Treatment of Inflammatory Bowel Disease GASTROENTEROLOGY BOARD REVIEW MANUAL Series Editor:

®
GASTROENTEROLOGY BOARD REVIEW MANUAL
STATEMENT OF
EDITORIAL PURPOSE
The Hospital Physician Gastroenterology Board
Review Manual is a study guide for fellows and
practicing physicians preparing for board
examinations in gastroenterology. Each quarterly manual reviews a topic essential to the
current practice of gastroenterology.
PUBLISHING STAFF
Treatment of Inflammatory
Bowel Disease
Series Editor:
Richard A. Wright, MD
Professor and Chief, Division of Gastroenterology/Hepatology,
Department of Medicine, University of Louisville School of Medicine,
Louisville, KY
PRESIDENT, GROUP PUBLISHER
Bruce M. White
EDITORIAL DIRECTOR
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SENIOR EDITOR
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ASSISTANT EDITOR
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EXECUTIVE VICE PRESIDENT
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EXECUTIVE DIRECTOR
OF OPERATIONS
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PRODUCTION DIRECTOR
Suzanne S. Banish
Contributors:
Jeffrey A. Tuvlin, MD
Clinical Assistant Professor, Division of Gastroenterology/Hepatology,
Department of Medicine, University of Louisville School of Medicine,
Louisville, KY
Miles Sparrow, MD
Inflammatory Bowel Disease Clinical Research Fellow, Section of
Gastroenterology and Nutrition, University of Chicago Medical Center,
Chicago, IL
Stephen B. Hanauer, MD
Professor of Medicine, Section Chief of Gastroenterology, Hepatology,
and Nutrition, University of Chicago, Chicago, IL
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NOTE FROM THE PUBLISHER:
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Medical Education
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Induction and Maintenance of Remission . . . . . . . . 2
Inflammatory Bowel Disease in Pregnancy . . . . . . . 7
Colorectal Cancer Risk. . . . . . . . . . . . . . . . . . . . . . . 9
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Cover Illustration by Scott Holladay
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Gastroenterology Volume 10, Part 3 1
GASTROENTEROLOGY BOARD REVIEW MANUAL
Treatment of Inflammatory Bowel Disease
Jeffrey A. Tuvlin, MD, Miles Sparrow, MD, and Stephen B. Hanauer, MD
INTRODUCTION
Ulcerative colitis and Crohn’s disease are two similar
but overlapping types of inflammatory bowel disease
(IBD). IBD is thought to be the result of overactivation
of the immune system directed at luminal antigens of
the gastrointestinal tract. Whereas a certain degree of
chronic inflammation in the intestines is normal, there
is failure of down-regulation in IBD, resulting in acute
inflammation. In ulcerative colitis, this inflammation is
limited to the colon. In Crohn’s disease, the inflammation may affect any portion of the gastrointestinal tract
from the mouth to the anus. In ulcerative colitis, the
colonic inflammation tends to be superficial, affecting
the mucosal layer of the bowel and resulting in the clinical manifestations of hematochezia, diarrhea, cramping, and urgency. In Crohn’s disease, the inflammation
may be transmural within the colon or small bowel,
leading to symptoms of abdominal pain, diarrhea, anemia, and the formation of strictures and enterocutaneous or entero-enteric fistulae. To diagnose IBD accurately, physicians rely on a combination of endoscopic,
radiologic, serologic, and histologic tests.
In North America and Europe, the prevalence of
Crohn’s disease is 26.0 to 198.5 and that of ulcerative colitis is 37.5 to 229 per 100,000.1 Once thought to be mostly a disease of Caucasians, the incidence of IBD among
African Americans seems to be higher than previously
thought,2 and IBD is seen in members of populations at
low risk when they move to Westernized cultures.
The importance of shared genetic and environmental influences on IBD are reflected by its familial association. Twin studies have revealed a concordance of
42%–58% and 6%–17% for Crohn’s disease and ulcerative colitis, respectively.3,4 First-degree relatives of patients with either disease have a relative risk of 10 to
15 of developing the same disease.5,6 The recently discovered NOD2/CARD15 gene is a cytosolic protein
with 3 major polymorphisms that appears to be associated with Crohn’s disease but not with ulcerative colitis.7 – 9 Persons who are heterozygous for mutated genes
carry a 2- to 4-fold increase in disease development.
Double-dose or compound heterozygous carriage car-
2 Hospital Physician Board Review Manual
ries a 20- to 40-fold increase in risk. Carriage of this risk
allele seems to be associated with ileal disease location.10,11 An understanding of how genetics are associated with increased or earlier risk of IBD complications
may allow for the initiation of earlier or more aggressive
therapy for individual patients.
INDUCTION AND MAINTENANCE OF REMISSION
GOALS OF THERAPY
When evaluating and treating a patient with IBD, the
major management goals are (1) to determine the disease extent and severity (Table 1), (2) to induce clinical
remission, and (3) to maintain clinical remission. It is
important to determine which areas of the gastrointestinal tract are involved and how severely each area is
affected. This information has implications for the
choice of therapy because different medications target
specific areas of the gastrointestinal tract, and certain
surgical procedures are appropriate for certain locations of disease activity. Medications vary in their effectiveness in treating ulcerative colitis and Crohn’s disease, and thus a clear diagnosis is paramount.
It is important to recognize that treatments used to
establish a remission may or may not be effective in the
long term in keeping patients well. For example, mesalamine preparations, often used to induce a remission in
ulcerative colitis, also are effective in maintaining remission. Corticosteroids, on the other hand, work well in
inducing remissions in ulcerative colitis and Crohn’s disease but are neither effective nor acceptable in maintaining remissions because of their long-term side effect
profile. Several options are available for treating a patient with IBD. The choice is based on patient factors
(eg, diagnosis, disease location, severity, special circumstances) as well as medication factors (eg, pharmacokinetics, pharmacodynamics, safety, cost, tolerability).
AMINOSALICYLATES
The 5-aminosalicylates (5-ASAs) have been the mainstay of treatment for mild-to-moderate ulcerative colitis
for more than 50 years and are successful in both the
Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e
induction and maintenance of remission. Their exact
mechanism of anti-inflammatory action is unknown.
Sulfasalazine, the first 5-ASA used for IBD, combines
the active 5-ASA (mesalamine) with sulfapyridine, the
combination being cleaved by colonic bacteria. Recognition in the 1970s that the 5-ASA component is the
active constituent and that adverse effects are largely
due to the sulfa compound led to the development of
newer 5-ASA products. Mesalamine now can be delivered topically (ie, via suppositories, enemas, and foams)
as well as orally. Oral mesalamine has been coated with
pH-dependent polymers (Asacol, Proctor & Gamble
Pharmaceuticals, Cincinnati, OH) or time-release,
pH-dependent ethylcellulose microgranules (Pentasa,
Shire US Inc., Newport, KY) or conjugated to other
5-ASA molecules via azo-bonds (olsalazine, balsalazide).
These newer aminosalicylates are as efficacious as sulfasalazine but are associated with fewer side effects.
In patients with ulcerative colitis, 5-ASAs are effective
in both the induction and maintenance of remission. In
left-sided colitis, mesalamine enemas are most effective,
although patients prefer oral formulations to enemas.
Mesalamine suppositories are effective for proctitis (disease extending < 12 cm from anus). Topical mesalamine is also the most effective maintenance agent for
proctitis or left-sided disease,12,13 although many patients can be converted to oral therapy.
For patients with pancolitis (disease extending beyond the splenic flexure), sulfasalazine 2 to 6 g/d or
mesalamine 2.4 to 4.8 g/d will induce remission in 70%
of patients.14 If distal symptoms such as urgency and
tenesmus are troublesome, topical therapy with mesalamine or a steroid preparation can be added. Oral ASAs
successfully maintain remission in extensive ulcerative
colitis. A general rule with 5-ASA products is that whatever dose or delivery was used to induce a remission
should be used to maintain the remission.
In patients with Crohn’s disease, the data on 5-ASAs
are less clear. A study comparing mesalamine at doses of
1, 2, and 4 g/d versus placebo demonstrated a 43% rate
of induction of remission in the 4-g mesalamine group
compared with 18% in the placebo group, but lower
doses of mesalamine were ineffective.15 The role of
aminosalicylates in the maintenance of a medically induced remission in Crohn’s disease is even less well defined. Despite the relative paucity of data to support
their use as maintenance agents in Crohn’s disease,
because of their high tolerability, they still are frequently used for this purpose.
Adverse effects occur in up to 30% to 40% of patients taking sulfasalazine at doses of 4 g/d.14 Hypersensitivity reactions to sulfasalazine, including fever and
Table 1. Evaluation of Ulcerative Colitis Severity
Finding
Mild
Severe
Fulminant
Stools/day
<4
>6
> 10
Blood in stool
Intermittent Frequent
Continuous
Temperature (°C)
Normal
> 37.5
> 37.5
Heart rate (bpm)
Normal
> 90
> 90
Hemoglobin
level
Normal
< 75%
normal
Transfusions
required
Erythrocyte sedimentation rate
(mm/h)
≤ 30
> 30
> 30
Radiographic
findings
None
Air, edema,
thumb
printing
Dilatation
Abdominal examination findings
None
Abdominal Abdominal
tenderness tenderness
and distention
NOTE: Moderate disease includes signs of both mild and severe disease.
Adapted from Truelove SC, Witts LJ. Cortisone in ulcerative colitis;
final report on a therapeutic trial. Br Med J 1955:1041–8.
rash, usually can be managed by changing to mesalamine. Kidney function should be followed in patients
taking a 5-ASA. Sulfasalazine causes a reduction in
sperm number and motility in 50% of males taking the
drug, although this is completely reversible within 6 to
8 weeks after stopping the drug. Because it impairs
folate absorption, supplementation with folic acid 1 mg
daily is recommended for all patients taking sulfasalazine. Rarely, mesalamine may cause a hypersensitivity
colitis with worsening of diarrhea. If a patient also is taking corticosteroids, this reaction may manifest itself as
“refractory colitis.” A short trial off of mesalamine
should be tried in such cases.14
ANTIBIOTICS
There is ample evidence that an imbalance between
luminal bacteria and the host inflammatory and immune
response is central to the pathogenesis of IBD.16 Antibiotics have multiple mechanisms of action in IBD, including a reduction in overall concentrations of luminal
bacteria; selective elimination of certain enteric bacterial
subsets; and reduction of bacterial translocation, decreasing tissue invasion and microabscess formation. Metronidazole and ciprofloxacin are the two most commonly
used antibiotics in IBD, with stronger evidence supporting their use in Crohn’s disease than ulcerative colitis.
In Crohn’s disease, antibiotics are indicated to treat
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complications such as intra-abdominal or perirectal abscesses, perianal fistula, enterovesical fistula, and small
bowel bacterial overgrowth. Although not considered a
first-line therapy, antibiotics offer an alternative to mesalamine or thiopurine immunomodulators if patients
are unresponsive or intolerant to these agents. The
National Cooperative Crohn’s Disease Study compared
metronidazole 10 and 20 mg/kg body weight daily to
placebo. A dose-dependent decrease in Crohn’s symptoms was noted in both metronidazole groups, but
remission results did not differ significantly from placebo.17 Subgroup analysis showed patients with colonic
disease responded best, with no improvement in patients with disease limited to the ileum. Other studies
have suggested a role for antibiotics in decreasing postoperative recurrence of Crohn’s disease at sites of surgical resection and treatment of perianal disease.18 Ciprofloxacin may be used alone or in combination with
metronidazole. Colombel et al prospectively compared
ciprofloxacin 500 mg twice daily to mesalamine 2 g twice
daily and demonstrated equal efficacy, with remission
rates of 56% and 55%, respectively.19 There are no studies to date evaluating antibiotics for the maintenance of
a medically induced remission in Crohn’s disease.
The data supporting the use of antibiotics in ulcerative colitis are limited,20 suggesting that the role of microflora in the two forms of IBD differ. Clinical situations in ulcerative colitis in which antibiotic use should
be considered include Clostridium difficile infection and
refractory or severe colitis.
Side effects of metronidazole occur in up to 20% of
patients and include nausea, anorexia, headaches, and
a metallic taste in the mouth. Peripheral neuropathy is
the most worrisome complication and is related to dose
and duration of therapy. Most neuropathies occur at
doses of more than 1 g/d for 6 months but may occur
at lower doses. Peripheral neuropathy is reversible in
most but not all patients upon cessation of the drug in
a timely manner.
Another avenue being researched for reducing the
intestinal immune response in patients with IBD is the
manipulation of the intestinal flora using probiotics, or
“healthy” bacteria. Probiotics’ lack of toxicity makes
them an attractive subject for future research as therapeutic agents in IBD, but at present they are a costly
therapy that is as yet unproven.
CORTICOSTEROIDS
Corticosteroids have proven successful in multiple trials for inducing remission in moderate-to-severe IBD,
although these agents have no role in the maintenance
of remission. Enthusiasm for their use must be balanced
4 Hospital Physician Board Review Manual
with a strong awareness of the many serious side effects
they possess and the risk of steroid dependency. Their
use should be restricted to only moderate and severe
cases of IBD, as other agents are equally effective for
milder disease and are associated with less toxicity. The
exact mechanism of action of corticosteroids is not yet
fully understood, but it likely involves multiple sites of
action, including inhibition of nuclear factor–κB and
anti-inflammatory and immunosuppressive effects on
leukocytes and their adhesion molecules as well as inhibition of eicosanoid inflammatory mediator production.21
Nonresponders to oral steroids may require hospitalization and intravenous steroids with or without bowel
rest and parenteral nutrition as dictated by clinical severity. Topical corticosteroid enemas and foams are available
for use in distal ulcerative colitis, although they are less
efficacious than topical 5-ASA products and systemic
absorption does occur. Steroid-sparing strategies must be
initiated from the beginning of steroid therapy. These
consist of using other therapeutic agents, such as ASAs
and antibiotics for milder disease and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) or infliximab for more severe disease.
Given the significant side effects and risk of steroid
dependency associated with corticosteroid use, research
has evolved toward the development of topically acting
steroids with minimal systemic absorption. Budesonide
is the prototypic topically acting steroid. Initially developed for the treatment of asthma, it is now approved in
its oral form for the treatment of ileal and colonic
Crohn’s disease and, in topical preparations, for the
treatment of distal ulcerative colitis. It has a 90% firstpass metabolism, which reduces systemic absorption,
and yet has a stronger affinity for the glucocorticoid
receptor than conventional steroids, which maximizes
efficacy. The most common formulation, Entocort
(AstraZeneca LP, Wilmington, DE), is a time- and pHdependent, controlled ileal-release formulation that
releases 70% of the drug in the distal ileum, cecum, and
ascending colon. At a dosage of 9 mg/d for at least
8 weeks, it has become widely accepted as a therapeutic
agent used in the induction of remission of mild-tomoderate ileal and right-sided colonic Crohn’s disease.
Because budesonide causes limited suppression of
the hypothalamic-pituitary-adrenal axis, tapering of
the drug is not necessary on its cessation. In contrast to
conventional corticosteroids, budesonide may have a
role in maintenance treatment of Crohn’s disease, prolonging the time to disease relapse and maintaining
remission in steroid-dependent patients while being
well tolerated, with no evidence of long-term side
effects, such as osteoporosis.22
Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e
IMMUNOMODULATORS
Azathioprine and 6-Mercaptopurine
The immunomodulatory drugs azathioprine and
6-mercaptopurine are widely used in the induction and
maintenance of remission of both Crohn’s disease and
ulcerative colitis. Azathioprine is converted rapidly to
6-mercaptopurine in the bloodstream, at which point it is
acted on by competing anabolic and catabolic pathways
that can potentially result in the formation of several compounds, of which 6-thioguanine is thought to be responsible for the therapeutic effect of the drug.23 Candy et al24
found that at 12 weeks, there was no statistically significant
difference in the rate of remission in Crohn’s disease
patients treated with 2.5 mg/kg of azathioprine versus
those given placebo (73% versus 63%, respectively). At
64 weeks, however, 42% of the azathioprine group had
maintained remission, compared with 7% in the placebo
group. Likewise, in a study of 55 children with newly diagnosed Crohn’s disease treated with 6-mercaptopurine
1.5 mg/kg versus placebo, both groups initially had a high
remission rate (85% with 6-mercaptopurine versus 86%
with placebo), but at 52 weeks, 85% of the 6-mercaptopurine–treated group had maintained remission compared with 54% in the placebo-treated group.25 Studies
support the use of azathioprine and 6-mercaptopurine
for the induction and maintenance of remission in ulcerative colitis as well as in Crohn’s disease.26
Toxicities associated with azathioprine and
6-mercaptopurine are limited but well described. Mild
leukopenia, increased transaminases, nausea, fever, and
rash are relatively common. Pancreatitis has been
reported in approximately 3% of IBD patients.27 A
genetic polymorphism of the activity of the enzyme
thiopurine methyltransferase (TPMT) has been identified that greatly affects the production of the metabolites 6-methylmercaptopurine and 6-thioguanine, with
implications regarding effective dosing as well as reducing adverse effects. Physicians now can measure the
activity of TPMT to assist in optimal dosing, limiting the
development of severe and rapid myelosuppression
that can occur with low levels of this enzyme. A further
aid to the treating physician has been the ability to measure the various metabolites of azathioprine and
6-mercaptopurine, allowing for doses to be adjusted
such that levels of toxic metabolites are limited yet therapeutic levels of efficacious metabolites are achieved.
Although the possibility of developing lymphoma
with these medications has been a concern,28 nontransplant patients treated with azathioprine or 6-mercaptopurine have not consistently been shown to be at
increased risk.29 Furthermore, patients with IBD are at
slightly increased risk for developing lymphoma than
the general population, which may explain any cases
observed in IBD patients treated with these drugs.
Methotrexate
The idea that methotrexate might be efficacious for
IBD came from its success in treating rheumatoid arthritis. Although methotrexate has not been shown to be
effective in the treatment of active ulcerative colitis,30 it
has been shown to be effective in both the induction and
maintenance of remission in Crohn’s disease.31–33 In a
study of 141 patients with chronic steroid-dependent
Crohn’s disease, 39% of patients treated for 16 weeks
with 25 mg/wk of intramuscular (IM) methotrexate
were steroid free and in remission compared with 19%
of patients treated with placebo.32 The second part of
this study showed that patients induced to remission
with 25 mg/wk IM methotrexate were more likely to
maintain that remission when treated with 15 mg/wk IM
methotrexate (65%) compared with placebo (39%).33
Toxicities of methotrexate are well described and
include rash, nausea, mucositis, liver abnormalities
(manifested by increased liver enzymes and/or fibrosis), bone marrow suppression, and pulmonary disease
(ie, hypersensitivity pneumonitis). Folate should be
given orally to patients taking methotrexate. Because of
its known teratogenicity, methotrexate should not be
given to women who have the potential to become
pregnant. Methotrexate should not be used in diabetics, obese patients, or patients using alcohol excessively.
Abnormal results on liver function testing while on
methotrexate warrant consideration of performing a
liver biopsy prior to continuing the drug.
Cyclosporine
In patients with ulcerative colitis, cyclosporine is reserved for induction therapy for those who are nonresponders after 7 to 10 days of intravenous steroids.
Although results have been promising, they must be balanced with caution given the serious side-effect profile
of cyclosporine and the paucity of data to support its
long-term effectiveness. In a large retrospective series
that included 216 patients with ulcerative colitis, 50 patients who failed to respond to a standard regimen were
treated with intravenous cyclosporine.34 Twenty-eight of
these (56%) responded and were switched to the oral
form of the drug. Of these 28, however, 8 patients
relapsed after discharge and underwent colectomy,
yielding a longer-term efficacy of 40% (mean followup, 19 months). In recent years, investigators have initiated another immunomodulator (eg, azathioprine or
6-mercaptopurine) at the time that cyclosporine therapy was begun, and this addition appears to have
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improved the remission rates of medical therapy to approximately 80%.35
The most frequent side effects of cyclosporine are
nephrotoxicity, hypertension, headaches, tremor, paresthesias, seizures (especially in hypocholesterolemic
patients), and opportunistic infection. Owing to the
risk of infection, double-strength trimethoprimsulfamethoxazole therapy is recommended while the
patient is taking cyclosporine.
The role of cyclosporine in Crohn’s disease is less
well defined, with mostly anecdotal evidence at best to
support its use in colonic but not small bowel disease.
Other potential indications for cyclosporine in Crohn’s
disease include perianal or enteric fistula and pyoderma gangrenosum.36
INFLIXIMAB
Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor–α (TNF-α), is the first
biologic agent approved for use in the treatment of
IBD. As TNF-α is a cytokine at the beginning of the
inflammatory cascade, blockage of TNF-α with antiTNF antibodies has been successful in inducing and
maintaining remission in many patients with Crohn’s
disease. Several short-term studies showed efficacy of
infliximab over placebo in patients with either luminal
or fistulous Crohn’s disease.37 – 39 Results of small studies
examining the use of infliximab in ulcerative colitis
have been conflicting,40 – 43 and larger studies are underway. At present, the efficacy of infliximab for treatment
of ulcerative colitis is unclear, but large studies have led
to US Food and Drug Administration approval of infliximab for induction and maintenance of both luminal
and fistulous Crohn’s disease.
Many important issues regarding the use of infliximab are actively under investigation, including ideal
dosage, possible side effects, long-term consequences,
and whether it can be given alone or must it be given with
other medications. Initial dosing studies demonstrated
that a 5 mg/kg intravenous dose of infliximab was superior to 1 mg/kg, 10 mg/kg, or 20 mg/kg.37,38,44 Despite a
recent large trial of maintenance infliximab therapy
revealing 10 mg/kg to be slightly better than 5 mg/kg,39
most physicians initiate therapy with a 5 mg/kg dose,
increasing to 10 mg/kg dosing only if more frequent dosing is required or the degree of clinical benefit from the
5 mg/kg dose decreases. Owing to the chimeric nature
of infliximab, there is a tendency to develop human
antichimeric antibodies (HACAs) against the nonhuman portions of the drug. HACAs may lead to infusion
reactions or loss of effectiveness of infliximab over
time.45,46 Based on studies showing a greater response
6 Hospital Physician Board Review Manual
rate from patients receiving a 3-dose infusion induction
regimen compared to a single infusion39,47 and the current thought that 3-dose induction may decrease the formation of HACAs,45,46,48 the current recommendations
are to give a 5 mg/kg dose at time 0 followed by infusions
at week 2 and week 6. Most patients will develop symptoms that require re-infusion with infliximab approximately every 8 weeks. Therefore, routine maintenance
therapy with infliximab should be given every 8 weeks to
prevent clinical relapse. Some patients may require infusion more frequently than every 8 weeks or may require
infusion with a higher dose.
Physicians treating patients with infliximab need to
be aware of potential side effects and safety issues with
infliximab. The chimeric murine-human nature of the
molecule may result in the development of HACAs,
which may be responsible for acute infusion reactions,
delayed-type hypersensitivity reactions, and decreased
efficacy of infliximab. Acute infusion reactions are characterized by shortness of breath, chest discomfort or
tightness, urticaria, and headaches. Delayed-type
hypersensitivity reactions present 7 to 10 days after infusion and present with myalgias, rash, polyarthritis, and
edema.
A large percentage of patients treated with infliximab develop antinuclear antibodies and, to a lesser
degree, anti–double stranded DNA antibodies.49,50 Few
patients, however, develop clinical symptoms of lupus
(eg, myalgias, rash). One important potential complication of treatment with infliximab is re-activation of
latent tuberculosis, which has led to the recommendation that patients have a PPD test prior to treatment
with infliximab. If positive, patients should have a chest
radiograph, with treatment for latent tuberculosis if the
chest radiograph is negative and treatment for active
tuberculosis if the chest radiograph is abnormal. If the
patient may be anergic, a chest radiograph should be
ordered prior to infliximab therapy.
Given the likelihood of developing HACAs in
patients treated with infliximab, much investigation has
been done to determine whether patients receiving
infliximab develop fewer HACAs if treated with immunomodulators. There are increasing data to support
the notion that concomitant treatment with immunomodulators in patients receiving infliximab may decrease formation of HACAs and reduce infusion reaction rates, increasing the patient’s ability to tolerate
infliximab.39,51 In the rheumatoid arthritis literature, the
3-dose induction regimen (0, 2, 6 weeks) and the use of
methotrexate reduced the frequency of delayed-type
hypersensitivity reactions, decreased HACA formation,
and improved clinical results.45,52 In Crohn’s disease,
Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e
studies have shown that patients given combination
therapy consisting of infliximab with immunomodulators have shown improved clinical outcomes, decreased
HACA levels, decreased acute and delayed infusion reactions, and decreased antinuclear antibody formation.39,45,46,49,50 Until further studies are completed, it is
recommended that immunomodulators be given concomitantly in patients receiving infliximab.
Table 2. Ulcerative Colitis: Induction of Remission
Mild-to-moderate disease
Topical 5-ASA (distal disease)
Oral 5-ASA (extensive disease)
Oral + topical therapy
Moderate-to-severe disease
Steroid taper
TREATMENT ALGORITHMS
Armed with the understanding of (1) induction
therapy versus maintenance therapy; (2) medications
effective for Crohn’s disease, ulcerative colitis, or both;
and (3) side-effect/toxicity profiles of various therapies,
one can begin to develop treatment strategies depending on disease location and severity. Suggested algorithms for the induction of remission in ulcerative colitis (Table 2) and Crohn’s disease (Figure 1) as well as
maintenance therapy (Tables 3 and 4) for the two diseases are presented. It is important to remember that
no two patients with IBD are exactly alike, and different
combinations may work for different patients.
INFLAMMATORY BOWEL DISEASE IN
PREGNANCY
GENERAL CONSIDERATIONS
Several issues are raised when a woman with IBD
becomes pregnant. Potential parents may be concerned
about the risk of their children developing IBD or may
have concerns about their own fertility. It is important
for practitioners to understand the effect of pregnancy
on IBD and, conversely, of IBD on pregnancy. In addition, the safety of medications used to treat IBD on both
the developing fetus and nursing newborn must be carefully considered.
Accurate assessment of disease activity can become
difficult when an IBD patient becomes pregnant. Pregnant women have intermittent abdominal pain from
causes other than IBD, such as gastroesophageal reflux
disease or choledocholithiasis, conditions that are more
common during pregnancy. A careful history, physical
examination, and focused laboratory investigations usually can distinguish these conditions from a flare of IBD.
Diagnostic ultrasound and magnetic resonance imaging (MRI) both are safe imaging methods during pregnancy. Plain abdominal radiographs should be avoided
unless absolutely indicated by clinical conditions. If
endoscopy is required, flexible sigmoidoscopy rather
that colonoscopy should be performed.
Steroid-dependent disease
Azathioprine/6-mercaptopurine
Severe disease
Intravenous corticosteroids
Cyclosporine
Surgery
5-ASA = 5-aminosalicylate.
EFFECT OF IBD ON PREGNANCY
Approximately 90% of women with ulcerative colitis
are able to conceive, although case-controlled studies
have shown a higher rate of voluntary childlessness in
comparison to control subjects.53 In contrast, active
Crohn’s disease reduces fertility by several mechanisms,
depending on disease location. A large case-controlled
study of 275 patients revealed infertility in 42% of
Crohn’s disease patients versus 28% of control subjects.54 Terminal ileitis may cause inflammation and
fibrosis of the adjacent fallopian tubes and ovaries.
Crohn’s colitis also is associated with reduced fertility.
Sulfasalazine inhibits sperm counts and motility in 50%
of males; although not dose dependent, this effect is
reversed within 6 to 8 weeks of ceasing the drug.53
Two large retrospective series have shown that 83% of
patients with IBD experience an uncomplicated birth, a
rate that is comparable to that of the general population.53 Similarly, the rates of congenital abnormalities,
spontaneous abortions, and stillbirths in women with
IBD are are similar to those in healthy controls. In
women with active Crohn’s disease, the risk of prematurity and low-birth-weight infants is slightly increased. It
is particularly important to ensure that a woman with
IBD is in remission prior to conception. A quiescent disease period of at least 3 months is recommended.
EFFECT OF PREGNANCY ON IBD
Women with inactive IBD at the time of conception
usually remain in remission during pregnancy and
have uncomplicated deliveries at the same rate as the
general population. Generally speaking, of women who
Gastroenterology Volume 10, Part 3 7
Colonic disease:
Abx
Aminosalicylates
Response
Ileum–rt colon disease:
Budesonide
Response
No response
Mild disease:
Colon
Abx
No response
Moderate
disease
Mild disease:
Ileum–rt colon
Infliximab
Corticosteroids
Response
Corticosteroids
Infliximab
Relapse
No response
Response
Corticosteroids
Infliximab
Budesonide
(for rt colon disease)
Repeat
budesonide
AZA/6-MP/MTX
No response
Moderate-to-Severe Crohn’s Disease
Corticosteroids
Infliximab
Response
Corticosteroids
No response
Relapse
Response
AZA/6-MP/MTX
No response
Figure 1. Algorithm for the induction of remission in Crohn’s disease. Abx
= antibiotics; AZA = azathioprine; 6-MP = 6-mercaptopurine; MTX =
methotrexate; rt = right.
Infliximab
Limited disease:
resection
Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e
8 Hospital Physician Board Review Manual
Mild-to-Moderate Crohn’s Disease
Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e
Table 3. Maintenance Therapy in Crohn’s Disease
Table 4. Maintenance Therapy in Ulcerative Colitis
Induction
Maintenance
Induction
Maintenance
5-ASA
5-ASA
Oral 5-ASA
Oral 5-ASA
Antibiotics
Antibiotics
Topical 5-ASA
Topical 5-ASA +/– oral 5-ASA
Corticosteroids
Immunomodulator*
Corticosteroids
Oral 5-ASA or AZA/6-MP*
Infliximab
Cyclosporine
AZA/6-MP + ? 5-ASA
Infliximab
Infliximab (+ immunomodulator*)
Surgery
Immunomodulator*
? Infliximab
5-ASA = 5-aminosalicylate.
*Immunomodulator: azathioprine, 6-mercaptopurine, or methotrexate.
conceive while their IBD is active, approximately one
third will find that their disease activity remains the same,
one third will worsen, and one third will improve.55
MEDICAL THERAPIES DURING PREGNANCY
The use of IBD medications during pregnancy is a
source of considerable concern for both patients and
physicians. A key principle is that active disease rather
than medications poses the greatest risk to the mother
and fetus. Table 5 outlines the current guidelines for
medication safety during pregnancy and breast feeding.
A few medications deserve special mention. Sulfasalazine is safe in pregnancy, but because it interferes with
normal folate metabolism by competitively inhibiting the
enzyme folate conjugase, 2-mg folate supplementation
daily is recommended for pregnant women taking the
drug. Despite hesitancy in the past, most physicians treating IBD prescribe azathioprine or 6-mercaptopurine in
pregnancy if the disease severity dictates that they are
indicated. Methotrexate is contraindicated before or during pregnancy because of a spontaneous abortion rate as
high as 40% and a high risk of congenital anomalies,
such as spina bifida and craniofacial defects. Careful
counseling regarding the need for effective contraception is necessary when considering methotrexate. Methotrexate likewise is contraindicated when breastfeeding.
Data on the use of infliximab in pregnant IBD patients
are limited, although many physicians feel that it may be
used safely if clinically indicated.56
COLORECTAL CANCER RISK
RISK FACTORS
Individuals with ulcerative colitis or Crohn’s disease
5-ASA = 5-aminosalicylate; AZA = azathioprine; 6-MP = 6-mercaptopurine.
*AZA/6-MP may maintain remission in patients requiring frequent
corticosteroids.
are at increased risk for colorectal cancer. Although colorectal cancer in IBD accounts for only 1% to 2% of all
colorectal cancer cases in the general population,
among IBD patients it is the cause of death in 15% of
cases. The prevalence of colorectal cancer in persons
with ulcerative colitis is 3.7% overall and 5.4% in patients with pancolitis, creating an incidence of 3 per
1000 person-years’ duration.57 Several factors are known
to increase the risk of colorectal cancer in IBD, including duration of colitis, extent of disease, family history of
colon cancer, and associated primary sclerosing cholangitis. The risk of colorectal cancer in IBD patients with
primary sclerosing cholangitis may be as high as 33% at
20 years of disease duration.58
SURVEILLANCE AND PREVENTION
Prophylactic colectomy is the most definitive form of
colorectal cancer prevention in IBD patients, but most
patients prefer to keep their colon. For these patients, it
is recommended that they enter a surveillance colonoscopy program, although to date, the data regarding
whether this reduces mortality from colorectal cancer is
conflicting. The evidence is good, however, that even
though cancers may still arise in patients undergoing
colonoscopic surveillance, they are detected earlier in
these patients than in those not undergoing surveillance.
Colonoscopic surveillance should begin at 8 years of
disease duration and should consist of examination of the
entire colon with 4 quadrant biopsies every 10 cm. Figure 2 outlines one approach to surveillance of patients
with IBD. There is little argument among experts that
once high-grade dysplasia is detected and confirmed,
prompt colectomy is indicated owing to the high likelihood of concurrent or subsequent colorectal cancer. The
management of low-grade dysplasia is more controversial.
Many physicians feel that low-grade dysplasia demands
prompt colectomy, but if the patient refuses surgery or is
an especially poor surgical candidate, repeat surveillance
at 3- to 6-month intervals may be performed.
Gastroenterology Volume 10, Part 3 9
Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e
Table 5. Safety of Inflammatory Bowel Disease Medications During Pregnancy and Breastfeeding
Condition
Safe to Use When Indicated
Limited Data
Contraindicated
Pregnancy
Mesalamine (oral or topical), sulfasalazine with folate supplementation, corticosteroids, total
parenteral nutrition, loperamide
Olsalazine, azathioprine,
6-mercaptopurine, cyclosporine, metronidazole,
ciprofloxacin, infliximab
Methotrexate, thalidomide, diphenoxylate
Breastfeeding
Mesalamine (oral or topical), sulfasalazine, corticosteroids
Olsalazine, azathioprine,
6-mercaptopurine, infliximab
Methotrexate, thalidomide, cyclosporine, ciprofloxacin, metronidazole,
loperamide, diphenoxylate
Data from Kane S. Inflammatory bowel disease in pregnancy. Gastroenterol Clin North Am 2003;32:323–40.
High-grade dysplasia
Polyp
Low-grade dysplasia
Flat
Polyp
Indefinite dysplasia
No dysplasia
Repeat
colonoscopy in
6–12 mo
Repeat
colonoscopy in
1–2 y
Flat
or
Colectomy
Completely
removed and
no dysplasia
elsewhere?
No
Repeat
colonoscopy in
3–6 mo: LGD
confirmed?
Yes
Yes
No
Figure 2. Surveillance strategy in ulcerative colitis. LDG = low-grade dysplasia. (Reprinted from Itzkowitz SH. Cancer prevention in
patients with inflammatory bowel disease. Gastroenterol Clin North Am 2002;31:1138, with permission from Elsevier.)
Surveillance colonoscopy is a form of secondary prevention in that it detects already neoplastic tissue. Recently, research has turned to chemoprevention as primary prevention therapy. Investigators have postulated
that 5-ASA compounds may be chemopreventive based
on encouraging results in the sporadic colon cancer
population. One study reported up to a 75% risk reduction for colorectal cancer for IBD patients taking mesalamine regularly.59
IBD patients are at risk of folate deficiency owing to
reduced oral intake, increased intestinal losses, and, in
those taking sulfasalazine, reduced intestinal absorption.
Several studies have shown a trend towards colorectal
cancer risk reduction with folate supplementation,
although none have reached statistical significance.
10 Hospital Physician Board Review Manual
Given that the supplement is cheap and nontoxic, its use
should be considered in IBD patients.
Trials of ulcerative colitis patients with primary sclerosing cholangitis have shown that the use of ursodeoxycholic acid is associated with a decreased prevalence
of colonic neoplasia.60,61 Further trials are underway to
determine whether all IBD patients—including those
without primary sclerosing cholangitis—may benefit
from this agent.
CONCLUSION
The evaluation and treatment of patients with IBD
requires an understanding of the differences in ulcerative
Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e
colitis and Crohn’s disease as well as familiarity with the
various medications available for treatment. As IBD
often affects younger patients, issues frequently arise
regarding fertility, breastfeeding, genetics, and cancer
risks. A strong doctor-patient relationship and a commitment to aggressively treating to maintain remission
will increase the likelihood of a normal life expectancy
and a high quality of life.
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Copyright 2004 by Turner White Communications Inc., Wayne, PA. All rights reserved.
12 Hospital Physician Board Review Manual