization
Recommendation if
Initial Visit
Follow-up Visits
1 dose if previously
1 dose after age 50
unvaccinated and
if risk factors
born after 1957
present
on
Immunosuppressive
Therapy*
Measles-Mumps-Rubella
Contraindicated
(MMR)
Varicella Vaccine
Contraindicated
2-dose series if no
history of varicella
confirmed by
negative serologies
Zoster Vaccine
Contraindicated
Single dose for
patients age >60
89
Influenza Vaccine
Contraindicated
Annually
Annually
Recommended
Annually
Annually
Tetanus-Diphtheria-acellular Recommended
3-dose series if
Every 10 years with
Pertussis (Tdap)
unvaccinated, or 1-
Td (substitute 1-time
time booster with
dose of Tdap for Td
Td**
booster)
1 dose if not
5 years after initial
vaccinated within
dose
(Inactivated, Inhaled)***
Influenza Vaccine (Killed,
Intramuscular)***
Pneumococcal Vaccine
Recommended
past 5 years
Hepatitis B Virus Vaccine
Recommended
3-dose series if
seronegative or
with risk factors;
Consider checking
HBsAb status if
immunosuppressed
when vaccinated
Meningococcal Vaccine
Recommended
1 dose if risk
Consider 1-time
factors present
revaccination after 5
years if risk factors
still present
Human Papilloma Virus
Recommended
Vaccine
3-dose series for
females age 9-26,
consider for all
females with IBD,
especially if
immunosuppressed
*Patients on chronic immunosuppressive therapy (see text) are thought to be at higher risk of
infection than patients newly starting immunosuppressive therapy. However we would advise
these guidelines regardless of duration of immunosuppressive therapy, and at least 3-6 months
after the discontinuation of immunosuppressive therapy
**Td: tetanus and diphtheria vaccination
***Use either influenza vaccine in given year based on immunosuppression status
References
1. Toruner M, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, Colombel JF,
Egan LJ. Risk factors for opportunistic infections in patients with inflammatory bowel disease.
Gastroenterology. 2008 Apr; 134(4):929-36.
2. Melmed GY, Ippoliti AF, Papadakis KA, Tran TT, Birt JL, Lee SK, Frenck RW, Targan SR,
Vasiliauskas EA. Patients with inflammatory bowel disease are at risk for vaccine-preventable
illnesses. Am J Gastroenterol. 2006 Aug; 101(8):1834-40.
3. Kroger AT, Atkinson WL, Marcuse EK, Pickering LK; Advisory Committee on Immunization Practices
(ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on
immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep. 2006 Dec 1;55(RR-15):1-48.
4. Rahier JF, et al, European evidence-based Consensus on the prevention, diagnosis and
management of opportunistic infections in inflammatory bowel disease, Journal of Crohn's and
Colitis (2009), doi:10.1016/j.crohns.2009.02.010
5. Sands BE, Cuffari C, Katz J, Kugathasan S, Onken J, Vitek C, Orenstein W. Guidelines for
immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2004 Sep;
10(5):677-92.
6. Duchet-Niedziolka P, et al. Vaccination in adults with auto-immune disease and/or drug related
immune deficiency: results of the GEVACCIM Delphi survey. Vaccine. 2009 Mar 4;27(10):1523-9.
91
IBD and Colon Cancer
Q.I. #23: Surveillance Colonoscopy
Q.I. #23
IF a patient with UC has had colitis for 8-10 years,
THEN surveillance colonoscopy should be performed every 1-3
years
BECAUSE surveillance colonoscopy may permit earlier
detection of colorectal cancer and improve prognosis.
Summary: There are no placebo controlled randomized trials comparing
surveillance colonoscopy to no surveillance due to practical and ethical
reasons. However, there are several epidemiological studies that support the
value of surveillance colonoscopy in early detection of colorectal cancer.
Details
Colorectal cancer (CRC) is a feared long-term complication of ulcerative colitis (UC). In the
past, colectomy was recommended for patients with extensive UC of long duration in an effort to
reduce CRC mortality. With the availability of colonoscopy and correlation of mucosal
dysplasia, surveillance has been initiated in the 1970’s to limit CRC mortality while avoiding
colectomy.
Many variables have been associated with the development of CRC and dysplasia in patients
with UC. A review in 2006 reported the duration of inflammatory bowel disease, extent of
inflammatory bowel disease, presence of primary sclerosing cholangitis (PSC), severity of
inflammatory bowel disease, family history of colon cancer, and age at UC diagnosis as
independent risk factors for CRC.1 Studies have devoted special attention to the duration of
disease and anatomic extent of disease in the practice of surveillance.
A cohort study of 401 patients with extensive UC reported a cumulative risk of developing CRC
of 3% at 15 years, 5% at 20 years, and 9% at 25 years.2 In the study, no CRC was diagnosed
less than 10 years form the onset of colitis. Additionally, a meta-analysis of 116 studies showed
an overall prevalence of CRC in any UC patent to be 3.7% (95% CI = 3.2-4.2%).3 The incidence
rate of CRC increased with increasing UC disease duration. The study also showed that after 8
to 10 years of disease, the risk of CRC becomes greater than that of the general population.
Based on the concept that CRC risk increases with longer duration of colitis, the Crohn’s and
Colitis Foundation of America (CCFA) committee recommended that a screening colonoscopy
be performed 8 to 10 years after the onset of symptoms of UC.4 More recently, the American
College of Gastroenterology (ACG) set out guidelines that also recommend initiation of
surveillance at 8 to 10 years of disease symptoms due to these studies.5
PSC is also recognized as an independent risk factor for CRC in UC patients. A Swedish cohort
study of 125 patients with PSC identified CRC in 12 patients.6 Although a small number of
patients were enrolled, the study reported a cumulative risk of 16% for CRC 10 years after the
diagnosis of PSC. Another cohort study showed the development of CRC or dysplasia in 25%
of patients with UC and PSC compared to 5.6% of control patients with UC alone (p<0.001).7
They also showed that the age of onset of UC is significantly lower and disease extent at
colonoscopy is significantly greater in patients with UC and PSC compared to patients with UC
alone. The ACG recommends the start of colonoscopic surveillance as soon as the coexisting
diagnoses of UC and PSC are established and annually as a result of the increased risk of
CRC.5
Cancer-related mortality as a primary outcome measure of surveillance is difficult to study and
would require lifelong evaluation, patient compliance, and physician compliance. Additionally, a
prospective randomized control study would not be ethical. The identification of neoplastic
lesions by surveillance colonoscopy and cancer staging may therefore serve as outcome
measures, however lead-time bias must be considered in evaluating the effectiveness of
surveillance programs.
In a review of a longstanding UC surveillance program, 15 patients with neoplastic lesions were
identified on initial screening but 31 patients with neoplastic lesions were identified on
subsequent surveillance examinations.8 A percentage of patients with CRC did not have visible
lesions on colonoscopy but showed evidence of dysplasia on histology. Further, a cohort study
of 418 patients showed a 3-fold increase in neoplasia in patients with an increase in microscopic
inflammation.9 Current recommendations for nontargeted biopsies is essential in surveillance
and complements endoscopic visualization. The CCFA recommends a minimum of 33 biopsies
in patients with extensive disease. This involves taking 4-quadrant biopsies every 10 cm
throughout the colon and additional biopsies of suspicious lesions.
A cohort study of a surveillance program detected CRC in 5% of the population.10 They reported
a 5-year survival rate of 100% for Dukes’ A cancer, 80% for B, 80% for C, and 0% for
93
disseminated malignancy. Surveillance showed benefit in Dukes’ A, B, and C cancers.
Similarly, a cohort study of 211 patients with total colitis or left-sided colitis found CRC in 8
patients undergoing surveillance colonoscopy. Of the 8 patients, 7 remained alive at the end of
the study.11 It has been reported that patients with colitis-associated CRC at Dukes’ A and B
have a good survival rate, but those with Dukes’ C have poor prognosis.12 Surveillance
colonoscopy is important in early detection of CRC and may therefore improve prognosis.
A proposed model for CRC surveillance in 1988 recommended optimal spacing intervals based
on patient-specific hazard rates and the number of affordable and tolerable tests over the
lifetime of disease.13 This study supplements the current recommendations and allows for
patient-specific care. Patients with UC who have had colitis for 8-10 years should have
surveillance colonoscopy performed every 3 years as recommended but patients with increased
risk factors for CRC should have more frequent surveillance. Patients with PSC who have an
increased risk for CRC should be surveyed annually. Further, surveillance colonoscopy may
permit earlier detection of CRC and is likely associated with better CRC-related prognosis.
References:
1. Loftus, E.V., Jr. Epidemiology and risk factors for colorectal dysplasia and cancer in ulcerative colitis.
Gastroenterol. Clin. N. Am. 35, 517-531 (2006).
2. Lennard-Jones, J.E., Melville, D.M., Morson, B.C., Ritchie, J.K., Willliams, C.B. Precancer and cancer
in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 31, 800-806 (1990).
3. Eaden, J.A., Abrams, K.R., and Mayberry, J.F. The risk of colorectal cancer in ulcerative colitis: a
meta-analysis. Gut 48, 526-535 (2001).
4. Itzkowitz, S.H. and Present, D.H. Consensus conference: colorectal cancer screening and
surveillance in inflammatory bowel disease. Inflamm. Bowel Dis. 11(3), 314-321 (2005).
5. Kornbluth A, Sachar DB, and the practice parameters committee of the American college of
gastroenterology. Ulcerative colitis practice guideline in adults: American college of gastroenterology,
practice parameters committee. Am. J. Gastroenterol. 105, 500-523 (2010).
6. Kornfeld, D. Ekbom, A., and Ihre, T. Is there an excess risk for colorectal cancer in patients with
ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut 41,
522-525 (1997).
7. Shetty, K., Rybicki, L., Brzezinski, A. et al. The risk for cancer or dysplasia in ulcerative colitis patients
with primary sclerosing cholangitis. Am. J. Gastroenterol. 94(6), 1643-1649 (1999).
8. Rubin DT, Rothe JA, Hetzel JR, Cohen RD, Hanauer SB. Are dysplasia and colorectal cancer
endoscopically visible in patients with ulcerative colitis? Gastr. Endo. 65, 997-100 (2007).
9. Gupta, R.B., Harpaz, N., Itzkowitz, S. et al. Histologic inflammation is a risk factor for progression to
colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterol. 133, 1099-1105 (2007).
10. Rutter MD, Saunders BP, Wilkinson KH et al. Thirty-year analysis of a colonoscopic surveillance
program for neoplasia in ulcerative colitis. Gastroenterol. 130,1030-1038 (2006).
11. Lindberg, J. Stenling, R., Palmqvist, R. and Rutegard, J. Efficiency of colorectal cancer surveillance
in patients with ulcerative colitis: 26 years’ experience in a patient cohort from a defined population area.
12. Heimann, T.M., Martinelli, G., Szporn, A. et al. Colorectal carcinoma associated with ulcerative
colitis: a study of prognostic indicators. Am. J. Surg. 164(1), 13-17 (1992).
13. Lashner, B.A., Hanauer, S.B., and Silverstein, M.D. Optimal timing of colonoscopy to screen for
cancer in ulcerative colitis. Ann. Int. Medicine 108(2), 274-278 (1988).
95
Q.I. #24: Biopsy of colonic strictures
Q.I. # 24
IF you have a patient with colitis who has a stricture,
THEN a colonoscopy should be performed to biopsy the stricture
BECAUSE a colonic stricture in the setting of ulcerative colitis or
Crohn’s colitis is associated with an increased risk of dysplasia and
cancer.
Summary: The reported prevalence of dysplasia and cancer in colonic strictures
associated with ulcerative colitis (UC) varies in the literature and comes
exclusively from retrospective studies. However, the data are consistent in their
suggestion that UC-associated colonic strictures frequently harbor dysplasia or
cancer. Expert opinion, professional guidelines and the aforementioned
retrospective data support the practice of endoscopic biopsies in this setting.
Colonic strictures, associated with Crohn’s disease (CD) may also harbor a high
malignancy rate, and complete examination with endoscopic biopsy should be
performed.
There are insufficient data to comment on the ideal approach or effectiveness of
endoscopic monitoring in inflammatory bowel disease (IBD) associated colonic
strictures. Even with negative endoscopic biopsies, clinicians need to be
cognizant of the possibility of missed pathology, especially when dealing with
long standing disease.
Details
Ulcerative Colitis: Guidelines suggest that colonic strictures in the setting of UC be considered
malignant until proven otherwise. As such, a full assessment and complete endoscopic biopsy
of the stricture is recommended1.
Several retrospective studies have looked into the prevalence of dysplasia and cancer in colonic
strictures occurring in the setting of ulcerative colitis3,4,5,6,8. These publications revealed variable
results: historically earlier findings noted low rates or the absence of cancer or dysplasia in UC
strictures. In contrast, later series suggested that the prevalence could be anywhere from 24%
to 86%3,4,8. A possible reason for the somewhat disparate results stems from differences in
stricture definition. Early case-series used barium enema (BE) as the predominant diagnostic
modality and may have included colonic ‘strictures’ that actually represented reversible
narrowing secondary to muscular hypertrophy or spasm, with later reports using colonoscopic
findings.
In a retrospective review of 469 patients from the University of Chicago, Lashner and
colleaguesl found 15 individuals with a ‘true’ stricture,3 defined as localized narrowing that
persisted on repeat BE with various maneuvers or confirmed endoscopically. 11 of the 15 had
multiple strictures with the majority of strictures located principally in the left colon. 25 strictures
in 13 patients were found to have low-grade dysplasia (LGD), high-grade dysplasia (HGD) or
cancer. These 13 patients all went to colectomy. 6 adenocarcinomas were discovered, and all
were located at the site of the pre-operatively located stricture. Only 2 of these malignancies
were identified preoperatively by colonoscopic biopsy.
Hunt and colleagues reported a similar prevalence in their study on colonic strictures8. They
found 6 of 7 patients with dysplasia or carcinoma in non-spastic ulcerative colitis-associated
strictures. No dysplasia was seen among 17 patients with reversible strictures.
In the largest restrospective study to date, (1156 UC patients with 70 colonic strictures) from
The Mount Sinai Hospital in New York City, 17 of 70 (24%) strictures in 59 patients were found
to be malignant with the other 53 benign4. Investigators identified three principal features that
distinguished malignant from benign strictures: (1) appearance late in the course of the disease
(61% probability of malignancy in strictures that develop after 20 years of disease compared to
0% probability of malignancy in those occurring before 10 years); (2) location proximal to the
splenic flexure (86% probability of malignancy compared to 47% in the sigmoid colon, 10% in
the rectum, and 0% in the splenic flexure and descending colon); and (3) symptomatic large
bowel obstruction (100% probability of malignancy v only 14% in the absence of obstruction or
constipation).
Reiser and colleagues reported a case series of three patients in whom UC-associated
strictures were found to harbor advanced adenocarcinoma despite previous endoscopic
examinations that had failed to demonstrate dysplasia or carcinoma2. Despite the low number of
patients, this reports calls into question the reliability of endoscopic monitoring of UC patients
with colonic strictures. By using surgical pathology as the gold standard, however, these series
may harbor inherent selection biases by excluding benign strictures that did not come to
surgery.
97
Strictures in Crohn’s disease. Guidelines and relevant review articles discuss colonic strictures
occurring in the setting of Crohn’s colitis as being, “mostly benign.”1 However, data addressing
this topic are scant. Only 1 retrospective study of 175 Crohn’s disease associated colonic
strictures was identified7. In this series, the rate of malignancy was 6.8% compared with 0.7% in
patients without stricture in this surgical series. The proportion of strictures that were malignant
increased with duration of disease. All malignancies occurred in ‘short’ colonic strictures
(strictures that did not extend over one anatomical segment of colon). Despite this being the
only relevant study that was identified, it appears to be prudent to endoscopically biopsy a
colonic stricture associated with Crohn’s disease in the same way you would for UC.
As outlined above, retrospective data indicate a high prevalence of dysplasia and cancer in IBDassociated colonic strictures, especially in UC. These articles and subsequent societal
guidelines have therefore recommended endoscopic biopsy. However, it should be noted that
this approach is best adopted when the stricture can be fully examined. Even with negative
biopsies from the full length of a stricture, the possibility of sampling error exists and the patient
may still be at very high risk for a malignancy. There are no studies that address optimal biopsy
technique or appropriate endoscopic surveillance intervals.
References.
1. ASGE guideline: endoscopy in the diagnosis and treatment of inflammatory bowel
disease. Gastrointestinal Endoscopy, 2006 63(4):558-565
2. Reiser JR, Waye JD, Janowitz HD, et al. Adenocarcinoma in strictures of ulcerative
colitis without antecedent dysplasia by colonoscopy. Am J Gastroenterol. 1994
Jan;89(1):119-22
3. Lashner BA, Turner BC, Bostwick DG, Frank PH, Hanauer SB. Dysplasia and Cancer
Complicating Strictures in Ulcerative Colitis. Digestive Diseases and Sciences. March
1990. 35(3):349-352
4. Gumaste V, Sachar DB, Greenstein AJ. Benign and malignant colorectal strictures in
ulcerative colitis. Gut, 1992, 33:938-941
5. deDombal FT, Watts J, Watkinson G, Goligher JC. Local complications of ulcerative
colitis: Stricture, pseudopolyposis and carcinoma of the colon and rectum. BMJ 1966;
1:1442-7.
6. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Gut 1964;5: 122.
7. Yamazaki Y, Ribeiro MB, Sachar DB, Aufses AH Jr, Greenstein AJ. Malignant colorectal
strictures in Crohn’s disease. Am J Gastroenterol. 1991 Jul;86(7):882-5
8. Hunt RH, Teague RH, Swarbrick ET, Williams CB. Colonoscopy in Management of
Colonic Strictures. BMJ, 1975 Aug. 3, 360-361.
Q.I. #25: Discuss implications of surveillance
Q.I. #25
IF you have a patient at high risk for colon cancer, such as those with
extensive colitis or colitis with PSC,
THEN there should be documentation about risks of colon cancer,
including the following elements: (1) implications of dysplasia, (2)
limitations of surveillance, (3) risks of colonoscopy.
BECAUSE the risk of dysplasia and colorectal cancer is increased relative
to the general population and current surveillance practices do not
guarantee against the development of malignancy.
Summary: No studies have directly assessed the effect of physician documentation
of the risks of colon cancer in appropriate patients with inflammatory bowel disease.
However, expert opinion has suggested that, prior to initiating a program of
screening and surveillance, providers document the risks, benefits and limitations of
their chosen approach.
Details
There are no published studies identified that address the process of documentation of
colorectal cancer (CRC) risk in IBD patients with extensive colitis or colitis associated with PSC.
Despite general acceptance by the GI community that this population warrants entrance into a
colonoscopic CRC screening and surveillance program, the proportion of patients being
adequately surveilled is unknown. Furthermore, we do not know whether patients under
surveillance appreciate the limitations of current approaches, or understand the implications of
finding various dysplastic lesions.
Expert opinion has been offered with respect to compliance and consent for dysplasia
surveillance. As part of a consensus conference on colorectal cancer screening and
surveillance in inflammatory bowel disease, it was noted that patients should be informed that
while colonoscopic surveillance represents the best approach currently available, it has
limitations1. This group discussed the idea of a general form to be signed by both the patient
and physician outlining the proposed surveillance program. They suggested that this document
include the risks and benefits of colonoscopic surveillance in addition to highlighting the
importance of patient compliance with scheduled examinations.
99
References
1. Itzkowitz SH, Present DH. Consensus Conference: Colorectal Cancer Screening and
Surveillance in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2005. 11(3):314-318.
Q.I. #26: Surveillence in Crohn’s colitis
Q.I. #26: IF a patient with Crohn's has colitis involving >1/3 of the
colon,
THEN surveillance should be initiated (as with UC),
BECAUSE patients with extensive Crohn’s colitis (i.e.
>1/3 of colon) have increased risk to colon cancer, and
surveillance colonoscopy may reduce the risk of colon
cancer.
Summary: Crohn’s patients with extensive colonic involvement have an
increased risk of colon cancer as compared to healthy controls and this risk is
similar to ulcerative colitis patients. Thus, Crohn’s patients with extensive
colonic involvement should undergo the same dysplasia surveillance
programs that are available for ulcerative colitis patients.
Details
A meta-analysis of 12 observational studies demonstrated that the overall relative risk of colon
cancer in Crohn’s disease patients was 2.5 (95% confidence interval: 1.3-4.7) and the
cumulative 10-year risk of colon cancer following diagnosis was 2.9% (Table 1). Crohn’s
patients with colonic involvement were at over 4.5 fold increased risk, whereas patients with
isolated ileal disease were not at increased risk of colon cancer. The risk of colon cancer in
Crohn’s disease was similar to ulcerative colitis1. Several other studies, not included in the
meta-analysis, have demonstrated high rates of dysplasia and colon cancer in Crohn’s disease
patients2-4. Thus, Crohn’s disease patients with extensive colonic involvement should be
afforded the same surveillance practices as ulcerative colitis. Prospective randomized controlled
studies assessing the effectiveness of interval colonoscopies for dysplasia surveillance in
reducing the risk of colon cancer is lacking in ulcerative colitis and Crohn’s disease. While a
survival benefit of surveillance for dysplasia in ulcerative colitis and Crohn’s disease is lacking,
current guidelines from the American Society for Gastrointestinal Endoscopy support dysplasia
surveillance in ulcerative colitis patients and in Crohn’s patients with extensive colitis.
Relative Risk of Colon Cancer among Crohn’s disease patients1
101
Author
Year
N
Country
RR (95% CI)
Weedon, et al,5
Gyde, et al,6
Greenstein, et al,7
Kvist, et al,8
Gollop, et al,9
Fireman, et al,10
Ekbom, et al,11
Gillen, et al,12
Persson, et al,13
Mellemkjaer, et
al,14
Berstein, et al,15
Jess, et al,16
1973
1980
1981
1986
1988
1989
1990
1994
1994
449
513
579
473
103
365
1655
281
1251
US
UK
1981
Denmark
US
Israel
Sweden
UK
Sweden
20.0 (8.6, 34.4)
4.3 (2.0, 8.2)
6.9 (2.8, 14.2)
2.1 (1.0, 3.3)
2.0 (0.04, 3.7)
0.4 (0.01, 2.3)
2.5 (1.3, 4.3)
3.4 (1.5, 6.7)
0.84 (0.27, 1.9)
2000
2645
Denmark
1.1 (0.6, 1.9)
2001
2004
2857
374
Canada
Denmark
2.6 (1.7, 4.1)
1.1 (0.13, 2.9)
1. Canavan C, Abrams KR, Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in
patients with Crohn's disease. Aliment Pharmacol Ther. Apr 15 2006;23(8):1097-1104.
2.
Munkholm P, Langholz E, Davidsen M, Binder V. Intestinal cancer risk and mortality in patients
with Crohn's disease. Gastroenterology. Dec 1993;105(6):1716-1723.
3.
Friedman S, Rubin PH, Bodian C, Harpaz N, Present DH. Screening and surveillance
colonoscopy in chronic Crohn's colitis: results of a surveillance program spanning 25 years. Clin
Gastroenterol Hepatol. Sep 2008;6(9):993-998; quiz 953-994.
4.
Lutgens MW, Vleggaar FP, Schipper ME, et al. High frequency of early colorectal cancer in
inflammatory bowel disease. Gut. Sep 2008;57(9):1246-1251.
5.
Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF. Crohn's disease and cancer. N
Engl J Med. Nov 22 1973;289(21):1099-1103.
6.
Gyde SN, Prior P, Macartney JC, Thompson H, Waterhouse JA, Allan RN. Malignancy in Crohn's
disease. Gut. Dec 1980;21(12):1024-1029.
7.
Greenstein AJ, Sachar DB, Smith H, Janowitz HD, Aufses AH, Jr. A comparison of cancer risk in
Crohn's disease and ulcerative colitis. Cancer. Dec 15 1981;48(12):2742-2745.
8.
Kvist N, Jacobsen O, Norgaard P, et al. Malignancy in Crohn's disease. Scand J Gastroenterol.
Jan 1986;21(1):82-86.
9.
Gollop JH, Phillips SF, Melton LJ, 3rd, Zinsmeister AR. Epidemiologic aspects of Crohn's
disease: a population based study in Olmsted County, Minnesota, 1943-1982. Gut. Jan
1988;29(1):49-56.
10.
Fireman Z, Grossman A, Lilos P, et al. Intestinal cancer in patients with Crohn's disease. A
population study in central Israel. Scand J Gastroenterol. Apr 1989;24(3):346-350.
11.
Ekbom A, Helmick C, Zack M, Adami HO. Increased risk of large-bowel cancer in Crohn's
disease with colonic involvement. Lancet. Aug 11 1990;336(8711):357-359.
12.
Gillen CD, Andrews HA, Prior P, Allan RN. Crohn's disease and colorectal cancer. Gut. May
1994;35(5):651-655.
13.
Persson PG, Karlen P, Bernell O, et al. Crohn's disease and cancer: a population-based cohort
study. Gastroenterology. Dec 1994;107(6):1675-1679.
14.
Mellemkjaer L, Johansen C, Gridley G, Linet MS, Kjaer SK, Olsen JH. Crohn's disease and
cancer risk (Denmark). Cancer Causes Control. Feb 2000;11(2):145-150.
15.
Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel
disease: a population-based study. Cancer. Feb 15 2001;91(4):854-862.
16.
Jess T, Winther KV, Munkholm P, Langholz E, Binder V. Intestinal and extra-intestinal cancer in
Crohn's disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
Aliment Pharmacol Ther. Feb 1 2004;19(3):287-293.
103
Q.I.#27: Biopsy Adjacent Mucosa of Polypoid Lesions
Q.I. #27 IF a patient with colitis is undergoing surveillence
colonoscopy, and a polypoid lesion is encountered
THEN the lesion and adjacent area should be biopsied
and placed in separate jars.
BECAUSE if adjacent mucosa contains flat dysplasia or
margins are not clear the patient may require colectomy
due to an increased risk for carcinoma.
Summary: Retrospective studies have shown that there is an
increased risk of synchronous or metachronous HGD or CRC
in patients with flat dysplasia. Thus, with increased
retrospective data supporting the safety of endoscopic
treatment and surveillance of polypoid lesions, biopsy of the
surrounding mucosa is important in order to establish the
patient’s risk for other areas of dysplasia or cancer which will
have an impact on management.
Details
Patients with colitis are at a risk for occult and polypoid dysplastic lesions occurring in the
setting of inflammation, and continue to remain at risk for sporadic adenomas who development
is unrelated to the underlying colitis. The sporadic adenoma rate is 30% in asymptomatic
adults.1,2 Confusion exists concerning the nomenclature of raised, dysplastic lesions in colitis.
Dysplastic raised lesions outside of colitis should be considered adenomas; unresectable
dysplastic lesions within colitis should be considered DALMs (dysplasia associated lesions or
masses); and resectable lesions within colitis should be considered adenoma-like lesions, as
currently there are no molecular or other features that can adequately distinguish colitis-related
adenomas from sporadic adenomas.
Unressectable dysplastic lesions (DALMs) are treated with colectomy due to their high risk of
metachronous or synchronous cancers (which is not the focus of this quality measure).3
However, management distinctions exist for lesions which occur within and outside colitic and
non-colitic mucosa.3,4
The prevalence of polypoid lesions in UC patients has been reported as 28 and 42%.5,6
The fate of patients who underwent endoscopic resection of polypoid lesions was examined in
two retrospective studies. Rubin and colleagues followed 48 patients (mean follow up 4.1 years)
with chronic colitis without flat dysplasia who underwent endoscopic resection of polyps and
biopsy of adjacent mucosa. Sixty polyps in colitis and 10 polyps in non-colitic areas were
ressected. Polyps in colitic mucosa were 95% LGD, 3% high grade dysplasia, and 2%
carcinoma. For those patients who underwent non-operative treatment and surveillance, 48%
had additional polyps but none had carcinoma.7
Englselgjard and colleagues examined the impact of polypectomy in UC for patients with what
their group called “adenoma-like DALMs” in UC. Twenty-four patients with polypoid lesions
within areas of colitis underwent polypectomy and biopsy of surrounding areas. 58% developed
adenomas over a 3.5 year (mean) follow up. Only one patient who underwent colectomy and
had LGD. They also examined 10 patients with resection of polypoid lesions outside areas of
colitis. Half had recurrent polyps outside the areas of colitis with no flat dysplasia or cancer.8
Odze conducted a more extensive study from the same institution with double the follow-up time
in these patients. There was no significant difference in the prevalence of polyps between the
adenoma-like DALM group and the sporadic adenoma groups highlight the safety of endoscopic
surveillance.9 No cancers developed in either group and recurrent polyp rates were similar in
both groups suggesting that surveillance and endoscopic management are appropriate.
In the above studies, the polypoid lesions occurred in areas of colitis without flat dysplasia. It is
important to rule of flat dysplasia in the surrounding mucosa because patients with flat dysplasia
may harbor synchronous or metachronous colon cancer or high grade dysplasia (11%, N=11)
based on a study conducted at Mount Sinai.10 Other (but not all) studies have demonstrated
rates of synchronous CRC when flat LGD patients underwent surgery10, 11,12. Therefore, if a
lesion occurs within an area of colitis, adjacent biopsies are needed in order to ensure that clear
margins exist after polypectomy and confirm the presence or absence of flat
dysplasia which would impact management (USPSFT GRADE A per AGA technical review).3, 1
105
References:
1
Rex, D, Lehman GA, Ulbright TM et al. Colonic neoplasia in asymptomatic persons with negative fecal
occult blood tests: influence of age, gender, and family history. Am J Gastro 1993; 88:825-31.
2 Lieberman DA, Smith FW. Screening for colon malignancy with colonoscopy. Am J Gastro 1991;86:946951.
3 AGA Technical Review on the Diagnosis and Management of Colorectal Neoplasia in IBD.
Gastroenterology 2010;138;746-774.
4 Friedman S, Odze R, Farraye F. Management of neoplastic polyps in inflammatory bowel disease.
Inflamm Bowel Dis 2003; 9:260-266.
5 Butt JH, Konishi F, Morson BC et al. Macroscopic lesions in dysplasia and carcinoma complicating
ulcerative colitis. Dig Dis Sci 1983;28:18-26.
6 Connell WR, Sheffield JP, Kamm MA, Ritchie JK, Hawley PR, Lennard-Jones JE. Lower gastrointestinal
malignancy in Crohn’s disease. Gut 1994;35(3):347-352.
7 Rubin P, Friedman S, Harpaz N et al. Colonoscopic polypectomy in chronic colitis: conservative
management after endoscopic resection of dysplastic polyps. Gastroenterology 1999; 117:1295-1300.
8 Engelsgjerd M, Farraye F, Odze R. Polypectomy maybe adequate treatment of adenoma-like dysplastic
lesions in chronic ulcerative colitis. Gastroenterology 1999;117;1288-94.
9 Odze R, Farraye F, Hecht J, Hornick J. Long-term follow-up after polypectomy treatment for adenomalike dysplastic lesions in ulcerative colitis. Clinical Gastroenterology and Hepatology 2004;2:534-541.
10Ullman T, Croog V, Harpaz N, et al. Progression of flat low-grade dysplasia to advanced neoplasia in
patients with ulcerative colitis. Gastroenterology 2003;125:1311-9
11Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance
colonoscopy in ulcerative colitis? [see comments]. Lancet 1994;343:71-4.
12Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year analysis of a colonoscopic surveillance
program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030-8.
13 Itzkowtiz S, Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel
disease. Gastroenterology 2004;126:1634-1648.
Q.I. #28: Surveillence colonoscopy in P.S.C.
Q.I. #28
IF a patient with UC has co-existing PSC (of any duration)
THEN surveillance colonoscopy should be performed every 1-3
years
BECAUSE PSC confers a greater risk of dysplasia and cancer
compared to IBD patients without UC.
Summary: Retrospective cohort and case-control studies show an increased risk of
dysplasia and colorectal cancer in patients with concomitant PSC and UC leading to an
earlier need for dysplasia screening and surveillance in this population..
Details
The literature on this topic shows that there is an increased risk of colonic dysplasia or
colorectal cancer in patients with UC/PSC compared to those with UC alone.
There were no prospective studies examining this issue, and current evidence is
derived from retrospective case-control studies. There were no studies to examine the
appropriate time selection for screening or the subsequent interval for surveillance.
Colorectal cancer (CRC) prevalence is 13-28% in patients with UC and PSC.11 This is
higher than the rate in UC matched controls without PSC.1 A meta-analysis published
by Soetinko et al. showed a dysplasia prevalence of 19.0% and a CRC prevalence of
12% in patients with PSC-UC.2
Over time, there is an increased cumulative probability of dysplasia. One study showed
a 10-year probability of 16%, a 20-year probability of 33%, and a 30-year probability of
107
40%.3 Among patients who have undergone orthotopic liver transplantation, the risk for
dysplasia and CRC remains high. Loftus et al. showed a 1% per person/year risk of
CRC after orthotopic liver transplant.4
Shetty et al., using a case-control study of PSC-UC versus UC alone, showed a relative
risk of 3.15 (95% CI 1.37-7.27) for developing dysplasia or cancer after adjusting for
age, sex, extent of disease and disease onset.1 A meta-analysis of 11 studies
demonstrated a similarly high OR of 4.79 (95% CI 2.89-5.76) for developing CRC in
PSC-UC patients versus UC patients.4 One study contradicted these findings. In a study
of patients with PSC-IBD (86% UC), the adjusted HR was not statistically significant
(HR 1.9, 95% CI 0.6-4.9), however the unmatched analysis suggested that PSC was an
independent risk factor for CRC.5 Although these results did not reach statistical
significance, they suggest a trend in PSC-UC patients to greater dysplasia and CRC.
In a pediatric retrospective study of 52 PSC-IBD patients, 10% had dysplasia on
colonoscopy. Of note, this study highlights that many pediatric patients with PSC-IBD
can be asymptomatic with regards to IBD, a potential rationale for initiation surveillance
at the time of diagnosis.6
Guidelines and consensus statements vary in their language. The US Agency for
Healthcare Policy and Research Panel makes no specific recommendations for patients
with PSC.7 The British Society of Gastroenterology and Canadian Association of
Gastroenterology recommend annual colonoscopy for patients with PSC.81 Both the
CCFA Consensus statement and AGA guidelines call for initiating surveillance at the
time of PSC diagnosis when IBD is present. (Itzkowitz/Present, IBD; Farraye et al,
Gastro 2010).
References:
Broome U, Lindberg G, Lofberg R. Primary sclerosing cholangitis in ulcerative colitis—a risk factor for the
development of dysplasia and DNA anuepolidy? Gastroenterology 1992;102:1877-80.
2 Soetinko R, Lin O, Heindenreich P et al. Increasing risk of colorectal neoplasia in patients with primary
sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointestin Endosc 2002;56:48-54.
3 Kornfeld, D, Eckboom A, Ihre T. Is there an excess risk for colorectal cancer in patients with ulcerative
colitis and concomitant primary scleroscing cholangitis? Gut 1997;41(4)522-25.
4 Loftus EV, Aguilar HI, Sandborn WJ et al. Risk of colorectal neoplasia in paitnets with primary sclerosing
cholangitis and ulcerative colitis following orthotopic liver transplantation. Heaptology 1998;27(3):685-90.
5 Loftus EV, Harewood, Loftus CG et al. PSC-IBD: a unique form of inflammatory bowel disease
associated with primary sclerosing cholangitis. Gut 2005;54:91-96.
6 Faubion WA, Loftus EV, Sandborn WJ et al. Pediatric “PSC-IBD”:A descriptive report of associated
inflammatory bowel disease among pediatric patients with PSC. Journal of Pediatr Gastroenterol and
Nutr 2001; 33(3):296-300.
7 Winawer S, Fletcher R, Rex D et al. Colorectal cancer screening surveillance: clinical guidelines and
rationale—update based on new evidence. Gastroenterology 2003;124:544-560.
8 Cairns, S, Scholfeild J, Steele R et al. Guidelines for colorectal cancer screening and surveillance in
moderate and high risk groups. Gut 2010;59:666-690.
9 Leddin D, Hunt R, Champion M. et al. Canadian Association of Gastroenterology and the Canadian
Digestive Health Foundation: Guidelines for colon cancer screening. Can J Gastroenterol 2004;18(2):9399.
109
Q.I. #29: Flat Low Grade Dysplasia
Q.I. #29:
If a patient with UC is found to have confirmed low-grade
dysplasia in flat mucosa
THEN proctocolectomy or repeat surveillance in 3-6 months
should be offered.
BECAUSE there is sufficient evidence to suggest that the
finding of flat low-grade dysplasia is associated with a
heightened risk of both synchronous high-grade dysplasia or
colon cancer and/or progression to more advanced
neoplasia (high-grade dysplasia or colon cancer) with
continued follow-up.
SUMMARY: With respect to the risk of synchronous advanced neoplasia, a number of singlecenter studies detailing the results of long-term dysplasia surveillance programs for patients with
ulcerative colitis have demonstrated that the finding of low grade dysplasia (in most instance
unifocal flat low-grade dysplasia) was associated with the finding of synchronous high-grade
dysplasia or colon cancer in 19-27% of resected colectomy specimens when colectomy was
performed either immediately or within six months of the initial diagnosis of low grade
dysplasia.1-3 This rate was 50% in one study that retrospectively examined the final pathology
of all patients who underwent proctocolectomy for all indications in a single center, although this
was a surgical series that included patients referred for surgery for dysplasia or colorectal
cancer.4 A meta-analysis of 20 surveillance studies that included a total of 477 patients with flat
low grade dysplasia found a 22% positive predictive value of synchronous colon cancer and a
36% positive predictive value of either high-grade dysplaisa or colon cancer in resected
colectomy specimens.5 With respect to the risk of progression over time to advanced neoplasia
when immediate colectomy is not undertaken, there is considerable heterogeneity in the
literature. Rates of progression to advanced neoplasia at approximately 5 years of follow up
range from 0-54%.2, 3, 6-10 Other studies with longer-term follow up have found lower rates of
progression to advanced neoplasia. A meta-analysis of 8 studies demonstrated that the finding
of flat low-grade dysplasia was associated with a 14.6% positive predictive value for subsequent
progression to advanced neoplasia, but that advanced neoplasia was more likely to take the
form of high grade dysplasia than colon cancer.5
DETAILS:
The primary objective of a dysplasia surveillance program is to reduce the risk of death from
colon cancer in the setting of chronic ulcerative colitis. With respect to the issue of finding flat
low-grade dysplasia, two key questions arise. Firstly, what is the risk that the finding of flat lowgrade dysplasia represents a “field effect” that confers a risk of synchronous advanced
neoplasia (high-grade dysplasia or colon cancer; findings that would normally result in an
unequivocal recommendation for immediate proctocolectomy)? Secondly, what is the risk that
flat low-grade dysplasia can progress over time to advanced neoplasia if proctocolectomy is not
immediately undertaken? Importantly, all the data we have at our disposal to assess these
questions are derived from studies that did not used advanced techniques to diagnose
dysplasia such as chromoendoscopy with or without high magnification or confocal
endomicroscopy. This is important, as these techniques have been found to have a higher yield
in detecting dysplasia.11, 12
RISK OF SYNCHRONOUS ADVANCED NEOPLASIA:
Four separate studies and a meta-analysis of surveillance studies provides insight into the risk
of advanced neoplasia at the time of finding flat low-grade dysplasia. A study from Mount Sinai
retrospectively reviewed the records of 46 patients with ulcerative colitis in a surveillance
program who were found to have flat low-grade dysplasia. In this study, 11 patients underwent
proctocolectomy within 6 months of the diagnosis of dysplasia. Of these 11 patients, 3 (27%)
were found to have advanced neoplasia (2 colon cancer and 1 high-grade dysplasia).2 A
previous systematic review of 10 prospective studies found that 3 of 16 (19%) patients found to
have low-grade dysplasia who underwent immediate proctocolectomy were found to have colon
cancer. In this study, the morphology of low-grade dysplasia was not described so whether
these lesions were all flat is not known.1 Similarly, a study from St. Mark’s in the United
Kingdom prospectively evaluated 600 patients with ulcerative colitis who underwent 2627
colonoscopies encompassing a total of 5932 patient-years of follow up. In this study, 46
patients were found to have low-grade dysplasia of whom 10 were referred for immediate
proctocolectomy. Two of these ten (20%) were found to have colon cancer in their resected
specimens.3 A retrospective study from New York reviewed the final pathology specimens of
590 patients who underwent proctocolectomy in the setting of ulcerative colitis, including
111
patients with known colorectal cancer and ulcerative colitis. A total of 18 patients had a finding
of low-grade dysplasia (morphology not specified) of whom an alarmingly high rate (9/18) had
colon cancer found within the colon.4 However, the indications for proctocolectomy were not
well defined in this study. Finally, a meta-analysis of 20 surveillance studies described a total of
477 patients with flat low-grade dysplasia.5 This analysis found that finding flow low-grade
dysplasia was associated with a positive predictive value of 22% for synchronous colon cancer
and 36% for advanced neoplasia as a whole (both high-grade dysplasia and colon cancer
combined).
RISK OF PROGRESSION TO ADVANCED NEOPLASIA WITH FOLLOW-UP
SURVEILLANCE:
There is considerable heterogeneity in the literature addressing the risk of progression to
advanced neoplasia when patients or their physicians elect to pursue ongoing surveillance
rather than immediate proctocolectomy. A retrospective study from the Mayo Clinic reviewed
the records of 18 ulcerative colitis patients with flat low-grade dysplasia who underwent
continued surveillance.7 A total of 9 of the 18 eventually progressed to advanced neoplasia with
the 5-year rate being calculated at 33%. However, only one patient developed adenocarcinoma
after 74 months of follow-up, and 20 months after their last surveillance examination. In a
similar retrospective study from New York, the 5-year rate of progression to advanced neoplasia
among patients with flat low-grade dysplasia was 53% and it is important to note that cancers
detected in this study tended to be at an earlier stage.2 The most robust data is from a 30-year
prospective surveillance program.3 In this study, 36 patients with low–grade dysplasia were
followed for a median of 4 years and 12 patients were later found to develop advanced
neoplasia (9 with HGD and 3 with CRC). The 5-year rate of progression to advanced neoplasia
in another study presented in abstract form was 22%.8 However, a separate long-term
prospective study from the United Kingdom found a significantly lower rate of progression.10 Of
29 patients who were found to have low-grade dysplasia and still had an intact colon after 10
years of follow up only 3 of 29 progressed to advanced neoplasia. An even lower rate of
progression to advanced neoplasia was noted in a Scandinavian prospective study that followed
60 patients with flat low-grade dysplasia for at least ten years.9 In only 2 cases was their
progression to high-grade dysplasia and in both instances, this was found in the setting of a
dysplasia associated lesion or mass (DALM). Studies that have evaluated even longer periods
of follow-up have, however, found higher rates of progression. A Swedish study found a 35%
rate of progression to advanced neoplasia after 20 years of follow-up while a Japanese study
found a 22% rate of progression after more than 20 years (though in the latter study, 4 of the 9
patients followed for low-grade dysplasia were lost to follow-up so this could be an
underestimate).13, 14 As noted above, the meta-analysis of 8 studies estimated a 14.6% positive
predictive value for progression to advanced neoplasia with more high-grade dysplasia being
found than colon cancer.5
In a novel approach to determing whether immediate proctocolectomy versus continued
surveillance at 3, 6, 12 months and then annually, a medical decision analysis found
proctocolectomy to be dominant over continue surveillance from the standpoint of both costeffectiveness and quality adjusted life-years when unifocal flat low-grade dysplasia was found.15
Table 1: Summary of Risk of Synchronous Advanced Neoplasia in the Setting of LGD
Study
Number of Patients with LGD
Rate of Advanced Neoplasia
Undergoing Proctocolectomy
2
Ullman
11
3/11 (27%) (2 CRC, 1 HGD)
Bernstein1
16
3/16 (19%)#
Rutter3
10
2/10 (30%)#
Gorfine4
18
9/18 (50%)&
Thomas5
98
36/98 (37%)% (25 CRC, 11 HGD)
#
Only evaluated rate of CRC. Rate of progression to HGD unknown.
&
Retrospective review of colectomy specimens, operated for all indications
%
Meta-analysis
LGD=low-grade dysplasa, HGD=high-grade dysplasia, CRC=colorectal cancer
Table 2: Summary of Risk of Progression to Advanced Neoplasia on Follow-Up
Study
Number of Patients with
Follow-Up
Rate of Advanced Neoplasia
LGD Undergoing
Surveillance
Ullman7
18
Median 32 mo
9/18 (50%)# (1 CRC,8 HGD)
Ullman2
35
Variable
10/35 (29%) (5 CRC, 5 HGD)
113
Rutter3
36
Median 4 yrs
12/36 (33%) (3 CRC, 9 HGD)
Brentnall8
40
Mean 5 yrs
9/40 (22%)
Lim11
10
10 yrs
3/29 (10%)
Befrits12
60
>10 yrs
2/60 (3%) (2 HGD in DALM)
Lindberg13
37
20 yrs
13/37 (35%) (5 CRC, 8 HGD)
Hata14
9
23 yrs
2/9 (22%)$ (1 CRC, 1 HGD)
Variable
14.6%% PPV for AN
Thomas5
#
5-year rate of progression was 33%
%Meta-analysis
$4
of 9 patients lost to follow-up, therefore may be underestimate
LGD=low-grade dysplasia, HGD=high-grade dysplasia, CRC=colorectal cancer, AN=advanced neoplasia,
PPV=positive predictive value
References
1.
Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance
colonoscopy in ulcerative colitis? Lancet 1994:71-74
2.
Ullman T, Croog V, Harpaz N, Sachar D, Itzkowitz S. Progression of flat low-grade dysplasia to
advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003;125:1311-9.
3.
Rutter MD, Saunders BP, Wilkinson KH, Rumbles S, Schofield G, Kamm MA, Williams CB, Price
AB, Talbot IC, Forbes A. Thirty-year analysis of a colonoscopic surveillance program for
neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030-8.
4.
Gorfine SR, Bauer JJ, Harris MT, Kreel I. Dysplasia complicating chronic ulcerative colitis: is
immediate colectomy warranted? Dis Colon Rectum 2000;43:1575-81.
5.
Thomas T, Abrams KA, Robinson RJ, Mayberry JF. Meta-analysis: cancer risk of low-grade
dysplasia in chronic ulcerative colitis. Aliment Pharmacol Ther 2007;25:657-68.
6.
Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors
affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology
1994;107:934-44.
7.
Ullman TA, Loftus EV, Jr., Kakar S, Burgart LJ, Sandborn WJ, Tremaine WJ. The fate of low
grade dysplasia in ulcerative colitis. Am J Gastroenterol 2002;97:922-7.
8.
Brentnall T, Emond M, Kimmey M, al. e. A prospective study of low-grade dysplasia in ulcerative
colitis using an extensive biopsy surveillance protocol. Gastroenterology 2005:A566.
9.
Befrits R, Ljung T, Jaramillo E, Rubio C. Low-grade dysplasia in extensive, long-standing
inflammatory bowel disease: a follow-up study. Dis Colon Rectum 2002;45:615-20.
10.
Lim CH, Dixon MF, Vail A, Forman D, Lynch DA, Axon AT. Ten year follow up of ulcerative colitis
patients with and without low grade dysplasia. Gut 2003;52:1127-32.
11.
Kiesslich R, Fritsch J, Holtmann M, Koehler HH, Stolte M, Kanzler S, Nafe B, Jung M, Galle PR,
Neurath MF. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia
and colon cancer in ulcerative colitis. Gastroenterology 2003;124:880-8.
12.
Kiesslich R, Goetz M, Lammersdorf K, Schneider C, Burg J, Stolte M, Vieth M, Nafe B, Galle PR,
Neurath MF. Chromoscopy-guided endomicroscopy increases the diagnostic yield of
intraepithelial neoplasia in ulcerative colitis. Gastroenterology 2007;132:874-82.
13.
Lindberg B, Persson B, Veress B, Ingelman-Sundberg H, Granqvist S. Twenty years'
colonoscopic surveillance of patients with ulcerative colitis. Detection of dysplastic and malignant
transformation. Scand J Gastroenterol 1996;31:1195-204.
14.
Hata K, Watanabe T, Kazama S, Suzuki K, Shinozaki M, Yokoyama T, Matsuda K, Muto T,
Nagawa H. Earlier surveillance colonoscopy programme improves survival in patients with
ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the
Japanese population. Br J Cancer 2003;89:1232-6.
15.
Nguyen GC, Frick KD, Dassopoulos T. Medical decision analysis for the management of unifocal,
flat, low-grade dysplasia in ulcerative colitis. Gastrointest Endosc 2009;69:1299-310.
115
IBD Surgical Issues
Q.I. #30: Surgical drainage
Q.I. #30 IF a patient with CD has suppurative perianal/fistulizing disease
THEN he or she should be treated with surgical draining with or without
a non-cutting seton
BECAUSE surgical draining with or without non-cutting seton can
control local sepsis and can preserve anal sphincter function and
prevent fecal incontience.
Summary: Surgical draining with or without placement of a non-cutting seton for
suppurative perianal/fistulizing CD has been studied in multiple retrospective cohort
studies and review articles. All of these studies recommend surgical draining to treat
local sepsis. In addition, placement of a non-cutting seton has been shown to preserve
anal sphincter function and prevent fecal incontinence. However, surgical drainage with
or without seton placement does not prevent recurrence of disease.
Details
15 studies evaluated the use of surgical draining with or without a non-cutting seton for the
treatment of suppurative perianal/fistulizing disase in Crohn’s patients. (1-15) All of these
studies recommended surgical drainage if suppurative perianal/fistulizing disease was present
because it may control local sepsis. In addition, if complex fistulizing disease was present and a
non-cutting seton was placed, patients had improved anal sphincter preservation and decreased
fecal incontinence. Seton placement was recommended for complex fistulizing disease;
however, seton placement was associated with a high reoccurrence rate of fistulae.
Four review articles were identified in the search. (3, 4, 7, 12) These articles reviewed the
treatment pathways for perianal/fistulizing Crohn’s disease. All of these articles recommend
surgical drainage as an essential step if suppurative disease is present as it may prevent local
sepsis. Seton placement was also recommended to improve drainage and to prevent the need
for more invasive surgical interventions that have worse outcomes.
Eleven retrospective studies were identified (1, 2, 5, 6, 8-11, 13-15) all of which recommended
the placement of a non-cutting seton if complex fistulizing disease was present. Seton
placement was found to be a safe and effective method for providing drainage and for
preserving sphincter function and preventing incontinence. Seton placement prevented further
need for surgical intervention; however, it did not prevent reoccurrence of perianal or fistulizing
disease.
References
1: Galis-Rozen E, Tulchinsky H, Rosen A, Eldar S, Rabau M, Stepanski A, Klausner JM, Ziv Y. Long-term
outcome of loose seton for complex anal fistula: a two-centre study of patients with and without Crohn's
disease. Colorectal Dis. 2010 Apr;12(4):358-62. Epub 2009 Feb 7.
2: Thornton M, Solomon MJ. Long-term indwelling seton for complex anal fistulas in Crohn's disease. Dis
Colon Rectum. 2005 Mar;48(3):459-63. PubMed PMID: 15719188.
3: Rutgeerts P. Review article: treatment of perianal fistulizing Crohn's disease. Aliment Pharmacol Ther.
2004 Oct;20 Suppl 4:106-10. Review. PubMed PMID:15352905.
4: Judge TA, Lichtenstein GR. Treatment of fistulizing Crohn's disease. Gastroenterol Clin North Am.
2004 Jun;33(2):421-54, xi-xii. Review. PubMed PMID: 15177547.
5: Topstad DR, Panaccione R, Heine JA, Johnson DR, MacLean AR, Buie WD. Combined seton
placement, infliximab infusion, and maintenance immunosuppressives improve healing rate in fistulizing
anorectal Crohn's disease: a single center experience. Dis Colon Rectum. 2003 May;46(5):577-83.
PubMed PMID: 12792431.
6: Takesue Y, Ohge H, Yokoyama T, Murakami Y, Imamura Y, Sueda T. Long-term results of seton
drainage on complex anal fistulae in patients with Crohn's disease. J Gastroenterol. 2002;37(11):912-5.
7: Rutgeerts P. Management of perianal Crohn's disease. Can J Gastroenterol. 2000 Sep;14 Suppl C:7C12C. Review.
8: Makowiec F, Jehle EC, Becker HD, Starlinger M. Perianal abscess in Crohn's disease. Dis Colon
Rectum. 1997 Apr;40(4):443-50.
9: Sangwan YP, Schoetz DJ Jr, Murray JJ, Roberts PL, Coller JA. Perianal Crohn's disease. Results of
local surgical treatment. Dis Colon Rectum. 1996 May;39(5):529-35.
10: Faucheron JL, Saint-Marc O, Guibert L, Parc R. Long-term seton drainage for high anal fistulas in
Crohn's disease--a sphincter-saving operation? Dis Colon Rectum. 1996 Feb;39(2):208-11.
11: Sugita A, Koganei K, Harada H, Yamazaki Y, Fukushima T, Shimada H. Surgery for Crohn's anal
fistulas. J Gastroenterol. 1995 Nov;30 Suppl 8:143-6.
12: Williamson PR, Hellinger MD, Larach SW, Ferrara A. Twenty-year review of the surgical
management of perianal Crohn's disease. Dis Colon Rectum. 1995 Apr;38(4):389-92. Review.
13: Koganei K, Sugita A, Harada H, Fukushima T, Shimada H. Seton treatment for perianal Crohn's
fistulas. Surg Today. 1995;25(1):32-6. PubMed PMID: 7749287.
14: Williams JG, MacLeod CA, Rothenberger DA, Goldberg SM. Seton treatment of high anal fistulae. Br
J Surg. 1991 Oct;78(10):1159-61. PubMed PMID: 1958973.
117
15: White RA, Eisenstat TE, Rubin RJ, Salvati EP. Seton management of complex anorectal fistulas in
patients with Crohn's disease. Dis Colon Rectum. 1990 Jul;33(7):587-9.
Q.I. #31: Discuss options for UC surgery
Q.I. #31
IF a patient with UC is referred for surgery
THEN the patient should be informed about the different
operations available (TPC with ileostomy vs IPAA) and
risks/benefits of each.
BECAUSE short and long term complications as well as quality
of life may differ among each procedure
Summary
No studies have directly compared the outcome of TPC with ileostomy vs
IPAA. However, there are differences both in the procedures themselves and
the type of potential complications associated with each.
Details
Surgery in patients who suffer with UC can be emergent or elective. Emergency indications for
operation include fulminant disease refractory to medical therapy, extensive rectal bleeding, and
toxic megacolon(1). In the case of emergency surgery, subtotal colectomy with preservation of
the rectum for a future restorative procedure is recommended. However, the small risk of further
hemorrhage needs to be appreciated and appropriately monitored.
Elective surgery is performed on patients with chronic disease who experience continued
symptoms despite medical therapy, an unacceptable quality of life, severe limitation of activities,
documented or strongly suggested carcinoma or dysplasia, and growth retardation in children.
In the case of elective surgery, patients should be informed of the different options available.
These include a total proctocolectomy (TPC) with permanent ileostomy, or the ileal pouch anal
anastomosis (IPAA) procedure, sometimes referred to as restorative proctocolectomy. The
patient should be made aware of the risks and benefits of each surgery. Recently, laparoscopic
or laparoscope-assisted surgery has become more common as compared to open surgery and
this option should be discussed with the patient as well(2).
119
Although less frequently performed than previously, TPC with ileostomy remains the benchmark
procedure for the treatment of UC. The advantages of TPC with ileostomy are as follows; 1) the
diseased colon is completely removed, 2) UC medications can be stopped after surgery, 3)
patients are able to return to near normal health, 4) the risk of colorectal cancer is almost
completely obviated, and 5) the procedure could be performed in one stage. Any UC patient
undergoing surgery is a candidate for this procedure irrespective of age, sex, and body habitus.
The disadvantages of TPC with ileostomy include: 1) the need for a permanent ileostomy/stoma
appliance; 2) a lack of control over stool evacuation; 3) complications associated with pelvic
dissection; and 4) the potential for a perineal wound. Furthermore, a substantial proportion of
patients with an ileostomy will experience complications such as skin irritation, stoma retraction,
or parastomal herniation among others. In spite of the need to wear an appliance, patients with
ileostomy are generally very satisfied with their quality of life after surgery(3). However, they
report more restrictions on daily activities compared to patients with either an IPAA or a Koch
pouch.
TPC with IPAA has become the most commonly performed operation for UC, and is performed
in one, two, or three stages, depending on the patient’s clinical status at the time of the first
surgery and the judgment and experience of the surgeon. The advantages of TPC with IPAA
are similar to that of TPC with ileostomy: 1) all of the diseased colon is removed; 2) patients
may stop UC medications after surgery; 3) patients return to health and normal activity; 4) the
cancer risk is almost completely obviated. In addition, it has the advantages of: 5) stool is
passed through the anus, and 6) anorectal continence is preserved. The disadvantages are
that: 1) in the majority of cases, it requires two or three stages; 2) complications associated with
pelvic dissection; 3) a mean stool frequency of 6 movements per day following surgery; 4)
incontinence rates varying from 5 to 20%; 5) need to take antidiarrheal medications for many
patients; 6)acute and sometimes chronic pouchitis occurring in up to 50% of patients; and 7) in
the event of a change of diagnosis to Crohn’s disease, the patient may need to undergo take
down the IPAA leading to an ileostomy(4, 5). Patients with an IPAA report a higher levels of
satisfaction compared to patients with either a Brooke or permanent ileostomy.
With the increase in TPC with IPAA performed, there is increasing recognition of the potential
complications following this procedure. Besides pouchitis, which may occur in up to 50% of
patients during long-term follow-up, a variety of surgical complications may occur including
anastomotic leak, pelvic sepsis/abscess, anastomotic stricture, re-operation, and bowel
obstruction. In addition to the risks described above, patients should be counseled regarding the
effects of the IPAA on fertility and sexual function. A meta-analysis of eight series found a
threefold increase in infertility in women after IPAA, compared with women with UC treated
medically(6). Fecundity among women with UC after surgery decreases to 20 % of fecundity
rates of controls control population(6-8). Dyspareunia or fecal incontinence can also occur in
women after surgery as well. The risk of sexual dysfunction in men after surgery was 4%
according to a meta-analysis of 43 observational studies(9). However, most men note
improvement in overall sexual quality of life after IPAA (9, 10).
References
1. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of
Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2004 Jul;99(7):1371-85.
2. Larson DW, Cima RR, Dozois EJ, Davies M, Piotrowicz K, Barnes SA, et al. Safety, feasibility, and
short-term outcomes of laparoscopic ileal-pouch-anal anastomosis: a single institutional case-matched
experience. Ann Surg. 2006 May;243(5):667-70; discussion 70-2.
3. Tariverdian M, Leowardi C, Hinz U, Welsch T, Schmidt J, Kienle P. Quality of life after restorative
proctocolectomy for ulcerative colitis: preoperative status and long-term results. Inflamm Bowel Dis. 2007
Oct;13(10):1228-35.
4. Tulchinsky H, Dotan I, Halpern Z, Klausner JM, Rabau M. A longitudinal study of quality of life and
functional outcome of patients with ulcerative colitis after proctocolectomy with ileal pouch-anal
anastomosis. Dis Colon Rectum. Jun;53(6):866-73.
5. Ferrante M, Declerck S, De Hertogh G, Van Assche G, Geboes K, Rutgeerts P, et al. Outcome after
proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. Inflamm Bowel Dis. 2008
Jan;14(1):20-8.
6. Waljee A, Waljee J, Morris AM, Higgins PD. Threefold increased risk of infertility: a meta-analysis of
infertility after ileal pouch anal anastomosis in ulcerative colitis. Gut. 2006 Nov;55(11):1575-80.
7. Ogilvie JW, Jr., Goetz L, Baxter NN, Park J, Minami S, Madoff RD. Female sexual dysfunction after
ileal pouch-anal anastomosis. Br J Surg. 2008 Jul;95(7):887-92.
8. Olsen KO, Juul S, Bulow S, Jarvinen HJ, Bakka A, Bjork J, et al. Female fecundity before and after
operation for familial adenomatous polyposis. Br J Surg. 2003 Feb;90(2):227-31.
9. Hueting WE, Buskens E, van der Tweel I, Gooszen HG, van Laarhoven CJ. Results and
complications after ileal pouch anal anastomosis: a meta-analysis of 43 observational studies comprising
9,317 patients. Dig Surg. 2005;22(1-2):69-79.
10. Berndtsson I, Oresland T, Hulten L. Sexuality in patients with ulcerative colitis before and after
restorative proctocolectomy: a prospective study. Scand J Gastroenterol. 2004 Apr;39(4):374-9.
121
Q.I. #32: Surgery for colonic perforation
Q.I. #32:
IF a hospitalized patient with severe UC has a perforation
THEN surgery should include a subtotal colectomy
rectosigmoid mucous fistula or Hartmann’s closure,
with
BECAUSE subtotal colectomy with rectosigmoid mucous fistula or
Hartmann’s closure reduces risk of mortality and complications
compared to primary total proctocolectomy.
Summary
Perforation is a lethal complication of UC that is accompanied with a high risk of
mortality. Emergency surgery by means that decreases this risk and the complications
related to surgery is indispensable.
Detail
When the clinical situation allows, the surgical procedure of choice in more elective UC
cases is a total proctocolectomy and ileostomy. However, in urgent situations like
perforation, most surgeons favor a subtotal colectomy, mucous fistula or a Hartman
stump, and ileostomy, as this approach is associated with a lower morbidity and
mortality than is total proctocolectomy(1, 2). It removes the diseased part of the
intestine, preserves future surgical options, and avoids a potentially difficult and
hazardous pelvic dissection. Creation of an ileostomy without a primary anastomosis is
crucial because of an unacceptably high anastomotic leak rate. Perforation is the most
lethal complication of acute colitis and occurs very frequently in the setting of toxic
megacolon. Furthermore, perforation was the most important factor that affected the
mortality rate in fulminant UC patients with toxic megacolon(3).
References
1. Gan SI, Beck PL. A new look at toxic megacolon: an update and review of incidence, etiology,
pathogenesis, and management. Am J Gastroenterol. 2003 Nov;98(11):2363-71.
2. Berg DF, Bahadursingh AM, Kaminski DL, Longo WE. Acute surgical emergencies in inflammatory
bowel disease. Am J Surg. 2002 Jul;184(1):45-51.
3. Greenstein AJ, Sachar DB, Gibas A, Schrag D, Heimann T, Janowitz HD, et al. Outcome of toxic
dilatation in ulcerative and Crohn's colitis. J Clin Gastroenterol. 1985 Apr;7(2):137-43.
Miscellaneous
Q.I. #33: Inquire about CAM
Q.I. #33
IF a patient has IBD
THEN the physician should inquire about the use of
complementary and alternative medicines
BECAUSE of the widespread use by patients with IBD.
Summary
Several studies have shown that patients with IBD commonly use complementary and
alternative medicine (CAM). Healthcare providers of patients with IBD should
understand the reasons why patients use CAM, counsel patient on risk and benefit of
CAM as well as potential interactions.
Detail
CAM refers to a group of medical and health care systems, practices and products that
are not part of conventional medicine.1 CAM is grouped into 5 categories as defined by
the National Center for Complementary and Alternative Medicine: whole medical
systems, mind-body medicine, biologically based practices, manipulative and body
based practices, and energy medicine.1 (see table 1)
Table 1
Type of CAM
Examples
Whole Medical Systems
Homeopathic Medicine
Naturopathic Medicine
Traditional Chinese Medicine
Aryuvedic Medicine
Meditation
Prayer
Art, music, dance
Mind-Body
123
Biologically Based Practices
Manipulative and Body-Based
Practices
Herbs
Dietary Supplements
Vitamins
Massage
Reflexology
Osteopathy
Chiropractic
Reiki
Bioelectromagnetic field therapy
Energy
CAM use in adult IBD patients is common, ranging from 11 to 60%.2-6 IBD patients
more commonly use the biologically based CAM of herbs, vitamins and dietary
supplements.4, 5
Factors associated with CAM use in IBD include more severe disease, higher steroid
requirement, desire to feel in control of disease, use of CAM for other purposes, fear of
surgery, lack of confidence in their physician, younger age, and higher education.6-8
Patients believe CAM differs from much conventional medicine by taking a holistic
approach to patient care, calling on self-healing by the body and being applied in an
individualized way. Several studies show that IBD patients using CAM are satisfied with
the results.2, 9 The most common reported benefit is improved sense of well being and
control over disease.5, 10
There are few studies that provide sufficient high quality evidence to support use of
CAM in IBD. (table 2)
Author
11Gerhardt
et
al
12Gupta
et al
13Hanai
et al
CAM and Study
design
N
Findings
Boswellia Root in CD
compared to
mesalamine
Boswellia Root in UC
compared to
sulfasalazine
Curcumin in UC in
102
Equal efficacy to
mesalamine for
remission of CD
Equal efficacy to
sulfasalazine for
remission of UC
Recurrence rates
30
99
combination with
mesalamine
14Joos
et al
Accupuncture in CD
compared to sham
51
15Joos
et al
Accupuncture in UC
compared to sham
29
Maintenance
treatment with VSL#3
compared to placebo
for chronic relapsing
pouchitis
40
16Gionchetti
al
et
showed significant
difference between
curcumin and placebo
(P=.049). curcumin
improved both Colitis
activity index (P=.038)
and Endoscopic index
(P=.0001),
reduction in the CDAI
score, improved sense
of well being, but no
difference in remission
rates
decrease in colitis
activity index,
improvement in quality of
life, but not statistically
significant
85% of VSL#3 group
compared to 0% in
placebo remained in
remission at end of study
period
It is important for providers to be familiar with CAM and its potential side effects and
interactions with other medications and alcohol. There are several resources including
textbooks and internet databases that evaluate the available evidence of CAM use in
IBD. This information is available to healthcare providers to aid in counseling and
guiding patients about CAM use in IBD.
References:
1. what is CAM? , 2007. (Accessed at www.nccam.nig.gov/health/whatiscam.)
2. Hilsden RJ, Scott CM, Verhoef MJ. Complementary medicine use by patients with
inflammatory bowel disease. The American journal of gastroenterology 1998;93(5):697701.
3. Rawsthorne P, Shanahan F, Cronin NC, et al. An international survey of the use and
attitudes regarding alternative medicine by patients with inflammatory bowel disease.
The American journal of gastroenterology 1999;94(5):1298-303.
4. Langmead L, Chitnis M, Rampton DS. Use of complementary therapies by patients
with IBD may indicate psychosocial distress. Inflammatory bowel diseases
2002;8(3):174-9.
125
5. Hilsden RJ, Verhoef MJ, Best A, Pocobelli G. Complementary and alternative
medicine use by Canadian patients with inflammatory bowel disease: results from a
national survey. The American journal of gastroenterology 2003;98(7):1563-8.
6. Langhorst J, Anthonisen IB, Steder-Neukamm U, et al. Patterns of complementary
and alternative medicine (CAM) use in patients with inflammatory bowel disease:
perceived stress is a potential indicator for CAM use. Complementary therapies in
medicine 2007;15(1):30-7.
7. Bensoussan M, Jovenin N, Garcia B, et al. Complementary and alternative medicine
use by patients with inflammatory bowel disease: results from a postal survey.
Gastroenterologie clinique et biologique 2006;30(1):14-23.
8. Li FX, Verhoef MJ, Best A, Otley A, Hilsden RJ. Why patients with inflammatory
bowel disease use or do not use complementary and alternative medicine: a Canadian
national survey. Canadian journal of gastroenterology = Journal canadien de
gastroenterologie 2005;19(9):567-73.
9. Burgmann T, Rawsthorne P, Bernstein CN. Predictors of alternative and
complementary medicine use in inflammatory bowel disease: do measures of
conventional health care utilization relate to use? The American journal of
gastroenterology 2004;99(5):889-93.
10. Hilsden RJ, Verhoef MJ, Rasmussen H, Porcino A, Debruyn JC. Use of
complementary and alternative medicine by patients with inflammatory bowel disease.
Inflammatory bowel diseases.
11. Gerhardt H, Seifert F, Buvari P, Vogelsang H, Repges R. [Therapy of active Crohn
disease with Boswellia serrata extract H 15]. Zeitschrift fur Gastroenterologie
2001;39(1):11-7.
12. Gupta I PA, Malhotra P, Gupta S, Lüdtke R, Safayhi H, Ammon HP. Effects of gum
resin of Boswellia serrata in patients with chronic colitis. Planta Med 2001 Jul;67(5):3915 2001.
13. Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative
colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol
Hepatol 2006;4(12):1502-6.
14. Joos S, Brinkhaus B, Maluche C, et al. Acupuncture and moxibustion in the
treatment of active Crohn's disease: a randomized controlled study. Digestion
2004;69(3):131-9.
15. Joos S, Wildau N, Kohnen R, et al. Acupuncture and moxibustion in the treatment of
ulcerative colitis: a randomized controlled study. Scandinavian journal of
gastroenterology 2006;41(9):1056-63.
16. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance
treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial.
Gastroenterology 2000;119(2):305-9.
Q.I. #34: Ophthalmology referral
Q.I. #34
IF a patient with IBD has eye pain, inflammation, or
sudden visual changes,
THEN he or she should be referred to an ophthalmologist.
BECAUSE opthalmalogic evaluation can provide an accurate
diagnosis and treatment of the specific eye disease and prevent
ocular morbidity.
Summary: Only one small study has shown that opthalmalogic evaluation
and treatment led to adequate control of ocular inflammation in majority of
patients while all patients had improvement or maintenance of their
vision.1 Some even advocate yearly opthalmalogic evaluation to detect
and treat subclinical/ asymptomatic disease.
Details:
In a study of 19 IBD patients evaluated by ophthalmology for scleritis, episcleritis or uveitis, 16
(84%) achieved adequate control of ocular inflammation using either local, systemic, or surgical
therapy, while vision was improved or maintained in all patients. 1
Indirect evidence from Yilmaz et al revealed that opthalmalogic evaluation of 116 IBD patients
enrolled in the study regardless of eye symptoms found significant irreversible visual loss in
4/6(66%) of patients with uveitis, and reversible vision loss in 6/6 (100%) of patients with
cataract. 2
In children, asymptomatic uveitis could exist and annual opthalmalogic exams are
recommended as Daum et al observed asymptomatic uveitis in 6/12 children while Hofley et al
reported 6/97 children all with Crohn’s disease, no cases with UC. 3,4
In adults, the data is varied, where up to 43% of IBD patients on opthalmalogic exam had some
type of asymptomatic ocular disease while another study showed 0% of asymptomatic uveitis in
179 consecutive IBD patients evaluated. 5, 6
127
Studies also recommend that patients with prednisone use are at higher risk of cataracts so this
should be monitored. In pediatric patients (up to 9 years), cataracts can cause deprivational
amblyopia suggesting an importance in early diagnosis and treatment. 7
References:
1. Soukiasian SH, Foster CS, Raizman MB. Treatment strategies for scleritis and uveitis associated with
inflammatory bowel disease. Am J Ophthalmol. 1994;118(5):601-11.
2. Yilmaz S, Aydemir E, Maden A, et al. The prevalence of ocular involvement in patients with
inflammatory bowel disease. Int J Colorectal Dis. 2007;22(9):1027-30.
3. Daum F, Gould HB, Gold D, et al. Asymptomatic transient uveitis in children with inflammatory bowel
disease. Am J Dis Child 1979;133:170–1.
4. Hofley P, Roarty J, McGinnity G, et al. Asymptomatic uveitis in children with chronic inflammatory
bowel diseases. J Pediatr Gastroenterol Nutr 1993;17:397–400.
5. Felekis T, Katsanos K, Kitsanou M, et al. Spectrum and frequency of ophthalmologic manifestations in
patients with inflammatory bowel disease: a prospective single-center study. Inflamm Bowel Dis.
2009;15(1):29-34.
6. Verbraak FD, Schreinemachers MC, Tiller A, et al. Prevalence of subclinical anterior uveitis in adult
patients with inflammatory bowel disease. Br J Ophthalmol. 2001 Feb;85(2):219-21.
7. Rychwalski PJ, Cruz OA, Alanis-Lambreton G, et al. Asymptomatic uveitis in young people with
inflammatory bowel disease. J AAPOS. 1997;1(2):111-4.
Q.I. #35: Weight and Nutrition
Q.I. #35
IF a patient with IBD is admitted to the hospital
THEN he or she should be weighed and their nutritional needs
assessed.
BECAUSE providing IV nutrition to patients with clinical
malnutrition can have early, rapid, and lasting improvement in
physiological function and prevent protein loss. Patients with
weight loss without evidence of malnutrition can be provided
diet counseling and treatment of underlying etiology of poor
oral intake.
Summary: Only one small study has evaluated the direct effect of IV nutrition in
acutely hospitalized pts with IBD. Evaluation of weight and nutrition status is
recommended in order to diagnose and treat those that are at risk of or have
malnutrition.1 One study determined the etiology of reduced food intake in Crohn’s
patients without evidence of malabsorption was due to depressed mood and
decreased desire to eat rather than due to increased energy cost of disease.
Evaluation of weight loss in the absence of malabsorption requires careful
treatment of its etiology which may entail diet education or treatment of underlying
depression.2
Details
Two studies evaluated weight and nutritional needs in hospitalized IBD patients.
In a small study from New Zealand, 19 clinically malnourished patients hospitalized for
acute exacerbation of their IBD were evaluated for the effect of a 14-day course of IV
nutrition.1 Total body protein, plasma proteins, respiratory muscle function, and skeletal
muscle function were measured at 0, 7, 14 days, and after recovery approximately 200
days later. Compared with matched controls, these patients had lost approximately 35% of
their body protein stores with accompanying physiological impairments of 20%-40% in
129
skeletal muscle function and respiratory muscle function. After 4 days of IV nutrition, there
were improvements in all the physiological measurements (approximately 12%) but no
significant change in total body protein. During recovery phase, however further
improvements in physiological function along with an increase in body stores of protein
were found. IV nutrition in patients hospitalized for IBD exacerbation can provide early
and rapid improvement in physiological function as well as prevent protein loss.1
A French study of 63 consecutive patients hospitalized for Crohn’s disease without
evidence of malabsorption were analysed.2 This study revealed that Energy and protein
intakes were lower in patients with weight loss (30/63) than in those with stable weight
(33/63) (P < 0.01). 2 Of those with weight loss, food restrictions were more numerous (P <
0.01) and visual analog scales showed less hunger, decreased appetite, and fewer
sensations of pleasure related to eating, as compared to those without weight loss (P <
0.01). 2They also found a relation to depressive mood and medical advice for food intake
reduction. No differences were found between the two groups in fecal energy wasting and
resting energy expenditure.2
Evaluation of weight and nutritional needs are recommended for any IBD patient admitted
to the hospital per ECCO guidelines and BSG.
References:
1. Christie PM, Hill GL. Effect of intravenous nutrition on nutrition and function in acute attacks of
inflammatory bowel disease. Gastroenterology. 1990, 99:730-6.
2. Rigaud D, Angel LA, Cerf M, et al. Mechanisms of decreased food intake during weight loss in adult
Crohn's disease patients without obvious malabsorption. Am J Clin Nutr. 1994,60:775-81.
References: