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Overview of the medical management of mild to moderate

Crohn's disease in adults


Authors
INTRODUCTION Crohn's disease is an inflammatory condition of unknown etiology that
can affect any portion of the gastrointestinal tract from the mouth to the perianal area. Its
transmural inflammatory nature coupled with the variability of organ distribution gives rise to
a spectrum of clinical presentations, each of which has to be considered separately in
deciding upon the proper therapeutic approach. (See "Clinical manifestations, diagnosis and
prognosis of Crohn's disease in adults".)

DEFINITIONS OF SEVERITY Clinical trials of Crohn's disease often use formal grading
systems to describe disease severity. Two commonly used systems are the Crohn's Disease
Activity Index (CDAI) and the Harvey-Bradshaw Index (HBI) which is a simplified
derivative of the CDAI. The HBI has been shown to correlate with the CDAI [2]. A drop in
the CDAI of 100 points corresponds to a 3-point drop in the HBI. A CDAI of <150 (clinical
remission) corresponds to an HBI of <4.

The following working definitions may be more practical for clinical practice [3]:

Asymptomatic remission (CDAI <150) Patients who are asymptomatic either


spontaneously or after medical or surgical intervention. Patients requiring steroids to
remain asymptomatic are not considered to be in remission but are referred to as being
"steroid-dependent."
Mild to moderate Crohn's disease (CDAI 150-220) Ambulatory patients able to
tolerate an oral diet without dehydration, toxicity, abdominal tenderness, mass,
obstruction, or >10 percent weight loss.
Moderate to severe Crohn's disease (CDAI 220-450) Patients who have failed
treatment for mild to moderate disease or patients with prominent symptoms such as
fever, weight loss, abdominal pain and tenderness, intermittent nausea or vomiting, or
anemia.
Severe-fulminant disease (CDAI >450) Patients with persisting symptoms despite
conventional glucocorticoids or biologic agents (infliximab, adalimumab,
certolizumab pegol, or natalizumab) as outpatients, or individuals presenting with
high fevers, persistent vomiting, intestinal obstruction, significant peritoneal signs,
cachexia, or evidence of an abscess.

STEP-UP VERSUS TOP-DOWN THERAPY There are two general approaches to the
treatment of mild to moderate Crohn's disease: step-up therapy and top-down therapy. Step-
up therapy typically starts with medications that are less potent and (often) associated with
fewer side effects. If those therapies are ineffective, more potent (and potentially more toxic)
medications are used. Top-down therapy starts with more potent therapies, such as biologic
therapy or immunomodulator therapy, relatively early in the course of the disease before
patients become glucocorticoid dependent, and possibly even before they receive
glucocorticoids. (See "Overview of the medical management of severe or refractory Crohn's
disease in adults".)

The relative merits of these strategies have not been extensively studied. One of the largest
controlled trials included a total of 133 patients with newly diagnosed Crohn's disease who
were randomly assigned to combined immunosuppression (with infliximab and azathioprine)
or conventional management with glucocorticoids followed by azathioprine and infliximab as
needed [4]. Significantly more patients in the initial immunosuppression (top-down) group
were in clinical remission at 26 weeks (60 versus 36 percent) and at 52 weeks (62 verus 42
percent). Serious adverse events were seen in a similar proportion of both groups (31 versus
25 percent).

Given the heterogeneity of the disease and multiple options for combining therapy, it is
unlikely that sufficient controlled trials will ever become available to guide treatment for
every clinical circumstance. In addition, the cost of therapy, patient compliance, and
individual susceptibility to drug toxicity are equally relevant factors for making decisions at
the bedside.

As a general rule, we favor step-up therapy, beginning treatment with less potent drugs that
have relatively long track records and good safety profiles. We then progress to more potent
treatments in patients with severe or refractory disease. (See "Overview of the medical
management of severe or refractory Crohn's disease in adults".)

TREATMENT OF ACTIVE DISEASE Outpatient therapy with oral medications is


appropriate for most patients with mildly to moderately active Crohn's disease. However,
hospitalization is required for patients who present with severe symptoms or who appear
toxic. (See "Overview of the medical management of severe or refractory Crohn's disease in
adults".)

For patients with mild to moderate Crohn's disease, treatment will in part depend upon the
site of disease.

Oral lesions Aphthous ulcerations are the most common oral manifestation of Crohn's
disease. A wide variety of additional lesions have been described, including granulomatous
masses, cheilitis, and granulomatous sialadenitis. These abnormalities can be severe and may
dominate the clinical picture by causing enough pain to impair nutrition. They usually occur
with coexistent intestinal disease and respond to treatment directed at the intestinal disease.
Topical medications, such as triamcinolone acetonide in Orabase, can provide local symptom
relief. (See "Oral lesions", section on 'Treatment'.)

Gastroduodenal Crohn's disease Fewer than 5 percent of patients with Crohn's disease
have gastroduodenal disease, most often in association with concurrent distal intestinal
involvement. The distal antrum and duodenum are most commonly affected.

The clinical presentation is often confused with that of peptic ulcer disease and symptoms
may include epigastric pain, nausea, and postprandial vomiting. Treatment with a proton
pump inhibitor, H2 receptor antagonist, or sucralfate may provide partial or complete relief of
symptoms. The slow release form of mesalamine encapsulated in ethylcellulose
microgranules (Pentasa) is partially released in the proximal small bowel and theoretically
may be of use in duodenal Crohn's disease. There are, however, no clinical trials to confirm
its efficacy in this setting.

Ileitis and colitis The ileum is the region of the small bowel most commonly involved in
Crohn's disease. Patients with active ileitis typically present with diarrhea and abdominal
pain; they can also have weight loss (usually related to decreased oral intake), low-grade
fever, and anemia. Patients with active ileocolitis or Crohn's disease limited to the colon may
present with abdominal pain, bloody or nonbloody diarrhea, fever, and weight loss. (See
"Clinical manifestations, diagnosis and prognosis of Crohn's disease in adults".)

For patients with mild to moderate disease, we usually begin therapy with oral 5-
aminosalicylates (5-ASA) drugs, though, as noted below, experts disagree about the efficacy
of 5-ASA drugs for Crohn's disease. We then progress to treatment with antibiotics,
glucocorticoids, and immunosuppressive agents depending upon the response (algorithm 1).

The optimal management of patients who are asymptomatic or minimally symptomatic is


unclear. Some data suggest that the use of 5-ASA drugs may decrease the risk of colon
cancer. As a result, we typically suggest treatment with a 5-ASA drug for such patients if
their Crohn's disease involves the colon. However, whether any treatment alters the natural
history of the disease in such patients is unproven. (See "Sulfasalazine and 5-aminosalicylates
in the treatment of ulcerative colitis", section on 'Effect in prevention in colon cancer'.)

5-ASA drugs The use of 5-ASA drugs for Crohn's disease is controversial. Studies
evaluating the efficacy of 5-ASA drugs in Crohn's disease have produced mixed results:

A 2011 meta-analysis examined the role of 5-ASAs in patients with Crohn's disease
for both induction of remission and maintenance of remission [6]. The meta-analysis
included 22 randomized trials (6 trials looking at 5-ASAs for the induction of
remission, 13 for maintenance of remission, and 3 for both induction and maintenance
of remission). The meta-analysis found that:

5-ASAs taken as a group were superior to placebo for the induction of remission.
Failure to achieve remission was seen in 68 percent of patients treated with 5-ASAs
compared with 75 percent of patients treated with placebo (relative risk [RR] 0.89;
95% CI 0.80-0.99). The study found that in order to achieve remission in one patient
with active Crohn's disease, 11 patients would need to be treated.

There was no significant benefit in remission rates when only trials using
mesalamine were examined. Similarly, when studies using sulfasalazine were
examined, the benefit was of borderline statistical significance (RR 0.83; 95% CI
0.69-1.00, p = 0.05). However, higher doses of mesalamine (1.5 g/day) were
associated with achieving a combined endpoint of remission or symptom
improvement (RR 0.96; 95% CI 0.48-.098, number needed to treat [NNT] of 6).
Sulfasalazine plus a glucocorticoid was not superior to a glucocorticoid alone for the
induction of remission.
One trial compared olsalazine with placebo and found olsalazine to be inferior to
placebo (RR of failure to improve 1.62; 95% CI 1.18-2.21).
There was no benefit with 5-ASA treatment for the maintenance of remission.
Patients treated with 5-ASAs had a relapse rate of 56 percent compared with 57
percent for patients who received placebo.

Additional findings from a 2010 meta-analysis of 19 randomized trials included:

Sulfasalazine was more likely to induce remission than placebo (RR 1.38; 95% CI
1.02-1.87), with the benefit being confined primarily to patients with colitis.
Sulfasalazine was inferior to glucocorticoids for inducing remission (RR 0.66, 95%
CI 0.53-0.81).
Neither low-dose mesalamine (1 to 2 g/day) nor high-dose mesalamine (3 to 4.5
g/day) was superior to placebo for induction of remission.
5-ASAs were inferior to budesonide (RR 0.56; 95% CI 0.40-0.78) in one trial.

A 2011 meta-analysis with six trials specifically looked at the use of 5-ASA drugs for
the maintenance of remission [6]. In that analysis, there was a trend toward a benefit
with sulfasalazine compared with placebo, but there was no definite benefit of
mesalamine compared with placebo.
In a 2011 study that was not included in the above meta-analyses, mesalamine and
budesonide were similarly effective for the induction of remission in patients with
mildly to moderately active Crohn's disease [7]. Three hundred nine patients were
assigned to receive budesonide 9 mg/day, budesonide 3 mg three times per day, or
Eudragit-L-coated mesalamine 4.5 g/day. The remission rates were similar between
those who received budesonide and those who received mesalamine (70 versus 62
percent).

The uncertainty about the benefit of 5-ASA drugs is reflected in variable guidelines from
gastroenterology societies and recommendations from experts.

The Practice Parameters Committee of the American College of Gastroenterology and


the British Society of Gastroenterology both recommend 5-ASA drugs for use as first-
line therapy in patients with mildly to moderately active Crohn's disease [8,9].
The European Crohn's and Colitis Organization Consensus recommends that 5-ASAs
not be used for Crohn's disease [10].
Some experts recommend that 5-ASA drugs other than sulfasalazine not be used in
the treatment of Crohn's disease for either induction or maintenance of remission.
However, sulfasalazine (3 to 6 g/day over a course of 16 weeks) may be an option in
patients with mild to moderate colonic (left-sided) Crohn's disease [11-13].
By contrast, we and others argue that 5-ASAs should be tried in patients with mild
Crohn's disease based upon their relative safety compared with glucocorticoids,
immunomodulators, and biologic agents, particularly given the potential
chemopreventative benefits of 5-ASAs in patients with longstanding Crohn's colitis.

For patients with ileitis and mild symptoms, we often begin treatment with a slow release oral
5-ASA drug (table 1), such as Pentasa (2 g/day) or Asacol (2.4 g/day). The dose is then
increased to a maximum of 4 g/day for Pentasa or 4.8 g/day for Asacol, depending upon
the clinical response. By contrast, sulfasalazine is less useful for ileitis because colonic
bacteria must cleave the drug to release the active 5-ASA moiety.

For patients with ileocolitis or colitis and mild to moderate symptoms, we initiate therapy
with sulfasalazine (2 g/day) or one of the mesalamine drugs (2 to 2.4 g/day, depending upon
the drug used) (table 1). Again, the doses of the medications are increased based upon the
patient's clinical response.

Side effects of these medications include nausea, headache, fever, rash, pancreatitis, and
pneumonitis (table 2) and are more common with sulfasalazine. (See "Sulfasalazine and 5-
aminosalicylates in the treatment of ulcerative colitis", section on 'Side effects'.)

Conventional glucocorticoids Oral glucocorticoids continue to be a mainstay of treatment


for patients with mild to moderate disease who are unresponsive to the above measures, or for
those presenting with more severe initial symptoms (but who are not so ill that they require
hospitalization and intravenous glucocorticoids) [11,14,15]. A 2011 meta-analysis failed to
show a statistically significant benefit with glucocorticoids compared with placebo for the
induction of remission due to heterogeneity between the included studies (RR of failure to
achieve remission 0.46, 95% CI 0.17-1.28). However, the individual studies included in the
analysis both showed a benefit [11,14].

The initial dose of prednisone is 40 to 60 mg/day. Sixty to 80 percent of patients will respond
to this dose, usually within 10 to 14 days. At that point, a gradual tapering by 5 mg/week
should be considered with the definite goal of discontinuing the prednisone. Glucocorticoids
should not be used long-term due to significant side effects. (See "Major side effects of
systemic glucocorticoids".)

5-ASA drugs and antibiotics can be used concomitantly with prednisone. One controlled trial
demonstrated that the combination of sulfasalazine and prednisone was better than either
alone [14], though not all studies have shown a benefit with combination therapy (see '5-ASA
drugs' above). Once remission is achieved and the prednisone tapered and stopped,
maintenance therapy with an oral 5-ASA drug at a dose of 3 to 3.6 g/day (depending upon the
drug chosen) should be considered (table 1). (See 'Maintenance therapy' below.)

Non-systemic glucocorticoids Controlled ileal release (CIR) budesonide is a


glucocorticoid with a high first-pass hepatic metabolism that may be used as an alternative to
prednisone for patients with active ileitis or right-sided Crohn's colitis, particularly in those
with prior intolerance or contraindications to systemic glucocorticoids. Systemic side effects
are seen to a lesser extent with budesonide than with conventional glucocorticoids. (See
"Budesonide in the treatment of Crohn's disease".)

Antidiarrheal medications Symptomatic treatment with antidiarrheal drugs should be


considered in patients not responding completely to first-line therapy. We suggest
loperamide because of its efficacy and relative safety [18]. Cholestyramine is another
consideration for patients with non-stenosing ileitis who have chronic watery diarrhea. It is
also indicated for patients with previous ileal resections who have bile salt diarrhea. The
initial dose is 4 g/day, which is increased as needed to 12 g/day in three divided doses. For
patients intolerant of cholestyramine because of dyspepsia, colestipol, a similar binding resin,
is often a suitable alternative. (See "Lipid lowering with drugs other than statins and
fibrates".)

Probiotics Probiotics are viable microorganisms with beneficial physiologic or therapeutic


activities. Limited clinical trials suggest that selected probiotic species, alone or in
combination, can prevent recurrent intestinal inflammation and possibly treat active
inflammatory bowel disease. The best results have been observed in patients with pouchitis,
while mixed results have been reported in other settings. (See "Probiotics for gastrointestinal
diseases".)

MAINTENANCE THERAPY Once a patient has achieved remission using a 5-ASA drug,
antibiotics, and/or a glucocorticoid, we suggest maintenance therapy with a 5-ASA drug. In
patients with ileal disease, mesalamine (Pentasa, Asacol) at a dose of 3 to 3.6 g/day
should be considered as long-term therapy, with the hope of preventing disease relapse [21-
24]. However, it must be acknowledged that there is inconsistent evidence supporting this
approach. (See '5-ASA drugs' above and "Sulfasalazine and 5-aminosalicylates in the
treatment of ulcerative colitis", section on 'Maintaining remission'.)

Limited data also suggest that antibiotics are effective for the maintenance of remission [25].
(See "Antibiotics for treatment of inflammatory bowel diseases", section on 'Crohn's
disease'.)

Budesonide may be effective for the short-term maintenance of remission (three to six
months), but studies suggest it is not effective for long-term maintenance [16]. Conventional
glucocorticoids are not effective for preventing relapses in patients in remission [3,26,27].
(See "Budesonide in the treatment of Crohn's disease".)

REFRACTORY CROHN'S DISEASE Patients with Crohn's disease who relapse while on
treatment, who fail to respond to the above treatments, or who cannot be successfully tapered
off of steroids may require treatment with immunomodulators or biologic therapy. The
management of these patients is discussed separately. (See "Overview of the medical
management of severe or refractory Crohn's disease in adults".

Overview of the medical management of severe or refractory


Crohn's disease in adults
Authors
Richard J Farrell, MD

INTRODUCTION Crohn's disease is an inflammatory condition of unknown etiology that


can affect any portion of the gastrointestinal tract from the mouth to the perianal area. Its
transmural inflammatory nature coupled with the variability of organ distribution gives rise to
a spectrum of clinical presentations, each of which has to be considered separately in
deciding upon the proper therapeutic approach. (See "Clinical manifestations, diagnosis and
prognosis of Crohn's disease in adults".)

Clinical trials of Crohn's disease often use formal grading systems to describe disease
severity. Two commonly used systems are the Crohn's Disease Activity Index (CDAI)
(calculator 1) and the Harvey-Bradshaw Index (HBI) (calculator 2) [1], which is a simplified
derivative of the CDAI. The HBI has been shown to correlate with the CDAI [2]. A drop in
the CDAI of 100 points corresponds to a 3-point drop in the HBI. A CDAI of <150 (clinical
remission) corresponds to an HBI of <4.

The following working definitions may be more practical for clinical practice [3]:

Asymptomatic remission (CDAI <150) Patients who are asymptomatic either


spontaneously or after medical or surgical intervention. Patients requiring steroids to
remain asymptomatic are not considered to be in remission but are referred to as being
"steroid-dependent."
Mild to moderate Crohn's disease (CDAI 150-220) Ambulatory patients able to
tolerate an oral diet without dehydration, toxicity, abdominal tenderness, mass,
obstruction, or >10 percent weight loss.
Moderate to severe Crohn's disease (CDAI 220-450) Patients who have failed
treatment for mild to moderate disease or patients with prominent symptoms such as
fever, weight loss, abdominal pain and tenderness, intermittent nausea or vomiting, or
anemia.
Severe-fulminant disease (CDAI >450) Patients with persisting symptoms despite
conventional glucocorticoids or biologic agents (infliximab, adalimumab,
certolizumab pegol, or natalizumab) as outpatients, or individuals presenting with
high fevers, persistent vomiting, intestinal obstruction, significant peritoneal signs,
cachexia, or evidence of an abscess.

SEVERE DISEASE Outpatient therapy with oral medications is appropriate for most
patients with mildly to moderately active Crohn's disease. However, hospitalization is
required for patients who present with severe or fulminant disease. Hospitalization for
intravenous glucocorticoids is also generally required for patients who fail to respond to
outpatient therapy.

Therapy for patients with severe or fulminant disease should consist of bowel rest, parenteral
nutrition, and intravenous glucocorticoids. Patients who do not respond to steroids may
require treatment with biologic therapy. Although parenteral nutrition has no proven benefit
in inducing remission, patients are often too ill to take adequate oral nutrition.

REFRACTORY DISEASE A common and challenging problem is how to manage


patients with Crohn's disease who are refractory to treatment with first-line agents (eg,
glucocorticoids, 5-ASAs, antibiotics). (See "Overview of the medical management of mild to
moderate Crohn's disease in adults".)

Patients are refractory if they:

Repeatedly relapse after achieving remission with first-line agents


Remain symptomatic despite adequate doses of glucocorticoids (steroid-resistant), 5-
ASAs, and antibiotics
Flare when glucocorticoids are decreased or stopped (steroid-dependent)

Options for the treatment of such patients include azathioprine, 6-mercaptopurine,


methotrexate, and biologic therapies. In addition, some authorities recommend using these
drugs early in the course of disease, before patients become steroid-dependent or resistant,
though we do not favor this approach. (See "Overview of the medical management of mild to
moderate Crohn's disease in adults", section on 'Step-up versus top-down therapy'.)

Azathioprine and 6-mercaptopurine Many patients with refractory Crohn's disease are
treated with azathioprine or its active metabolite, 6-mercaptopurine (6-MP). The response
rate to these medications is 60 to 70 percent in both small bowel and colonic disease.
Treatment can be initiated with either drug at a dose of 50 mg/day. If needed, the dose of 6-
MP can be increased to a maximum of 2 mg/kg per day (though more commonly 1.5 mg/kg is
given as the maximum dose) and the dose of azathioprine can be increased to 2.5 mg/kg per
day, provided there is no bone marrow suppression. (See "Immunomodulator therapy in
Crohn's disease", section on 'Adverse effects'.)

A response to these medications will usually be seen within three to six months. During this
period, patients often require concomitant steroid therapy with a gradual reduction in the
steroid dose after one to two months of treatment with azathioprine or 6-MP. Patients
receiving these drugs require regular monitoring for toxicity. Testing for metabolites as well
as susceptibility to toxicity (by measuring TPMT activity) is available; TPMT testing is
suggested by the US Food and Drug Administration (FDA) prior to beginning therapy. While
not required by the FDA, we recommend TPMT testing prior to initiating therapy. In addition
to bone marrow suppression, these agents have also been associated with malignancy. (See
"6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in the treatment of
inflammatory bowel disease with 6-MP or azathioprine" and "Immunomodulator therapy in
Crohn's disease", section on 'Azathioprine and 6-mercaptopurine'.)

Methotrexate Methotrexate is an alternative for the patient who does not tolerate or does
not respond to azathioprine or 6-MP, and may be preferable to azathioprine or 6-MP in
patients with troublesome Crohn's disease-related arthropathy. To guarantee bioavailability,
the drug should be initiated intramuscularly at a dose of 25 mg per week. A response should
be seen within three months. For patients on steroid therapy, the steroid should be continued
during this period with a gradual lowering of the dose. Once a response to intramuscular
methotrexate is achieved, the patient can be switched to oral methotrexate with an attempt to
lower the dose gradually over several months to 15 mg per week. A discussion of the data
supporting the efficacy of methotrexate is available elsewhere. (See "Immunomodulator
therapy in Crohn's disease", section on 'Methotrexate'.)

Concomitant therapy with folic acid 1 mg/day may diminish adverse effects to methotrexate.
Patients are at risk for hepatotoxicity, but optimal strategies for surveillance liver biopsies in
these patients have not been established. A liver biopsy can be considered in patients who
have received a cumulative dose of 1000 to 1500 mg. However, accumulating experience
suggests that the incidence of hepatotoxicity is low and that surveillance liver biopsies based
upon the cumulative methotrexate dose may not be warranted [4]. (See "Major side effects of
low-dose methotrexate" and "Hepatotoxicity associated with chronic oral methotrexate for
nonmalignant disease".)

Biologic therapies

Anti-TNF therapies Three anti-tumor necrosis factor (anti-TNF) therapies are approved
for treatment of Crohn's disease in adults in the United States and all are effective in
treatment of luminal Crohn's disease [5]: infliximab, adalimumab, and certolizumab
pegol (which is not approved in Europe). However, patients with fibrostenotic Crohn's
disease without active inflammation are unlikely to benefit from anti-TNF therapy. Patients
who are intolerant to one anti-TNF agent may tolerate a different agent. (See "Infliximab in
Crohn's disease", section on 'Use in the setting of intestinal strictures'.)

A meta-analysis found that patients treated with anti-TNF agents were less likely to fail to
achieve remission compared with placebo (RR 0.87) and that the number of patients who
would need to be treated to achieve remission in one patient was eight [6]. In addition, anti-
TNF agents were also less likely to be associated with relapse in a patient in remission (RR
0.71). The analysis estimated that four patients would need to be treated with an anti-TNF
agent to prevent one relapse.

The selection among these three drugs will depend upon several issues:

Route of administration
Adalimumab and certolizumab are given subcutaneously, whereas infliximab is given
intravenously. Adalimumab is given every two weeks and certolizumab is given every
four weeks.
Self-administration of adalimumab or certolizumab could lead to incomplete
compliance and thereby loss of efficacy.

Labeling indications

Infliximab and adalimumab have broader labeling indications; both are approved for
reducing signs and symptoms of Crohn's disease and inducing and maintaining
clinical remission, whereas certolizumab does not have an explicit maintenance
indication. However, the remission rates in clinical trials have not revealed an
important difference in remission rates compared with the other two drugs.

Length of experience with the drugs

Experience with adalimumab for patients who have lost response to or had an adverse
reaction to infliximab is greater than with certolizumab, although data suggest that
certolizumab is also effective in such patients [7-11].
The safety record with infliximab and adalimumab is longer than with certolizumab.
(See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

Safety and adverse events

Adalimumab has been associated with injection site reactions and pain at a higher
frequency than certolizumab, although the two have not been directly compared.
The use of these agents during pregnancy and breast feeding is discussed elsewhere.
(See "Fertility, pregnancy, and nursing in inflammatory bowel disease", section on
'Anti-TNF agents'.)

Infliximab Prior to the introduction of biologic agents in the late 1990s, patients with
moderate to severe Crohn's disease or fistulous Crohn's disease had few nonsurgical options.
Infliximab is a chimeric mouse/human monoclonal antibody against tumor necrosis factor
alpha. It is a powerful tool for the treatment of moderately to severely active Crohn's disease
that is refractory to conventional therapy. Treatment can be effective in patients with and
without fistulizing disease (including those with internal fistulae, such as enterovesicle
fistulae).

Clinical trials and experience have demonstrated significant utility of infliximab for induction
of remission in moderately active, steroid refractory Crohn's disease and for maintenance of
remission in these patients for up to 54 weeks after initial infusion. In addition, its use has
been associated with improved quality of life. (See "Infliximab in Crohn's disease".)

At the present time, we suggest that infliximab not be used as first-line therapy until
appropriate clinical trials have demonstrated its value as primary therapy and the long-term
effects of infliximab have been fully evaluated. Infliximab should be used primarily in
patients who are refractory to standard therapy or in patients who are steroid dependent, in
order to help taper them off of steroids and transition them to effective long-term
maintenance therapy using infliximab.
Adalimumab and certolizumab pegol The roles of adalimumab and certolizumab for
treatment of Crohn's disease are evolving. Similar to infliximab, these agents are probably
best reserved for patients refractory to primary therapy or who are steroid dependent. They
are also options for patients who have lost response to or had an adverse reaction to
infliximab. (See "Adalimumab for treatment of Crohn's disease in adults" and "Certolizumab
pegol for treatment of Crohn's disease in adults".)

Safety of anti-TNF therapies A number of adverse events have been described following
treatment with anti-TNF-alpha agents. These are summarized separately along with
recommendations for screening patients prior to starting these medications. (See "Tumor
necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-
alpha inhibitors: Risk of bacterial, viral, and fungal infections" and "Tumor necrosis factor-
alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors:
Risk of malignancy".)

Natalizumab An alternative to anti-TNF therapy is natalizumab. Natalizumab is a


humanized monoclonal antibody directed against alpha-4 integrin. It acts by blocking
leukocyte migration to sites of inflammation. The use of natalizumab has been limited by its
association with progressive multifocal leukoencephalopathy. (See "Natalizumab for
treatment of Crohn's disease in adults" and "Progressive multifocal leukoencephalopathy:
Epidemiology, clinical manifestations, and diagnosis".)

Continued disease resistance There are two medical approaches to patients with active
Crohn's disease despite therapy with 5-ASA agents, antibiotics, immunomodulators, and/or
biologic agents: chronic low-dose steroid therapy and total parenteral nutrition. In addition,
surgery should be considered if a limited resection or other conservative procedure is
possible. (See "Surgical management of inflammatory bowel disease".)

Some patients can only achieve a relative degree of remission with low-dose prednisone.
Such patients should be maintained on the lowest dose that results in decreased symptoms;
alternate-day therapy can be tried for maintenance to minimize toxicity [12]. This approach
should be considered only in patients who have failed both immunomodulator and biologic
therapy since maintenance glucocorticoids have not been proven to reduce the rate of relapse
and are associated with many side effects [13]. (See "Major side effects of systemic
glucocorticoids".)

An alternative for steroid-refractory Crohn's disease is total parenteral nutrition (TPN) or


enteral feeding with an elemental or polymeric diet [14]. In a retrospective study of 100
patients treated with TPN and complete bowel rest, 77 achieved clinical remission [15]. The
remission rates were similar in patients with subacute bowel obstruction, inflammatory
masses, and uncomplicated severe active disease; approximately 60 percent of these patients
were in remission at one year. A lower initial response rate (63 percent) and one year
remission rate (36 percent) were seen in patients with fistulae.

However, patients may relapse when feedings are resumed. In addition, many patients will
not tolerate subsequent attempts at enteral feeding, and long-term TPN carries the risk of line
sepsis and thrombophlebitis. Nevertheless, these nutritional approaches should be considered
in refractory patients and can be lifesaving in those with short bowel syndrome.
VENOUS THROMBOEMBOLISM Studies have demonstrated an increased risk of
venous thromboembolism and pulmonary embolism in patients with IBD in both population-
based and hospital-based cohorts [16-18]. Current guidelines recommend prophylaxis for
venous thromboembolism or consideration of prophylaxis for hospitalized patients with IBD
[19,20]. (See "Prevention of venous thromboembolic disease in medical patients", section on
'Prevention of VTE'.)

MEDICAL MANAGEMENT OF CROHN'S DISEASE COMPLICATIONS

Fistulae The transmural inflammatory nature of Crohn's disease predisposes to the


formation of fistulae, a complication that may dominate the clinical picture (picture 1). The
drugs with the best established roles for the medical treatment of active Crohn's fistulous
disease are infliximab, azathioprine, and 6-MP. Steroids and sulfasalazine have not been
successful for inducing fistula closure [21]. A meta-analysis found that patients treated with
biologic therapy were less likely than patients treated with placebo to have a nonhealing
fistula (RR 0.88) [6].

For most patients with fistulae, especially those with actively draining fistulae or high output
enteroenteric fistulae, we suggest infliximab 5 mg/kg administered at weeks 0, 2, and 6. We
do not generally use infliximab in conjunction with azathioprine or 6-MP due to a possible
increased risk of hepatosplenic T-cell lymphoma. (See "Infliximab in Crohn's disease",
section on 'Use of immunosuppressive agents in combination with infliximab'.)

Traditionally, patients with perianal fistulae have been managed with antibiotics, though the
data supporting this practice are limited. (See "Perianal complications of Crohn's disease",
section on 'Patients with mild to moderate symptoms'.)

Patients with enterovesical fistulae present with recurrent polymicrobial urinary tract
infections, pneumaturia, and fecaluria. Antibiotics will usually control the urinary tract
infection, but azathioprine or 6-MP should be considered to heal the fistula. Most patients
with this complication will ultimately require surgery. However, some patients have been
maintained on courses of antibiotics and continuous immunomodulator therapy [21].

Localized peritonitis Patients with small bowel Crohn's disease frequently present with
fever, chills, and right lower quadrant pain associated with leukocytosis. Such patients have
often suffered a microperforation with localized peritonitis that is contained by the
surrounding mesentery and bowel loops. Appendicitis in the patient without prior
appendectomy is also a consideration in this setting. An abdominal and pelvic computed
tomography scan at the time of admission may help to distinguish among the diagnostic
possibilities.

The management of localized peritonitis includes bowel rest and broad-spectrum antibiotics.
A response to therapy is usually seen within three to four days and intravenous antibiotic
therapy is continued for 7 to 10 days. A subsequent two- to four-week course of outpatient
oral therapy with ciprofloxacin and metronidazole should be considered. Intestinal resection
should be considered in nonresponders.

There is some controversy as to the role of glucocorticoids in this setting. For patients already
on steroids, a small increase in the dose may be required. However, for those not previously
on steroids, we suggest withholding steroids to avoid masking any further sepsis. There are,
however, few data demonstrating an increase in complications in such patients who receive
steroid therapy, though one study did show an increase in the risk of developing an
intraabdominal or pelvic abscess in patients with penetrating Crohn's disease who received
steroids (RR 9.0) [22].

Abscesses The management of patients with abscesses depends upon the clinical setting,
history of prior bowel surgery, and characteristics of the abscess. As a general rule, three
approaches have been described: medical management with antibiotics (and possibly
steroids), percutaneous drainage, and surgery with resection of involved intestinal segments.

The largest series comparing these approaches included a group of 51 patients who were
identified retrospectively from medical charts covering a 10-year period [23]. Patients who
had undergone surgical management were significantly less likely to develop a recurrent
abscess compared with those who had been managed with antibiotics (with or without
steroids) or percutaneous drainage (12 versus 56 percent). Nevertheless, medical management
and percutaneous drainage prevented subsequent surgery in nearly one-half of patients during
an average of 3.75 years of follow-up, suggesting that it is a reasonable approach for some
patients. Similar results for percutaneous drainage have been described in other reports with
long-term follow-up [24].

Small bowel obstruction Small bowel obstruction is common in longstanding Crohn's


disease. It may result from a stricture causing mechanical obstruction, a stenotic area with
superimposed inflammation and spasm, a stenotic area in which undigested food has
impacted, an enterolith or, in patients who have had prior surgery, intestinal adhesions.

Affected patients most commonly present with partial obstruction and, except in those who
have had an adhesion, the mechanism is non-strangulating. Conservative therapy with
intravenous hydration, nasogastric suction, and parenteral nutrition is often successful, with a
response seen within 24 to 48 hours. Parenteral glucocorticoids should be considered in
nonresponders. Surgery is reserved for those patients who do not respond to these
noninvasive measures or who have evidence of small bowel ischemia. (See "Surgical
management of inflammatory bowel disease".)

Medical prophylaxis of postoperative Crohn's disease


Authors
Puneeta Tandon, MD, FRCPC
Robert M Penner, BSc, MD, FRCPC, MSc

INTRODUCTION Crohn's disease is a chronic inflammatory bowel disease that results in


significant morbidity and economic burden [1,2]. Surgical intervention rates are
approximately 70 percent after ten years from diagnosis, although improvements in medical
therapy may be decreasing the need for surgery [3,4]. The most common indications for
surgery are failure of medical therapy and intestinal obstruction. The high rate of
postoperative recurrence has stimulated multiple studies of prophylactic therapy.

RECURRENCE Postoperative recurrence can be defined by endoscopic findings or


clinical symptoms.
Endoscopic Endoscopic recurrence precedes clinical recurrence. It occurs most commonly
at the site of surgical anastomosis, and is characterized initially by aphthous and serpiginous
ulceration [5]. A meta-analysis of the placebo rates of severe endoscopic recurrence in
postoperative Crohn's disease estimated that among patients treated with placebo, the clinical
relapse rate was 24 percent and the severe endoscopic recurrence rate was 50 percent [6].

Other studies have provided estimates of the time frame of endoscopic recurrence. In a cohort
of 89 patients who had undergone ileal resection, endoscopic findings were present in 73
percent of patients within one year and 85 percent within three years of resection [5,7].
Similar findings were described in another report in which 72 percent of patients had
endoscopic findings present after one year without a significant increase in recurrence in a
10-year period (77 percent) [8].

The recurrence rate may be much lower in patients with Crohn's colitis who undergo a total
colectomy and ileostomy as compared to ileal resection. Such patients have only a 10 percent
recurrence rate in the small intestine at 10 years, usually in the bowel immediately above the
stoma [4,9,10].

The explanation for this difference in recurrence rate between those who have a resection and
anastomosis versus colectomy and ileostomy may be related to contact with intestinal
contents in the neoterminal ileum [11,12]. In an illustrative report, three patients with Crohn's
disease who had undergone a curative ileocolonic resection with ileocolonic anastomosis and
temporary protective proximal loop ileostomy had no evidence of ileitis six months after
resection [11]. However, infusion of the ileostomy contents into the bypassed ileal segment
for seven days resulted in morphologic evidence of focal inflammation on ileal biopsy. Thus,
intestinal contents including bile salts, digestive enzymes, bacteria, and dietary antigens may
trigger the postoperative recurrence of Crohn's disease in the terminal ileum proximal to the
ileocolonic anastomosis in the first days after surgery. These findings suggest that
prophylactic therapy should begin soon after resection and anastomosis are performed, and
continue indefinitely.

Whether the severity of endoscopic findings correlates with the clinical course is uncertain.
While some studies have found that severe radiologic or endoscopic findings (such as
stricture, deep ulceration, cobblestoning, or fistulization) predicted symptomatic recurrence
[5,13], others have shown poor correlation between symptoms, endoscopy, and repeat
surgery [13-16].

Clinical Clinical recurrence is based upon signs and symptoms of disease. The Crohn's
disease activity index (CDAI) has often been used to provide a more objective measure of
clinical activity (calculator 1). In one report, symptomatic recurrence based on elevation of
the CDAI was observed in 20 and 34 percent of patients with endoscopic recurrence at one
and three years, respectively [5]. Clinical recurrence rates as high as 55 percent at 5 years and
76 percent at 15 years have been described in other reports [14].

A meta-analysis of the placebo rates of clinical relapse in postoperative Crohn's disease


estimated that among patients treated with placebo, the pooled clinical relapse rate was 24
percent [6]. Follow-up duration among the included trials ranged from three to up to five
years. However, there was significant variability among the studies in part due to differences
in the length of follow-up.
Repeat surgery is required in approximately 25 percent of patients within five years [17-20].
After ileocolonic resection and anastomosis, approximately 50 percent of patients presenting
with clinical symptoms have repeat surgery within 10 years [17-20].

PREDICTORS OF RECURRENCE Disease patterns, surgical techniques, and clinical


variables have been found to be risk factors for postoperative recurrence, although the quality
and consistency of the data are variable [21].

Disease duration Shorter preoperative disease duration is associated with an


increased rate of recurrence [22].
Widespread disease The presence of proximal gastrointestinal (duodenum or
jejunum) and diffuse widespread disease that involves the colon has been associated
with clinical and endoscopic recurrence [18,23-26].
Stricturing versus penetrating disease The data regarding this feature are conflicting.
One series found that recurrence after conservative surgery was more likely in young
patients with stricturing disease [27]. In contrast, another series found no cases of
recurrence within three years in 12 patients with stricturing disease compared with 12
of 22 patients (55 percent) who had penetrating disease [28].
Fistulization Conflicting data also exist regarding whether presentation with
intestinal fistulas increases the risk of recurrence [22,29-31]. One report suggested
that the risk of recurrence with another fistula was increased, although the overall risk
of recurrence was not [32]. A later study suggested a significantly increased risk of
recurrence in patients with fistulizing disease (odds ratio 4.09) [33]. In general,
patients with a history of fistulas have a worse prognosis [10].
Perianal disease The presence of perianal fistulous disease is a risk factor for
increased risk of recurrence [34].
Surgical technique Side to side anastomosis of an ileocolic resection is associated
with lower recurrence rates than end to end anastomosis [35].
Smoking Several studies have suggested that smoking increases the risk of clinical,
endoscopic, and surgical recurrence [36-40], although a larger prospective population-
based study did not support this conclusion [41].
Genetics Whether genetic factors predict disease recurrence has not been well
studied. One report found that patients with the Nod2/CARD15 mutation had a higher
rate of postoperative recurrence and required surgery earlier compared with patients
with Crohn's not carrying the mutation [42]. (See "Immune and microbial
mechanisms in the pathogenesis of inflammatory bowel disease".)

POSTOPERATIVE SURVEILLANCE Colonoscopy is the best modality for assessing


recurrence of mucosal Crohn's disease at anastomotic sites and the ileum. Since mucosal
inflammation precedes clinical recurrence, we suggest performing a colonoscopy within the
first year after surgery and then treatment should be modified based on patient's risk factors
and endoscopic findings.

MEDICAL PROPHYLAXIS The high rate of postoperative recurrence has stimulated


multiple studies of prophylactic therapy. However, optimal approaches have not yet been
defined. A meta-analysis, including 23 studies, of the use of medical therapies for the
prevention of postoperative recurrence of Crohn's disease concluded that nitroimidazole
antibiotics, mesalamine, and immunosuppressive therapies with azathioprine/6-
mercaptopurine (AZA/6-MP), all appear superior to placebo for the prevention of
postoperative recurrence of Crohn's disease [43]. There were insufficient randomized
controlled trials of infliximab, budesonide, tenovil, interleukin 10, and probiotics to draw
conclusions regarding efficacy. Despite several randomized trials evaluating the efficacy of
sulfasalazine in the prevention of postoperative recurrence, the benefit of their use has not
been established [43-46].

The risks and benefits of individual treatments need to be weighed. As an example, the use of
immunosuppressive therapy in the postoperative period may be considered problematic.
However, a review of perioperative safety profiles of drugs commonly administered for
Crohn's disease found compelling evidence of adverse effects on wound healing only for
glucocorticoids, but not for immunomodulators or anti-tumor necrosis factor (anti-TNF)
agents [47]. (See "Immunomodulator therapy in Crohn's disease" and "Infliximab in Crohn's
disease".)

Antibiotics The observation that recurrent disease develops only when the mucosa is re-
exposed to luminal contents suggests that bacteria may have a role in promoting disease
recurrence and provides a rationale for controlled trials of antibiotic prophylaxis [11,12].

In two studies, the use of nitroimidazole antibiotics appeared to reduce the risk of clinical and
endoscopic recurrence relative to placebo [48,49].

An initial trial included 60 patients who underwent curative ileal resection and
primary anastomosis, who were randomly assigned to three months of therapy with
metronidazole (20 mg/kg daily) or placebo one week after surgical resection [48].
Compared with placebo, metronidazole therapy resulted in a lower rate of total (52
versus 75 percent) and severe (13 versus 43 percent) endoscopic recurrence in the
neoterminal ileum at three months and a lower clinical recurrence rate at one year (4
versus 25 percent).
A second study included 80 patients who had undergone ileal or ileocolonic resection
who were randomly assigned to ornidazole (not available in the United States) or
placebo for one year [49]. The clinical recurrence rate was significantly lower in the
ornidazole group at 12 months (8 versus 38 percent). Adverse effects requiring
discontinuation of medication were significantly more common in the treatment group
(32 versus 13 percent). The majority of dropouts were due to a metallic taste and
gastrointestinal upset. Paresthesias and peripheral neuropathy were self-limited after
discontinuation of the drug and overall side effects were less common than have been
reported with metronidazole.

These data suggest a modest benefit from the short-term use of nitroimidazole antibiotics in
preventing postoperative recurrence during the first year after resection in patients with ileal
or ileocolonic disease. However, their role is uncertain, particularly considering the need for
long-term therapy and the potential for adverse effects when these medications are prescribed
for long periods.

Mesalamine Multiple randomized controlled trials have evaluated mesalamine agents for
prevention of postoperative recurrence but have produced discordant results [50-56]. A 2011
meta-analysis of nine randomized controlled trials found that mesalamine agents were more
effective than placebo for preventing relapse following surgery (odds ratio 0.7) [57]. The
number needed to treat to prevent one recurrence was approximately 16 to 19.
A 2009 meta-analysis included five studies that examined the effect of mesalamine compared
with placebo. That analysis found that mesalamine therapy was associated with a
significantly reduced risk of severe endoscopic recurrence (RR = 0.5) and clinical recurrence
(RR = 0.76) compared with placebo [43]. Patient withdrawal and serious adverse events were
similar in both treatment groups.

Another study of 256 patients compared the effect of high dose mesalamine (4 grams daily)
versus low dose (2.4 grams daily) with placebo for one year following resection. The rate of
any endoscopic recurrence at one year was greater in the low-dose group than in the high-
dose group (62 versus 46 percent), yet there was no significant difference in the rate of severe
endoscopic recurrence between the two doses [58].

These data suggest that mesalamine prophylaxis is associated with a modest benefit in
preventing relapse. Although there remains uncertainty about its efficacy, mesalamine is
generally safe and well tolerated and, thus, it is a reasonable option in some patients. Such
patients include those who appear to benefit from mesalamine prior to resection, those
without high-risk features for relapse, or those unwilling to consider agents with more side
effects.

Azathioprine and 6-MP Most of the experience with AZA (2.0 to 2.5 mg/kg daily) or 6-
MP (50 mg daily) following surgical resection has come from patients with Crohn's disease
who have undergone intestinal resection, rather than colectomy. In patients requiring
resection secondary to complications such as obstruction, fistula, perforation, or abscess, it is
preferable not to resect other areas of the intestinal tract that are minimally involved, and in
which complications have not occurred. In these circumstances, AZA or 6-MP may be
effective for maintaining remission in the minimally involved areas, and delaying recurrence
in the area of resection.

The magnitude of benefit of AZA and 6-MP was best demonstrated in two meta-analyses of
controlled trials involving patients who had undergone surgery for Crohn's disease [43,59].
Compared with placebo, AZA or 6-MP was associated with a significantly decreased risk of
clinical recurrence (RR = 0.59) and severe endoscopic recurrence (RR = 0.64) [43]. Both
agents were significantly more effective than placebo with or without antibiotic induction and
were also more effective than mesalamine in preventing clinical recurrence at one [43] and
two years [59], and preventing severe postoperative endoscopic recurrences at one year
[43,59]. While drug withdrawal because of adverse effects was significantly higher in the
patients treated with AZA or 6-MP (17 versus 10 percent) than in placebo, with or without
antibiotic induction or mesalamine, serious adverse events were similar among treatments
[59].

In contrast to the findings in these meta-analyses, a study performed in a highly selected


patient population of laparoscopically treated Crohn's disease patients with terminal ileal
disease found that the use of immunosuppressive prophylaxis (mostly AZA and 6-MP) was
not associated with a delay in recurrence [60].

The optimal duration of therapy with immunomodulators is unknown. In a study of 326


Crohn's disease patients after their first intestinal surgery, treatment with AZA or 6-MP for
>36 months decreased the risk of surgical recurrence by 41 percent compared with no
treatment or treatment for less than 3 months [40]. (See "Immunomodulator therapy in
Crohn's disease".)
Other therapies Other therapies have been reported for the medical prophylaxis of
postoperative Crohn's disease; however, there are insufficient randomized controlled trials to
draw conclusions.

Infliximab There is limited experience with infliximab for prevention of relapse. A


nonrandomized study compared seven patients who received infliximab plus low dose
methotrexate with 16 patients who received mesalamine alone [66]. None of the patients in
the infliximab/methotrexate group had endoscopic or clinical recurrence during two years of
follow-up compared with 12 of 16 patients with recurrence in the mesalamine group.

A randomized controlled trial in 24 patients who had undergone ileocolonic resection found a
significantly lower endoscopic recurrence rate one year postoperatively with
infliximab compared with placebo (9 versus 85 percent) [67]. As a secondary outcome, the
trial also showed a nonsignificant trend towards improved clinical remission rates.

In a postoperative cohort study of 12 patients treated with infliximab (5 mg/kg at two, six,
and eight weeks following surgery and then every eight weeks for 24 months), 10 of 12
patients experienced endoscopic relapse within four months of discontinuing the medication
[68]. All patients without recurrence were then treated with a lower dose of infliximab (3
mg/kg every eight weeks) with resolution of endoscopic disease in all patients at one year.

Adverse events such as infusion reactions, demyelinating disease, heart failure, and less
common side effects have been described following treatment with infliximab. These risks
must be weighed against the potential benefits when considering this agent for prevention of
relapse. (See "Infliximab in Crohn's disease" and "Tumor necrosis factor-alpha inhibitors: An
overview of adverse effects".)

Elemental enteral nutrition A single small nonrandomized trial in 40 patients evaluated


long-term postoperative enteral nutrition for prevention of endoscopic and clinical relapse
[69]. Patients were given an unrestricted, unsupplemented postoperative diet or a low fat diet
with nocturnal enteral supplementation with an elemental formulation. After 12 months,
clinical recurrence rates were significantly lower in the supplemental group (5 versus 35
percent).

Patients were selected for enteral nutrition if they had previously demonstrated compliance
with such an approach. In a previous study, the authors noted low compliance with long-term
enteral feeding. Thus, further studies are needed to clarify the efficacy and acceptability of
this approach.

INFORMATION FOR PATIENTS UpToDate offers two types of patient education


materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.
SUMMARY AND RECOMMENDATIONS Postoperative recurrence of Crohn's disease
can be defined by endoscopic findings or clinical symptoms. Consensus has not been
achieved on optimal strategies for prevention of recurrent Crohn's disease after surgery.

Disease patterns, surgical techniques, and clinical variables appear to be risk factors
for postoperative recurrence. We recommend identifying those patients at high risk
and considering the risk versus benefit of treating these patients more aggressively.
(See 'Predictors of recurrence' above.)
Smoking cessation should be strongly encouraged for all patients who smoke based
on the benefits of smoking cessation in general and the benefits for Crohn's disease
recurrence. (See 'Predictors of recurrence' above.)
We suggest extended (often lifelong) prophylactic medical therapy for all patients
with Crohn's disease after surgery (Grade 2B).

Treatment options with demonstrated efficacy include mesalamine, imidazole antibiotics,


azathioprine, and 6-MP:

We use mesalamine (3 to 4 g daily) in patients who appeared to benefit from


mesalamine prior to resection and who do not have high-risk predictive factors for
recurrence as listed above, or those unwilling to consider agents with potential for
more side effects. (See 'Predictors of recurrence' above and 'Mesalamine' above.)
Imidazole antibiotics have more consistent clinical effects than mesalamine in the
short-term, but their long-term use (beyond three months) is greatly limited by side
effects. We recommend three months of imidazole antibiotic maintenance therapy in
all patients starting immunosuppressive therapy (see below) and patients unwilling to
consider other long-term therapies or in those with contraindications to
immunosuppressive therapy. (See 'Antibiotics' above.)
We use long-term azathioprine (2.0 to 2.5 mg/kg daily) or 6-MP (1.5 mg/kg daily)
with metronidazole (250 mg three times daily for the first three months) in patients
who have high-risk predictive factors for recurrence or poor outcomes following
recurrence. (See 'Azathioprine and 6-MP' above.)

Factors that put patients at increased risk include:

Jejunal or extensive ileal-colonic disease


Initial presentation requiring surgery
Age less than 30 years
Fistulizing disease
Patients undergoing a second resection
Failure of medical management

In patients with active disease who require resection despite taking adequate doses of
azathioprine or 6-MP, we consider anti-tumor necrosis factor (anti-TNF) maintenance
therapy postoperatively

Infliximab in Crohn's disease


Authors
Richard P MacDermott, MD
Gary R Lichtenstein, MD

INTRODUCTION Infliximab (Remicade) is a chimeric IgG 1 monoclonal antibody


comprised of 75 percent human and 25 percent murine sequences, which has a high
specificity for and affinity to tumor necrosis factor (TNF)-alpha. Infliximab is available for
treatment of patients with moderately to severely active Crohn's disease and patients with
fistulizing Crohn's disease, who have had an inadequate response to conventional therapy.

TNF-alpha has several biologic activities that may be directly related to the pathogenesis of
inflammatory bowel disease and there is increasing evidence suggesting a central role for
TNF-alpha in Crohn's disease [1]. As an example, stool TNF-alpha levels are elevated in
patients with Crohn's disease and correlate with disease activity [2]. (See "Immune and
microbial mechanisms in the pathogenesis of inflammatory bowel disease".)

Infliximab neutralizes the biologic activity of TNF-alpha by inhibiting binding to its


receptors. However, infliximab's mechanism of action most likely involves the destruction of
activated effector cells through apoptosis and/or other mechanisms [3-7]. Treatment of
patients with infliximab markedly decreases endoscopic and histologic disease activity in
Crohn's colitis [8,9].

When given as a single infusion intravenously at 5 mg/kg body weight, infliximab has a half
life of approximately 10 days. Infliximab does not accumulate when given in three doses at
zero, two, and eight weeks, or when given in repeated doses at eight-week intervals.

The role of infliximab in Crohn's disease will be reviewed here. A summary of clinical trials
and prescribing information is also provided by the manufacturer, and is available on their
website (www.centocor.com). Conventional, alternative, and other types of
immunomodulator therapy for Crohn's disease are discussed separately. (See appropriate
topic reviews.) The American Gastroenterological Association (AGA) guideline for
glucocorticoids, immunomodulators, and infliximab in inflammatory bowel disease [10], as
well as other AGA guidelines, can be accessed through the AGA website at
www.gastro.org/practice/medical-position-statements. In addition, the American College of
Gastroenterology (ACG) has issued practice guidelines that can be accessed through the ACG
website at: www.acg.gi.org/physicians/clinicalupdates.asp#guidelines.

INDUCTION OF REMISSION IN PATIENTS WITH ACTIVE CROHN'S


DISEASE Multiple studies have evaluated the efficacy of infliximab in patients with
active, non-fistulizing Crohn's disease. Several centers have also published their clinical
experience with infliximab, which provides further insight into the effectiveness of infliximab
outside of the clinical trials setting. A meta-analysis found that patients treated with
infliximab were less likely to fail to achieve remission than patients treated with placebo (RR
0.68) [11]. (See 'Experience in clinical practice' below.)

Approval was based upon the results of two randomized controlled trials (a single dose trial
and multiple dose trial) involving a total of 653 patients with moderately to severely active
Crohn's disease (CDAI 220 and 400 (calculator 1)) who had responded inadequately to
conventional therapy [12,13].
The single dose trial included 108 patients with moderate to severe Crohn's disease who were
randomly assigned to a single two-hour intravenous infusion of either placebo or
infliximab [12]. The dose-ranging portion of the study identified the most effective single-
infusion dose by comparing doses of 5, 10, and 20 mg/kg with placebo. At four weeks of
follow-up, 22 of 27 patients (81 percent) who received infliximab at a dose of 5 mg/kg, 14 of
28 (50 percent) who received 10 mg/kg, and 18 of 28 (64 percent) who received 20 mg/kg
had a clinical response compared to 4 of 24 (17 percent) who received placebo. Remission
occurred significantly more often in those randomized to infliximab (33 percent of the treated
group overall versus 4 percent of the placebo group). The clinical response persisted in many
patients over the 12 weeks of follow-up (41 versus 12 percent). Statistical analyses
demonstrated no effect of concomitant medication or disease location on the response rates or
remission rates. There was no statistically significant difference between the three doses of
infliximab used in the trial, although the 5 mg/kg body weight dose consistently yielded the
highest response and remission rates.

When comparing the efficacy of infliximab, infliximab plus azathioprine or and azathioprine
therapy alone in patients who had not undergone, those treated with infliximab alone or in
combination with azathioprine were more likely to have a glucocorticoid free clinical
remission (44 and 57 versus 30 percent respectively) at week 26.

Results of the multiple dose trial (A Crohn's Disease Clinical Trial Evaluating Infliximab in a
New Long-Term Treatment Regimen [ACCENT I]) are discussed below. (See 'Maintenance
of response and remission' below.)

INDUCTION OF REMISSION IN FISTULIZING DISEASE Infliximab was approved


for use in fistulizing Crohn's disease based upon the results of two randomized controlled
trials [14,15].

One study included 94 patients who were unresponsive to at least three months of
conventional therapy who were randomly assigned to receive three doses of infliximab (5 or
10 mg/kg) or placebo at weeks 0, 2, and 6 [14]. After a follow-up of 26 weeks, significantly
more patients receiving infliximab had a reduction in the number of draining fistulas without
requiring an increase in other medications (68 and 56 percent in the 5 or 10 mg/kg arm,
respectively, versus 26 percent for placebo). Closure of all fistulas was observed in 55 and 38
percent of patients receiving the 5 and 10 mg/kg dose, respectively, compared to 13 percent
of those receiving placebo. The median time to response was two weeks, and the median
duration of response was 12 weeks. The effects seen with infliximab on fistulas were not
dose-dependent. This study demonstrated the rapid response that infliximab can achieve
when used for fistulizing Crohn's disease. This study did not address issues such as relapse
rate after initial success or the potential benefit of combining infliximab with
immunomodulators or antibiotics.

Advantages to concomitant immunosuppressive fistula therapy for patients on


infliximab have been reported [16]. These include a decrease in the rate of adverse reactions
related to antibody formation to infliximab, the preservation of drug efficacy, and more
prolonged response rates

Whether the combination of infliximab and oral antibiotics improves efficacy is unclear. A
randomized controlled trial involving 24 patients with severe perianal disease concluded that
the combination of infliximab plus ciprofloxacin (500 mg orally twice daily) was more
effective than infliximab alone [17].

MAINTENANCE OF RESPONSE AND REMISSION Scheduled, maintenance therapy


with infliximab has substantial clinical benefits (compared with episodic treatment) in
patients who achieved remission with initial infliximab induction therapy [13,18-21]. Such
therapy:

Is associated with an increased likelihood of achieving and maintaining remission


Improves quality of life
Decreases glucocorticoid requirements
Reduces the likelihood of developing antibodies to infliximab
Results in fewer hospitalizations

Patients without fistulizing disease The largest and most comprehensive study of
maintenance therapy (ACCENT I) was a multicenter randomized double-blind international
trial studying retreatment and remission maintenance in Crohn's disease patients treated with
infliximab [13,20]. The goal of the ACCENT I trial included a number of objectives:

Evaluation of every eight-week maintenance therapy as compared to a single dose of


infliximab
Determination of response (CDAI decrease >70 and 25 percent decrease from
baseline), remission (CDAI <150), and quality of life (as assessed by measurement of
the IBDQ)
Documentation of the time to loss of response
Evaluation of the steroid sparing effect of infliximab
Determination of the effectiveness of infliximab treatment on mucosal healing at
week 10 and week 54
Documentation of the safety of long-term retreatment therapy with infliximab

The study included patients who had moderate to severe non-fistulizing Crohn's disease
(CDAI 220 to 400) for at least three months. Patients who were receiving therapy with 5-
ASA agents, glucocorticoids, azathioprine, or 6-MP were eligible.

The study design was complex, in part to allow for comparisons of several subgroups of
patients and also to permit additional therapy in patients who were clinically unwell. At week
0, all patients received a single 5 mg/kg intravenous infusion of infliximab. They were then
stratified according to their response and then randomly assigned to one of three groups:

Group 1 Placebo infusions at weeks 2, 6, and every 8 weeks thereafter until week 46
Group 2 5 mg/kg of infliximab at weeks 2 and 6 followed by 5 mg/kg every 8 weeks
Group 3 5 mg/kg of infliximab at weeks 2 and 6 followed by 10 mg/kg every 8
weeks thereafter

At week 14 or later, patients who had responded at anytime to infliximab therapy but then
worsened clinically were eligible to crossover to active, episodic treatment with infliximab
(5, 10, 15 mg/kg for patients originally assigned to group 1, 2, and 3, respectively). The
findings have been reported in a series of publications, which will be summarized below
[13,19,22,23].
Initial clinical response A total of 473 of 573 (83 percent) patients ultimately responded to
treatment [13]. Of the 573 patients entered into the study, 335 (58 percent) had a clinical
response to infliximab at two weeks. Of the 473 responders, 325 (69 percent) responded by
week 2, and another 127 (27 percent) by week 10.

After 10 weeks, there was a statistically significant improvement in the response and
remission rates in the two groups that received scheduled maintenance therapy (ie, groups 2
and 3). Sixty-five percent of the patients had a clinical response (including 40 percent who
achieved remission), while 31 percent demonstrated mucosal healing. In contrast, only 28
percent of patients who received a single initial dose had entered remission.

Maintenance The initial clinical response was maintained significantly more often in the
two groups that received scheduled maintenance therapy (43 and 53 versus 17 percent in the
5 mg/kg, 10 mg/kg versus single dose groups, respectively). The following other observations
were made:

After 54 weeks, the median duration of response was only 19 weeks for patients in the
single dose group, compared to 38 weeks for the infliximab 5 mg/kg every eight
weeks group, and greater than 54 weeks for patients in the infliximab 10 mg/kg every
eight weeks group.
In patients who initially had a clinical remission, maintenance of remission occurred
in only 14 percent of patients in the single dose group compared to 28 percent of
patients maintained on infliximab 5 mg/kg every eight weeks and 38 percent of
patients on infliximab 10 mg/kg every eight weeks [13].
CDAI scores were consistently better in the 10 mg/kg scheduled maintenance groups
from weeks 10 to 54, while response and remission rates were significantly higher
from weeks 10 to 30 in the scheduled maintenance groups.
Antibodies against infliximab developed in a lower proportion of patients in the
scheduled maintenance groups (9 and 10 versus 28 percent in the 5 and 10 mg/kg
versus the single dose groups, respectively).
Patients receiving scheduled therapy had significantly fewer Crohn's disease-related
hospitalizations (23 versus 38 percent) and surgeries (3 versus 7 percent).
Between 31 to 38 percent of patients eventually failed treatment despite higher doses
of infliximab. Dose escalation was required in 49 percent of the single-dose group, 30
percent of the 5 mg/kg group, and 31 percent of the 10 mg/kg group.

Steroid tapering After 54 weeks clinical remission and successful tapering of the patient
off steroids was observed significantly more often in the two scheduled maintenance groups
(28 and 32 versus 9 percent in the 5 and 10 mg/kg groups versus the single infusion group,
respectively). Of particular importance, significantly more patients receiving scheduled
infliximab had discontinued glucocorticoids and were also in clinical remission with a CDAI
<150 (31 and 36.8 versus 10.7 percent for the 5 mg/kg and 10 mg/kg doses versus placebo,
respectively).

Quality-of-life Patients assigned to the scheduled maintenance groups had significant


improvement in quality-of-life as measured by a validated instrument (IBDQ) [19].
Furthermore, patients who could be maintained in remission had increased employment and
fewer hospitalizations and surgeries [22].
Toxicity Infusion reactions were more frequent in the regularly scheduled groups (a
reaction occurred in 6 percent of each regularly scheduled 5 mg/kg infusion compared with 3
percent of each episodic infusion). Otherwise, toxicity was generally similar between the
groups. Serious infections occurred in 3 to 4 percent of all groups. There were six
malignancies (1 percent overall), all randomly distributed between the groups. There were
three deaths (one due to sepsis).

Limitations There are potentially important limitations to the ACCENT I findings [23].

Only 27 to 35 percent of patients were taking concomitant immunosuppressive agents,


such as 6-MP, azathioprine, or methotrexate, which inhibit antibody formation when
infliximab is used while also helping to maintain remission. The study did not
compare outcomes of patients on these drugs versus those who were not receiving
them. As demonstrated in a subsequent randomized controlled trial, the combination
of azathioprine/6-MP plus infliximab (three infusions without maintenance therapy)
was significantly more effective than azathioprine/6-MP alone in achieving steroid-
free clinical remission at 24 weeks in patients who were steroid dependent [24]. The
benefit was seen particularly in those younger than 26, who had not received
thiopurines before, and who had colonic Crohn's disease. The steroid-free remission
rate at 52 weeks (40 percent) was comparable to that seen in ACCENT I. An ongoing
study is evaluating whether maintenance therapy with infliximab combined with
azathioprine/6-MP achieves an even greater long-term clinical benefit.
A statistically significant benefit on the clinical endpoints was observed only during
some of the time-points that were evaluated. The 10 mg/kg scheduled infusion dose
was significantly better at maintaining remission than the episodic group in only two
of the eight evaluated time periods. Similarly, a statistically improved clinical
response (ie, 70-point CDAI) was observed on only three time periods.
Only a minority of patients in the 5 mg/kg scheduled group completed the study as it
was designed (26 percent discontinued without crossover while 30 percent were
crossed to the 10 mg/kg rescue therapy). Thus, it is possible that the scheduled 5
mg/kg strategy is no better than the episodic strategy.

Use of immunosuppressive agents in combination with infliximab There are conflicting


opinions regarding the use of immunosuppressive agents in combination with infliximab.
When originally used, infliximab was given "on demand" (as needed). However, the long
intervals between infusions led to increased antibodies to infliximab, which were associated
with loss of response. The use of concomitant immunosuppressive agents decreased the rate
of formation of antibodies to infliximab and resulted in a better response and remission rates.

Data from the SONIC study demonstrated that patients with moderate to severe CD treated
with the azathioprine (2.5 mg per kg daily) in combination with infliximab (5 mg per kg at
weeks 0, 2, and 6 and then every eight weeks), or infliximab alone, were more likely to have
a glucocorticoid-free clinical remission than patients treated with azathioprine alone (57 and
44 versus 30 percent, respectively) [25].

However, the occurrence of hepatosplenic T-cell lymphomas (HSTCLs) in patients on


infliximab (or other anti-TNF biologics) in combination with azathioprine or 6-MP, along
with an increased incidence of opportunistic infections in patients on more than one
immunosuppressive agent, has led to the recommendation that infliximab be given as
monotherapy without concomitant immunosuppressives.
Long-term thiopurine use (more than two years) appears to be a common denominator in
cases of HSTCL, and may be particularly important in young men. In a systematic review
that included 36 patients with HSTCL, all patients had received a thiopurine (16 as
monotherapy and 20 in combination with infliximab) [26]. The duration of thiopurine use
was known in 30 patients, and in all but one case it had been used for at least two years prior
to the diagnosis of HSTCL (mean 5.5 years, range 1 to 13.5 years). Of the 31 patients whose
gender was known, 29 (94 percent) were male. In addition, of the 30 patients whose age was
known, 27 (90 percent) were under the age of 35 years.

Because of the risks of combination therapy, most pediatric gastroenterologists believe that
infliximab should only be used as monotherapy. Current estimates suggest that the risk of
HSTCL in patients with IBD who receive thiopurines is exceedingly rare, at 1:45,000
patients. This is estimated as follows: among the approximately 3.6 million patients with IBD
in the United States and Europe, there have been 36 cases of HSTCL; if 44.5 percent of this
group (1.6 million people) had been exposed to thiopurines, then the absolute risk is 1:44,444
[27]. However, based upon the available data, the risk in men under the age of 35 who are
exposed to thiopurines is significantly higher, on the order of 1:7500, and in those receiving
both thiopurines and anti-TNF agents the risk is approximately 1:3500 [26].

Because of the risks of combination therapy, consideration can be given to using combination
therapy initially and then transitioning to monotherapy with an anti-TNF agent. This
approach was examined in a study of patients whose disease had been controlled for at least
six months on maintenance infliximab combined with immunosuppressive agents [28].
Patients were randomly assigned to continue or stop the immunosuppressive agents while
continuing infliximab maintenance therapy for up to two years. The primary endpoint was the
proportion of patients who required a shortening of the infliximab dosing interval or stopped
infliximab therapy. Although this study has been criticized for being underpowered, a similar
proportion of patients achieved the primary endpoint (60 versus 55 percent, respectively).
Thus, discontinuation of immunosuppressive agents after six months did not adversely affect
either the response to infliximab or the rate of remission at the end of two years. C-reactive
protein levels were higher and infliximab trough levels were lower in the group randomly
assigned to stopping the immunosuppressive agents, but the clinical consequences were
unclear. The authors concluded that continuation of immunosuppressive agents beyond six
months offered no clear benefit over scheduled infliximab monotherapy.

Based upon the available data, we suggest continuing to use infliximab as monotherapy in
adult Crohn's disease patients with mild to moderate uncomplicated disease because the
SONIC study was carried out in Crohn's disease patients with moderate to severe disease
[25]. Consideration can be given to starting adult Crohn's disease patients with moderate to
severe disease on combination therapy on the basis of the results of the SONIC study. In
addition, when deciding upon what therapy to give, we consider the prognosis of the
patient. Combination therapy may be more appropriate in a patient with a poorer prognosis
(eg, patients with fistulizing disease, patients who require ongoing steroid use, or patients
who smoke), whereas patients with a better prognosis can be started on monotherapy with an
anti-TNF agent.

In patients on infliximab in combination with an immunosuppressive agent, we suggest either


using a low dose of the immunomodulator or discontinuing the immunosuppressive after six
months of combination therapy. In patients who have been on long-term immunomodulators
plus infliximab in combination for many years and who have had an excellent response or are
in remission, it is reasonable either to use a low dose of the immunomodulator or to
discontinue the immunomodulator.

Patients with fistulizing disease As noted above, ACCENT I excluded patients with
fistulizing disease. Such patients were the focus of a second major trial (ACCENT II), which
included 306 adults with one or more draining abdominal or perianal fistulas of at least three
months duration [15]. Prior medications included azathioprine or 6-MP in 92 to 96 percent of
patients, suggesting that this was a truly medically refractory group of patients. The
objectives and design of ACCENT II were similar to ACCENT I.

All patients initially received an initial series of infliximab (5 mg/kg) given at weeks 0, 2, and
6. At 14 weeks, those who responded (defined as at least a 50 percent reduction in the
number of draining fistulas) were randomly assigned to either maintenance placebo or
infliximab (5 mg/kg) given at weeks 14, 22, 30, 38, and 46 and then followed until week 54.
Patients who subsequently lost a response were eligible to be crossed to either a 10 mg/kg
dose (for those receiving the 5 mg/kg dose) or a 5 mg/kg dose (for those receiving placebo).
Those without a response were also randomly assigned to a maintenance infliximab regimen
(5 mg/kg crossing over to 10 mg/kg if no response) or placebo (crossing over to 5 mg/kg if no
response).

A total of 282 patients were available for analysis (24 were excluded for various reasons). Of
these, a total of 195 patients had a response by week 14 (64 percent). The following
summarizes the main findings:

Time to loss of response was significantly longer for patients assigned to maintenance
infliximab (more than 40 weeks versus 14 weeks).
At week 54, significantly more patients assigned to maintenance therapy had
complete absence of draining fistulas (36 versus 19 percent).
There were no significant differences in response rates among non-responders who
were assigned to continued treatment versus placebo (16 versus 21 percent).
Among 41 patients who responded but subsequently lost their response (and were
therefore crossed over from placebo to active treatment), 25 (61 percent) reestablished
a response. Similarly, 12 of 21 (57 percent) who lost a response on the 5 mg/kg dose
subsequently responded to the 10 mg/kg dose.
Response rates were similar among patients with and without antibodies to infliximab,
although the former were more likely to have infusion reactions.
Adverse events occurred in 92 percent of patients in the placebo maintenance group
and 89 percent of patients in the infliximab group. The most frequent events occurring
more often in the infliximab maintenance groups were infusion reactions,
development of antinuclear antibodies, and development of antibodies against double-
stranded DNA. There were two deaths reported during long-term follow-up. In
addition, there were two cases of rectal cancer (one in a 42-year-old and the other in a
36-year-old patient). Infections requiring antimicrobial therapy developed in nearly
one-third of patients including 5 percent with serious infection. Opportunistic
infections included one case of cytomegalovirus infection (occurring 39 days after the
third induction infusion) and one case of cutaneous nocardia infection (occurring
eight days after the first infusion). One patient developed multiple sclerosis.
In a follow-up report of 192 patients who were classified as responders and
randomized to maintenance infliximab (5 mg/kg every eight weeks) or placebo, those
receiving infliximab had significantly fewer hospitalization days (0.5 versus 2.5),
surgeries and procedures (65 versus 126), inpatient surgeries and procedures (7 versus
41), and major surgeries (2 versus 11) [29].

Rectovaginal fistulas A separate report of the ACCENT II study described results in 25


women who had a total of 27 draining rectovaginal fistulas [30]. At weeks 10 and 14, 61 and
45 percent or fistulas were closed, respectively. Among responders, 13 of 18 fistulas were no
longer draining at week 14. The duration of closure was longer in the infliximab 5 mg/kg
maintenance group compared with the placebo group (median 46 versus 33 weeks).

EXTRAINTESTINAL MANIFESTATIONS Maintenance therapy with infliximab may be


helpful in resolving extraintestinal manifestations of Crohn's disease, particularly arthritis and
arthralgias [31]. In addition, iritis/uveitis, pyoderma gangrenosum, and fever may also
improve.

EXPERIENCE IN CLINICAL PRACTICE Experience with infliximab has accumulated


rapidly since the initial controlled trials. A report from the Mayo Clinic described the clinical
experience with 500 patients who received a median of three infusions and were followed up
for a median of 17 months [32]. Although the authors concluded that therapy was generally
well-tolerated, they warned that clinicians using infliximab should be vigilant for the
occurrence of infrequent but serious events. Serious adverse events were observed in 43
patients (9 percent) of which 30 (6 percent) were attributable to infliximab. Acute infusion
reactions occurred in 19 patients (4 percent). Three patients developed drug-induced lupus,
one developed a new demyelination disorder, while 48 patients had an infectious event (of
which 41 were attributable to infliximab). There were a total of 10 deaths of which five were
possibly related to infliximab. Nine patients had a malignant disorder of which three were
possibly related to infliximab.

A report from the University of Chicago that included 129 treated patients with intestinal
disease found the median time to initial response was eight days, with a 65 percent response
rate at three weeks. The median time to remission was nine days with a 31 percent response
rate [33]. In patients with fistulizing disease, the median time to initial response was nine
days with a 78 percent response rate at three weeks. The median time to remission was 10
days with a 24 percent remission rate [33]. Rates were higher in the patients concurrently
treated with 6-mercaptopurine or azathioprine. Relapse occurred in 78 percent of patients
with Crohn's disease of the intestine at a mean of 8.5 weeks and in 71 percent of patients with
fistulizing Crohn's disease at 12.2 weeks [33]. Steroid tapering was seen in more than 90
percent of patients with 54 percent able to stop steroids. Infusion-related reactions were seen
in up to 24 percent of patients [33].

A third report focused on 100 patients with Crohn's disease (53 women and 47 men) from
Boston and Providence [34]. Sixty percent of patients with active disease experienced a
greater than 50 percent reduction in the Harvey Bradshaw Index at two weeks (calculator 2),
with a mean duration of response of 8.2 weeks [34]. Sixty-nine percent of patients with
fistulizing Crohn's disease experienced greater than 50 percent reduction in the perianal
disease activity index at two weeks, with a mean duration of response of 10.9 weeks [34].
Four of 10 steroid dependent patients were able to discontinue steroid therapy [34].

A population-based study from Sweden identified 217 patients who had received
infliximab (191 with Crohn's disease, 22 with ulcerative colitis, and 4 with indeterminate
colitis) [35]. The overall response rate was 75 percent. However, there were a total of 42
severe adverse events in 41 patients. Three developed lymphoma (of which two were fatal),
two developed opportunistic infections (pneumocystis carinii pneumonia and listeria
meningitis) of which one was fatal, and two died from sepsis. The authors cautioned that use
of infliximab can be associated with a significant risk of deleterious and fatal adverse events,
particularly in elderly patients with severe IBD.

A longitudinal cohort study looked at whether remission was maintained in patients who,
after attaining remission on infliximab, discontinued the drug [36]. Forty-eight patients were
followed for up to seven years. Fifty percent of the patients relapsed within 477 days of
stopping infliximab, whereas 35 percent remained in remission at the end of follow-up. These
data suggest that the majority of patients will relapse after stopping infliximab.

Predictors of response Smoking status and concomitant use of immunosuppressive drugs


appear to have an important influence on the initial response and durability of response in
patients with inflammatory disease. A study from the Cleveland Clinic included 100 patients
with inflammatory or fistulous Crohn's disease who were followed for at least three months
after treatment [37]. In those with inflammatory disease, an initial response was significantly
more likely in nonsmokers (73 versus 22 percent) and in those taking concurrent
immunosuppressive medications (74 versus 39 percent). A prolonged response (more than
two months) was also more likely in nonsmokers (59 versus 6 percent) and in those taking
concomitant immunosuppressive medications (65 versus 18 percent). For those with fistulous
disease, overall response rates were not different between smokers and nonsmokers, but
nonsmokers had a longer duration of response. Concurrent use of immunosuppressive
medications had no effect on the rate or duration of response. However, the use of
azathioprine and 6-MP has been associated with an increased risk of hepatosplenic T-cell
lymphoma. (See 'Use of immunosuppressive agents in combination with infliximab' above.)

The degree to which patients develop antibodies against infliximab is an important


determinant of the duration of response and the risk of infusion reactions, and may possibly
explain the longer response seen in patients taking immunosuppressive medications. In a
study focusing on these issues, anti infliximab antibodies were detected in 61 percent of 125
patients with refractory Crohn's disease treated repeatedly during a 10-month period [38].
The presence of antibody titers at a level of 8.0 g per mL was significantly associated with a
shorter duration of response (35 versus 71 days) and a higher risk of infusion reactions
(relative risk 2.40). The concentration of infliximab was significantly lower at four weeks
among those patients who had an infusion reaction compared with those who never had an
infusion reaction. The concomitant use of immunosuppressive therapy was predictive against
low titers of anti infliximab antibodies and higher concentrations of infliximab four weeks
after infusion. These data are interesting from the standpoint of pathophysiology. However,
given the low positive and negative predictive values of these antibodies, it is the authors'
contention that their measurement should not be advocated as a predictor of response or
nonresponse and treatment should not be given or withheld based upon their presence or
absence.

An elevated serum C-reactive protein (CRP) level prior to treatment has also been associated
with a higher chance of having a response to infliximab [25,39]. In a study of 718 patients
with Crohn's disease who were receiving infliximab, patients with elevated CRP levels at
baseline were more likely to respond to infliximab than patients with normal levels (91 versus
83 percent, p = .014) [39]. Early normalization of the CRP level was associated with a
sustained long-term response and CRP levels remained significantly higher in patients who
lost their response to infliximab than in patients who had a sustained response.

DOSE The approved induction dose of infliximab for treatment of patients with
moderately to severely active Crohn's disease who had an inadequate response to
conventional therapy is 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every eight
weeks. Patients who respond to initial therapy will require repeat infusions to maintain
remission [13]. The zero-, two-, and six-week induction regimen, followed by reinfusions of
infliximab every eight weeks, is superior to a single dose for Crohn's disease patients [13].
Similarly, in patients with fistulizing disease, an initial 5 mg/kg dose is followed with 5
mg/kg at two and six weeks after the first infusion, and then every eight week reinfusions to
maintain remission [14].

Because antibodies to infliximab can reduce infliximab blood levels, a subset of patients will
lose their response and have recurrence of symptoms between the eight-week reinfusion
intervals. One approach to this problem is to decrease the intervals between reinfusions to 7,
6, 5, or 4 week intervals. The second approach is to increase the infliximab dose to 10 mg/kg
[12]. Some patients, who initially respond but who then lose their response, will eventually
need infliximab 10 mg/kg every four weeks to remain in remission.

Overall, our current approach to using infliximab is to continue it long-term if it induces


remission. Although discontinuing infliximab and bridging to 6-MP or azathioprine can be
attempted, this approach is often not successful in the long term.

USE IN THE SETTING OF INTESTINAL STRICTURES Patients with intestinal


strictures due to Crohn's disease may be less likely to respond to treatment and are also at risk
for developing acute bowel obstruction. These issues were examined in a review of data from
an ongoing observational trial (the TREAT Registry study) and the ACCENT I study [40]. In
the TREAT Registry study, symptomatic intestinal stenosis, strictures, or obstruction (SSOs)
occurred significantly more often in patients receiving infliximab compared with those
receiving other treatments. However, on multivariable analysis, the only independent
predictors of SSOs were the severity and duration of Crohn's disease, the presence of ileal
disease and new glucocorticoid use. In ACCENT I, no increase in SSOs was described in
those receiving infliximab maintenance therapy compared with those who received episodic
therapy. Thus, these data do not support a causal role for infliximab in development of SSOs.

Because the risk of developing obstruction cannot be predicted accurately in advance,


patients with significant strictures should be informed of the possibility that complete
obstruction could occur following treatment [41,42]. In addition, they should be seen by a
surgeon before infliximab infusion so that the patient and surgeon can discuss the possible
need for surgery and a planned approach should obstruction develop.

PEDIATRIC EXPERIENCE Experience with infliximab in children is growing. Initial


experience suggests a similar benefit to that observed in adults [43-49]. (See "Overview of
the management of Crohn's disease in children and adolescents".)

PREGNANCY Infliximab is not routinely recommended for pregnant women due to


insufficient data. It is currently rated as a class B medication for pregnancy. Infliximab
antibodies are detectable in newborns presumably because of transplacental transfer [50].
One report identified 131 pregnancies in which the women were exposed directly to
infliximab for treatment of Crohn's disease or rheumatoid arthritis [51]. Outcome data were
available for 96 of these women. The rate of live births, miscarriages, and therapeutic
termination were similar to those expected for the general United States' population of
pregnant women or pregnant women with Crohn's disease not exposed to infliximab. Despite
these encouraging observations, prospective data will be needed to more definitively
determine the risk of infliximab therapy prior to conception and during pregnancy. (See
"Fertility, pregnancy, and nursing in inflammatory bowel disease", section on 'Anti-TNF
agents'.)

ADVERSE EVENTS A number of adverse events have been described following


treatment with anti-TNF-alpha agents. These are summarized separately along with
recommendations for screening patients prior to starting these medications.

ADALIMUMAB VERSUS INFLIXIMAB VERSUS CERTOLIZUMAB Studies


evaluating the efficacy of infliximab, adalimumab, and certolizumab have generally shown
similar results but no studies have directly compared them. The decision whether to use
adalimumab, infliximab, or certolizumab in patients with Crohn's disease requiring anti-TNF
therapy is influenced by patient preference with regards to the convenience (and availability
in individual countries) of subcutaneously administered adalimumab and certolizumab pegol.
(See "Overview of the medical management of severe or refractory Crohn's disease in
adults", section on 'Anti-TNF therapies'.)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education


materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

SUMMARY AND RECOMMENDATIONS Infliximab has provided a powerful tool for


the treatment of moderately to severely active Crohn's disease that is refractory to
conventional therapy. Clinical trials have demonstrated significant utility of infliximab for
induction of remission in moderately active, steroid refractory Crohn's disease, improvement
in quality of life, and maintenance of remission in these patients for up to 54 weeks after
initial infusion. Subsequent clinical experience at large centers and throughout the world has
confirmed the results of the controlled trials. Long-term follow-up has underscored the
benefit of therapy.

We recommend infliximab for patients with moderate to severe Crohn's disease that is
refractory to conventional treatment (Grade 1B).
We recommend long-term maintenance treatment of patients who respond to initial
therapy every four- to eight-week interval at 5 mg/kg or 10 mg/kg, depending upon
how quickly relapse of the Crohn's disease symptoms occurs (Grade 1B).

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