The State of the Art in the Management of Inflammatory Bowel Disease
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TREATMENT UPDATE
The State of the Art in the
Management of Inflammatory
Bowel Disease
Stephen B. Hanauer, MD,* Daniel H. Present, MD†
*Section of Gastroenterology and Nutrition, University of Chicago, Pritzker School of Medicine, Chicago, IL;
†Department of Medicine, Mount Sinai Medical Center, New York, NY
Ulcerative colitis (UC) and Crohn’s disease (CD), collectively known as inflam-
matory bowel disease (IBD), afflict an estimated one million Americans and
produce symptoms that impair quality of life and ability to function. Progress
in IBD management strategies has led to optimized approaches for achieving
the two primary clinical goals of therapy: induction and maintenance of
remission. Although surgery is indicated to treat refractory disease or specific
complications, pharmacotherapy is the cornerstone of IBD management. The
efficacy of aminosalicylates for induction of remission in mild to moderate UC
and CD is well established, as is their role for maintenance of remission in UC.
The sulfa-free mesalamine formulation offers an adverse effect profile similar
to that of placebo, enabling the administration of higher, more effective doses.
Although corticosteroids provide potent anti-inflammatory effects, their benefits
are countermanded by the risk of intolerable and serious adverse effects, and
they are ineffective for maintenance therapy. Other agents effective in inducing
or maintaining remission are azathioprine, 6-mercaptopurine, infliximab,
cyclosporine, methotrexate, and antibiotics. Ongoing clinical trials of experimen-
tal therapies will generate new tools for IBD treatment. Currently, a broad range
of options allows physicians to tailor treatment to each patient’s needs and pref-
erences. Such considerations are essential for maximizing adherence to therapy.
[Rev Gastroenterol Disord. 2003;3(2):81–92]
© 2003 MedReviews, LLC
Key words: Inflammatory bowel disease • Ulcerative colitis • Crohn’s disease •
Pharmacotherapy
U
lcerative colitis (UC) and Crohn’s disease (CD), known collectively as
inflammatory bowel disease (IBD), afflict approximately one million
Americans.1 IBD produces a range of gastrointestinal (GI) and extrain-
testinal symptoms, including diarrhea, rectal bleeding, abdominal pain, weight
VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 81Managing IBD continued
loss, skin and eye disorders, and of individual agents. Because of the ferences have received little investi-
delayed growth and sexual matura- many available options, clinicians can gational attention. Indeed, in the past,
tion in children.1 These symptoms tailor treatments to patients’ unique women typically were excluded from
can greatly impact patients’ well- needs and preferences. Individualized early-phase clinical trials.7 Revised
being, quality of life, and capacity to treatment is essential to ongoing guidelines from the Food and Drug
function. Because IBD is chronic and adherence, which, in turn, is crucial Administration (FDA) have improved
typically has an onset before 30 to an optimal long-term outcome. this situation. Over the past several
years of age, patients generally It is increasingly being recognized years, women and men have partici-
require lifelong treatment. that sex differences must also be pated in clinical trials in similar
Pharmacotherapy is the foundation considered in treatment selection. numbers.8 As a consequence, more
of IBD management. Most of the cur- Although much is still to be learned information about the effect of sex
rently available agents act by down- regarding the impact of gender on differences on IBD treatments is likely
to become available in the future.
Ulcerative colitis and Crohn’s disease, known collectively as inflam- Medical Treatment of UC
matory bowel disease, afflict approximately one million Americans. UC is characterized by ulcerative
inflammation of all or part of the
colonic mucosa, most frequently
regulating chronic inflammation in the IBD and the response to treatment, including the rectum.9 Its symptoms
intestinal mucosa, which is believed several sex differences have long include rectal bleeding and urgency,
to underlie disease pathogenesis.2 been noted. For example, whereas tenesmus, and diarrhea. UC is accom-
Aminosalicylates are the cornerstone IBD affects men and women equally panied by serious short- and long-
of therapy for mild to moderate dis- overall, UC is 20% more common in term complications. The most serious
ease. Corticosteroids are frequently adult males than in adult females, short-term complications are fulmi-
used as well. The benefits of corti- and CD is 20% more common in nant colitis, toxic megacolon, and
costeroids, however, must be weighed women than in men.3 Certain extrain- perforation. Severe long-term com-
against the many short- and long- testinal complications occur more plications include osteoporosis and
term complications associated with frequently in men, whereas others colorectal cancer.
their use. In addition, they are inef- are found more commonly in women.4
fective for maintenance therapy. Women more often suffer from Induction of Remission in Patients
Antibiotics also are considered first- comorbid conditions that can com- with UC
line therapy for CD. More recent plicate treatment and affect quality of Therapies for inducing remission are
additions to the list of therapeutic life, such as depression and irritable selected based on the anatomic
options include immunomodulators bowel syndrome (IBS). Another extent of the disease and its clinical
such as azathioprine (AZA) and comorbidity, endometriosis, affects severity (Table 1). In terms of extent,
6-mercaptopurine (6-MP), which
are used in corticosteroid-resistant
or corticosteroid-dependent IBD, Individualized treatment is essential to ongoing adherence, which, in
methotrexate, and cyclosporine. turn, is crucial to an optimal long-term outcome.
Finally, biologic therapies, developed
via molecular engineering, have
been highly efficacious in CD and are only women, and menstrual cyclicity UC can be either distal or extensive.
likely to have an expanding role in itself can impact the level of symp- In distal UC, the inflammation is lim-
the treatment of IBD.2 toms.5 Finally, certain IBD-specific ited to the area below the splenic
The following considerations guide concerns, such as those related to flexure and is amenable to oral or
the selection of treatments: extent and childbearing, have a greater impact topical treatment. In extensive UC,
severity of disease, patient response on women than on men.6 inflammation extends proximal to
to current and prior treatments, the Less is known about the potential the splenic flexure and requires oral
presence of complications, the clinical effects of gender on pharmacokinetics, therapy. Extensive UC occasionally
goal (ie, induction or maintenance of safety, and efficacy of IBD treatments. benefits from supplementary topical
remission), and the side effect profile In large part, this is because sex dif- therapy to treat rectal symptoms of
82 VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERSManaging IBD
Table 1
Agents for Inducing Remission in Patients with Ulcerative Colitis
Combination
Extent and Oral 5-ASAs Topical and
Location of Topical or Oral 5-ASAs Topical Oral IV IV
Disease 5-ASAs Sulfasalazine or Sulfasalazine Corticosteroids Corticosteroids Corticosteroids Cyclosporine
Mild distal X X X X
Mild extensive X
Moderate distal X X X X X
Moderate extensive X X
Severe X X
5-ASA, 5-aminosalicylic acid; IV, intravenous.
Adapted from Stein RB, Hanauer SB,2 with permission from Elsevier Science.
urgency or tenesmus. Disease severity rate also increases, largely because of strated that mesalamine enemas were
is classified as mild (≤ 4 stools per day, the agent's sulfapyridine moiety. 10%–20% more effective than either
with or without blood, and no systemic Side effects include headache, nausea, oral mesalamine or most corticosteroid
signs of toxicity), moderate (≥ 4 stools vomiting, dyspepsia, and anorexia. enemas.11 However, long-term adher-
per day with minimal signs of toxic- Less frequent, but more serious, ence to topical mesalamine, which is
ity), or severe (> 6 bloody stools a day adverse effects include bone marrow necessary for the maintenance of
accompanied by signs of toxicity, suppression, connective tissue disor- treatment response, may be difficult
including fever, tachycardia, anemia, ders, megaloblastic anemia, hemolytic for some patients, who may object to
or elevated erythrocyte sedimentation anemia, and sperm abnormalities.9,10 the ongoing regular administration
rate).9 Remission in UC is achieved Pancreatitis, hepatotoxicity, allergic of enemas.
when inflammatory symptoms are reactions, and idiosyncratic nephro- Because of their potentially serious
absent (ruling out IBS, if diarrhea toxicity are infrequent side effects of adverse effects, oral corticosteroids
or cramps persist), the intact mucosa all of the 5-ASA agents. are reserved for patients with moder-
regenerates, and a histologic examina- The dose-limiting side effects ate to severe disease and for those
tion reveals absence of crypt abscesses. associated with sulfasalazine led to who do not respond to optimized
The 5-aminosalicylic acid (5-ASA) the development of sulfa-free amino- doses of aminosalicylates.2,9 Clinical
agents are the treatment of choice salicylate (mesalamine) preparations. improvement or remission occurs in
for mild to moderate disease. They Higher dosages of these compounds 45%–90% of patients treated with
are administered orally for extensive can be used without concomitant 15–60 mg/d prednisone, 300 mg/d
disease, and administered orally increases in adverse effects.2 Clinical hydrocortisone, 40–60 mg/d methyl-
and/or rectally for distal disease. improvement or remission is achieved prednisolone, or 80–120 g/d adreno-
Sulfasalazine, which consists of sul- in as many as 84% of patients corticotropic hormone.2 The benefits
fapyridine bonded to 5-ASA, was the at dosages of 1.5–4.8 mg/d.2 The of corticosteroid use must be weighed
first agent in this drug category.10 majority of sulfasalazine-intolerant against the risks. Side effects such as
The 5-ASA moiety, which is released patients—about 8 in every 10—will fluid and electrolyte disturbances, as
when the compound is cleaved tolerate mesalamine.9 well as GI, dermatologic, neurologic,
by enteric bacteria, is responsible for Mesalamine administered via ene- endocrine, ophthalmic, and metabolic
the drug's anti-inflammatory effects. mas or suppositories, or corticosteroids adverse events, are numerous.12 One
Sulfasalazine at dosages of 2–6 g/d administered via enemas or foam, are of the more serious consequences
achieves remission in 64%–80% of alternatives to oral aminosalicylates of long-term corticosteroid use is
patients, particularly when dosages for mild to moderate distal disease. osteoporosis.13 Therefore, a systematic
are greater than 3 g/d.2 However, as A recent meta-analysis of 67 trials taper of these agents is recommended
dosages are increased, the side effect for patients with distal UC demon- once remission has been achieved.9
VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 83Managing IBD continued Few clinical trials have been con- Mesalamine in enema or slow-release cyclosporine has been used for ducted in patients with severe disease. suppository form in dosages as low induction.18 Thus, treatment is guided by expert as 1 g/d has been shown to maintain opinion. The clinical consensus is remission for up to 1 year.14,15 Treatment of Refractory Disease that patients with severe symptoms Efficacy is usually optimized by daily A subset of patients is refractory to should be hospitalized. Intravenous administration, but some patients both induction and maintenance (IV) corticosteroids are currently rec- may maintain remission with treat- therapies, despite adequate dosages, ommended as the treatment of choice.9 ment every other day or three times optimal drug delivery, and sufficient An alternative approach includes IV a week.11,15 A combination regimen treatment duration.9 Several conditions cyclosporine. When these efforts fail, consisting of oral and topical may contribute to refractory disease, or when intolerable adverse effects mesalamine may provide the best including treatment nonadherence or develop as a result of medical treat- results for remission maintenance. concurrent use of nonsteroidal anti- ment, colectomy is indicated. A 1-year double-blind study of 72 inflammatory agents. Aminosalicylate Maintenance of Remission in Patients with UC A combination regimen consisting of oral and topical mesalamine may Once remission is established, ongoing provide the best results for remission maintenance. treatment is necessary to maintain clinical benefits. Again, it is impor- tant to note that complete remission patients who had experienced two or intolerance, intercurrent infections, must be achieved before initiating more relapses in the previous year, or concomitant IBS may mimic maintenance therapy.9 The choice of but were currently in remission, refractory disease. maintenance therapy is individualized demonstrated that relapse occurred In refractory patients with distal based on the induction regimen and in 64% of patients who received oral disease, treatment options include the patient's response to prior treat- therapy alone, but in only 36% of rectal mesalamine or AZA/6-MP. ment. Patients with mild to moderate patients who received oral mesalamine Patients with extensive disease UC who achieved remission using 1.6 g/d plus topical mesalamine may be treated with high dosages oral 5-ASA compounds can be con- 4 g/100 mL twice weekly.16 of oral mesalamine (4.8–6.0 g/d or tinued on the same drug at the same Corticosteroids are ineffective for higher). AZA/6-MP can be used in dosage. The most effective dosage of maintenance therapy.2 Therefore, when 5-ASA–intolerant or corticosteroid- sulfasalazine for maintenance therapy these agents have been used for induc- dependent patients. Colectomy repre- is 4 g/d, but many patients will be tion, aminosalicylates may be used as sents a final option, irrespective of unable to tolerate this dose. The effi- maintenance. For some patients, AZA disease extent. cacy of mesalamine is also likely to or 6-MP may be necessary to maintain be dose dependent up to 4.8 g/d.9 In remission after corticosteroids have Medical Treatment of CD the past, it was typical to reduce the been tapered. The utility of AZA in CD is a chronic transmural inflam- 5-ASA dosage when patients began corticosteroid-resistant and corticos- mation that may affect any part of maintenance therapy (mainly because teroid-dependent UC was demonstrat- the GI tract, from the mouth to the of the dose-related side effects of ed by Ardizzone and colleagues.17 In a anus. In approximately one third of sulfasalazine); however, the current retrospective analysis of 56 patients, cases, the disease is confined to the standard of care for patients taking all of whom were taking corticos- small intestine, whereas approxi- mesalamine compounds is to main- teroids when AZA treatment was mately one half of patients will have tain the induction dose. The newer oral initiated, remission with complete involvement of both the small intes- aminosalicylates have been shown to elimination of corticosteroids was tine and the colon (ileocolitis).19 In be as effective as sulfasalazine for achieved in more than 60% of patients approximately 20% of cases, only the maintenance therapy, but without with continued AZA treatment.17 In colon is involved.20 Most patients dose-limiting side effects.10 this study, two thirds of the patients present with symptoms of abdominal Topical 5-ASA therapy may be used were male. No sex-related differences pain and tenderness, chronic or noc- to maintain remission in patients in efficacy or safety were reported.17 turnal diarrhea, rectal bleeding, with left-sided disease when this reg- These immunomodulators can also weight loss, and fever.21 CD evolves imen has been used for induction. be used to maintain remission after over time from a primarily inflamma- 84 VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERS
Managing IBD
tory disease into one of two clinical
patterns: stricturing (obstructive) or Table 2
penetrating (fistulizing).22 In the Agents for Inducing Remission of Crohn's Disease
stricturing form, transmural inflam- and Their Therapeutic Dosages
mation produces fibromuscular prolif-
eration in the intestinal wall, followed Agent Dosage
by luminal narrowing. Symptoms of
Sulfasalazine 3.0–6.0 g/d
obstruction become common as CD
progresses. In the penetrating form, Mesalamine (5-ASA) 1.5–4.0 g/d (with increased efficacy at
sinus tracts form as inflammation 4.0-g dose)
tunnels through the bowel wall and Corticosteroids 0.25–1.0 mg/kg/d for PO prednisone;
breaches the serosal surface, fistuliz- 40–60 mg/d for IV methylprednisolone
ing into adjoining tissues and even Azathioprine 2–3 mg/kg/d
through the skin.
6-MP 1.5 mg/kg/d
Induction of Remission in Patients Metronidazole 10–20 mg/kg/d
with CD Methotrexate 15 mg/wk PO or 25 mg/wk IM or SC
Selection of inductive therapy is
Cyclosporine 5.0–7.5 mg/kg/d PO for chronically active
based on the severity of the disease,
CD
its location, and the patient’s previ-
ous response to therapy. Categories Infliximab 5 mg/kg/d IV weeks 0, 2, 6 for refractory
of severity include the following23: or fistulizing disease
• Mild-moderate disease: Patients CD, Crohn’s disease; 5-ASA, 5-aminosalicylic acid; 6-MP, 6-mercaptopurine; PO, oral;
who are ambulatory and able to IV, intravenous; IM, intramuscular; SC, subcutaneous.
tolerate oral alimentation without Adapted from Stein RB, Hanauer SB,2 with permission from Elsevier Science.
manifestations of dehydration,
toxicity (high fevers, rigors, pros-
tration), abdominal tenderness, it is essential that optimal therapeutic ducted. Because of its favorable bal-
painful mass, obstruction, or dosages are used (Table 2). Again, the ance of efficacy and tolerability,
greater than 10% weight loss efficacy of sulfasalazine is dose mesalamine is currently considered
• Moderate-severe disease: Patients related, but so too are the agent’s first-line therapy for CD.25
who have failed to respond to sulfa-related adverse effects. The Although corticosteroids are effec-
therapies for mild-moderate dis- efficacy of mesalamine is also dose tive inductive therapies for mild to
ease or those with more prominent related up to 4.8 mg/d; however, its moderate CD,2 their safety profile
symptoms of fevers, significant adverse effects do not increase with generally limits their use to patients
weight loss, abdominal pain or increasing dose. In the first trial with moderate to severe disease and
tenderness, intermittent nausea or to demonstrate the benefit of as add-on agents to the 5-ASA agents.
vomiting (without obstructive mesalamine, conducted by Singleton Even at low dosages, corticosteroids
findings), or significant anemia and colleagues,24 43% of patients may cause intolerable side effects
• Severe-fulminant disease: Patients who received mesalamine, 4 g/d, and dependency in approximately
with persistent symptoms despite achieved remission after 16 weeks of one third of patients.26 Corticosteroid-
the introduction of corticosteroids treatment, compared with 18% of sparing regimens should be used to
as outpatients or those presenting patients in the placebo group. establish remission in CD whenever
with high fever, persistent vomit- Efficacy increased progressively as possible. Moreover, they should be
ing, evidence of intestinal obstruc- dosage increased, with 23%, 24%, tapered and discontinued as soon
tion, rebound tenderness, cachexia, and 43% of patients responding as possible. Budesonide, a newer
or evidence of an abscess to daily doses of 1 g, 2 g, and corticosteroid with a lower systemic
The 5-ASA compounds are effec- 4 g, respectively.24 Additional trials bioavailability than the older cortico-
tive for establishing remission of designed to evaluate the efficacy of steroids, is indicated for mild to
mild to moderate CD. To maximize even higher dosages of mesalamine moderate CD involving the ileocecal
the likelihood of a complete response, (6.0 g/d) are currently being con- area. In one study, in which 3 dosages
VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 85Managing IBD continued of budesonide were compared with abdominal cramping. Serious adverse patient’s sensitivity to the therapy.39 placebo over an 8-week treatment events include peripheral neuropathy However, if white blood cell counts period, 33% of patients receiving and convulsive seizures.32 Cipro- are monitored carefully, combination 3 mg/d, 51% receiving 9 mg/d, and floxacin has also been used as induc- therapy of AZA/6MP and 5-ASA can 43% receiving 15 mg/d achieved tive therapy. A retrospective chart be safe and effective, offering the remission, compared with 20% of study, an open-label trial, and one potential benefit of administering a placebo-treated patients.27 In a sec- randomized controlled trial support lower dose or achieving more rapid ond study, budesonide and pred- its use either alone or in combination responses. Using a lower dose can also nisolone were compared in patients with metronidazole.33,34 lower the overall cost of therapy.40 with active ileal or ileocecal CD.28 At The immunomodulators AZA and Feagan and colleagues41 established 10 weeks, 53% of budesonide-treated 6-MP are used in conjunction the efficacy of the antimetabolite patients and 66% of prednisolone- treated patients had achieved remis- sion. Although there was a signifi- Rare drug interactions have been observed between AZA/6-MP and cant treatment benefit favoring pred- olsalazine, resulting in severe bone marrow suppression. nisolone (P = .001), budesonide was associated with fewer side effects.28 Despite its more favorable short-term with corticosteroids for establishing methotrexate as inductive therapy side effect profile, recent research has remission in patients with refractory for CD. In a 16-week randomized, demonstrated that long-term budes- moderate to severe CD and as corti- double-blind, placebo-controlled trial, onide use lacks maintenance benefits costeroid-sparing maintenance agents. methotrexate, 25 mg/wk, induced at dosages up to 6 mg/d, and at A meta-analysis of randomized, remission in 39.4% of patients, com- 9 mg/d is associated with accelerated placebo-controlled trials including a pared with 19.1% of placebo-treated bone loss within 1 year.29 total of 367 patients found an odds patients. The disadvantages of The antibiotics metronidazole and ratio (OR) for response of 3.09 (95% methotrexate treatment are its side ciprofloxacin are used to induce confidence interval [CI], 2.45-3.91), effects, which necessitate careful remission in mild to moderate CD, with an OR for a corticosteroid-spar- patient monitoring, and the numer- although the current efficacy data ing effect of 3.69 (95% CI, 2.12- ous contraindications to therapy. The for metronidazole are not particu- 6.42).35 Like sulfasalazine, however, most frequently occurring adverse larly strong. In a 105-patient place- the risk of toxicity with these agents events are nausea and vomiting, bo-controlled trial, metronidazole, increases with increasing dose, par- abdominal pain, joint pain, cold 10 mg/kg/d or 20 mg/kg/d, was asso- ticularly in the estimated 15% of symptoms, and fatigue.41 Methotrexate ciated with significant improvements patients considered to be slow metab- is associated with toxicities that in disease activity.30 Remission rates, olizers of the drug.36,37 Thus, patients include myelosuppression and hepa- however, were no different from those who receive these agents must be totoxicity, which necessitate regular achieved with placebo treatment. Even monitored carefully for signs and monitoring of blood cell counts and so, Bernstein and colleagues31 demon- symptoms of toxicity; in particular, liver enzymes.2 strated that metronidazole improved monitoring of the complete blood Cyclosporine is an option for the perianal manifestations of CD in cell (CBC) count must be conducted, severely ill patients who are unre- a small open-label trial involving at minimum, once every 3 months, sponsive to other agents but are patients with chronic, unremitting CD. as long as patients continue therapy. poor candidates for surgical inter- Metronidazole, 20 mg/kg/d, was asso- AZA or 6-MP can be given as part vention. It has been demonstrated ciated with decreased drainage, ery- of dual therapy in combination with that, in approximately 1 week, IV thema, and induration. Complete 5-ASA agents; however, 5-ASA com- cyclosporine, 4 mg/kg/d induces a healing was achieved in approximate- pounds are competitive inhibitors of response in at least 80% of patients ly one half of patients, and advanced thiopurine methyltransferase (TPMT). with refractory fistulas.42 The poten- healing in approximately one quarter Rare drug interactions have been tial for toxicity and adverse effects, of patients. Metronidazole is associ- observed between AZA/6-MP and such as hypertension, nephrotoxicity, ated with common side effects such as olsalazine, resulting in severe bone pulmonary toxicity, encephalopathy, nausea, headache, anorexia, vomit- marrow suppression.38 Furthermore, nausea and vomiting, paresthesias, ing, diarrhea, epigastric distress, and TPMT genotyping may elucidate a tremors, electrolyte imbalance, and 86 VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERS
Managing IBD
patients, Lochs and colleagues49
Table 3 reported no such postsurgical bene-
Agents for Maintaining Remission of Crohn’s Disease fit. Nevertheless, most of the evi-
and Their Therapeutic Dosages dence generally favors 5-ASA as a
therapeutic approach. As is the case
Agent Dosage with remission induction, adequate
Mesalamine ≥3 g/d dosing is crucial for remission main-
Corticosteroids Not indicated tenance. The optimal maintenance
dose is the induction dose; downward
Azathioprine 2.5 mg/kg/d
dose titration is not recommended.2
6-MP 1.5 mg/kg/d Higher dosages of mesalamine
Methotrexate 15-25 mg/wk (IM or SC) (4.8–6.0 g/d) are currently being
Infliximab 5 mg/kg IV every 8 weeks evaluated for maintenance therapy,
6-MP, 6-mercaptopurine; IV, intravenous; IM, intramuscular; SC, subcutaneous.
and these studies are likely to clarify
Data from Hanauer SB, Meyers S.21 the use of the 5-ASAs in mainte-
nance therapy.
In patients who have achieved
myelosuppression, is substantial. In avoided in patients with congestive remission with corticosteroids, AZA
addition, concomitant use of high- heart failure. A recent manufacturer- or 6-MP generally are effective in
dose corticosteroids may increase the sponsored phase 2 trial was discontin- maintaining remission. Six placebo-
risk of seizures.43 As a consequence, ued because of worsening of the con- controlled trials have evaluated the
these agents should be administered dition and death in some subjects.47 efficacy of AZA for maintenance
only in centers that have experience therapy. A meta-analysis of these
in doing so and are equipped to mon- Maintenance of Remission in studies revealed an overall OR of
itor blood levels on an ongoing basis.2 Patients with CD response of 2.27 (CI, 1.76-2.93).35
Infliximab, 5 mg/kg, is effective The goals of maintenance therapy Sixty-seven percent of AZA-treated
against fistulous CD and may be are to prolong periods of remission, patients responded to treatment,
effective in patients who are refrac- and improve quality of life. Two compared with 53% of placebo-treat-
tory to 5-ASAs, corticosteroids, or aspects of maintenance therapy are ed patients.35 Two studies reviewed in
other immunomodulators. Targan important to note. First, cortico- the meta-analysis reported that AZA
and colleagues25 evaluated the agent steroids are not suitable for mainte- had a corticosteroid-sparing effect. 6-
in 108 treatment-refractory patients
and found an overall response rate of
65% for active treatment, compared As is the case with remission induction, adequate dosing is crucial for
with 17% for placebo (P < .001). remission maintenance.
However, the use of infliximab is
associated with several risks. As of
June 2001, 84 cases of tuberculosis nance of remission (Table 3). MP maintenance therapy in pediatric
were reported in connection with Although the efficacy of 5-ASAs in patients demonstrated that combined
infliximab, and invasive fungal and inducing remission in CD is well 6-MP/prednisone treatment was sig-
other opportunistic infections have established, their role in maintaining nificantly superior to prednisone
also been reported.44 A total of 117 remission is not as well documented. monotherapy (P < .01).50 Furthermore,
cases of infliximab-associated tuber- Following a meta-analysis of 15 ran- at 12 months, total prednisone use was
culosis were reported to the FDA as domized, controlled trials involving significantly lower in the combined
of November 30, 2001.45 Infliximab a total of 2097 patients, Cammà and therapy group. Patients receiving this
has been implicated, along with colleagues48 reported that mesalamine therapy must undergo periodic blood
other antitumor necrosis factor significantly (P = .0028) reduced the monitoring since delayed leukopenia
(TNF)- therapies, in causing demyeli- risk of relapse when remission was is a possibility.21 Most recently, inflix-
nating central nervous system lesions surgically induced, but not when it imab was demonstrated to have main-
and activating latent multiple sclero- was medically induced. However, in tenance benefits for patients with
sis.46 Infliximab should also be their more recent study of 318 CD. After an inductive regimen of
VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 87Managing IBD continued
a broad range of therapies with a ileoanal anastomosis (IPAA). J pouches
Table 4 variety of mechanisms of action for are constructed most frequently,
Evolving and Future the treatment of IBD. These investi- whereas S pouches are reserved for
Therapies for gational therapies include agents tar- cases in which anatomic reach of the
Inflammatory Bowel Disease geted against TNF, leukocyte adhesion pouch to the anus is problematic.
molecules, T-cell subsets, and other A large proportion of women have
• Anti-TNF therapies molecules implicated in disease patho- reported an inability to conceive fol-
– CDP571 genesis (Table 4). Thus far, the agents lowing IPAA.54
– Soluble p55 receptor (onercept)
with the greatest promise are CDP571 Three additional techniques are in
– CNI-1493 (MAP kinase inhibitor)
– Thalidomide
and natalizumab. It is not yet clear use. For patients with toxicity, mega-
• Anti-leukocyte adhesion therapies
– Anti-4 integrin (natalizumab)
– Anti-47 (LDP-02) It is not yet clear which of the treatments now under investigation will
• Inhibitors of T-cell subsets eventually join the therapeutic armamentarium, but there is little doubt
– Anti-IL-12 that biologics and other emerging therapies will play a valuable future
– Anti-IFN-
– IL-10
role in IBD management.
– Anti-IL-2 receptor (daclizumab,
basiliximab)
• Anti-CD4 which of the treatments now under colon, perforation, and hemorrhage,
– cM-T412 investigation will eventually join the subtotal colectomy/ileostomy is used
– MAX therapeutic armamentarium, but there as a staging procedure. Total colecto-
– 16H5
is little doubt that biologics and other my/ileorectal anastomosis, now rarely
– BF-5
emerging therapies will play a valu- performed, may be considered for
• Growth factors
– Epidermal growth factor
able role in future IBD management. patients with minimal rectal involve-
– KGF-1 ment, for young female patients to
• Miscellaneous Surgical Options in the help maintain tube patency and fer-
– IFN- Treatment of IBD tility, and for patients with metastatic
– G-CSF (filgrastim) Ulcerative Colitis cancer complicating UC. Finally,
– GM-CSF (sargramostim) Between 30%–40% of patients with continent ileostomy, a complex oper-
– Growth hormone (somatotropin) UC will eventually require surgery.52 ation involving the creation of an
– IL-11 Surgical removal of the entire ileal reservoir from the terminal 60 cm
– Tacrolimus colonic and rectal mucosa in UC can of intestine, is indicated for patients
– 6-Thioguanine be curative.52 Surgery is required when who wish to convert from a Brooke
– Nicotine and nicotine agonists
– Probiotic bacteria (VSL#3,
Escherichia coli Nissle 1917)
Researchers are currently evaluating a broad range of therapies with a
– Medroxyprogesterone acetate
variety of mechanisms of action for the treatment of IBD.
TNF, tumor necrosis factor; MAP, mito-
gen-activated protein; IL, interleukin;
IFN, interferon; KGF, keratinocyte growth
factor; G-CSF, granulocyte colony-stimu- there is massive hemorrhage, perfo- ileostomy, to salvage a failed ileoanal
lating factor; GM-CSF, granulocyte-
macrophage colony-stimulating factors.
ration, or carcinoma. Surgery is also operation, and for patients with poor
indicated for severe colitis that is sphincter function.
unresponsive to medical therapy (or
5 mg/kg at 0, 2, and 6 weeks, either medical intractability). Surgery is Crohn’s Disease
5 mg/kg or 10 mg/kg sustained rarely performed to control extrain- Although most patients with CD will
remission in 2-week responders for at testinal manifestations or to correct require surgery at least once, and
least 1 year.51 growth retardation in children.9,53 many will need it several times,
Several surgical techniques are used efforts are generally made to avoid
The Future of IBD Therapy in UC. The current gold standard or postpone surgery for as long as
Researchers are currently evaluating is restorative proctocolectomy with possible. Many surgical options are
88 VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERSManaging IBD
available; however, it is generally
agreed that resection of diseased Table 5
intestinal segments is preferred over Suggested Approaches to Surgical Treatment of Crohn’s Disease
bypass procedures, and that every
attempt should be made to conserve Condition Suggested Approach
the bowel, especially the small bowel. Acute bowel obstruction Treat medically
The primary indications for surgery
Chronic, recurrent obstruction Resection or strictureplasty
in patients with CD are intestinal
obstruction and septic complications, Duodenal obstruction Strictureplasty or bypass procedure
such as internal fistula or abscess. Abdominal abscess Drain (if possible), then elective resection
Other indications include perforation, Symptomatic fistula Resection bowel
hemorrhage, medical intractability, Nonobstructed, nonperforated Treat medically
growth retardation, and carcinoma. segment
For treatment of colonic CD, surgical
alternatives include subtotal/total
colectomy with anastomosis for cancer.57 Nonadherence may take any bodies, attractiveness, intimacy, feel-
patients with rectal sparing, and of several forms, including failure to ing alone, sexual performance, and
subtotal/total colectomy without fill a prescription, consumption of too having children.6
anastomosis for patients with toxici- much or too little medication, alter- With regard to illness-related
ty/sepsis. Proctocolectomy and ation of dosing regimens, or incor- determinants of adherence, well-con-
ileostomy are performed in one or rect self-administration (which may trolled IBD with few flares is the set-
two stages in patients with pancoli- occur with topical therapies).55 ting in which maintenance therapy
tis. Surgical approaches are detailed Factors affecting adherence can be is most likely to be discontinued.
in Table 5. categorized as relating to the patient, Treatment-related factors that affect
the illness, or the treatment.55 adherence include efficacy, safety
Enhancing Adherence to Patient-related factors include degree and tolerability, convenience (includ-
IBD Therapy of education received from health- ing frequency of dosing and number
Because patients with UC and CD care providers, comprehension of of pills), formulation (including mode
require management from the time of instructions for proper medication use, of delivery and pill size), and cost
diagnosis throughout their lifespan, understanding of the consequences (which may prevent patients from
adherence to therapy is a difficult of nonadherence, extent of self- being able to purchase medication).55
problem. However, ongoing adher- management skills and abilities, and All of these issues are important,
but tolerability may be particularly
important. Therefore, patients should
Because patients with UC and CD require management from the time of diag- be questioned about which side effects
nosis throughout their lifespan, adherence to therapy is a difficult problem. they consider least problematic and
a regimen designed to suit those
preferences should be prescribed.
ence is vital, since lapses in adherence availability of a support system.55 Intolerance of the sulfa moiety of sul-
may result in relapse and the need to Gender is another important patient- fasalazine generally prevents titration
revert to an inductive regimen. related factor that impacts adher- to maximum response. Mesalamine
Patients with IBD are more likely to ence; in a study of 94 patients with lacks the sulfa moiety and can be
take medications when moderately quiescent UC treated with mesalamine, titrated to the most effective level
ill, and often discontinue them when nonadherence was found to be sig- without risking intolerability.59
the disease is quiescent. Adherence nificantly less common in females Because convenience of administra-
often decreases dramatically after 1 (P < .05).58 The reason for this differ- tion contributes to adherence, it is
or 2 years.55 This tendency is unfor- ence is not clear; however, it has worth noting that a recent study of
tunate, since ongoing adherence to been shown that, although men and dosing frequency demonstrated that
prescribed treatment not only pre- women with IBD share some con- concentrations of delayed-release
vents relapse56 but also provides a cerns, women have greater concerns mesalamine are the same regardless
prophylactic effect against colon about feelings related to their of whether the agent is administered
VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 89Managing IBD continued
in a single daily dose or in three colorectal cancer was 10 times high- when the clinician employs the full
divided doses.60 Immunomodulators er in nonadherent patients than it range of treatment options in a man-
are associated with side effects such was in adherent patients (31% vs 3%; ner consistent with the patient’s
as fever and rash, nausea, pancreatitis, P < .001). In another study, Eaden unique needs and desires.55
and leukopenia. However, except for and colleagues62 found that patients
leukopenia, these side effects generally who took mesalamine at a dosage Conclusion
occur only within the first month of of 1.2 g/d or more for a period of The chronic nature of IBD requires
administration. years reduced their cancer risk by optimal treatment strategies that, for
Adherence to pharmacotherapy can 91% (OR, 0.09; 95% CI, 0.03-0.28; many patients, will be needed across
also be promoted by educating P < .00001). the lifespan. Fortunately, manage-
patients about its associated benefits. Adherence is best optimized by ment strategies have continued to
IBD pharmacotherapy controls symp- educating the patient and family, evolve, in large part because of
research advances, growing clinical
experience, and new additions to the
IBD therapy is most likely to have a positive outcome when the clinician therapeutic armamentarium. Perhaps
employs the full range of treatment options in a manner consistent with just as important is the increased
the patient’s unique needs and desires. recognition that treatment selection
must be weighed to maximize adher-
ence. Optimized adherence, which
toms so that patients feel and function developing a productive physician– requires individualized treatment
better; in addition, as noted previously, patient interaction that fosters open suited to the patient's needs and pref-
there is a growing, though prelimi- communication, and individualizing erences, will help achieve the ultimate
nary, body of evidence suggesting therapy (based on the patient’s disease goal: the patient's commitment to the
that it may reduce colorectal cancer and treatment histories, responses to therapeutic objective.
risk—something that greatly concerns previous medications, history of tak-
most patients. For example, Moody ing medication as prescribed, and cost This article is based on presentations
and colleagues61 demonstrated in a considerations). IBD therapy is most given at a roundtable held in December
retrospective study that the risk of likely to have a positive outcome 2001 in Washington, DC. The roundtable
Main Points
• Ulcerative colitis (UC) and Crohn’s disease (CD), collectively known as inflammatory bowel disease (IBD), are life-long conditions,
characterized by periods of inflammation and remission, that can cause diarrhea, rectal bleeding, abdominal pain, weight loss, skin
and eye disorders, and delayed growth and sexual maturation in children.
• Pharmacotherapy with aminosalicylates, corticosteroids, immunomodulators such as azathioprine and 6-mercaptopurine, methotrex-
ate, cyclosporine, and biologic agents is the foundation of managing IBD, although surgery is also sometimes necessary.
• Treatment strategies for IBD should be patient-specific, as this helps ensure ongoing compliance, and guided by the extent and
severity of disease, patient response to current and prior treatments, the presence of complications, and the side effect profile of
individual agents.
• CD, a chronic transmural inflammation that can affect any part of the gastrointestinal tract, evolves over time from a primarily
inflammatory disease to either a stricturing (obstructive) or penetrating (fistulizing) disease that is more common in women than
in men.
• The 5-aminosalicyclic acid (5-ASA) agents, particularly mesalamine, are considered the first-line treatment for the induction of
remission in mild to moderate CD, and evidence generally favors them as a therapeutic approach.
• UC, an ulcerative inflammation of all or part of the colonic mucosa (including the rectum), in the short-term, can cause fulminant
colitis, toxic megacolon, and perforation, and, over long periods of time, osteoporosis, and colorectal cancer.
• Among patients with mild to moderate UC, the 5-ASA agents are the treatment of choice for inducing and maintaining remission.
Patients with severe disease require hospitalization, either intravenous (IV) corticosteroids or IV cyclosporine and, in the absence
of a response or intolerable adverse events, colectomy.
90 VOL. 3 NO. 2 2003 REVIEWS IN GASTROENTEROLOGICAL DISORDERSManaging IBD
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