My Treatment Approach to the Management of Ulcerative Colitis

DIAGNOSIS AND TREATMENT GUIDELINES
My Treatment Approach
My Treatment Approach to the Management of
Ulcerative Colitis
Seymour Katz, MD, MACG
Abstract
Ulcerative colitis diagnosis and management represent a challenge for clinicians. The disguises of ischemia
and acute infectious colitis continue to confound the diagnosis. The therapeutic options have remarkably
expanded in the way of immunomodulators, biologics, or ileoanal pouch surgery, yet all carry potential
considerable risks. These risks can confuse and impair patient acceptance, particularly elderly patients and
men younger than 30 years. Predictors of outcome of medical and surgical therapy have improved but are
far from complete. Nevertheless, therapies focused on the specific patient’s condition continue to offer
hope.
ª 2013 Mayo Foundation for Medical Education and Research
T
he diagnosis of ulcerative colitis (UC)
may be elusive and is often cloaked by
confusion with acute self-limited infectious colitis, ischemia, or drug effect. The management is daunting, considering no “one size
fits all,” and even after medical failure, the surgical options open new areas of morbidity. The
following approach is offered as a clinical guide
to diagnosis and management.
CHALLENGE THE DIAGNOSIS BEFORE
EMBARKING ON THERAPY
Is there sufficient evidence to substantiate the
diagnosis? Obtain all prior imaging studies,
seromarkers, and pathology slides for a second
opinion by expert gastrointestinal radiologists
and pathologists.
Have the following conditions, often diagnosed as UC, and infections been ruled out:
ischemia, Behçet disease, segmental colitis, celiac
disease, microscopic colitis, drug (eg, nonsteroidal anti-inflammatory drugs)einduced colitis,
diverticulitis (segmental colitis associated with
diverticulitis), Clostridium difficile, Campylobacter,
parasites (strongyloides) (particularly with travel
in an endemic area), or cytomegalovirus (CMV)?
Are there noneirritable bowel disease
(IBD) factors that contribute to diarrhea that
are misinterpreted as an IBD exacerbation
(eg, bile acid diarrhea, small intestinal bacterial
overgrowth, microscopic colitis, or sexually
transmitted diseases, such as chlamydia,
gonorrhea, syphilis, or AIDS mimicking proctitis)? If fecal calprotectin (FCP), C-reactive
protein (CRP), and albumin levels are within
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normal limits, a noninflammatory source (eg,
irritable bowel syndrome, sorbitol, or lactose
intolerance) should be ruled out.
GENERAL CONSIDERATIONS
Vaccination
At the first visit be sure that the patient’s vaccination schedule includes hepatitis A and B,
pneumonia, influenza, and, if necessary, human papillomavirus (Gardasil; Merck & Co,
Inc) and zoster (live attenuated vaccine). Live
attenuated vaccines are contraindicated once
immune suppression therapy commences.
From the Department of
Medicine, New York University School of Medicine,
New York, NY; North
Shore University HospitalLong Island Jewish Health
System, Manhasset, NY;
and St Francis Hospital,
Roslyn, NY.
Tobacco
Current tobacco use is not associated with a risk
of UC, but a history of former smoking is a risk
that may persist for decades after cessation of
smoking.1 Although it is a simple leap of faith
to consider nicotine as beneficial in UC because
smoking is “protective,” this has not been uniformly effective and has the added burden of
increased extraintestinal manifestations.2
Pregnancy in Women With UC
In the French Groupe d’Etude Thérapeutique
des Affections Inflammatories du Tube Digestif
(GETAID) study, infliximab use by pregnant
women with IBD had no different outcomes
than use by pregnant patients with IBD not taking biologics.3-5 However, the Pregnancy in Inflammatory Bowel Disease and Neonatal
Outcomes (PIANO) registry of 896 IBD-complicated pregnancies noted patients with UC to
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MAYO CLINIC PROCEEDINGS
have a 5 times greater spontaneous abortion
rate, more preterm births, and lower birth
weights than occurred with patients undergoing
immunomodulator and/or biologic therapy.6
The concern for discontinuing infliximab therapy in the last trimester because of its accelerated
transplacental movement persists. Nevertheless,
the administration of the rotavirus live attenuated vaccine must still be delayed for at least 6
months before administering it to newborns of
these mothers.
Stress
The recognized nexus between symptomatic
flares of IBD and stress can be associated
with markers of increased inflammation (eg,
CRP), glucocorticosteroid resistance, and a
reduced immune response.7 Whether cognitive and pharmacologic therapies directed at
stress-related flares can alter the disease course
remains to be explored.7,8
Adherence
Nonadherence is a considerable disappointment in IBD therapy.9,10 The young college
student, yuppie, or unmarried male is particularly at risk for a greater relapse rate. One
approach to enhance adherence is a face-toface patient-physician session at least 3 times
yearly even when the disease is quiescent.
Bone Health
Serum vitamin D levels should be measured.
A dual-energy x-ray absorptiometry scan is indicated if glucocorticosteroids are given for more
than 3 months. Calcium and vitamin D supplements will not be sufficient but may play a role
in reducing UC risk in women.11 Osteoporosis
often requires bisphosphonates but not in young
women anticipating pregnancy.
MEDICAL THERAPY FOR THE IBD
OUTPATIENT: OFFICE MANAGEMENT
5-Aminosalicylic Acid
The 5-aminosalicylic acid formulations remain
the standard of care for mild to moderate
UC populations seen in a community practice.
5-Aminosalicylic acid (mesalamine) offers comparable efficacy to sulfasalazine, but the latter is
less costly and may be the only alternative in a patient’s formulary (Table 1).12,13 The adverse effects of the sulfapyridine moiety of sulfasalazine
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requires more frequent monitoring of the complete blood cell (CBC) count and liver enzyme
levels. These concerns often favor mesalamine
at least for first-time users. Fifty percent of
whites are slow acetylators of sulfapyridine to
N-acetyl sulfapyridine, leading to accumulation
of sulfapyridines with adverse effects, such as
thrombocytopenia, leukopenia, and liver, lung,
and pancreatic disease in slow N-acetyl-transferase acetylators.14 Yet, a Mayo clinic study
revealed no significant differences between Nacetyl-transferase genotypes (rapid or slow) in
predicting response or toxicity.15 Periodic monitoring of CBC counts and liver enzyme levels is
recommended, particularly with the use of
sulfasalazine.
Although randomized controlled trials found
similar efficacy of 2.4 g/d vs 4.8 g/d, the higher
dose was more effective in patients with prior
use of glucocorticosteroids, rectal therapy, or
multiple medications.16 With the present drive
for deep remission (ie, clinical, endoscopic, and
histologic remission), 4.8 g/d was more effective
in achieving mucosal healing (ie, giving a higher
dose for longer period, eg, 12 weeks), especially
in patients with longer duration of disease (65%
with 4.8 g vs 58% with 2.4 g at 3 weeks and 80%
vs 68% at 6 weeks).17
A revisit of prior oral and rectal combined
therapy revealed a faster response of rectal
bleeding, often as soon as 2 days, and a decrease
in bowel movements within a median of 8 days.
Similar combined therapy could achieve clinical
and endoscopic healing within 3 weeks.16 If the
patient is still symptomatic, consider alternating
hydrocortisone or budesonide enemas at bedtime
and suppositories with 5-aminosalicylic acid
in the morning, even in patients with extensive
pancolitis, before embarking on immunomodulator and biologic therapy.
Rectal therapy is often forgotten as a necessary component of oral therapy because tenesmus, urgency, and fear of incontinence are
the overarching concerns of most patients. Patient education regarding topical therapy efficacy
is essential to overcome aversion to rectal agents.
Social concerns for the college student living in a
dormitory or a military recruit in barracks
require collaboration with the health service to
provide a private setting. Occasionally, severe
proctitis may become resistant to all medical
therapies. It is appropriate to consider surgery
despite such limited disease.
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MANAGEMENT OF ULCERATIVE COLITIS
TABLE 1. Management of UC Key Points
1. Challenge the diagnosis: Review all prior imaging endoscopic laboratory and surgical records. Consider second gastrointestinal pathologist’s opinion
2. Due diligence: Rule out other causes, including concomitant neoplasia and dysplasia
3. Confirm active disease by endoscopy, biopsy, and CRP and FCP measurement before embarking on therapy (ie, rule out IBS-like confounding
symptoms)
4. Customize therapy to patient’s disease severity (ie, mild-moderate to severe) and constraints of their daily activity (obstacles to regular dosing, followup appointment, procedures, and imaging studies)
5. Mild-moderate to severe UC: Add topical therapy to control tenesmus despite extent of disease
6. Adherence decisions: Consider once- vs twice-daily 5-aminosalicylic acid “toothbrush” approach
7. Predictors of relapse: Even with clinical remission (eg, biopsy with basilar plasmacytosis, increasing CRP and FCP levels, or change in SIBDQ)
8. Exit strategy: Glucocorticoid therapydalways limit to short-term use, never maintenance. Plan exit strategy with immunomodulator or biologics
9. Initial visit requirements: Baseline studies include purified protein derivative or Quantiferon gold test, stool culture and Clostridium difficile, pregnancy
test if indicated, vaccination status for hepatitis A and B, and TPMT enzyme if immunomodulator or biologic therapy is anticipated. MRI or CT
enterography if Crohn disease is suspected
10. Earlier use of biologics and immunomodulators is favored rather than risk long delays. Early surgical consultation if severe disease. Caution with
immunomodulator or biologics in frail elderly patients and in males <30 y for fear of HSTCL
CRP ¼ C-reactive protein; CT ¼ computed tomography; FCP ¼ fecal calprotectin; HSTCL ¼ hepatosplenic T-cell lymphoma; IBS ¼ irritable bowel syndrome; MRI ¼
magnetic resonance imaging; SIBDQ ¼ Short Inflammatory Bowel Disease Questionaire; TPMT ¼ thiopurine methyltransferase enzyme; UC ¼ ulcerative colitis.
5-Aminosalicylic AcideRelated Renal
Disease
Risks of renal disease are rare, such as interstitial nephritis, which occurs in 0.20%.18 Nevertheless, it is wise to avoid use in patients with
preexisting renal disease or renal calculous disease. Aging is associated with a decrease in
creatinine clearance when calculating the effects of 5-aminosalicylic acid. Nevertheless,
the greater decrease in creatinine clearance in
61 elderly patients with IBD was related to
the cumulative 5-aminosalicylic acid dose.19
This population requires vigilant monitoring,
even at the lowest effective 5-aminosalicylic acid
dose, with semiannual creatinine clearance testing.
Adherence Regarding Once- vs Twice-Daily
Use
No superior efficacy benefit exists for
5-aminosalicylic acid preparations over sulfasalazine except for cost and formulary availability.13,20 The mesalamine MMX formulation
of 5-aminosalicylic acid is as effective, but the
value of once-daily vs twice-daily dosing has
been challenged.21 In general, no superiority
of any one delivery system of 5-aminosalicylic
acid has been reported regarding adherence.21
Use the “toothbrush” approach: advise patients to take their medications when brushing
teeth in the morning and before sleeping, and
thus avoid a midday dose. Analysis of pharmacokinetic data on plasma and urinary 5aminosalicylic acid excretion indicates similar
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systemic exposure of all 5-aminosalicylic acid
formulations, 5-aminosalicylic acid prodrugs,
or their release profile of 5-aminosalicylic acid.20
Proctitis remains problematic because
most randomized controlled studies exclude
such patients. However, the combination of
topical and oral 5-aminosalicylic acid can
achieve notable rectosigmoid mucosal concentrations. Budesonide is preferred in enema or
suppository as an alternative to hydrocortisone to lessen systemic bioavailability.
When Response to 5-Aminosalicylic Acid Is
Poor
It is essential to rule out confounding factors, such
as CMV, sexually transmitted diseases (particularly with men who have sex with men), and
neoplasia, that may masquerade as indolent infections. Additional biopsy by a colorectal surgeon
and review by a second gastrointestinal pathologist is always appropriate. When UC is refractory
to medical therapy, it is appropriate to consider
surgery even for limited disease.22 If the disease
worsens while the patient is undergoing therapy,
consider a drug holiday because a small proportion (5%) of patients experience worsening with
5-aminosalicylic acid drugs.23
Predictors of Relapse
Do not be fooled by clinical remission alone (ie,
improved stool frequency and absent rectal
bleeding) because 42% of such patients have
continued mucosal inflammation that will signal
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inevitable relapse.24 Predicting relapse can be
difficult, especially in patients with apparently
favorable clinical and endoscopic (Mayo score
0) findings. However, a pathologist’s review of
histologic findings in the presence of endoscopic
remission may reveal active disease manifested
by basal plasmacytosis. In 21% of such patients,
this finding was predictive of a relapse with an
accuracy of 77%.25 Given such a finding, a
more aggressive optimization of therapy should
be considered.
Fecal calprotectin appears to be a more
consistent predictor of clinical relapse, mirroring the severity of inflammation, and is useful
in distinguishing IBD from irritable bowel syndrome when symptoms overlap.26 Fecal calprotectin better reflects endoscopic activity in
UC than CRP level, platelet count, hemoglobin
level, or leukocyte level.27
5-Aminosalicylic acid as a chemoprotective
agent against colorectal cancer remains a contentious issue. The initial optimistic reports28,29 and a
meta-analysis30 are challenged by the Mount Sinai
experience31 and a Canadian meta-analysis.32
Glucocorticosteroids: “Always Have an Exit
Strategy”
Moderate to severe UC has in the past been the
clarion call for corticosteroid use and advocated by the 2010 American College of Gastroenterology guidelines (Table 2).33 However,
the adverse events, corticosteroid dependency,
and lack of mucosal healing require caution.
The immediate salutary effects of glucocorticosteroids as an inexpensive and reproducible
benefit should still temper its use with a need
for an exit strategy for an alternative therapy.
The impressive efficacy and safety with antie
tumor necrosis factor (TNF) therapy and more
so with concomitant immunomodulator therapy
TABLE 2. American College of Gastroenterology Classification of UC Severitya
Classification
Mild
Moderate
Severe
Fulminant
a
Features
<4 Stools per day with or without blood, normal ESR, no sign of toxic effects
4 Stools per day with or without blood, minimal signs of toxic effects
>6 Stools per day with blood, evidence of toxic effects (fever,
tachycardia, anemia, or elevated ESR)
>10 Stools per day, continuous bleeding, toxic effects, abdominal
tenderness and distention, transfusion requirement, colonic dilation
on radiography
ESR ¼ erythrocyte sedimentation rate; UC ¼ ulcerative colitis.
Data from Am J Gastroenterol.33
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were documented in the Success trial and should
be considered.34 A limit of 3 months maximum
for continued tapering of glucocorticosteroids
will provide an opportunity for introduction of
alternate therapies and prevent further bone
loss.35,36
At this time a discussion regarding bone
density loss, opportunistic infections, cataracts, and avascular necrosis with long-term
glucocorticosteroid use should be documented
in the medical record. On occasion, reintroduction of high-dose 5-aminosalicylic acid
(4.8 g) has been successful in a select 20%
of patients maintaining remission with a glucocorticosteroid taper.37
The goal of mucosal healing is limited with
glucocorticosteroids; thus, the early introduction of immunomodulators and biologics is
reasonable with 2 exceptions: elderly, frail patients with IBD or young male patients (<30
years old). The latter have shown a proclivity
for hepatosplenic T-cell lymphoma with thiopurines alone or possibly in combination
with anti-TNFs. The number needed to harm
has been revised to 1:12,616.38
Budesonide is an alternative corticosteroid
preparation of first-pass metabolism category
cloaked in the mesalamine formulation, which
is presumed to enhance distal colon delivery.
This preparation was deemed safe because of a
lessened systemic effect. However, in one trial,
5-aminosalicylic acid granules were superior to
budesonide.39 The patients with UC in the
budesonide CORE I and II trials had a 17.7%
clinical and endoscopic remission with 9 mg
of budesonide vs 6.2% with placebo. Yet
31.3% of selected patients with left-sided disease taking budesonide, 9 mg, entered clinical
and endoscopic remission vs 5.9% of those taking placebo; 40.6% of patients taking budesonide achieved mucosal healing vs 26.0%
of patients taking placebo. No significant longterm adverse glucocorticosteroid effects were
seen with the 9-mg budesonide dose.40
This mesalamine formulation may fill the gap
in those patients in whom 5-aminosalicylic acid
therapy failed but who are not willing to accept
the hazards of systemic glucocorticosteroids.
Recapitulation
When are glucocorticosteroids appropriate to use?
Can UC be managed without glucocorticosteroids? Glucocorticosteroids are embedded in
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the American College of Gastroenterology guidelines, but caution is required because most patients
with UC are in moderate or mild categories and
usually do not require glucocorticosteroids.33
If there is an acute flare with fever, bloody
diarrhea, pain, elevated FCP and CRP levels,
elevated white blood cell count, and low albumin level, an abbreviated glucocorticosteroid
course has been recommended but always
with an exit strategy (ie, use for no longer
than 3 months and begin concomitant immunomodulator therapy while tapering).33
A subset of patients who achieve corticosteroid-induced remission may benefit from
a retrial of high-dose oral and rectal 5aminosalicylic acid before moving on to
immunomodulator and biologic therapy.37
In inpatients, intravenous glucocorticosteroid therapy administered for more than 3
days without symptomatic improvement is a
hazard signal; infliximab or cyclosporine and
surgery should then be considered.
Immunomodulators: “The Good and the
Bad”
The role of thiopurines (6-mercaptopurine
and azathioprine) is less well defined and has
lesser efficacy in UC than in Crohn disease.
The delay in onset of effect may be as long
as 12 weeks, making this drug inappropriate
for the acutely ill patient with UC.41 However,
usually a subset of patients responds within 4
to 6 weeks; these patients are generally males
with more severe extensive disease who require
hospitalization because of failing glucocorticosteroid therapy.
Immunomodulators play a role as an exit
strategy when tapering glucocorticosteroids
and are more effective in maintaining remission than 5-aminosalicylic acid.42
Thiopurine methyltransferase enzyme
(TPMT) should be measured before immunomodulator use and particularly if higher 6mercaptopurine and azathioprine dosage is
contemplated. A normal level is seen in 88%
of patients, but 11% have an intermediate
enzyme activity, and 0.3% of patients lack
the enzyme entirely and are at risk for severe
and rapid adverse effects, including myelosuppression and hepatic dysfunction. Yet 5% of
patients with adequate TPMT levels may still
experience myelosuppression.43
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Screening for TPMT alone should not substitute for monitoring the patient’s CBC count
or liver function test results.44
Considerations in ordering the 6-thioguanine
nucleotide metabolite (>230 pmol/8 108 is
the effective range) as a means of monitoring
the patient include whether it is worth the
cost and whether adherence difficulties are
anticipated.45,46 However, a mean corpuscular
volume to white blood cell count ratio greater
than 12 may give comparable data.47 There is
value in determining 6-methylmercaptopurine
and 6-thioguanine nucleotide metabolite levels when suspected hepatotoxicity emerges.
Should abnormal liver enzyme levels evolve
during immunomodulator use, rather than discontinuing use of the drug, adding allopurinol,
100 mg/d, with reduction of the immunomodulator dose to one-fourth prior levels usually
permits continued immunomodulator therapy
with liver enzyme resolution.48 The only
concern is that this approach may increase potential for infection.49
The emerging concern with long-term thiopurine use is lymphoma50-52 and nonmelanoma skin cancers.53,54 However, French
and Dutch patients with IBD reportedly had
a reduced incidence of colorectal cancer
when taking thiopurines, which was not true
for 5-aminosalicylic acid.55,56
A gratifying lack of thiopurine effect on
pregnancy has been established,57 permitting
pregnant patients to continue its use when it
effectively maintains remission. Irritable bowel
disease activity is almost always the greater
threat to the pregnancy and requires continued
thiopurine use. The lack of thiopurine effect on
the father’s (with IBD) ability to influence a
pregnancy was seen in a Spanish study.58
Anticipate that up to 50% of thiopurinetreated patients will discontinue the drug therapy by 1 year because of lack of efficacy or
adverse effects (eg, pancreatitis and infection).
Nausea can be controlled by bedtime dosing.
Patients should always be encouraged to contact the treating physician if any new or
different symptoms supervene.
Methotrexate’s limited role in UC has been
particularly hampered by adverse effects and
high dropout rate as noted in a recent Italian
trial. Clinical and endoscopic remission rates
of 82% and 72% in 17 patients were mitigated
after 3 months when only 9 of 17 patients
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continued its use.59 In an initial study with
methotrexate therapy in IBD only 40%
remained in remission at 59 weeks.60
Methotrexate is contraindicated in pregnancy. Its use is further limited by prospects
of hepatic fibrosis, hypersensitivity pneumonitis, alopecia, overall intolerance, and oligospermia.61 However, no greater liver enzyme
abnormalities are seen with low-dose methotrexate than with thiopurines.62 All patients
receiving methotrexate should receive folic
acid supplementation.
Probiotics
Other than one very small Italian study of probiotic preparation (VSL 3),63 there are few probiotic
studies to merit its use in UC patients. Yet patients
will continue to insist on using probiotics
and other complementary medications. Curcumin64,65 and Natura-a66 (Natrogen Therapeutics
Inc; a STAT-3 selective inhibitor that “rebalances”
the T helper cell type 17/T-regulatory axis) seem
promising, but there are no large randomized
controlled trials of significance.
Which Biologics and Why?
Infliximab has clinically important value in UC,
with overall better remission and response rates
than placebo, less need for dose escalation, and
longer duration of efficacy. In addition, UC
mucosal healing was correlated with a lesser
rate of colectomy in the Active Ulcerative Colitis Trial 1 in patients taking infliximab.67
Adverse effect mortality and morbidity appear
substantially greater with glucocorticosteroid
and narcotic use and thiopurines, yet the risk
of opportunistic infection persists with biologics, especially in elderly patients.68
The Active Ulcerative Colitis Trials 1 and 2
reported a doubling of the remission rate vs placebo. Sixty percent to 70% of infliximab-treated
patients had clinical and endoscopic improvement vs 40% of the placebo group, with a reduction in hospitalizations and colectomy.69,70 This
response was sustained at 3 years.71 Monitoring
a response with sigmoidoscopy alone may be
disappointing because the proximal colon heals
faster than the distal rectosigmoid.72 The Success
trial reaffirmed the benefits in UC, with remission rates of 63% for combined azathioprine
and infliximab (ie, mucosal healing), 55% for
infliximab alone, and 37% for azathioprine
alone.34 Mucosal healing with infliximab proved
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to be the best signal of a favorable long-term clinical outcome.67
Although no head-to-head trials exist between infliximab and adalimumab delineating
a definitive superiority or equivalence between these 2 agents, adalimumab as a
self-administered alternative to intravenous
infliximab was used in 248 patients with
UC.73 These patients had an induction remission rate of 16.5% vs 9.3% for the placebo
group at 8 weeks. There was maintenance of
remission at 52 weeks using 40 mg every
other week in 17.3% vs 8.5% of the placebo
group, which is a very modest to less than
expected rate.73 However, the initial adalimumab responders (50.4% at 8 weeks vs 34.5% in
the placebo group) maintained that response in
30.2% of patients vs 18.3% of those taking placebo at 52 weeks, with anticipated lower colectomy and hospitalization rates.74 If patients were
naive to anti-TNF, the remission rate at week 8
was 21.3% vs 11% for those taking placebo,
and when continued to week 52 these patients
had a 22% remission rate vs 12.4% for the placebo group. Mucosal healing was statistically
significantly higher in anti-TNFenaive patients.
Lymphoma is the most common concern of
patients when discussing biologics. The risk of
lymphoma is approximately 5.5 cases per
10,000 patient-years, with a standard incidence
ratio of 9.7 for anti-TNF therapy, which is only
slightly higher than that for the general population.75 Such discussions of biologic use with patients would be more accepted if the benefits of
biologics are emphasized in controlling inflammation, thereby lessening hospitalizations and
surgery. Indeed, a beneficial effect of anti-TNF
therapy on bone formation has also been noted.76
Once immune suppression has begun, vigilance is needed for opportunistic infections,
such as histoplasmosis, coccidiomycosis, and
blastomycosis, especially in endemic areas. Histoplasmosis can mimic community-acquired
pulmonary infections, resulting in a dangerous
delay in instituting appropriate therapy. Tuberculosis testing may include the QuantiFERONTB Gold test (Cellestis, Ltd) and a purified
protein derivative (tuberculin) skin test and
chest radiography, although most reported
tuberculosis cases have been extrapulmonary.
Isoniazid should be administered if test results
are positive, and immunomodulator or biologic therapy can begin before the completion
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of the full 6- to 9-month course of isoniazid.77
Nevertheless, cases of breakthrough tuberculosis (cervical lymphadenopathy and gastrointestinal tuberculosis) have occurred.78 Yearly
tuberculosis retesting while undergoing biologic therapy has been advocated, particularly
in vulnerable patients, such as American
Indians, Southeast Asians, Central Americans,
and patients with human immunodeficiency
virus.79 Untreated hepatitis B poses a lethal
threat with immunosuppressive therapy. A
patient’s global vaccination schedule should
be updated and precede immunomodulator
or biologic use. An antipapillomavirus antibody (Gardacil) and serial Papanicolaou
smears are required for young women, particularly those undergoing immunomodulator or
combined therapy. Although questioned by
some investigators, cervical dysplasia remains
a risk with immunomodulator therapy.80 An
antipapillomavirus antibody (Gardacil) has
also been considered for young men undergoing immunomodulator therapy.
Elderly patients remain at particular risk
for serious infection with the use of biologics,
and neoplasia during immunomodulator therapy appears to be a greater risk than during
biologic therapy.68,81
Earlier use of biologics is key to controlling
inflammation and thereby lessens the need for
hospitalization and surgery, but the risk of
serious infection remains elevated. The significant costs of these agents may be an impedance for use in select patients (Table 3).
MEDICAL THERAPY AND MANAGEMENT OF
THE HOSPITALIZED UC PATIENT
Although 91% of patients with UC have mild to
moderate disease, once severe symptoms
surface, 18% to 25% of patients will require hospitalization82,83 and 27% may require colectomy.84 Hospitalizations result most often
from failure of outpatient medical therapy and
the more dreaded complications of toxic megacolon, thrombotic disease, and opportunistic infections, including C difficile and hemorrhage.
Baseline laboratory studies are similar to those
described in the initial visit but now are required
daily, along with a CBC count with a differential
and albumin and electrolyte measurement.
Testing for C difficile by polymerase chain reaction is mandatory.
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Admission flexible sigmoidoscopy is safe
for further identifying disease activity and
obtaining biopsy specimens for CMV testing,
especially if deep excavated ulcers and patchy
involvement are noted. C difficile endoscopic
findings may lack pseudomembranes in 50%
of patients85 but may be suggested on biopsy
of a “volcano” effect, but this is not universally
true.
Colonoscopy should be avoided if colonic
dilation exists, suggesting transmural extension of the inflammatory process and thereby
risking perforation,86 although colonoscopy
has been used in acute UC flares. There is
concern in patients with severe disease about
the negative effect of the colon preparation
and endoscopic risks when compared with
controls with less severe UC.87
Medical therapy should begin with corticosteroids but with a clear exit strategy. If the clinical situation does not improve by the third day of
intravenous corticosteroid therapy (40 mg or 1
mg/kg maximum), surgery vs infliximab vs
cyclosporine should be considered. There is no
advantage to dividing the corticosteroid dosage
during 24 hours.88 Vigilance in recording the
daily number of bowel movements and daily
abdominal radiographs are needed. Intravenous
fluids, subcutaneous heparin for venous thromboembolism prophylaxis (which is not contraindicated in the presence of bloody bowel
movements), and topical rectal corticosteroids
should be administered. Venous thromboembolism incidence is increased 3-fold in IBD, especially with acute disease.89
Clinical remission and improvement in
corticosteroid-responsive patients can be
anticipated within 3 to 5 days. Nevertheless,
27% of patients may require colectomy, and
only 60% respond to intravenous corticosteroids, highlighting the importance of an early
colorectal surgical consultation.90
Immunomodulators have little role at this
point, considering they require 2 to 4 weeks
to reach a steady state and as long as 8 to 10
weeks for sustained clinical improvement. A
TPMT enzyme level should be determined at
this time when anticipating transition to an
immunomodulator.
Short of restricting oral intake in patients
undergoing surveillance for toxic megacolon,
hospitalized patients with severe IBD should
be allowed to eat. The effect of complete bowel
http://dx.doi.org/10.1016/j.mayocp.2013.05.001
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MAYO CLINIC PROCEEDINGS
rest does not influence the outcome in
corticosteroid-treated patients.91
Nutritional support is directed at concomitant malnutrition rather than consideration as
therapy. Hypoalbuminemia is a major risk factor, particularly if surgery is contemplated.92
Severe to fulminant UC may require cyclosporine, with glucocorticosteroid failure as the
last resort before surgery,93 although the French
GETAID randomized controlled trial of infliximab vs cyclosporine revealed no statistical
difference inducing a glucocorticosteroid-free
remission with either an intact colon or colectomy.94 Because most clinicians are more
comfortable with infliximab because it produces
fewer adverse effects and does not require monitoring of cyclosporine levels, infliximab appears
to be the favored drug in this difficult situation
because its adverse effects are more manageable
than those of cyclosporine (eg, hypocholesterinemic seizures, renal insufficiency, and renal
failure). Cyclosporine therapy cannot be
continued for maintenance even if a desired
result occurs. Only 41% of patients taking cyclosporine will avoid colectomy, and 38% to 78%
will require colectomy in a 5- to 7-year followup.95,96 Tacrolimus can then be substituted for
cyclosporine for oral maintenance therapy, but
data on its efficacy are limited.97
Surgery
Recourse to surgery should not be considered
a failure of treatment but rather an extension
of a therapeutic plan. It is just as appropriate
to recommend early consultation with a colorectal surgeon and colectomy for intractable
distal left-sided disease or proctitis as it is for
pancolitis.
Predictors of colectomy in severe corticosteroid- or infliximab-refractory colitis include temperature higher than 37.5 C, tachycardia, heart
rate greater than 90 beats/min, elevated CRP level,
and low albumin level.97 Elevated FCP and fecal
lactoferrin levels and persistent basilar plasmocytic mucosal infiltrates often forecast corticosteroid and infliximab unresponsiveness, indicating
more urgent need for colectomy.25-27,98,99 Prior
hospitalization, especially in men older than 65
years, is an added risk factor for colectomy.100
Surgical intervention for hemorrhage, toxic megacolon, or dysplasia is indisputable.
Predictors for emergency colectomy with
medical failure included the Simon Travis
848
Mayo Clin Proc.
n
index of 8 bowel movements (BMS) per day after 3 days or a CRP level greater than 45 mg/L
with more than 2 BMS per day, which yields an
85% positive predictive value for colectomy.
There is a 60% colectomy rate by day 7 with
more than 3 BMS per day or if blood is visible
in the stool, but most clinicians do not wait this
long.101,102
Once surgery is accepted, a lengthy discussion is needed regarding risks and benefits of
an ileal pouch-anal anastomosis. Risks include
incontinence with multiple bowel movements,
small bowel obstruction, acute and chronic
pouchitis, cuffitis, irritable pouch, ischemia,
CMV, prepouch ileitis (Crohn disease) (especially in patients with primary sclerosing cholangitis),103 and reduced fecundity in young
women.104,105 No patient likes surprises (eg,
“I wasn’t told this could happen.”). Thus, indepth discussion preoperatively is needed.
Surgery in acutely ill patients often requires
a 3-stage procedure with an emergency subtotal colectomy and ileostomy, then a 3-month
wait for nutritional improvement before undergoing an ileoanal J pouch procedure and
closure of ileostomy (ie, reversal). Surgery
often includes bringing the rectal bypassed
segment out as a mucous fistula or placing it
subcutaneously at the lower end of the incision. This approach could limit potential postoperative infection to the wound site rather
than risk an intra-abdominal abscess or perforation. The goal is reoperation in 3 months to
create an ileal pouch-anal anastomosis and
reverse the ostomy. Ileal pouch-anal anastomosis is an option for a fit but not frail older
patient. A total proctocolectomy and end ileostomy may be the alternative procedure for the
fragile elderly patient with multiple comorbidities or for patients with rectal cancer or preexisting sphincter incompetence.106
Toxic megacolon fortunately is found in only
7.9% of hospitalized patients with UC.107 A temperature greater than 38.6 C, heart rate greater
than 120 beats/min, a white blood cell count
greater than 10,500/mL, and anemia coupled
with dehydration or altered sensorium hypertension or electrolyte imbalance is enough to set in
motion a high-grade alert for surgical backup for
impending colectomy. C difficile may confound
management because that alone can mimic toxic
megacolon. Computed tomography is preferred
for detection of impending perforation with a
August 2013;88(8):841-853
n
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www.mayoclinicproceedings.org
MANAGEMENT OF ULCERATIVE COLITIS
TABLE 3. Drug Costs
Drug
Cost per mo ($)
Cost per y ($)
Lialda, 1.2 g (30 tablets; Shire US Inc)
Lialda, 2.4 g
Lialda, 4.8 g
Asacol, 400 mg (180 tablets; Warner Chilcott), 2.4 g/d
Asacol, 4.8 g/d
Pentasa, 500-mg tablets (30 tablets; Shire US Inc), 4 g/d
Colazal, 750 mg (270 tablets; Salix Pharmaceuticals Inc), 6.75 g/d
Colazal, 750 mg (540 tablets), 13.5 g/d
Sulfasalazine, 500 mg (120 tablets; generic), 2 g/d
Sulfasalazine, 500 mg (240 tablets), 4 g/d
Imuran, 50 mg (90 tablets; Prometheus Laboratories, Inc), 150 mg/d
Azathioprine, 50 mg (90 tablets; generic), 150 mg/d (Imuran generic)
Purinethol, 50 mg (60 tablets; Gate Pharmaceuticals) (6-mercaptopurine), 100 mg/d
Purinethol, 50 mg (60 tablets) (6-mercaptopurine generic), 100 mg/d
Rowasa enema, 7 enemas of 4 g/60 mL, 1 kit (Alaven Pharmaceutical, LLC)
Canasa, 1000 mg every day (30 suppositories; Aptalis)
UCERIS Budesonide MMX, 9 mg (Santarus Inc)
Methotrexate, 25 mg/wk (4 vials), 2 mL of 25 mg/mL (generic)
Hydrocortisone enema, 100 mg every day (28 enemas; generic)
Infliximab (Remicade; Janssen Biotech Inc) (3 vials), 100 mg, 1 kit (every 8 weeks)
Adalimumab (Humira; Abbott Laboratories), 40 mg/0.8 mL, 2 pens
210.00
420.00
840.00
412.50
824.00
88.80
75.00
150.00
18.00
36.00
480.00
24.00
470.00
90.00
300.00 (generic, 90.00)
630.00
2850.00
15.00
160.00
2505.00
2360.00
2520.00
5040.00
10,080.00
4950.00
9888.00
1065.00
900.00
1800.00
216.00
432.00
5760.00
288.00
5640.00
1080.00
3600.00 (generic, 1080.00)
7560.00
34,200.00
180.00
1920.00
30,060.00
28,320.00
Data are from www.goodrx.com.
dilated colon.108 Diagnostic invasive procedures, narcotics, antidiarrhea medications, and
anticholinergics are to be avoided. Patients
with toxic megacolon require intensive intravenous support with fluid electrolytes, nutrition,
and antibiotics, but nasogastric suction is unnecessary. Twice-daily laboratory tests and
abdominal radiographs are required, and urgent
surgery should be performed if no response
occurs within 24 to 48 hours, never waiting
beyond 72 hours.102,109
Pain management should be limited to acetaminophen or tramadol because narcotics are
associated with increased infection and mortality
as noted in the IBD TREAT registry.68 Unrelenting pain is often a marker for transmural extension of disease that warrants emergency surgery.
The importance of identifying C difficile,
even when least expected, cannot be overemphasized. C difficile infection in patients with
UC creates a more difficult and longer hospital
stay, with greater colectomy and mortality
rates.85,110 The absence of prior antibiotics
does not protect against C difficile because
39% of patients with IBD have C difficile without
such exposure,85 and this is especially true in
older patients with IBD with multiple comorbidities.110 There is also a greater incidence in
Mayo Clin Proc. n August 2013;88(8):841-853
www.mayoclinicproceedings.org
n
patients with IBD who undergo immunomodulator therapy. Recurrence of C difficile in IBD is
frequent, and repeated or pulsed courses of vancomycin are often necessary.85 The efficacy of
fecal transplant in IBD awaits further study.
Cytomegalovirus represents a conundrum
because detection by antigen levels does not
necessarily indicate disease severity.111 Nevertheless, the corticosteroid-refractory or immune
modulatoretreated patient is at risk for CMV
replication and dissemination, but this is not
necessarily so with anti-TNF therapy.111,112
However, endoscopic suspicion of CMV by the
presence of deep ulcerations, patchy involvement, or even pseudotumors with biopsyproven Cowdry type A intranuclear inclusions
merits therapy with ganciclovir and discontinuation of immunomodulator therapy.113
RECOMMENDATIONS
Therapy for IBD must be individualized. The
philosophy of “no one size fits all” is applicable
to this population, which needs a personalized
therapeutic approach. A conservative oral and
rectal 5-aminosalicylic acid program usually
suffices for mild to moderate UC, but the patient with severe UC may benefit from earlier
intervention with immunomodulators and
http://dx.doi.org/10.1016/j.mayocp.2013.05.001
849
MAYO CLINIC PROCEEDINGS
biologics to preclude further hospitalizations,
colectomy, or possibly cancer.
ACKNOWLEDGMENTS
The author thanks Seth Lipka, MD, for
research and technical assistance.
Abbreviations and Acronyms: BMS = bowel movements;
CBC = complete blood cell; CMV = cytomegalovirus; CRP =
C-reactive protein; FCP = fecal calprotectin; GETAID = Groupe d’Etude Thérapeutique des Affections Inflammatories du Tube Digestif; IBD = irritable bowel disease;
PIANO = Pregnancy in Inflammatory Bowel Disease and
Neonatal Outcomes; TNF = tumor necrosis factor;
TPMT = thiopurine methyltransferase; UC = ulcerative
colitis
Potential Competing Interests: Dr Katz is on the speaker's
bureau for Warner-Chilcott and UCB. He also receives
grants/research support from Abbott, BMS, Centocor, Forest, GSK, Hutchison, Millenium, Pfizer, Prometheus, Quest,
Shire, and UCB.
Correspondence: Address to Seymour Katz, MD, MACG,
1000 Northern Blvd, Great Neck, NY 11021 (Seymourkatz.
[email protected]).
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