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COLON
TABLE 34-6: Thromboembolic Risk Stratification According to Indication for Therapy
Risk Classification
Indications for Therapy High Risk (>10% Annual Risk) Moderate Risk (5%-15% Annual Risk) Low Risk (<5% Annual Risk)
echanical heart valve Any mitral valve prosthesis
M
Any caged-ball or tilting disk aortic
valve
Recent (within 6 mo) stroke or TIA
Bileaet aortic valve AND ≥1 risk
factors:
Ab, prior stroke or TIA, HTN, DM, CHF,
age >75 yr
Bileaet aortic valve without
additional risk factor
171
Atrial brillation CHADS score 5-6
Recent (within 3 mo) stroke or TIA
CHADS score 3-4 CHADS score 0-2 without
history of stroke or TIA
Rheumatic valvular heart disease
VTE Recent (within 3 mo) VTE
Severe thrombophilia:
Protein C, S, or antithrombin
deciency or antiphospholipid
antibodies
VTE within 3-12 mo
Nonsevere thrombophilia:
heterozygous factor V; Leiden or
prothrombin gene mutation
Recurrent VTE
VTE >12 mo previous and no
additional risk factors
Cancer (treated in past 6 mo or palliative)
b, Atrial brillation; CHF, congestive heart failure; DM, diabetes mellitus; HTN, hypertension; TIA, transient ischemic attack; VTE, venous thromboembolism.
A
Modied from Gould MK, Garcia DA, Wren SM, etal. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 141(2 Suppl):e227S-77S, 2012.
uick onset and stable pharmokinetics and therefore do not require
TABLE 34-7: CHADS Score
Risk Factors P
ongestive heart failure 1
C
Hypertension 1
Age >75 yr 1
oints
q
close monitoring. However, their anticoagulation eect is not reversible with fresh frozen plasma or vitamin K. For this reason, emergency
surgery is ideally delayed until the drug is cleared. Aer surgery, bridging therapy is not necessary, and the medication can be started 4 to
6 hours aer surgery. e rst dose should be a reduced dose, aer
which the usual maintenance dose is resumed. Table 34-10 provides a
summary of these medications and perioperative recommendations.
As with anticoagulation, patients with cardiovascular disease who
Diabetes 1
are being treated with antiplatelet therapy also may require preoperative interruption in their therapy. Management of this antiplatelet ther-
Stroke or transient ischemic attack 2
apy is dependent on the patient’s cardiac risk and should only be made
aer a comprehensive assessment of risk is ascertained in conjunction
with either the cardiologist or neurologist who prescribed the therapy.
TABLE 34-8: Bleeding Risk Associated with
Endoscopic Procedures
Lo
w Risk High Risk
Flexi
ble sigmoidoscopy ± biopsy
Colonoscopy ± biopsy
Endosonography
Polypectomy
Laser ablation and coagulation
Pneumatic dilation
Treatment of varices
Because of the necessity of the drug therapy, a guiding principle is to
minimize antiplatelet therapy interruption when possible, especially in
patients with increased cardiac risk. Table 34-9 provides further rec-
ommendations to guide antiplatelet therapy management.
MANA
GEMENT OF PREOPERATIVE
ANEMIA
any gastrointestinal diseases result in blood loss, and thus ane-
M
mia is common in patients undergoing colon and rectal surgery. It
a
re determined to have a moderate to high risk of bleeding. Typically
warfarin is withheld for 5 days prior to surgery and for 24 hours aer
surgery. e international normalized ratio should be obtained on the
day of surgery to ensure adequate clearance of the drug. e decision
regarding use of an antithrombotic bridge is based on the patient’s risk
of thromboembolism. Table 34-9 summarizes indications for bridg-
ing. Traditionally, unfractionated heparin has been used for bridging
therapy. Although eective, it has the drawback of requiring inpatient
hospitalization. Recently, low molecular weight heparin (Lovenox) has
been used for bridging therapy. In addition to being ecacious, it has
a good safety prole and can be used in the outpatient setting. Regrettably, the published data have not been strong enough to obtain Food
and Drug Administration approval.
Within the past few years, many new oral antithrombotic medications have been used with increased frequency. Unlike warfarin, these
medications work independently of the vitamin K pathway and instead
target thrombin or Factor Xa. New oral antithrombotic agents have a
is estimated that more than 50% of patients with colon cancer are
anemic, with rates reaching 76% in patients with advanced cancer.
Anemia is not unique to patients with colorectal cancer. Approximately 22% of patients with ulcerative colitis are anemic, with the
prevalence tripling to 67% in the emergency setting. Although most
patients are asymptomatic from chronic anemia, when combined
with acute surgical blood loss, uid shis, and perioperative medications, an anemic patient may require allogenic blood transfusions
postoperatively. However, perioperative blood transfusions are
associated with increased adverse outcomes. Among patients with
colon and rectal cancer, transfusion has been linked to decreased
overall survival, higher recurrence rates, and increased morbidity.
Whether a true causal relationship exists between blood transfusions and adverse outcomes is a contentious topic, and concerns are being raised regarding the risk of untreated preoperative
anemia. Studies of patients with a hematocrit less than 28% who
required prostate or vascular surgery showed an increased risk for
172
PreoPera
tive Pre
Para
tion of the Patient for Colon and
reCt
al Surgery
TABLE 34-9: Management of Antithrombotic Therapy in Patients Undergoing High/Moderate Bleeding Risk
Operations
Thromboembolism or Cardiac Risk
Indications for Antithrombotic
Medication High Risk Moderate Risk Low Risk
echanical heart valve or atrial
M
brillation
Hold anticoagulation Hold anticoagulation Hold anticoagulation
Bridge with LMWH or UFH Consider bridge No bridge necessary
D
efer surgery if possible Hold anticoagulation Hold anticoagulation
VTE Bridge with LMWH or UFH Consider bridge Consider bridge if immobilized
Consider IVC lter if bridge
contraindicated
Antiplatelet therapy for
cardiovascular disease
R
Continue ASA through surgery Consider holding ASA Hold clopidogrel (Plavix) and ASA
for 7-10 days prior to surgery
Stop clopidogrel (Plavix) 7-10
days prior to surgery
Stop clopidogrel (Plavix) 7-10
days prior to surgery
Resume within 24 hr
esume clopidogrel (Plavix)
within 24 hr
SA, Aspirin; IVC, inferior vena cava; LMWH, low molecular weight heparin; UFH, unfractionated heparin; VTE, venous thromboembolism.
A
TABLE 34-10: Oral Antithrombotic Medication Summary and Perioperative Management
General Inf
Medication (Brand) Target Standard Dose Half Life, hr Low Risk High Risk
pixaban (Eliquis) Factor Xa 5 mg twice a day 10-14 Stop 24 hr prior
A
Rivaroxaban (Xarelto) Factor Xa 20 mg at bedtime 5-9
ormation Perioperative Recommendations
Based on Procedural Bleeding Risk*
Stop 48 hr prior
9-13 (elderly persons)
(48 hr if CrCl <50)
Stop 24 hr prior
(48 hr if CrCl <50)
(4 days if CrCl <50)
Stop 48 hr prior
(4 days if CrCl <50)
Dabigatran (Pradaxa) rombin 150 mg twice a day 14-17 Stop 48 hr prior
(72 hr if CrCl 30-50;
4 days if CrCl <30)
C
rCl, Creatinine clearance.
*Low-risk procedures: endoscopy or uncomplicated laparoscopy. High-risk procedures: cardiac, major cancer, urologic, or vascular surgery.
perioperative ischemia and cardiac complications. Similar ndings
have been shown in patients requiring colon and rectal surgery. Preoperative anemia increased the risk of 30-day mortality and cardiac
events in elderly persons and was an independent predictor of postoperative morbidity and increased length of stay.
Although no denitive guidelines exist, it is reasonable to consider preoperative treatment of anemia prior to an elective colorectal operation, especially in elderly patients or those with increased
cardiac risk. Treatment options include allogenic blood transfusion,
autologous donation, erythropoietin, or iron supplementation.
underlying disease. Malnutrition is associated with an increase in
postoperative morbidity, including delayed wound healing, central
line infections, and surgical site infections, as well as an increase in
intensive care unit admission and overall hospital length of stay.
Many factors that may not be obvious from observation alone
contribute to a patient’s nutritional assessment. It is estimated that
10% to 15% of obese patients are nutritionally deficient, commonly because of a loss of muscle mass. Albumin level (<3.0 g/
dL) is a valuable predictor of surgical outcome, but because of its
long turnover time, it is not a good nutritional marker. The pre-
Stop 48 hr prior
(4 days if CrCl 30-50;
6 days if CrCl <30)
albumin level is a more appropriate nutritional marker. In addition, a tool called the Nutritional Risk Score 2002 (NRS 2002)
MANA
GEMENT OF PREOPERATIVE
MALNUTRITION
M
alnutrition is common in patients requiring colon and rectal surgery, especially among those with cancer, because of an inability
to tolerate oral intake, malabsorption, or metabolic stress from the
has been developed by the European Society for Clinical Nutrition and Metabolism (ESPEN). It has been validated in numerous
studies, including some studies of patients with colorectal cancer.
The NRS 2002 (Table 34-11) considers two factors: pre-existing
nutritional status and the metabolic stress due to the severity of
the underlying disease. A total score from these two categories
TABLE 34-11: Nutrition Risk Score 2002
Score Category
Severity of Disease
Nutritional Status
0 No
rmal Normal nutritional
1 Weight loss >5% in 3 mo or
food intake <50%-75%
2 Weight loss >5% in 2 mo or
BMI 18.5-20.5 plus impaired
condition or
food intake <25%-50%
3 Weight loss >5% in 1 mo or
BMI <18.5 plus impaired
condition or
food intake 0-25%
alculate score:
C
dd nutritional status score with severity of disease score.
1. A
f patient is age 70 years or older, add 1 to total.
2. I
f score ≥3, start nutritional support.
3. I
ody mass index; COPD, chronic obstructive pulmonary disease; ICU,
BMI, B
intensive care unit.
o
f 3 or greater is deemed malnutrition, and nutritional support is
recommended.
e goal of adequate preoperative nutrition is to support wound
healing, attenuate the inammatory, immune, and hypermetabolic
response to surgery, and optimize perioperative glucose control.
Identication of malnourished, high-risk patients before surgery
allows for preoperative nutritional supplementation, which can
reduce surgical morbidity up to 50%. Although enteral supplementation is preferred to parenteral nutrition by the American Society
for Parenteral and Enteral Nutrition and the Society of Critical Care
Medicine, it can be dicult for patients to achieve caloric goals with
enteral intake alone. erefore, ESPEN guidelines recommend 7 to
10 days of parenteral nutrition in severely undernourished patients
(Metabolic Stress)
requirements
Hip fracture
Chronic illness (cirrhosis,
COPD)
Dialysis dependence
Major abdominal surgery
Stroke
Severe pneumonia
Hematologic malignancy
Head injury
Bone marrow transplant
ICU patient
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ed as those with weight loss >10% to 15% in 6 months, body
(den
mass index <18 kg/m
2
r serum albumin <3.0 g/dL) who cannot
, o
173
obtain caloric goals enterally.
Recently, improved outcomes have also been demonstrated
with the use of nutritional supplements with immune-modulating
substrates. Preoperative immune-enhancing drinks, which commonly contain a combination of fish oil, arginine, nucleic acids,
and antioxidants, have been shown to reduce infectious and overall complications. However, conflicting data have been reported,
and more recent randomized trials have failed to demonstrate a
benefit.
g g e
u
S
Ama
to A, Pescatori M. Perioperative blood transfusions for the recurrence of
colorectal cancer. Cochrane Database Syst Rev. 2006;(1). CD005033.
Billmoria KY, Liu Y, Paruch JL, Zhou L, et al. Development and evalua-
tion of the universal ACS NSQIP surgical risk calculator: a decision aid
and informed consent tool for patients and surgeons. J Am Coll Surg.
2013;217(5):833–842.
Burden S, Todd C, Hill J, Lal S. Pre-operative nutrition support in patients un-
dergoing gastrointestinal surgery. Cochrane Database Syst Rev. 2012;(11).
CD008879.
Douketis JD, etal. Perioperative management of antithrombotic therapy: An-
tithrombotic erapy and Prevention of rombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest. 2012;141(2 suppl):e326S–e350S.
Fleisher LA, Beckman JA, Brown KA, etal. 2009 ACCF/AHA focused update
on perioperative beta blockade incorporated into the ACC/AHA 2007
guidelines on perioperative cardiovascular evaluation and care for non-
cardiac surgery: a report of the American College of Cardiology Foun-
dation/American Heart Association Task Force on Practice Guidelines.
Circulation. 2009;120(21):e169–e276.
Lip GY, Nieuwlaat R, Pisters R, etal. Rening clinical risk stratication for
predicting stroke and thromboembolism in atrial brillation using a novel
risk factor-based approach. Chest. 2010;137:263–272.
Richards CH, Leitch F, Anderson J, etal. e revised ACPGBI model is a sim-
ple and accurate predictor of operative mortality aer potentially curative
resection of colorectal cancer. Ann Surg Oncol. 2011;18:3680–3685.
Senagore AJ, Warmuth AJ, Delaney CP, et al. POSSUM, P-POSSUM, CR-
POSSUM: implementations issues in a United States health care system
for prediction of outcome for colon cancer resection. Dis Colon Rectum.
2004;47(9):1435–1441.
Smith JJ, Tekkis PP. Risk prediction in surgery. < http://www.riskprediction.
org.uk. > updated March 23, 2016 Accessed March 23, 2016.
Warschkow R, Guller U, etal. Perioperative blood transfusion do not impact
overall and disease-free survival aer curative rectal cancer resection: a
propensity score analysis. Ann Surg. 2014;259(1):131–138.
S t
e d
R
a d i n g
e
M
T
U C
O C
Aar
on Brzezinski
ULCERA
lcerative colitis (UC) is a chronic idiopathic inammatory disease that
U
aects the mucosa of the colon. Even though the cause of the disease is
unknown, certain risk factors such as cigarette smoking cessation, use
of nonsteroidal antiinammatory drugs (NSAIDs), and infections have
been identied. e incidence of UC in the United States is 12 cases
per 100,000 persons. e disease can present at any age. e incidence
is similar in men and women and does not vary signicantly by race.
e most typical presenting features are rectal bleeding and diarrhea,
but urgency to have bowel movements, tenesmus, abdominal pain, and
extraintestinal manifestations are common.
The inflammatory process in UC begins in the rectum and
extends proximally in a continuous distribution. The extent of disease is the single most important determinant of both prognosis
and response to medical therapy. In a series of 1116 patients followed up for at least 5 years, 46% of patients presented with proctosigmoiditis, 17% had left-sided disease (to the splenic flexure),
and 37% had pancolitis. Patients with pancolitis were more likely
to experience toxic megacolon, refractory symptoms, malignancy,
extraintestinal manifestations and to require surgery. The extent
with 56% of patients who initially presented with limited disease
experiencing a proximal extension of the inflammation. About 5%
to 10% of patients with extensive UC have a mild inflammatory
process of the terminal ileum, termed “backwash ileitis.” Patients
with limited disease may have inflammatory changes in the periappendiceal area that are referred to as a “cecal patch.” This condition should not be confused with a skip lesion characteristic of
Crohn disease.
e choice of treatment depends on the extent and severity of
the disease. Most of the indices of disease severity are based on that
developed in 1955 by Truelove and Witts (Table 35-1). e “Montreal
Classication” of 2005 is also useful (Table 35-2). In this classica-
tion the parameters of disease severity are labeled as S1 (mild), S2
(moderate), and S3 (severe). S0 denotes quiescent disease, and extent
of disease is represented as E1 (proctitis), E2 (le-sided or distal UC),
and E3 (pancolitis).
Clinically, a patient with mild disease is ambulatory and does
not have systemic symptoms. ese patients have fewer than four
bowel movements per day, with or without the presence of blood.
Moderate disease is associated with more than four bowel movements a day with minimal systemic manifestations. e simplest
clinical measure to distinguish mild from moderately active colitis
is the presence of mucosal friability (i.e., bleeding upon light contact
with the rectal mucosa at sigmoidoscopy). Patients with severe disease are oen bed bound, have more than six bowel movements a
day with visible blood, and also have systemic symptoms. Although
most acute ares of UC are mild and manageable on an outpatient
basis, 15% of patients require hospitalization because they have
more severe disease.
174
TIVE COLITIS
Diagnosis
e diagnosis of UC is based on typical endoscopic features (super-
cial ulcerations, granularity, and distorted mucosal vascular
pattern extending from the rectum proximally in a continuous distribution), negative stool cultures, and exclusion of all reasonable
alternatives in the dierential diagnosis. e dierential diagnosis of UC is presented in Table 35-3. Ischemic bowel disease and
diverticulitis are especially important diagnoses to exclude in the
patient with UC who is initially diagnosed when he or she is older
than 50 years.
reatment
T
e goals of treatment in persons with UC are to induce remission,
maintain remission, decrease complications of the disease, improve
quality of life, and decrease the need for hospitalizations or surgery
(Table 35-4). Medical treatment for UC may be divided into con-
ventional and alternative therapies. Conventional agents are those
approved in the United States for use in persons with UC. Alternative
therapies are treatments approved for other indications that are used
to treat patients with UC. e treatment is divided in two phases:
induction of remission and maintenance of remission.
Diet
Even though UC is considered a disease of the gastrointestinal tract,
the role that diet plays in the cause and treatment of the disease is
debatable. Some studies show that a diet high in rened sugar, meat,
and fat increases the risk of UC. Conversely, a high intake of fruits and
vegetables is associated with a decreased risk of UC. However, once a
patient has UC, diet has not been shown to play a role in induction or
maintenance of remission. During an acute exacerbation, it is important to maintain adequate nutrition. Anecdotally, patients with active
UC appear to best tolerate a low-ber diet, likely because of lower
ingestion of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (the FODMAP diet). Complete bowel rest with
total parenteral nutrition is not eective in patients with UC; the only
situations in which nothing by mouth status is required are when the
patient has toxic colitis or toxic dilatation of the colon or when the
patient is being prepared for surgery.
5-Aminosalycilic Acid
Mild to Moderate Ulcerative Colitis
e rst-line treatment of patients with mild to moderately active
UC is 5-aminosalycilic acid (5-ASA), also known as mesalamine or
mesalazine. e antiinammatory action of 5-ASA is mostly topical
and involves inhibition of cyclooxygenase, lipoxygenase, B cells, and
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175
TABLE 35-1: Truelove and Witts Classification of
Disease Severity
Mild
Activity
Criteria
B
owel movements/day ≤4 ≥4 ≥6
(S1)
Blood in stool Small
Moderate
Activity
(S2)
> 50% Visible
amounts
Mean evening
<37.5°C ≤37.5°C ≥37.5°C
temperature
Temperature 2 out of 4
<37.5°C ≤37.8°C ≥37.8°C
days
Pulse <90 bpm ≤90 bpm ≥90 bpm
Sedimentation rate <20 mm/hr ≤30 mm/hr ≥30 mm/hr
Hemoglobin >11.5 g/dL ≥10.5 g/dL ≤10.5 g/dL
T
ABLE 35-2:
and Se
verity of Ulcerative Colitis
Classification T
E1 U
Montr
eal Classification of the Extent
ype of Disease Description
lcerative proctitis Involvement limited to the
rectum (proximal extent of
inammation is distal to
the rectosigmoid junction)
E2 Le-sided UC
(distal UC)
Involvement limited to a
portion of the colorectum
distal to the splenic exure
E3 Extensive UC
(pancolitis)
UC, U
lcerative colitis.
Involvement extends proximal
to the splenic exure
vere
Se
Activity
(S3)
blood
TABLE 35-3: Differential Diagnosis of Ulcerative
Colitis
Disease Risk Factor Evaluation
ebic
Am
dysentery
Bacterial
infection
Clostridium
dicile
Crohn disease Always in the dif-
Ischemic colitis Hypotension, low-ow
Microscopic
colitis
Viral or parasite Travel history,
Radiation
colitis
Diverticular
colitis
Travel to high-risk
areas
Antiamebic antibodies,
fresh stool ova and
parasites; typical
punched-out ulcers
on colonoscopy
Always a possibility;
history
Stool culture, including
Escherichia coli
O157:H7
Highest risk antibiotic
use, immunosuppression, but may
C. dicile toxin A & B
Pseudomembranes on
colonoscopy
occur in any person
Clinical history, patchy,
ferential
longitudinal ulcers on
colonoscopy + biopsy,
small bowel imaging
Limited distribution,
state
patchy wide ulceration on colonoscopy
and biopsy
Suspect when a patient
has nonbloody stool
or a history of celiac
Normal colon on colo-
noscopy; diagnosed
with a biopsy
sprue
Colonoscopy + biopsy,
epidemic, immuno-
stool tests
compromised
Clinical history Endoscopy + biopsy
Age Endoscopy + biopsy
several key inammatory cytokines. 5-ASA also activates selective
peroxisome proliferator–activated receptor ligand–γ. is nuclear
receptor controls cell proliferation and apoptosis and modulates the
inammatory response of macrophages and monocytes. 5-ASA is
more eective in the treatment of UC than of Crohn disease, likely
because of the interaction of 5-ASA with the damaged epithelium.
Because Crohn disease is transmural, a medication that works on the
mucosa can be expected to have little eect on the course of the disease.
Sulfasalazine was the rst 5-ASA compound used in the treatment of UC. It was synthesized in 1938 by Nanna Svartz and was rst
used for the treatment of “rheumatic polyarthritis.” Its eectiveness
in treating UC was discovered soon aer. Sulfasalazine is composed
of a molecule of 5-ASA linked by a diazo bond to sulfapyridine. In
the colon, bacterial azoreductases cleave the diazo bond, and the sulfapyridine that is responsible for most of the adverse eects of this
medication is absorbed. Only a small fraction of the 5-ASA that is
the active moiety responsible for the therapeutic eect is absorbed.
is aspect is relevant because to be eective, 5-ASA needs to be in
contact with the colonic mucosa.
e usual dose of sulfasalazine for induction of remission is 4 g
per day; however, patients who are rapid acetylators require a higher
dose of up to 6 g per day. Some investigators recommend decreasing
the dose of mesalamine to 2 g daily for maintenance of remission.
However, patients with frequent recurrence of symptoms when taking a lower dose and patients with more aggressive disease require
higher doses of 5-ASA to maintain remission.
When 5-ASA is administered without a carrier, it is readily
absorbed in the small intestine. Dierent preparations were developed to prevent this phenomenon. Alternative drugs are more costly,
but they are also better tolerated, and a Cochrane systematic review
showed a slight trend in benet compared with sulfasalazine. However, if sulfasalazine is tolerated, it is the drug of choice because it is
less expensive than other 5-ASA compounds. e 5-ASA compounds
available in the United States are olsalazine (Dipentum), mesalamine (Asacol, Delzicol, Pentasa, Lialda, and Apriso), and balsalazide
(Colazal; Table 35-5). Olsalazine is composed of two 5-ASA molecules
linked by a diazo bond. Although olsalazine is eective, it is rarely
prescribed because a profound secretory diarrhea occurs in more
than 10% of patients. Asacol and Delzicol are delayed-release formulations that consist of 5-ASA in a pH-sensitive capsule. When the pH
approaches 7 in the terminal ileum, the capsule dissolves and 5-ASA
is released. Asacol can be taken with or without food, but Delzicol
176
Medic
al Trea
TMenT of UlceraTive coliTis
and oT
her coliTides
TABLE 35-4: Medications Used in the Treatment of Ulcerative Colitis
Indication:
Medication
SA Mild to moderate disease A Remission induced by 5-ASA A
5-A
Remission
Induction of
Corticosteroids Moderate to severe disease B Not indicated
Anti-TNF-α Moderate to severe disease A Indicated A
iopurine Not indicated Indicated B
Cell adhesion molecule inhibitor Indicated Indicated
onsistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evi-
A = C
dence, usual practice, expert opinion, or case series.
5-ASA, 5-aminosalicylic acid; TNF, tumor necrosis factor.
Evidence
Rating
Indication: Maintenance of
Remission Evidence Rating
TABLE 35-5: 5-Aminosalicylic Acid Preparations Available in the United States and the Sites of Maximal Ef-
fect in the Gastrointestinal Tract
Medication Unit Dose Dose Indication
ulfasalazine 500 mg 2 to 4 g/day (3 divided doses) Induction and maintenance of remission
S
Pentasa
250 mg; 500 mg
*
o 4 g/day (4 divided doses; 500 mg,
2 t
Induction and maintenance of remission
two po qid)
Asacol HD
Delzicol
800 mg
400 mg
800 mg 3 times daily
800 mg 3 times daily
Induction of remission
Maintenance of remission
Balsalazide 750 mg 750 mg to 2.25 g 3 times daily Induction of remission
Lialda 1200 mg 2.4 to 4.8 once daily Maintenance of remission
Apriso 375 mg 1.5 g once daily Induction of remission
Rowasa enemas 4 g 4 g once daily Induction of remission, distal ulcerative colitis
Canasa suppositories 1 g 1 g/day Induction and maintenance of remission
*500 mg is the more commonly used unit dose.
hould be taken 1 hour before or 2 hours aer meals. Balsalazide is
s
5-ASA linked by a diazo bond to an inert carrier molecule. Colonic
bacterial cleavage of the diazo bond is required to release the 5-ASA.
erefore, balsalazide is eective only for colonic inammation.
Pentasa consists of 5-ASA packaged in a time-release ethylcellulose
sulfasalazine, it is recommended that serum creatinine be monitored
every 3 to 6 months for the rst year and then annually. Adverse
eects of mesalamine include headache, diarrhea, abdominal pain,
pancreatitis, interstitial nephritis, dizziness, Stevens-Johnson syn-
drome, hypersensitivity reactions, and hair loss.
compound, releasing 5-ASA evenly throughout the small and large
bowel. Two newer formulations that improve compliance because
they are taken once daily, Lialda and Apriso, are available. Lialda is a
proprietary delivery system based on Multi Matrix Technology. e
formulation is composed of 5-ASA with hydrophilic and lipophilic
excipients enclosed within a gastro-resistant, pH-dependent coating
that releases in the terminal ileum. Apriso is mesalamine in a delivery system with the proprietary name Intellicor, which is a delayed
and extended-release preparation. is preparation begins releasing
mesalamine in the distal terminal ileum at a pH of 6 or greater and
gradually distributes it throughout the colon.
e most common adverse eects of sulfasalazine are nausea,
vomiting, dyspepsia, and headache. Sulfasalazine is also associated
with decreased male fertility because of reversible sperm abnormalities caused by sulfapyridine. Sulfasalazine is a competitive inhibitor
Proctitis and Left-Sided Ulcerative Colitis
Rectally administered 5-ASA preparations are the rst-line treatment for ulcerative proctitis. ese preparations are more eective
than oral 5-ASA or topical steroids, which are used as second-line
treatment in patients who are intolerant of topical 5-ASA. Rectally
administered 5-ASA improves symptoms faster than orally administered 5-ASA, and except for rectal discomfort and cramps, it has
fewer adverse eects because it is poorly absorbed. Some patients
with proctitis have urgency related to decreased rectal compliance
and cannot retain suppositories or enemas. A hydrocortisone foam
formulation that is available in the United States is better retained and
better tolerated than the liquid enema. When topical treatment is not
tolerated, patients are treated with an oral 5-ASA.
of folic acid absorption, and thus folate-binding proteins should be
overwhelmed with an oral supplement of folic acid. Severe adverse
eects including aplastic anemia and brosing alveolitis have been
reported. Before starting sulfasalazine, it is recommended that a
complete blood cell count (CBC) be performed, and a CBC should
then be performed every 2 weeks for the rst 3 months. Aer starting
Left-Sided Disease
Le-sided UC is disease that extends proximal to the rectum but
stops distal to the splenic exure. Patients with le-sided disease are
best treated with an oral 5-ASA with or without rectally administered
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177
SA. In some patients with le-sided disease, the most signicant
5-A
symptoms are related to proctitis. In these patients, the combination
of oral and rectal mesalamine is more eective than either therapy
alone. In patients with mild to moderately severe disease, response
rates are between 40% and 70%, and remission rates are 15% to 20%.
Patients who do not respond to 5-ASA within 2 to 4 weeks, and
patients whose symptoms worsen, should be treated with systemic
steroids. 5-ASA is eective in maintenance of remission in patients
with a rst are requiring treatment with steroids.
Extensive Disease
Similar to patients with le-sided disease, patients with extensive
disease are best treated with oral 5-ASA with or without rectally
administered 5-ASA. If there is no response to treatment, then oral
corticosteroids are added to the treatment. If remission is not maintained as the steroids are tapered, or if the patient has frequent exacerbations, then administration of a thiopurine or a biologic agent is
initiated.
Lack of Response to 5-Aminosalycilic Acid
In patients with mild or moderately active UC that does not respond
to conventional treatment, it is important to exclude confounding
factors such as cytomegalovirus (CMV) infection, Clostridium di-
cile infection, mesalamine-induced diarrhea, Crohn disease, NSAID
use, and rare diseases such as Behçet disease, as well as common variable immunodeciency. It is also important to question compliance
with treatment regimens, particularly in single young college students and in patients treated with suppositories or enemas.
Oral Budesonide
Budesonide is a potent antiinammatory corticosteroid with high
glucocorticoid eect and minimal mineralocorticoid eect. An
advantage of budesonide compared with conventional corticosteroids
is that it has minimal adverse eects; however, it is very expensive.
Aer absorption it is subject to high rst-pass metabolism (80% to
90%) and is biotransformed to metabolites with negligible (<1/100)
glucocorticoid eect. erefore, to be eective, budesonide needs to
be delivered to the colon to exert a therapeutic eect. Budesonide
MMX is an oral preparation that uses Multi Matrix Technology to
deliver the medication to the entire colon. It is indicated for induction of remission in patients with mild to moderately active UC. At
a dose of 9 mg daily, clinical and endoscopic improvement is seen
in 43% of patients, clinical remission occurs in 24%, and histologic
healing occurs in 17%. Budesonide is not indicated for maintenance
of remission. An enema preparation is available in Canada but not in
the United States.
Corticosteroids
Severe Ulcerative Colitis
Severe UC is potentially life threatening. In patients with severe UC,
oral or intravenous corticosteroids are eective in inducing remission. In patients with proctosigmoiditis, hydrocortisone enemas may
be used; however, patients with severe proctitis tolerate foam formulations better than liquid enemas. e mode of action of corticosteroids is through inhibition of phospholipase A
ausing a decrease in
, c
2
prostaglandin and leukotriene levels. Ambulatory patients who do not
have signs of toxicity can be treated initially with oral corticosteroids.
e dose of oral prednisone to achieve maximal eect with the fewest adverse eects is 0.75 to 1 mg/kg/day. e most commonly used
dose is 40 to 60 mg/day. A dose higher than 60 mg/day has not shown
to improve response and has more side eects. e dose of 0.75 to
1 mg/kg has been used in clinical trials and for a 60 kg person is
40-60mg. A signicant improvement is expected in the rst 2 weeks of
treatment, and the dose is then tapered. No trials of dierent tapering
regimens have been performed. e most common recommendation
is to taper the total daily dose of prednisone by 5 to 10 mg per week.
If a signicant improvement is not seen aer 3 to 5 days or if
symptoms worsen, the patient should be admitted to the hospital for
treatment with intravenous steroids. e most commonly used intravenous steroids are hydrocortisone, 100 mg three times a day or four
times a day, or methylprednisolone, 20 mg three times a day; higher
doses do not have a higher ecacy and should not be used.
Corticosteroids should be used with caution because signicant
adverse eects are associated with short- and long-term use. Principal adverse eects include infections, glucose intolerance, acne, moon
face, insomnia, weight gain, fat deposition (particularly increased
fatty tissue in the face, supraclavicular area, upper trunk, and back),
psychosis, headache, hypertension, hyperlipidemia, hirsutism, striae,
avascular necrosis, and myopathy.
Patients with severely active disease and signs of toxicity such as
tachycardia, dehydration, fever, and continuous abdominal pain and
those with electrolyte abnormalities are too sick to be managed on an
outpatient basis. 5-ASA agents are not eective in this setting, and oral
prednisone oen is not eective. If symptoms do not improve within
the rst 72 hours of starting an intravenously administered steroid,
then this treatment is discontinued and an alternative treatment is
recommended. Surgery is oen the best option in these patients, but
salvage therapy with an anti–tumor necrosis factor–α agent, or intravenous cyclosporine, can be considered as long as the patient has no
evidence of toxic colitis and the colon is not dilated. In a clinical trial
of patients who did not respond to intravenously administered steroids, 17 of 24 patients (71%) improved and avoided a colectomy aer
a single dose of iniximab, 5 mg/kg. If no improvement occurs aer
one dose of iniximab, or if the patient does not respond to cyclosporine within 14 days (response is usually within the rst 7 days), then
surgery should be recommended. Patients with severe disease require
close monitoring, including a daily plain radiograph of the abdomen.
If at any moment evidence of impending perforation or worsening
clinical status is noted, patients should undergo surgery. If cyclosporine induces remission, patients will need a thiopurine to maintain
remission. If a patient responds to iniximab, use of this agent can be
continued to maintain remission.
Cyclosporine
Cyclosporine, an 11–amino acid cyclic polypeptide, is used as an
immunosuppressant in organ transplantation. It reversibly inhibits
interleukin-2 (IL-2) gene transcription, which in turn reduces proliferation and activation of T-helper lymphocytes. Cyclosporine is 80%
b
ound to lipoproteins, and because it is secreted in the bile, it requires
an intact enterohepatic circulation to maintain levels. It is metabolized and inactivated by the hepatic cytochrome p450 system and by
drugs that induce cytochrome p450 aect levels.
In a randomized clinical trial by Lichtiger etal, 20 patients with
severely active UC who were refractory to intravenously administered steroids received intravenous cyclosporine, 4 mg/kg/day, or
placebo. By day seven, 9 of 11 patients (82%) treated with cyclosporine had a clinical response compared with none of the 9 patients
treated with placebo. e trial was terminated early because of ethical
considerations. Patients who responded to intravenous cyclosporine
were discharged with a prescription for oral cyclosporine. It is important to note that 6 of the original 11 patients (55%) had a colectomy
within 6 months of discharge.
In 2013, Chang et al published a systemic review and metaanalysis of studies comparing cyclosporine and iniximab as rescue
therapy in patients with steroid-refractory UC. Six studies with a total
of 456 patients met the criteria for analysis. Data were available for
321 patients—142 treated with cyclosporine and 179 treated with
iniximab. e colectomy rate for patients treated with cyclosporine
and iniximab was similar at 3 and 12 months. At 3 months, 30%
taking cyclosporine and 32% taking iniximab had a colectomy. At
178
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and oT
her coliTides
onths, colectomy rates were 45% for patients treated with cyclo-
12 m
sporine and 42% for patients treated with iniximab. e studies
included in the meta-analysis had a great variation in the colectomy
rate at 3 months. For cyclosporine, the range was 6% to 63%, and
for iniximab, it was 17% to 40%. e complication rate, including
adverse drug reactions, postoperative complications, and deaths, was
similar. In spite of the limitations of the meta-analysis, it appears that
the short-term response to cyclosporine and to iniximab in patients
with severe steroid-refractory UC who do not need urgent surgery
is similar. When deciding on treatment, it is important to keep in
mind that whereas iniximab is also eective in maintenance of
remission, cyclosporine is eective only for induction of remission.
In patients who do not require hospitalization, the bioavailability of
oral microemulsion is similar to that of intravenous cyclosporine.
Because cyclosporine has many drug interactions and adverse eects
and drug levels need to be monitored, it should be prescribed only
by physicians familiar with this medication, and usually in tertiary
care centers. Nephrotoxicity, hepatotoxicity, hypertrichosis, gingival
hyperplasia, tremors, paresthesia, seizures, and lymphoproliferative
disorders are the most common adverse eects of cyclosporine.
Azathioprine and 6-Mercaptopurine
e purine analog 6-mercaptopurine (6-MP) causes chromosome
breaks and has antiproliferative eects on activated lymphocytes.
Because these medications are slow acting and an eect is usually
not seen for 2 to 3 months, they are indicated for maintenance of
remission and steroid sparing, and in some patients they improve
and prolong the response of anti-TNF-α agents. e bioavailability
of oral azathioprine (27% to 83%) is better than that of 6-MP (5%
to 37%). Aer absorption, azathioprine undergoes a rapid nonenzymatic conversion to 6-MP. Subsequently there are three metabolic
pathways that result in one active and two inactive metabolites. e
active metabolite is 6-thioguanine nucleotide (6-TG), which has antiproliferative eects on activated lymphocytes and bone marrow. Its
level is associated with the clinical response. e pathways of 6-MP
to inactive metabolites are via thiopurine methyltransferase (TPMT)
to 6-methylmercaptopurine (6-MMP), and via xanthine-oxidase to
6-thiouric acid. TPMT activity is determined by a genetic polymorphism. Approximately 10% of Caucasians and African Americans
inherit one nonfunctional TPMT allele (heterozygous) and have
intermediate TPMT activity, and 0.3% inherit two nonfunctional
TPMT alleles (homozygous) and have low or absent TPMT activity.
Nonfunctional alleles are less common in Asians. Low TPMT activity
is associated with higher 6-TG levels and an increased risk of bone
marrow toxicity.
Because one of the pathways of metabolism of these medications
is via the xanthine oxidase system, in patients receiving allopurinol,
a lower dose is used to decrease the risk of bone marrow toxicity.
In patients with normal TPMT enzyme activity, the dose of azathioprine is 2 to 2.5 mg/kg/day, and for 6-MP it is 1 to 1.5 mg/kg/day.
Regardless of the TPMT enzyme activity, blood tests are indicated in
all patients. When the treatment is initiated, it is recommended that a
CBC with dierential be obtained once a week for 4 weeks, then every
other week for 4 weeks, then once a month for 6 to 9 months, and
every 3 months thereaer. Liver enzyme tests are performed 4 weeks
aer initiation of treatment and then every 3 months. Whenever the
dose is adjusted, it is important to monitor the CBC every other week
and liver tests every 4 to 12 weeks until a stable dose is achieved. It
has been suggested that the dose of immunosuppressant be increased
until mild leukopenia develops. However, 6-TG and 6-MMP can be
measured, and it appears that the ecacy and safety are improved
by following the blood level. In persons with Crohn disease, clinical
remission is correlated with an erythrocyte 6-TG level greater than
230 pmol/8 × 10
8
ed blood cells (RBCs). In UC the data are lacking,
r
but the therapeutic level is likely similar. In patients who respond to
treatment, the value of measuring metabolites is debatable, because
it increases the cost of care and is not likely to improve outcomes.
However, in patients who do not respond to treatment, monitoring
metabolite levels to ensure a therapeutic 6-TG level of 235 to 400
pmol/8 × 10
8
C helps determine whether the lack of response is
RB
due to poor compliance, absorption problems, or problems metabolizing the medication. If the 6-TG level is low, as long as the white
blood cell count is greater than 3, results of liver tests are normal, and
the 6-MMP is not greater than 5600, the dose can be adjusted.
Azathioprine and 6-MP have a more favorable adverse eect prole than do corticosteroids. As with all immunosuppressive agents,
the risk of infections is increased. In approximately 2% of patients
the drugs will need to be discontinued as a result of bone marrow
suppression; in addition, 3% will experience acute pancreatitis and
2% will experience an allergy characterized by abdominal pain, high
fever, joint stiness, and rash. According to population-based studies
and a meta-analysis, patients have a two- to fourfold increased risk
of lymphoma and of nonmelanoma skin cancers. It is important to
advise patients to use sunscreen cream and to see a dermatologist on
a yearly basis for a skin examination.
Biologic Agents
e advent of biologic agents is one of the most signicant advances
in the treatment of inammatory bowel disease (IBD). e two
classes of biologic agents used in UC are anti-TNF-α and antiadhesion molecules. Iniximab was approved for induction and maintenance of remission in UC in 2005, followed by adalimumab in 2012
and golimumab in 2013. e antiadhesion molecule vedolizumab
was approved in 2014. Given this timeline, there is vast experience
with the use of anti-TNF-α agents in UC, but the information on the
clinical use of antiadhesion molecules is limited. Iniximab is administered intravenously, whereas adalimumab and golimumab are
administered by subcutaneous injection. e three agents are monoclonal antibodies against TNF-α. Iniximab is a chimeric monoclonal antibody consisting of 75% human immunoglobulin (Ig)G and
25% murine components that actively bind membrane-bound and
membrane-soluble TNF-α. Adalimumab and golimumab are subcutaneous recombinant humanized monoclonal IgG1 TNF-
α a
ntibodies that have only human peptide sequences. Similar to iniximab,
adalimumab and golimumab bind TNF-α with high anity and neutralize its activity by blocking the interaction between this cytokine
and the cell surface receptors. e ecacy of anti-TNF-α agents in
induction of remission is similar to that of glucocorticoids.
Infliximab
Iniximab is indicated for the induction and maintenance of remission in adults and in children 6 years of age and older. e initial
dose is 5mg/kg intravenously at 0, 2, and 6 weeks. In patients with a
clinical response, it is continued at the same dose every 8 weeks. In a
Cochrane analysis, at 8 weeks, iniximab was more eective than placebo in inducing clinical remission (odds ratio [OR], 3.22; 95% condence interval [CI], 2.18 to 4.76); endoscopic remission (OR, 1.88;
95% CI, 1.54 to 2.28) and clinical response (OR, 1.99; 95% CI, 1.65
to 2.41). Patients who do not respond to the rst two doses are not
likely to respond at all, and a dierent treatment should be initiated.
Loss of Response
t is known that antibodies can develop in pa-
. I
tients receiving anti-TNF-α agents with a loss of response to treatment. e most signicant determinant for the formation of antiiniximab antibodies is episodic treatment with long intervals between infusions. When iniximab treatment is episodic, anti-iniximab antibodies are detected in 30% to 60% of patients, compared
with only 7% to 10% when iniximab treatment follows a schedule.
Anti-iniximab antibodies are important because patients with high
titers have a higher frequency of infusion reactions and/or loss of response. When patients lose response to iniximab, measurement of
drug level and antibodies can guide treatment. Some of these patients
regain response when the dose of iniximab is increased or when it is
COLON
179
stered at shorter intervals. A higher dose or more frequent ad-
admini
ministration increases the cost of care and decreases patients’ quality
of life, and eventually iniximab is discontinued because of adverse
eects or lack of response. Anti-iniximab antibodies are directed
against the murine portion of the molecule; therefore, a patient in
whom response is lost as a result of antibody formation may respond
to a dierent anti-TNF-α agent.
Infusion Reactions
ild infusion reactions occur in 5% to
. M
13% of patients, but severe infusion reactions requiring iniximab
discontinuation occur in 1% or fewer of patients. ese reactions
can occur while the medication is being infused, within 2 hours of
nishing the infusion, or 3 to 12 days aer the infusion. e most
common immediate infusion reactions include fever, chills, headache, chest tightness, shortness of breath, tachycardia, hypotension
or hypertension, and rash. ese infusion reactions are not true
allergic type 1 IgE-mediated reactions. Mild reactions usually respond to slowing or stopping the infusion, and in most patients the
infusion can be completed. When the reaction is more severe, the
symptoms usually respond to the administration of an antipyretic
agent, an antihistamine, and intravenous steroids. In severe cases,
the administration of epinephrine and hospitalization for observation are required. Infusion reactions are anaphylactoid reactions to
the murine component of the medication and not true anaphylactic
reactions.
Delayed Reactions
elayed reactions occur 3 to 12 days aer
. D
the administration of iniximab. ese reactions result from the activation of circulating antibody-antigen complexes. ere is no change
in levels of serum complement, however, so these reactions are better
termed “serum sickness–like” reactions. Delayed infusion reactions
have been reported in as many as 25% of patients who resume iniximab 2 to 4 years aer the last dose, and 60% of reactions are severe.
Adalimumab
Two clinical trials explored the benet of adalimumab in induction
and maintenance of remission in UC. e main dierences between
the trials were whether or not patients had received iniximab, and
in the trial with patients who were biologic naïve, besides the induction regimen of 160 mg/80 mg/40 mg every other week, there was a
separate induction arm of 80 mg/40 mg/40 mg. e endpoints were
clinical remission at week 8 and week 52. e benet of treatment was
modest; remission at 8 weeks was observed in 21.3% of patients naïve
to anti-TNF-α (32/150) and in 9.2% of patients with prior exposure
(9/98), compared with 11% (16/145) and 6.9% (7/101) in patients
who received placebo. e remission rate at 52 weeks in patients
naïve to anti-TNF-α was 22% (33/150), and in patients with prior
exposure it was 10.2% (10/98), compared with 12.4% (18/145) and
3% (3/101) in patients who received a placebo.
Golimumab
Golimumab is eective in induction and maintenance of remission
in patients with moderate to severely active UC. Published, randomized, double-blind, placebo-controlled studies include a phase II dose
range study with 291 patients and a phase III ecacy study with
774 patients. For induction of remission, an initial dose of 200 mg
by subcutaneous injection is followed by 100 mg 2 weeks later. At 6
weeks, improvement is observed in about 52% of patients and remission is observed in about 18% of patients. In patients with a clinical
response, the maintenance dose is 100 mg every 4 weeks. At 1 year, a
sustained clinical response is seen in about half the patients.
How to Choose an Anti-TNF-α Agent
Because no head-to-head studies have been performed to compare
iniximab with Humira, and because clinical trials have dierent
endpoints, the decision about which agent to use depends on cost
and the patient’s preference. In a single-center long-term followup of a cohort of patients treated with adalimumab or iniximab,
the response rate as assessed by normalization of bowel movements, absence of rectal bleeding, and cessation of corticosteroid use was similar. e response to the induction regimen for
iniximab was 96.4% (27/28), and for adalimumab it was 80.0%
(20/25). e ecacy of both agents in maintenance of remission
was also comparable; for iniximab it was 77.8%, and for adalimumab it was 70.0%.
Complications
Infections are one of the most common and signicant complications
related to the use of these medications. Infections can be either a result
of reactivation of “latent organisms” or they can be opportunistic
infections, particularly those in which the infection is controlled by
macrophages. Some of the most signicant infections that have been
reported include tuberculosis, aspergillosis, histoplasmosis, bacterial
infections such as Listeria monocytogenes, and viral infections such as
CMV. Other complications that have been reported are optic neuritis, peripheral neuropathy, seizures, and new-onset or exacerbation of
clinical symptoms and/or radiographic evidence of central nervous
system demyelinating disorders, liver toxicity, drug-induced lupus,
and worsening of congestive heart failure. Treatment with biologic
agents is frequently associated with autoimmunity with the formation
of antinuclear antibodies (ANAs) and antibodies to double-stranded
deoxyribonucleic acid, particularly in women. e development of
ANAs is no reason to discontinue therapy. In some patients, use of
anti-TNF-α must be discontinued because of a severe psoriasiform
reaction characterized by a pruritic and papulosquamous rash.
What to Do Before Starting Anti-TNF-α Therapy
• Conrmthediagnosis.
surethat
•En
f C-reactive protein, fecal markers of inammation, and exible
o
mptomsarerelatedto
sy
ac
tive
seasethroughuse
di
sigmoidoscopy.
xclude
•E
xclude
•E
b
erculosis, human immunodeciency virus, moderate to severe
ectionssuch
inf
ntraindications
co
icile and CMV.
aC. d
uch
s
as h
epatitis
B, h
epatitis
C, tu-
heart failure, history of lymphoma, current malignancy, multiple
sclerosis or other demyelinating disease, optic neuritis, and active
infections.
xclude
•E
•Inp
diog
eviewandupdate
•R
o
f age should receive a human papillomavirus vaccination, a
ngenitalor
co
atientswithsevere
uired
acq
sease,obtain
di
imm
raph taken in the upright position.
ations.Womenbetween
vaccin
unodeciency.
idney-ureter-bladder
ak
9and26y
ra-
ears
pneumonia vaccine should be administered every 5 years, and a
hepatitis B vaccine should be administered. If mumps and rubella
vaccines are administered, wait 6 weeks before beginning treatment with an immunosuppressant agent.
•Inp
vaccin
atientswith
ation, assess antibody titers. If a varicella-zoster virus vac-
ahi
storyof
ricella,herpes
va
zos
ter,or
va
ricella
cine is administered, do not start an immunosuppressant agent
for 3 weeks.
•P
rovidethepatientwith
•Useco
mbinationtreatmentwith
m
ent to less than 2 years in patients younger than 35 years and do
inf
ormationaboutthetherapy.
at
hiopurine.Limitsuchtreat
not use such treatment in patients older than 65 years.
What to Do Once Treatment with an Anti-TNF-α Agent Is Started
emind
•R
ave an annual dermatologic examination.
h
•P
erform
c
al dysplasia in women.
atients
p
ay
earlyscreeningforhumanpapillomavirusand
to p
rotect
a
gainst
ltraviolet
u
radi
ation
and to
cervi-
-
180
Medic
al Trea
TMenT of UlceraTive coliTis
and oT
her coliTides
estforlatenttuberculosisandhepatitis
•T
unity every 1 to 3 years.
m
•A
r
•A
•W
p
dminister
us.
dminister
ithhold
re g nancy.
auvaccinea
ap
neumonia
iniximab and ad
nnually;
vaccinee
donotusen
very
alimumab
Binp
5y
ears.
in the l
atientswithout
im-
asalattenuatedvi
ast
t
rimester
of
Antiadhesion Molecules
A characteristic of IBD is the abnormal recruitment of leukocytes, particularly T cells, and the retention of these cells at the site of inammation. Leukocytes circulate in blood vessels, and the endothelial cells
serve as a barrier between the leukocytes and the intestinal mucosa.
Endothelial cells have various adhesion and homing receptors and
ligands (addressins). Mucosal addressin–cell adhesion molecule-I
(MAdCAM-I) is an addressin that is primarily expressed in high endothelial venules in the small intestine and in Peyer patches and in the
colon. Leukocytes have a variety of transmembrane glycoproteins such
as L-selectins and integrins that are integral part of the cytoskeleton of
the cell. ese integrins are transmembrane receptors that can dynamically alter their adhesive properties and interact with endothelial
adhesion receptors. e interaction of α4β7 integrin and MAdCAM-I
is believed to contribute to chronic inammation in the intestine.
Vedolizumab is a humanized IgG1 monoclonal antibody against
α4β7 integrin. It blocks lymphocyte transit only in the gut and does
not block lymphocyte transit in other tissues; therefore, the eect
is “gut specic.” In a phase 3, randomized, double-blind, placebocontrolled trial to investigate the ecacy of vedolizumab in induction and maintenance of remission, patients with moderately to
severely active UC were enrolled who had not responded to either
a thiopurine or an anti-TNF-α agent. At week 6, the proportion of
patients in clinical remission in the vedolizumab arm was 47% compared with 25% in the placebo arm (95% CI, 11.6 to 31.7; P <.0001).
Patients were subsequently enrolled in a maintenance of remission
study. At 52 weeks, 42% of patients receiving vedolizumab, 300 mg
every 8 weeks, and 45% of patients receiving vedolizumab, 300 mg
every 4 weeks, were in clinical remission, compared with only 16% of
patients receiving placebo.
Alternative Therapies
Nicotine
Since the initial observation in 1976 by Samuelsson that persons who
were smokers were lacking in cohorts of patients with UC, numerous
studies of the relationship of cigarette smoking and UC have conrmed that UC is primarily a disease of nonsmokers and ex-smokers.
Interesting case reports and remarkably consistent epidemiologic
studies have shown that cigarette smoking confers protection from
the development of UC. At time of diagnosis, fewer than 20% of
patients with UC are smokers, compared with a smoking rate of up to
35% in the U.S. adult population. In a 1989 meta-analysis by Calkins,
the pooled odds ratio for UC in smokers versus nonsmokers was 0.41
(95% CI, 0.34 to 0.48), and in former smokers versus nonsmokers it
was 1.64 (95% CI, 1.36 to 1.98). Furthermore, the protective eect
of nicotine is dose dependent, and current smokers with UC have
milder disease with fewer relapses, reduced need for steroid use, and
a lower hospitalization rate compared with nonsmokers.
Randomized clinical trials comparing transdermal nicotine versus
placebo have shown that the use of transdermal nicotine is superior
to placebo for induction of remission in patients with UC. However, most randomized clinical trials were small, and many patients
withdrew because of adverse eects. erefore, until evidence from
clinical trials shows that nicotine is eective, transdermal nicotine
is not indicated for induction of remission in persons with UC. e
only group of patients in whom it is reasonable to use transdermal
nicotine as adjuvant treatment is ex-smokers with mild or moderately
active UC. With the use of a nicotine patch instead of nicotine gum,
the typical adverse eects of “nicotine rush” (i.e., a parched throat,
tachycardia, a headache, and nausea) are lessened. Nicotine addic-
tion is not a problem if therapy lasts less than 8 weeks. Maintenance
therapy with nicotine patches is not eective. Active smokers with
UC should be encouraged to stop smoking and use alternative formulations of nicotine.
Clinical Scenarios
Various common clinical scenarios for patients with UC suggest different treatment strategies; some of these strategies are summarized
in Table 35-6.
Quiescent Disease
In patients with 5-ASA–induced remission or those who have rapid
improvement with prednisone, 5-ASA is the rst-line treatment for
maintenance of remission (see Table 35-4). In patients who required
prolonged treatment with corticosteroids, remission is maintained
with either a thiopurine or an anti-TNF-α agent. In patients who
received an anti-TNF-α agent for induction of remission, the same
medication is continued.
Fulminant or Toxic Colitis
A risk of treating patients who have fulminant or toxic colitis with medications is increased morbidity and mortality by delaying surgery. e
medical options for these patients are limited, and the focus should be on
stabilizing and the patient and optimizing conditions for surgery. Treatment with intravenous corticosteroids, cyclosporine, iniximab, and
adalimumab are the only presurgical options. It is reasonable to consider
TABLE 35-6: Clinical Scenarios of Ulcerative Colitis
and Recommended Medical Options
Clinical Scenario Recommended Medical Options
Q
uiescent disease Depends on the agent used to induce
remission
Maintain remission with:
5-Aminosalicylic acid
Azathioprine or 6-mercaptopurine
Anti-TNF-α
Vedolizumab
Mildly or moderately
active disease
Severely active colitis IV corticosteroids, iniximab, cyclo-
Fulminant or toxic
colitis
Refractory disease and
steroid dependence
Pregnancy 5-Aminosalicylic acid, corticosteroids,
Cancer risk Surveillance colonoscopy for detection
V, Intravenous; TNF, tumor necrosis factor.
I
5-Aminosalicylic acid, corticosteroids,
iniximab, adalimumab, golimumab,
vedolizumab
sporine IV, vedolizumab
IV corticosteroids or cyclosporine; if no
benet in 72 hours, consider surgery
Azathioprine or 6-mercaptopurine,
anti-TNF-α, vedolizumab
anti-TNF-α
iopurines
of dysplasia; surgery depends on the
disease