The State of the Art in the Management of Inflammatory Bowel Disease

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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 •

                                                         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

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Managing 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

Managing IBD

                                                           Table 1
                               Agents for Inducing Remission in Patients with Ulcerative Colitis

 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

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   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-

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,
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            85
Managing 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

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        87
Managing 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,
 • 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

Managing 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          89
Managing 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.

Managing IBD

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