ACG Guidelines For Ulcerativecolitis PDF

American Journal of Gastroenterology ISSN 0002-9270
C
2004 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2004.40036.x
Published by Blackwell Publishing
PRACTICE GUIDELINES
Ulcerative Colitis Practice Guidelines in Adults (Update):
American College of Gastroenterology, Practice
Parameters Committee
Asher Kornbluth, M.D. and David B. Sachar, M.D.
The Henry D. Janowitz Division of Gastroenterology, The Department of Medicine, Mount Sinai School of
Medicine; and The Practice Parameters Committee of the American College of Gastroenterology
Guidelines for clinical practice are intended to indicate preferred approaches to medical problems as established
by scientically valid research. Double-blind placebo-controlled studies are preferable, but compassionate use
reports and expert review articles are utilized in a thorough review of the literature conducted through Medline
with the National Library of Medicine. When only data that will not withstand objective scrutiny are available, a
recommendation is identied as a consensus of experts. Guidelines are applicable to all physicians who address
the subject without regard to the specialty training or interests and are intended to indicate the preferable but not
necessarily the only acceptable approach to a specic problem. Guidelines are intended to be exible and must be
distinguished from standards of care, which are inexible and rarely violated. Given the wide range of specics in
any health-care problem, the physician must always choose the course best suited to the individual patient and the
variables in existence at the moment of decision.
Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice
Parameters Committee and approved by the Board of Trustees. Each has been extensively reviewed and revised by
the Committee, other experts in the eld, physicians who will use them, and specialists in the science of decision
of analysis. The recommendations of each guideline are therefore considered valid at the time of their production
based on the data available. New developments in medical research and practice pertinent to each guideline will
be reviewed at a time established and indicated at the publication in order to assure continued validity.
INTRODUCTION
Ulcerative colitis (UC) is a chronic disease characterized by
diffuse mucosal inammation limited to the colon. It involves
the rectum in about 95% of cases and may extend proximally
in a symmetrical, circumferential, and uninterrupted pattern
to involve parts or all of the large intestine. The hallmark
clinical symptom is bloody diarrhea often with prominent
symptoms of rectal urgencyandtenesmus. The clinical course
is marked by exacerbations and remissions, which may oc-
cur spontaneously or in response to the treatment changes
or intercurrent illnesses (1, 2). UC affects approximately
250,000500,000 individuals in the United States with an
incidence of 27/100,000 population per year; the incidence
has remained relatively constant over the last ve decades
(3, 4). The disease accounts for a quarter million physician
visits annually, 20,000 hospitalizations, and loss of over a
million work-loss days per year. The annual nancial costs
approach half a billion dollars annually and include hospi-
tal costs of $192 million, and drug costs of $138 million
(4).
The quality of evidence on which a recommendation is
based is as follows:
Grade A: Homogeneous evidence from multiple well-
designed randomized (therapeutic) or cohort (descrip-
tive) controlled trials, each involving a number of par-
ticipants to be of sufcient statistical power.
Grade B: Evidence from at least one large well-designed
clinical trial with or without randomization, fromcohort
or case-control analytic studies, or well-designed meta
analysis.
Grade C: Evidence based on clinical experience, descrip-
tive studies, or reports of expert committees.
RECOMMENDATIONS FOR DIAGNOSIS AND ASSESSMENT
In a patient presenting with persistent bloody diarrhea, rectal
urgency, or tenesmus, stool examinations and sigmoidoscopy
and biopsy should be performed to conrm the presence of
colitis and to exclude the presence of infectious etiologies.
Characteristic endoscopic and histologic ndings with nega-
tive evaluationfor infectious causes will suggest the diagnosis
of UC.
The diagnosis of UC is suspected on clinical grounds
and supported by the appropriate ndings on proctosigmoi-
doscopy or colonoscopy, biopsy, and by negative stool ex-
amination for infectious causes. Inquiries should be made
regarding factors known to exacerbate symptoms of UC,
e.g., recent or past smoking cessation or nonsteroidal drug
use (5). Infectious etiologies of colitis can produce clinical
1372 Kornbluth and Sachar
ndings indistinguishable from idiopathic UC, so microbi-
ologic studies for bacterial (including specic assays for E.
coli 0157:H7) and parasitic infection, as well as serologic
testing for amoeba when clinical suspicion is high, should
be performed in each new patient, and should be considered
in patients in remission or with mild stable symptoms who
unexpectedly develop a severe exacerbation. Similarly, pa-
tients who have recently been hospitalized or treated with
antibiotics should have stools examined for Clostridium dif-
cile, although antibiotic-associated diarrhea may be present
in the absence of C. difcile toxin.
Proctosigmoidoscopy or colonoscopy will reveal the mu-
cosal changes characteristic of UC, consisting of loss of the
typical vascular pattern, granularity, friability, and ulceration
(6). These changes typically involve the distal rectum and
proceed proximally in a symmetric, continuous, and circum-
ferential pattern to involve all or part of the colon. However,
isolated patchy cecal inammation may be seen discontinu-
ous frommore distal inammation in UCpatients with other-
wise only distal disease (7). Since none of these endoscopic
ndings is specic for UC, histologic ndings obtained with
biopsies may be helpful in the differential diagnosis. A small
bowel radiograph series may also be helpful in the differential
diagnosis when the diagnosis of Crohns disease is being con-
sidered. In the patient with acute onset of bloody diarrhea, the
mucosal biopsy may help in distinguishing UC from infec-
tious colitis. In UC, more commonly than in infectious colitis,
the mucosa demonstrates separation, distortion, and atrophy
of crypts; acute and chronic inammatory cells in the lam-
ina propria, preferential homing of neutrophils to the crypt
epithelium; increased number of plasma cells near the crypt
bases; and basilar lymphoid aggregates (810). Villous mu-
cosal architecture and Paneth cell metaplasia on rectal biopsy
are other features favoring the diagnosis of UC (11). Crypt
abscesses, on the other hand, are a nonspecic indication of
inammation and do not indicate a specic diagnosis (12).
Crohns disease may be suggested by certain histologic
ndings such as noncaseating granulomas or microscopic
focality, but their absence does not rule out the possibility
of Crohns disease. Furthermore, in acute self-limited colitis,
muciphage granulomas, or intraepithelial granulomas in the
presence of ruptured crypts, may be seen and are therefore
not pathognomonic for Crohns disease (11). Other histologic
ndings that may suggest an infectious etiology, include gran-
ulomas in tuberculosis (and even less commonly in schisto-
somiasis, syphilis, and Chlamydia trachomatous), amoebic
trophozoites, pseudomembranes in C. difcile colitis, and vi-
ral inclusions in cytomegalovirus or herpetic colitis. In the
appropriate clinical settings, sigmoidoscopy or colonoscopy
and biopsy may also distinguish the various noninfectious
colitides from UC. These include ischemia, radiation, col-
lagenous and microscopic colitis, drug-induced colitis, and
the solitary rectal ulcer syndrome (12).
Perinuclear antineutrophil cytoplasmic antibodies
(pANCA) have been identied in 6070% of UC patients,
but are also found in up to 40% of patients with Crohns
disease. These pANCA-positive Crohns patients typically
have a clinical phenotype resembling left-sided UC, so
ANCA detection alone is of little value in distinguishing
between UC and Crohns colitis (13). In a cohort of patients
already known to have IBD, the combination of a positive
pANCA and a negative anti-Saccharomyces cervisiae
antibody (ASCA) had a positive predictive value of 75%,
while a negative ANCA and a positive ASCA had a positive
predictive value of 86% for the diagnosis of Crohns disease
(14). While, pANCA and ASCA assays at this stage of
knowledge are neither a rst step nor a denitive step in
differential diagnosis or clinical decision-making, they may
be useful in the patient in whom all other clinical features
do not allow a distinction between UC and Crohns colitis.
While this distinction is not always essential, it may have
direct consequences in terms of counseling, prognosis,
cancer risk, and medical and surgical therapies (15).
APPROACH TO MANAGEMENT
Goals of treatment are directed at inducing and then main-
taining remission of symptoms and mucosal inammation in
order to provide an improved quality of life.
Once the diagnosis of UCis conrmed, the anatomic extent
is assessed endoscopically. The key question to be addressed
at this point is whether the inammation is distal (i.e., lim-
ited to below the splenic exure and thus within reach of
topical therapy) or extensive (i.e., extending proximal to
the splenic exure, requiring systemic medication). There-
fore, a delineation of the proximal margin of inammation, if
not achieved on initial evaluation, is desirable at some point
in the management of the case once the patients condition
permits.
From a practical standpoint, the anatomic extent and clin-
ical severity of an acute attack determine the approach to
therapy. Therapeutic decisions rarely are based upon histo-
logic severity of inammation.
Based upon clinical and endoscopic ndings the disease is
characterized as to its severity and extent. Severity is dened
as mild, moderate, severe, or fulminant (16, 17). Patients with
mild disease have less than four stools daily, with or without
blood, no systemic signs of toxicity, and a normal erythrocyte
sedimentation rate (ESR). Moderate disease is characterized
by more than four stools daily but with minimal signs of tox-
icity. Severe disease is manifested by more than six bloody
stools daily, andevidence of toxicityas demonstratedbyfever,
tachycardia, anemia, or an elevated ESR(16). However, some
patients even with the most severe colitis may not demon-
strate an elevated ESR. Patients with fulminant disease have
features which include more than 10 bowel movement daily,
continuous bleeding, toxicity, abdominal tenderness and dis-
tension, blood transfusion requirement, and colonic dilation
on abdominal plain lms (17).
In addition to the evaluation of the colitis extent and
activity, a global assessment of the patient should include
attention to extraintestinal manifestations, general health
Ulcerative Colitis Practice Guidelines 1373
concerns, and quality of life issues. Patients should be asked
whether they have noted symptoms of ocular, oral, joint or
skin or mood changes, and laboratory evaluation for anemia
and liver function test abnormalities should be performed.
Concerns regarding quality of life should be addressed: im-
pairment of function at school, work or in personal relation-
ships, social and emotional support, nancial resources, and
adequacy of patient education regarding their disease (5).
RECOMMENDATIONS FOR MANAGEMENT
OF MILD-MODERATE DISTAL COLITIS
Patients with mild-to-moderate distal colitis may be treated
with oral aminosalicylates, topical mesalamine, or topical
steroids (Evidence A). Topical mesalamine agents are su-
perior to topical steroids or oral aminosalicylates (Evidence
A). The combination of oral and topical aminosalicylates are
more effective than either alone (Evidence A). In patients
refractory to oral aminosalicylates or topical corticosteroids,
mesalamine enemas or suppositories may still be effective
(Evidence A). The unusual patient who is refractory to all of
the above agents in maximal doses, or who is systemically
ill, may require treatment with oral prednisone in doses up to
4060 mg per day (Evidence C).
The therapeutic plan here is largely determined by the
patients preference since either oral or topical therapy is
effective; however, a metaanalysis of controlled trials indi-
cates that topical mesalamine is superior to oral aminosal-
icylates in achieving clinical improvement in patients with
mild-moderate distal colitis (18).
Oral therapy with the aminosalicylates, sulfasalazine, ol-
salazine, mesalamine, or balsalazide, is benecial in achiev-
ing and maintaining remission (1, 19, 20, 25). Effective doses
of sulfasalazine range between 4 and 6 g a day in four di-
vided doses (21, 22); for mesalamine 24.8 g per day in
three divided doses (23, 24), for balsalazide 6.75 g per day
in three divided doses (2527), and for olsalazine 1.53 g/d
in divided doses (2831), although efcacy of olsalazine in
active UC is not conclusively established, perhaps in part be-
cause of a confounding dose-related diarrhea. These drugs
generally act within 24 wk (1120) and are effective in
4080% of patients (1820). Intolerance to the sulfapyri-
dine moiety of sulfasalazine is fairly common and may re-
sult in nausea, vomiting, dyspepsia, anorexia, and headache.
More severe, but less common, adverse effects include aller-
gic reactions, pancreatitis, hepatotoxicity, drug-induced con-
nective tissue disease, bone marrow suppression, interstitial
nephritis, nephrotoxicity, hemolytic anemia, or megaloblastic
anemia. Abnormal sperm counts, motility, and morphology
are also related to the sulfapyridine moiety of sulfasalazine
and are not seen with the mesalamine preparations (32). Ap-
proximately 80% of the patients intolerant to sulfasalazine
are able to tolerate olsalazine, mesalamine, and balsalazide
(19, 31, 3335). However, several of the allergic reactions
previously thought to be due to the sulfa moiety have been
seen with newer aminosalicylates as well (19).
An alternative to oral aminosalicylates is topical therapy
with either mesalamine suppositories or enemas, or hydrocor-
tisone foamor enemas. Mesalamine suppositories in a dose of
500 mg twice a day are effective in the treatment of proctitis
(36), and maintenance of remission (37), while mesalamine
enemas in doses of 14 g are able to reach as proximal as
the splenic exure and are effective in inducing (38, 39) and
maintaining remission in distal colitis (4043). Topical cor-
ticosteroids, available in the United States as a 100 mg hy-
drocortisone enema, or as a 10% hydrocortisone foam, are
effective in acute therapy of distal colitis (4446) but have not
proven effective in maintaining remission (18). Mesalamine
enemas in a dose of 4 g have been more successful than corti-
costeroid enemas in inducing remission in two double-blind
controlled studies (4749). One-gram mesalamine enemas
may prove as effective as the standard 4-g formulation for
induction of remission in patients with left-sided colitis (18).
Budesonide, a second generation corticosteroid that under-
goes rst pass hepatic metabolism has also been evaluated:
the optimal budesonide enema dose, 2 mg, not yet available
in the United States, seems to be at least as effective as the
standard hydrocortisone preparation with fewer side effects
(50, 51).
Advantages of topical therapy include a generally quicker
response time and a less frequent dosing schedule than oral
therapy. The choice of topical vehicle is also guided by pa-
tient preference as well as by the proximal extent of disease:
suppositories reaching approximately 10 cm, hydrocortisone
foam reaching approximately 1520 cm, and enemas reach-
ing up to the splenic exure (5256), although in daily clinical
practice the actual extent distribution may vary.
Some patients may achieve maximum benet from the
combination of oral and topical therapy; a combination of
oral mesalamine 2.4 g/d and 4 g/d mesalamine enema was
more effective in achieving clinical improvement, as well as
an earlier response, than either agent alone (57).
RECOMMENDATIONS FOR MAINTENANCE OF REMISSION
IN DISTAL DISEASE
Mesalamine suppositories are effective in the maintenance
of remission in patients with proctitis, while mesalamine en-
emas are effective in patients with distal colitis when dosed
even as infrequently as every third night (Evidence A). Sul-
fasalazine, mesalamine, and balsalazide are also effective in
maintaining remission; the combination of oral and topical
mesalamine is more effective than the oral mesalamine alone
(Evidence A). Topical corticosteroids including budesonide,
on the other hand, have not proven effective for maintaining
remission in distal colitis (Evidence A).
Mesalamine suppositories in doses of 500 mg daily or
twice a day are effective in maintaining remission with an
apparent dose-response relationship; only 10% of patients
treated with 500 mg twice a day relapsed at 1 yr, compared
with a relapse rate of 36% with once daily dosing (58, 59).
Mesalamine enemas in doses of 24 g maintained remission
when dosed daily (78% effective), every other day (72% ef-
fective), or even as infrequently as every third day (65% ef-
fective) (18). Sulfasalazine in a dose of 2 g/day, olsalazine
1 g/day, Eudragit-S coated mesalamine 3.2 g/day, and bal-
salazide 36 g/day (60, 61) were all effective in maintain-
ing remission in distal disease. The combination of oral
mesalamine 1.6 g/day and mesalamine enema 4 g enema
twice weekly, was more effective than the oral mesalamine
alone (62). Topical corticosteroids, whether hydrocortisone
or budesonide, have not proven effective for maintaining re-
mission in distal colitis (18, 63).
RECOMMENDATIONS FOR MANAGEMENT OF
MILD-MODERATE EXTENSIVE COLITIS: ACTIVE DISEASE
Patients with mild-to-moderate extensive colitis should begin
therapy with oral sulfasalazine in daily doses titrated up to
46 g per day, or an alternate aminosalicylate in doses up to
4.8 g per day of the active 5-ASA moiety (Evidence A). Oral
steroids are generally reserved for patients who are refractory
to oral aminosalicylates with or without topical therapy, or
for patients whose symptoms are so troubling as to demand
rapid improvement (Evidence C). 6-Mercaptopurine (6-MP),
or azathioprine are effective for patients who do not respond
to oral prednisone but are not so acutely ill as to require
intravenous therapy (Evidence C).
When the inammation extends proximal to the reach of
topical therapy (i.e., mid-descending colon-splenic exure)
oral therapy is required, either solely or in combination with
topical therapy (though this latter option has not been stud-
ied in randomized controlled trials). For clinically mild-to-
moderate, but anatomically extensive disease, the rst-line
therapy traditionally has been sulfasalazine. Responses are
dose-related with up to 80% of patients who receive daily
doses of 46 g manifesting complete clinical remission or
signicant clinical improvement within 4 wk (21, 22) and ap-
proximately half achieving sigmoidoscopic remission (21).
However, the benets of greater efcacy with the higher
dose are offset by the increase in side effects. The advan-
tages of sulfasalazine compared with the newer aminos-
alicylates are its longer track record and considerably lower
cost. If these higher doses of sulfasalazine are not well toler-
ated, or if there is concern regarding potential toxicity then
a 5-aminosalicylate containing compound should be used at
doses of at least 2 g per day, titrating up to 4.8 g per day of
the active 5-aminosalicylate moiety (24).
The newer aminosalicylatesbalsalazide (2527), ol-
salazine (2831), Eudragit-Scoatedmesalamine (23, 24), and
ethylcellulose-coated mesalamine (64)are all superior to
placebo and equivalent to sulfasalazine in acute therapy (19).
As withsulfasalazine, therapeutic benet is dose-related, with
daily doses less than 2 g being ineffective (19, 23, 24, 65).
Although controlled trials have not studied the combina-
tion of oral aminosalicylates with topical treatments, patients
often note a more prompt resolution of rectal symptoms when
a topical therapy is added.
Controlled trials have demonstrated that transdermal
nicotine patches are effective in achieving clinical improve-
ment (66) and clinical remission (67) in patients with mild-
moderate UC, with a dose-response effect between 15 and
25 mg of nicotine daily, but their success rates are generally
lower than with traditional aminosalicylate therapy. Benet
was more evident in ex-smokers than in those who had never
smoked (66, 68) and was better tolerated in the ex-smokers
(66). The most common adverse effects were skin irritation,
dizziness, and nausea. Transdermal nicotine in a daily dose of
15 mg was not effective in maintenance of remission (69) and
the long-term consequences of long-term transdermal usage
are uncertain. At present, it is uncertain where nicotine ts
into the therapeutic algorithm.
Oral prednisone demonstrates a dose-response effect be-
tween 20 and 60 mg per day (7073), with 60 mg per day
modestly more effective than 40 mg per day but at the ex-
pense of greater side effects (72). No randomized trials have
studied steroid taper schedules; many authorities (20, 73)
recommend 4060 mg per day until signicant clinical im-
provement occurs and then a dose taper of 510 mg weekly
until a daily dose of 20 mg is reached. At this point tapering
generally proceeds at 2.5 mg/wk.
The frequency and severity of steroid toxicity are sig-
nicant and may involve virtually every organ system and
many metabolic activities. These include the appearance of
cushingoid features, emotional and psychiatric disturbances,
infections, glaucoma, cataracts, gastroduodenal mucosal in-
jury, skinstriae, impairedwound-healing, andmetabolic bone
disease. The latter can present insidiously with osteopenia
and osteoporosis, or with the more dramatic bone fracture or
unpredictable osteonecrosis. Steroid-induced metabolic dis-
turbances include hyperglycemia, sodiumand uid retention,
hypokalemia, metabolic alkalosis, hyperlipidemia, and accel-
erated atherogenesis (32).
The National Institute of Health have recently published
their consensus statement regarding the prevention, diagno-
sis, and therapy of osteoporosis: any patient who is treated
with a daily dose of at least 5 mg of prednisone for more
than 2 months should be considered for measurement of
bone mass density (74). Prospective studies on successful
osteoporosis-prevention strategies in steroid-treated UC pa-
tients are lacking (75, 76). However, the American Col-
lege of Gastroenterology and American Gastroenterological
Association have both recently published guidelines for the
diagnosis and management of osteoporosis in IBD (77, 78).
DXA bone testing should be considered in IBD patients with
a number of risk factors for osteoporosis such as smoking,
low body mass, sedentary lifestyle, hypogonadism, family
history, and nutritional deciencies. IBD patients at great-
est risk for fracture are over age 60 and all these subjects
should be considered for DXA testing. Patients using corti-
costeroids beyond 3 months consecutively or who are recur-
rent users should likewise be considered for DXAtesting and
even prevention with bisphosphonate therapy (77). It is ad-
visable to prescribe a bisphosphonate for IBD patients at a T
score below 2.5. For patients on long-term corticosteroids,
or with other important risk factors such as previous frac-
tures, it may be reasonable to prescribe a bisphosphonate at
T scores below 1.0 (77).
Calcium supplementation 1,0001,500 mg/day and vi-
tamin D 800 units/day should be considered as well as
estrogen replacement in the postmenopausal woman (78).
Controlled trials have demonstrated efcacy for alendronate
(79), risedronate (80), and etidronate in the prevention of
corticosteroid-induced osteoporosis (81) in non-IBD popu-
lations. Modiable risk factors, such as cigarette smoking,
alcohol use, and a sedentary lifestyle should be addressed.
For the patient with signicant bone loss, referral to a spe-
cialist should be considered.
Controlled (82, 83) and uncontrolled trials (84, 85) of aza-
thioprine in doses up to 1.52.5 mg per kg per day have
demonstrated its effectiveness in patients who do not respond
to, or cannot be weaned from steroids. Uncontrolled series
have also demonstrated its value in achieving remission in
patients refractory to high doses of oral steroids (84, 86). In
this capacity, its use in acute induction of remission is some-
what limited by its slow onset of action; up to 36 months of
treatment may be necessary to appreciate an optimal effect
(87).
Azathioprine and 6-MP toxicities include bone marrow
suppression, particularly leukopenia, which is usually dose-
dependent. Serious infections are infrequent and are usually,
but not always, related to leukopenia and often occur with
concomitant steroid use. Liver abnormalities occur in ap-
proximately 2% of patients and usually represent a reversible
drug-induced hepatitis. Allergic reactions occur in approxi-
mately 25% of patients and usually present as some com-
bination of fever, rash, myalgias, or arthralgias. Pancreatitis
occurs as a hypersensitivity reaction in approximately 2% of
patients (88). Long-term use has not been associated with
increased neoplasia risk (89, 90).
Some (91, 92) but not all (93, 94) recent retrospective data
have suggested that measurement of azathioprine and 6-MP
metabolites may be useful in dose adjustments since serum
6-thioguanine nucleotide (6-TGN) levels of greater than 235
pmol/8 10
8
erythrocytes may be associated with a greater
response rate than patients with lower 6-TGN levels. Hepa-
totoxicity, on the other hand, may correlate with the elevated
levels of 6-methylmercaptopurine (6-MMP). A retrospective
study (95) found that a subset of patients with 6TGN lev-
els of less than 235 pmol/8 10
8
erythrocytes may remain
refractory to dose escalations of 6-MP/AZA since they may
preferentially metabolize 6-MP/AZA to 6-MMP and main-
tain suboptimal 6TGNlevels (95). Given the conicting data,
the retrospective nature of these studies, and the limited pos-
itive and negative predictive values for these particular uses,
the utility of these tests need prospective controlled evalua-
tion before their routine use can be recommended. However,
these metabolite markers can be of value in assessing whether
a patient is noncompliant with their immunomodulator ther-
apy. Leukopenia was observed in only 8% of responders,
indicating that it is not a necessary condition for effective
dosing (91).
6-MP and its prodrug azathioprine are both metabolized
by thiopurine methyltransferase (TPMT), an enzyme that ex-
hibits variation as a result of a genetic polymorphism of its
alleles and this enzyme can now be measured by commercial
laboratories. Approximately 0.3% of the general population
have low to absent enzyme activity, 11% have intermediate,
and 89% have normal to high levels of activity (96). How-
ever, only about a quarter of cases of leukopenia in practice
are associated with one of these genetic polymorphisms (97).
Therefore, prospective studies of dose-optimization based on
measurements of TPMT, 6-TG, or 6-MP levels to monitor
clinical response are still needed before the routine use of
these assays can be recommended as providing much incre-
mental benet to the traditional routine of monitoring the
CBC, liver associated laboratory chemistry abnormalities,
and clinical response.
As described below, azathioprine has been found effec-
tive in maintaining remission in a controlled drug withdrawal
study (98), while retrospective studies have demonstrated the
value of 6-MP in maintaining long-term remission (99, 100)
and is generally well tolerated during the long-term use (88
90, 99).
Methotrexate has not been proven to be effective in UC
when administered in a weekly dose of 12.5 mg/day (101);
higher doses, or administration by a parenteral route has not
been studied in controlled trials.
RECOMMENDATIONS FOR MILD-MODERATE EXTENSIVE
COLITIS: MAINTENANCE OF REMISSION
A maintenance regimen is usually required when the acute
attack is controlled, especially in patients with extensive,
or relapsing disease. Sulfasalazine, olsalazine, mesalamine,
and balsalazide are all effective in reducing relapses (Evi-
dence A). As a rule, patients should not be treated chron-
ically with steroids. Azathioprine or 6-MP may be use-
ful as steroid-sparing agents for steroid-dependent patients
and for maintenance of remission not adequately sustained
by aminosalicylates, and occasionally for patients who are
steroid-refractory but not acutely ill (Evidence C).
Sulfasalazine reduces relapse rates in UC in a dose-related
fashion, with benets demonstrated at 24 g per day (102
104). Although the 4 g per day regimen is the most effective
in preventing relapse, up to one quarter of patients cannot
tolerate the side effects at this dose, thus limiting its over-
all utility (104). The newer aminosalicylate preparations
including olsalazine (105, 106), mesalamine (107115), and
balsalazide (116)have relapse-prevention properties virtu-
allythe same as, but not greater than, those of equivalent doses
of sulfasalazine (19, 117). Because of the well-documented
efcacy of sulfasalazine in relapse-prevention, most (107,
108, 110, 111, 114, 119124) but not all (115, 118), 5-ASA
relapse-prevention trials have used sulfasalazine as the con-
trol. As with sulfasalazine, most (115, 124127), if not all
(128, 129), comparison studies of mesalamine have demon-
strated increased efcacy with higher doses up to 4 g per
day of 5-ASA. However, unlike sulfasalazine, use of larger
doses of 5-ASA in the newer preparations are generally well
tolerated, lending these analogues an advantage over sul-
fasalazine for relapse-prevention. On the other hand, the cost
of sulfasalazine, especially when considered for long-term
use, is considerably lower. Although the maximum length
of remission-maintenance benet has not been established,
most experts recommend permanent maintenance; however,
the patient with a mild rst episode, or with very infrequent
mild relapses that are easily controlled, may opt for being
followed without long-term medical maintenance therapy.
The immunomodulators azathioprine and 6-MP have been
studied for relapse-prevention. (As with induction of remis-
sion in UC, there have been no studies comparing 6-MP with
azathioprine.) In patients whose remission was achieved with
azathioprine, continuation of active drug reduced the 12-
month relapse rate to 36%, compared to 59% on placebo
(98). Similarly, uncontrolled retrospective data from 105 pa-
tients treated with continued long-term 6-MP (99), and 351
patients treated with long-term azathioprine (100) appear to
conrm the efcacy of these agents continued long-term in
maintaining remissions of UC. The risk-benet ratio of indef-
inite azathioprine or 6-MP use, especially when compared to
colectomy, for the maintenance of remission, is not known,
although a recent retrospective series of 621 IBD patients
treated during a 30-yr interval indicated that azathioprine is
generally well tolerated (89) and is not associated with an
increased cancer risk (90) or mortality (100).
RECOMMENDATIONS FOR MANAGEMENT
OF SEVERE COLITIS
The patient with severe colitis refractory to maximal oral
treatment with prednisone, oral aminosalicylate drugs, and
topical medications, or the patient who presents with toxic-
ity, should be hospitalized for a course of intravenous steroids
(Evidence C). Failure to demonstrate signicant improve-
ment within 710 days is an indication for either colectomy
(Evidence C) or treatment with intravenous cyclosporine (Ev-
idence A) in the patient with severe colitis. Long-term re-
mission, in these patients is signicantly enhanced with the
addition of long-term maintenance 6-MP (Evidence C).
The patient who continues to have severe symptoms de-
spite optimal doses of oral steroids (4060 mg of prednisone
daily), oral aminosalicylates (46 g of sulfasalazine, 4.8 g of
mesalamine, or 6.75 g of balsalazide), and topical medica-
tions as tolerated, should be hospitalized for further treatment
(130137). Superimposed infection with enteric pathogens
and C. difcile should be excluded. The mainstay of therapy
at this point is an intravenous steroid in a daily dose equivalent
to 300 mg of hydrocortisone or 60 mg of methylprednisolone
if the patient has received steroids in the prior month, or
perhaps intravenous ACTH if the patient has not recently re-
ceived steroids, as has been suggested by some, but not all
series (134136). There is no benet to treatment with a much
higher daily dose of steroids and it exposes the patient to a
higher potential rate of side effects (137). The clinical impres-
sion that continuous infusion is preferable to bolus therapy
has not been subjected to a controlled trial. Controlled tri-
als of antibiotics, however, have demonstrated no therapeutic
benet from the use of oral vancomycin (138), intravenous
metronidazole (133), or ciprooxacin (139), when added to
intravenous steroids. However, protocols outlining treatment
regimens for severe colitis generally include broad-spectrum
antibiotics for patients with signs of toxicity, or with worsen-
ing symptoms despite maximal medical therapy (130132).
There is a prevalent tendency to place patients with severe
colitis almost routinely on total parenteral nutrition (TPN).
Controlled studies on this subject, however, show no benet
from this maneuver (140, 141) as a primary therapy for UC,
which may even be detrimental by depriving the colonic ente-
rocytes of the short-chain fatty acids vital to their metabolism
and repair (142). However, TPN may be useful as a nutri-
tional adjunct in patients with signicant nutritional depletion
(143).
There are no studies to demonstrate that an oral aminos-
alicylate is of clinical benet in this setting either, so it is
generally withheld if the patient is NPO, but it may be con-
tinued if the patient is eating and has been tolerating this
drug. Likewise, no controlled studies have conrmed any in-
cremental benet of topical medications in this setting, but
they are still often prescribed if they can be retained and tol-
erated. Since the failure rate of medical therapy in patients
hospitalized for severe colitis is approximately 40% (144),
these patients should be followed closely in conjunction with
a surgeon experienced in the management of patients with
inammatory bowel disease.
Infrequently, cytomegalovirus superinfection may occur in
the patient with severe colitis and this possibility should be
considered in the patient who is not responding to maximal
immunosuppressive therapy. CMV superinfection can be di-
agnosed with sigmoidoscopic biopsy and viral culture and
treatment with gancyclovir may lead to clinical improvement
(145, 146).
In patients with either toxic signs (fever, leukocytosis, or
worsening symptoms) or megacolon, medications with anti-
cholinergic or narcotic properties should be avoided for fear
of worsening colonic atony or dilatation. Patients with severe
colitis who do not improve signicantly after 710 days of
maximal medical therapy are unlikely to benet fromprolon-
gation of this medical treatment (132, 134) and should either
be referred for surgery (see below) or offered treatment with
intravenous cyclosporine. In one placebo-controlled double-
blindtrial, 82%of patients withsteroid-refractorysevere coli-
tis, treated with intravenous cyclosporine in a dose of 4 mg per
kg per day improved and were able to avoid colectomy in the
acute stage (147); another series demonstrated similar ef-
cacy with an intravenous cyclosporine dose of 2 mg/kgday
1
(148). Patients with fulminant colitis are treated similarly
but decisions regarding surgery versus cyclosporine should
be made within a few days of initiating intravenous steroid
therapy.
No randomized controlled trials have been performed
studying the addition of azathioprine or 6-MP to cy-
closporine. Retrospective series with long-term follow-up of
up to 5.5 yr (149) indicate a signicantly higher long-term
success rate when azathioprine or 6-MP were added during
the oral cyclosporine phase (148152), although the ideal
dose or time to add 6-MP or azathioprine has not been stud-
ied. In the largest reported series the long-term success rate,
dened as the avoidance of subsequent courses of intravenous
steroids or colectomy, was 76% when 6-MP was added, ver-
sus 23% in patients in whom 6-MP was not added, during
follow-up of 3.6 yr (150).
Signicant toxicity may occur with cyclosporine use in
UC. Severe adverse events include nephrotoxicity, infection,
and seizures (particularly in patients with associated hypoc-
holesterolemia or hypomagnesemia). More common, but less
severe side effects include paresthesias, hypertension, hy-
pertrichosis, headache, abnormal liver function tests, hyper-
kalemia, and gingival hyperplasia (153). Based on data from
a small series, it has been suggested that cyclosporine does
not increase the rate of postoperative complications in pa-
tients undergoing proctocolectomy (154) while the preop-
erative use of corticosteroids in patients with inammatory
bowel disease does substantially increase the risk of postoper-
ative infections in patients undergoing elective bowel surgery
(155).
Patients with fulminant colitis or toxic megacolon should
be treated as above; in addition they should be kept NPO,
have a small bowel decompression tube if a small bowel ileus
is present, and instructed to rotate frequently into the prone or
knee-elbow (156) position to aid in evacuation of the bowel
gas. Broad-spectrum antibiotics are usually used empirically
in these patients. The duration of medical treatment of mega-
colon is controversial; some experts advocate surgery within
72 h if no signicant improvement is noted (157) while oth-
ers take a more watchful stance if no toxic symptoms are
present (156). All agree, however, that any clinical, labora-
tory, or radiologic deterioration on medical therapy mandates
immediate colectomy.
RECOMMENDATION FOR SURGERY
Absolute indications for surgery are exsanguinating hemor-
rhage, perforation, and documented or strongly suspected
carcinoma (Evidence C). Other indications for surgery are
severe colitis with or without toxic megacolon unresponsive
toconventional maximal medical therapy, andthe patient with
less severe, but medically intractable symptoms or intolerable
medication side effects (Evidence C).
There are no prospective randomized trials comparing
medical treatment to surgery for any indication in UC, but
three situations are absolute indications for surgery since con-
tinuedmedical therapyis doomedtofailure andpotentiallyfa-
tal: exsanguinating hemorrhage, frank perforation, and doc-
umented or strongly suspected carcinoma, i.e., high-grade
dysplasia or possibly low-grade dysplasia in at mucosa (see
in section Recommendations for Cancer Surveillance).
Massive hemorrhage in UC is due to diffuse mucosal ul-
ceration. If the hemorrhage is exsanguinating or even per-
sisting despite maximal medical therapy (see above), it is an
indication for emergency surgery. If the patients condition
permits, total proctocolectomy may be the most reliable pro-
cedure since a small group (approximately 12%) of patients
may have continued hemorrhage fromthe retained rectal seg-
ment if only a subtotal colectomy is performed (158, 159).
On the other hand, subtotal colectomy with the preservation
of the rectum for a future restorative procedure is an accept-
able choice, so long as the small risks of further hemorrhage
are appreciated and appropriately monitored.
Perforation, fortunately occurring in only 23% of hospi-
talized UC patients at tertiary referral centers (160), is the
most dreaded and most lethal complication of toxic colonic
dilation. In a univariate analysis, perforation had a more ad-
verse impact onsurvival thananyother single clinical variable
(160). Moreover, it is essential to recognize that perforation
can occur without being preceded by megacolon. The surgical
procedure of choice inthis settingis a subtotal colectomywith
rectosigmoid mucous stula or Hartmanns closure (160).
Other indications for surgery include the patient with se-
vere colitis or toxic megacolon unresponsive to maximal in-
travenous medical therapy (see above). The patient with less
severe but medically intractable symptoms, resulting in phys-
ical debility, psychosocial dysfunction, or intolerable steroid
side effects, may also be best served by colectomy. However,
uncontrolled series suggest that approximately 2/3 of these
patients may achieve remission with the use of the immuno-
suppressive drugs azathioprine or 6-MP (85, 99).
Only rarely is surgery necessary to control the extrain-
testinal manifestations of UC (161). Likewise, patients with
severe, progressive pyoderma gangrenosum, in whomthe py-
oderma activity parallels the activity of the colitis (162), or
with hemolytic anemia refractory to steroids and splenec-
tomy, may benet from colectomy (163, 164). By contrast,
the course of primary sclerosing cholangitis (PSC) is inde-
pendent of the activity of the colitis and is not affected by
colectomy (165).
Whatever the indication for surgery, patients should be
informed of the different operations available (i.e., total proc-
tocolectomy with permanent ileostomy vs the ileoanal anas-
tamosis procedure) and be aware of the risks and benets of
these operations within different clinical settings.
RECOMMENDATIONS FOR THE MANAGEMENT
OF POUCHITIS
Patients who develop the typical symptoms of pouchitis after
the ileoanal pouch anastomosis (IPAA) should be treated with
a short course of antibiotics (Evidence A). Although con-
trolled data are scarce, metronidazole in a dose of 250 mg
thrice a day or ciprooxacin 500 mg twice a day are most
commonly used (Evidence C).
Patients who undergo the IPAA procedure may develop
an idiopathic inammation termed pouchitis, which typi-
cally presents with variable symptoms of increased stool fre-
quency, rectal bleeding, abdominal cramping, rectal urgency,
tenesmus, incontinence, fevers, and the appearance of ex-
traintestinal manifestations (166). The diagnosis can be made
clinicallyandis associatedwithcharacteristic endoscopic and
histologic features (167); symptoms do not always correlate
with endoscopic and histologic ndings (168). Demonstrat-
ing the diagnosis with pouchoscopy as opposed to empiric
treatment with metronidazole may be a cost-effective strat-
egy (169). Pouchitis occurs in up to 50% of patients after
a mean follow-up of 40 months (170) and occurs more fre-
quently in patients with PSC or other preoperative extrain-
testinal manifestations (171). Only rarely does refractory or
recurrent pouchitis occur because of the missed diagnosis
of Crohns disease (172), and pouch excision is required in
fewer than 5% of patients in most series. Some patients with
episodes of increased stool frequency and cramping, but with
normal endoscopic and histologic ndings in the pouch, may
be experiencingirritable pouch symptoms andmayrespond
to anticholinergics, antidepressants, and antidiarrheals. Other
patients may have inammation limited to a short cuff of re-
tained rectal mucosa (cuftis) and may respond to topical
hydrocortisone or mesalamine (173).
Controlled drug trials for the treatment of pouchitis are
very limited (174, 175). Metronidazole 400 mg thrice a day
was effective in the treatment of chronic active pouchitis
(177), while other controlled trials demonstrated at least simi-
lar efcacy to metronidazole with ciprooxacin 500 mg twice
a day (175), or with budesonide enema 2 g daily (176). Nu-
merous uncontrolled trials demonstrate similar efcacy with
metronidazole as well as with other antibiotics (170, 178), as
well as oral mesalamine, andtopical mesalamine andsteroids.
Anoral probiotic formulationVSL-3(containinglactobacilli,
bidobacteria, and Streptococcus salivarius), was effective in
the prevention of pouchitis for up to 1 yr following surgery)
(179), and in the prevention of pouchitis relapse (180).
RECOMMENDATIONS FOR CANCER SURVEILLANCE
After 810 yr of colitis, annual or biannual surveillance
colonoscopy with multiple biopsies at regular intervals
should be performed (Evidence B). The nding of high-grade
dysplasia in at mucosa, conrmed by expert pathologists
review, is an indication for colectomy, while the nding of
low-grade dysplasia in at mucosa may also be an indica-
tion for colectomy to prevent progression to a higher grade
of neoplasia (Evidence B).
Patients with UC are at increased risk for colorectal can-
cer; the degree of risk is related to the duration of disease and
anatomic extent of colitis (181, 182). After 10 yr of universal
disease, the cancer risk is in the range of 0.51% per year
(181185). Even patients with left-sided colitis reach similar
levels of cumulative cancer-risk after 34 decades of disease
(182, 186, 187); patients with proctitis or proctosigmoiditis
are not at increased cancer risk. Although some data suggest
a later onset of cancer risk in left-sided than in more extensive
colitis (181), this evidence is not sufciently strong to jus-
tify different guidelines for surveillance in the two groups.
Determination of anatomic extent in assessing cancer risk
has historically been based on macroscopic rather than histo-
logic inammation. On the other hand, both macroscopic and
microscopic healing may occur, but once extensive colitis is
documented, the cancer risk should be assumed to correlate
with the greatest previously determined extent. Some (188,
189), but not all (190, 191) groups have found that patients
with UCand PSChave an increased risk of colorectal cancer.
Whether this observation reects a true biologic phenomenon
or a statistical artifact of longer than appreciated colitis dura-
tion, it is prudent to start colonoscopic surveillance as soon as
the coexisting diagnoses of UCand PSCare established (190,
191). In a recent, prospective randomized, placebo-controlled
trial, ursodeoxycholic acid in daily divided doses of 13
15 mg/kg, signicantly reduced the risk for developing col-
orectal neoplasia in patients with UC and PSC (192).
UCpatients with a family history of colorectal cancer have
a ve-foldriskof cancer comparedwiththe matchedcontrols-
(193). On the other hand, population-based data suggest that
there is a reduced relative cancer risk in patients who are
taking at least 2 g/day of an aminosalicylate (194, 195), or
who visit a physician at least twice a year (194). Similarly,
a chemoprotective effect has been suggested in some (196,
197), but not all series (198), for sulfasalazine; an effect that
may be confounded in part by its effect on folate metabolism
(198).
Compared with noncolitis associated colorectal cancer,
colitis-associated cancers are more often multiple, broadly
inltrating, anaplastic, and uniformly distributed through-
out the colon, and seem to arise from at mucosa instead
of following the usual adenoma-cancer sequence (182, 187,
199). Furthermore, colitis-associated colorectal cancer often
occurs in a much younger patient population than does col-
orectal cancer in the general population (182, 184).
Simplystated, the goals of anycancer surveillance program
in UCare to prevent cancer and to save lives. There are no ran-
domized studies comparing different surveillance protocols
or, for that matter, even surveillance versus no surveillance.
Nonetheless, at present, the best practical recommendation
for patients who are surgical candidates, based upon review
of dysplasia surveillance series calls for annual or biannual
colonoscopy, avoiding periods of clinical relapse, with multi-
ple biopsies at 10-cmintervals (200202). Examination every
second year would reduce the cost but at the expense of re-
ducing likelihood of early cancer detection (200), especially
in patients with longer disease duration since hazard rates
increase with time (203, 204). Whatever schedule might be
theoretically most advisable, being both frankly informative
and programmatically exible with patients is important to
compliance. The cost of such a surveillance programfor each
successful detection of precancer or cancer compares favor-
ably with the cost of population-wide screening by exible
sigmoidoscopy for all subjects at average risk for colorectal
cancer (201). Patients with longstanding UC may also be of-
fered the option of a prophylactic total proctocolectomy, but
patients in remission rarely opt for this approach.
The standardization of high-grade and low-grade
dysplasia published by the Inammatory Bowel Disease
Dysplasia Morphology Group (IBD-DMG) has been widely
adopted and has served to make the diagnosis of dysplasia
more stringent (205). Whencoloncancer is identiedthe need
for surgery is obvious; similarly, the colonoscopic biopsy di-
agnosis of high- or low-grade dysplasia in at mucosa is often
indicative of a concurrent or future cancer and is an absolute
indication for colectomy for patients with high-grade dyspla-
sia (206, 207), and should prompt consideration of colectomy
in patients with low-grade dysplasia as well.
The nding of low-grade dysplasia in a mass lesion (208)
that does not resemble a typical sporadic adenoma (see be-
low), or a stricture that is symptomatic, or is not passable
during colonoscopy (209, 210) especially in longstanding
disease, are likewise often seen in conjunction with colon
cancer and colectomy is advisable. The ndings of low-grade
dysplasia in at mucosa may also be an indication for colec-
tomy since an analysis of 10 prospective series of dysplasia
surveillance in 1,225 patients found cancer at colectomy im-
mediately after colonoscopic biopsy evidence of low-grade
dysplasia in 19% of patients (211), while the 5-yr predictive
value of low-grade dysplasia for either cancer or high-grade
dysplasia is as high as 54% (212214).
How to manage the patient with longstanding UC, who
is found to have a polypoid mass within a colitic area, that
resembles a typical sporadic adenoma, i.e., an adenoma-like
mass (215)? Two recent series reported 72 such patients who
had a polypoid mass resected in its entirety by colonoscopic
polypectomy (216, 217) and who had no dysplasia in the ad-
jacent at mucosa. Although longer-term data are required,
during a mean follow-up of 3.9 yr no dysplasia in at mu-
cosa or carcinoma was found, suggesting that vigilant follow-
up surveillance colonoscopy may sufce for these patients.
Polyps with a plaque or carpet-like morphology were ex-
cluded from these studies and should continue to be consid-
ered dysplasia associated with a lesion or mass (DALM) and
requires surgery.
Guidelines for the patient found to have low-grade or
high-grade dysplasia are discussed above. It is essential to
obtain corroborating pathologic review to conrm the un-
equivocal distinction between denite neoplastic dysplasia
and regenerative atypia due to inammation and repair. How-
ever, attempts to repeatedly demonstrate dysplasia on subse-
quent examinations before recommending colectomy should
not be undertaken without the awareness by both patient
and physician of the high risk of concomitant or subsequent
advanced neoplasia. On the other hand, the patient whose
biopsies are interpreted as indenite for dysplasia should
have the slides reviewed by an expert gastrointestinal pathol-
ogist and should undergo repeat surveillance colonoscopy
at a briefer interval (205), since these patients may have an
elevated risk of subsequent progression to denite dysplasia
(218).
ACKNOWLEDGMENT
We gratefully acknowledge the assistance of Michele
Kissous-Hunt in the preparation of this manuscript.
Reprint requests and correspondence: Asher Kornbluth, M.D.,
The Mount Sinai Medical Center, 1751 York Avenue, New York,
NY 10128.
Received April 5, 2004; accepted April 6, 2004.
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