reduced AZA and 6-MP clearance, thereby increasing the risk of severe
myelosuppression and hepatotoxicity.
Methotrexate (MTX), a folate antagonist, impairs DNA synthesis. Data suggest that
MTX (15–25 mg intramuscular [IM] weekly) may have a role for both initial and
chronic treatment of CD. The onset and degree of effect is comparable to that with 6-
33 Most experts and recent guidelines suggest reserving MTX use for
patients with CD intolerant of, or refractory to, 6-MP or AZA treatment.
effects with MTX include stomatitis, neutropenia, nausea, hypersensitivity
pneumonitis, alopecia, and hepatotoxicity.
Cyclosporine (CSA), which selectively inhibits T-cell–mediated responses, has
been used to treat severe, acute UC.
35 Because of serious adverse effects, CSA is
usually reserved for patients with severe UC refractory to corticosteroids. A
randomized controlled trial found equal efficacy (about 85% response) with a 2-
mg/kg daily IV dose compared with the standard 4-mg/kg dose.
the tumor necrosis factor drugs for IBD has caused CSA use to significantly decline.
ANTITUMOR NECROSIS FACTOR AGENTS
Infliximab is a recombinant chimeric monoclonal antibody that binds to human tumor
necrosis factor (TNF) α, neutralizing its biological activity. Infliximab is indicated
for inducing and maintaining remission in patients with moderate-to-severe active
UC and CD refractory to other treatments.
Infliximab is effective for healing CD
fistulae, with data showing that chronic treatment can maintain fistula closure and
decrease the need for surgery.
39 The response to infliximab is usually rapid, often
occurring within several days. Since infliximab is a monoclonal antibody, a number
of immunologic-mediated adverse effects are associated with therapy. Antibodies to
infliximab have been detected in up to 60% of CD patients using the drug, and
emerging data suggest that patients who develop these antibodies may be at more
risk, not only for infusion-related reactions but also for reduced efficacy over
Immediate infusion-related reactions such as fever, chills, pruritus,
urticaria, and (rarely) severe cardiopulmonary symptoms can occur. Infectious
complications, including pneumonia, cellulitis, sepsis, and cholecystitis have also
been reported. All TNF α blockers carry black-box warnings for their risk of serious
infections and malignancy, particularly lymphoma.
Success with infliximab in IBD has led scientists to develop and test other biological
in the United States: the fully humanized anti-TNF-α antibody adalimumab, pegylated
humanized Fab′ fragments against TNF-α (certolizumab pegol), and the humanized
-integrin antibodies natalizumab and vedolizumab. Adalimumab is approved for
the treatment of moderate-to-severe UC and CD and may be particularly useful in
patients with an attenuated response to infliximab.
43 Certolizumab and natalizumab
are approved for patients with moderate-to-severe CD, whereas vedolizumab was
most recently approved for both moderate-to-severe UC and CD. These agents will
be further discussed in Case 24-2.
The precise place in therapy of the newer biologic agents is controversial. Most
experts consider infliximab the biologic agent of first choice with the other agents
reserved for a loss or lack of efficacy or adverse effects.
Because an infectious etiology has been proposed for IBD, it stands to reason that
antibiotics may have some utility.
4 However, most studies evaluating antibiotics have
shown little benefit with the exception of ciprofloxacin or metronidazole in
fistulizing disease and metronidazole in perianal or perhaps postoperative CD
3,45,46 Common adverse effects with chronic, high-dose metronidazole include
metallic taste and peripheral neuropathy.
Nutritional therapies for IBD have been used because dietary intraluminal antigens
may stimulate a mucosal immune response.
4 Patients with active CD respond to
bowel rest, total parenteral nutrition (TPN), or total enteral nutrition. Enteral
nutrition, with elemental or peptide-based preparation, appears to be as efficacious
as TPN, without its associated complications. Unfortunately, poor compliance often
limits this modality. Such therapy is used more commonly in the pediatric population
Symptomatic management of IBD is important to the patient’s quality of life. This
includes pain relief and diarrhea control. Loperamide or diphenoxylate with atropine
may be used to treat mild symptoms provided obstruction or toxicity is not evident.
Severe worsening of symptoms and abdominal distension may indicate toxic
megacolon caused by the inability to empty rapidly produced secretory products of
the bowel. Patients should be monitored for iron and vitamin B12 deficiencies,
especially if ileal involvement is extensive or resection has been performed.
Surgery is indicated in the treatment of IBD when the patient fails to respond to
medical management; demonstrates intestinal complications such as perforation,
obstruction, hemorrhage, toxic megacolon, or fistula formation; fails to grow and
develop at a normal rate; or exhibits carcinoma of the rectum or colon.
Furthermore, patients with UC for longer than 10 years or who demonstrate
premalignant changes on rectal biopsy may be managed surgically as a prophylactic
measure. In patients with CD, surgical intervention is common.
Pathophysiology and Clinical Presentation
occasional over-the-counter acetaminophen for body aches or headaches.
White blood cell (WBC) count, 17,500/μL with 82% PMNs
Alanine aminotransferase (ALT), 33 units/mL
Sigmoidoscopy showed evidence of granular, edematous, and friable mucosa with continuous ulcerations
what is the evidence for this?
A.C.’s presentation is typical of a patient with new-onset UC. Drug-induced
(pseudomembranous colitis) and infectious (parasitic) causes of diarrhea have been
ruled out by history (no travel outside the United States, no recent camping, no
antibiotic use) and stool examination. As discussed previously, UC is an
inflammation of the mucosal layer of the colon and rectum.
inflammation does not extend beyond the submucosa, and transmural ulcers are rare.
On examination, the mucosa appears erythematous and is friable. Differentiation from
CD is made by endoscopic and radiologic evidence of continuous distribution of
pathologic disease (as opposed to segmental), as well as the anatomic location
(confined to colon and rectum).
A.C. presents with the classic triad of UC clinical symptoms: chronic diarrhea,
rectal bleeding, and abdominal pain. Diarrhea is secondary to decreased colonic
absorption of water and electrolytes and diminished colonic segmental contractions
that normally serve to decrease the flow of bowel content. A good indication of the
severity of a patient’s disease is the volume of stool passed per day.
severity of the disease increases, incontinence and nocturnal diarrhea commonly
occur. Stools are usually soft, mushy, formed, and often contain small amounts of
mucus mixed with blood. In addition to diarrhea, the malabsorption of water and
electrolytes causes dehydration, weight loss (as observed in A.C.), and electrolyte
A.C.’s rectal bleeding is secondary to colonic mucosal erosions and occurs in
most patients with UC. Generally, bright red blood mixed in the stools indicates a
colonic origin, whereas blood-streaked stools indicate an anal or rectal origin. The
anemia associated with UC is generally secondary to this rectal bleeding. It presents
as a hemorrhagic or iron-deficiency anemia, depending on the acuteness of the
bleeding. Hemoglobin and hematocrit laboratory values often are decreased as in
A.C.’s case. Chronic inflammatory disease–induced hypoalbuminemia is often
A.C.’s abdominal pain and cramping are caused by spasm of the irritated and
inflamed colon. This abdominal pain is commonly associated with urgency to
defecate. As illustrated by A.C., the pain is usually relieved with defecation, even
though the stool volume may be small.
A.C.’s arthritis and elevated ALT are indicative of the extraintestinal
manifestations that occur in IBD.
51 Her nonspecific symptoms (i.e., anorexia, fatigue,
weight loss, anxiety, tachycardia) could become profound during an exacerbation of
UC. Fever, leukocytosis, and increased ESR are also systemic manifestations of an
inflammatory disease. Rehydration is important to assure fluid balance and maintain
good renal function. Given her anemia, tachycardia, elevated ESR, and frequency of
bloody stools, A.C.’s disease would be classified as severe.
CASE 24-1, QUESTION 2: How should A.C.’s diarrhea be managed?
Treatment of the diarrhea associated with UC is often difficult. In patients with
mild-to-moderate disease, antidiarrheals, such as loperamide or diphenoxylate with
atropine, may help minimize chronic diarrhea. Extreme caution must be used,
however, especially in patients with severe disease because of the chance of
inducing toxic megacolon, a life-threatening condition and medical emergency. For
this reason, antidiarrheals are best avoided in patients with severe active disease,
such as with A.C. Bulk-forming agents (i.e., psyllium) may be helpful for patients
suffering from constipation caused by ulcerative proctitis.
CASE 24-1, QUESTION 3: What agents can be used to induce disease remission in A.C.?
Corticosteroids are the most effective agents to induce remission of acute, severe
exacerbations of UC. Clinical improvement or remission occurs in 45% to 90% of
patients taking up to 60 mg/day of prednisone, with a recommended dose of 40 to 60
53 However, corticosteroids are not beneficial for maintaining remission. One
strategy to minimize adverse effects of corticosteroid therapy is to taper them by 5 to
10 mg/week over 1 to 2 months after demonstrated improvement. Unfortunately, a
subset of patients will experience a disease flare if the corticosteroid dosage is
decreased or tapered too quickly. IV corticosteroids are an important option,
especially in patients who have poor oral intake. Patients with active distal disease
can be treated with hydrocortisone enemas; however, topical 5-ASA therapy is more
efficacious. Biologic agents and cyclosporine may be considered for induction of
remission in patients with fulminant disease or have failed other agents.
A.C. is of childbearing age, a pregnancy test should be obtained and results taken into
consideration when choosing current and future drug therapy, particularly if pregnant
(see Chapter 49, Obstetric Drug therapy).
CASE 24-1, QUESTION 4: Methylprednisolone at a dosage of 40 mg IV every 6 hours is ordered. What are
The goal of parenteral corticosteroid therapy for A.C. is to achieve a rapid
therapeutic response as measured by decreased frequency of stools, decreased pain,
and decreased fever and heart rate. This goal may be attained with a high initial dose,
followed by a gradual dosage reduction to minimize the development of
corticosteroid adverse reactions.
Poorly nourished patients in whom oral intake is expected to be absent for more
than 7 days should receive parenteral nutrition, and treatment should be continued
until oral feeding is tolerated.
55 An adequate response is defined as resolution of
fever and tachycardia, improved patient well-being, and less abdominal tenderness
on palpation. Diarrhea is usually considered to be resolved with four or less bowel
are rarely formed at this stage, but macroscopic bleeding has stopped. Patients can
then receive oral prednisone, a 5-ASA drug, and a light diet. If the patient does not
respond within 72 hours of starting high-dose corticosteroids, infliximab or surgery
may be indicated. Once A.C.’s symptoms are controlled, the goal should be to switch
to oral corticosteroids and discharge her from the hospital.
CASE 24-1, QUESTION 5: A.C. is responding well to methylprednisolone. She is afebrile, her abdominal
corticosteroid administration indicated in UC? What are the most appropriate dosages?
Oral corticosteroids are effective for the initial treatment of mild-to-moderate
In addition, they should be substituted for parenteral corticosteroids once
a satisfactory initial response of more severe exacerbations has been achieved.
Prednisone of 40 mg/day was significantly more efficacious than 20 mg/day in
controlling ambulatory patients with moderately severe acute UC, but prednisone
doses of 60 mg/day had no additional therapeutic value, while causing more adverse
In addition, a single 40-mg morning dose of prednisone was as effective as
and more convenient than an equivalent divided dose (10 mg 4 times a day [QID]).
Therefore, the initial dose of corticosteroid for a patient with moderately severe
acute UC is 40 mg of prednisone or its equivalent administered once daily in the
Although corticosteroids are effective for inducing remission in many cases of
24 Additionally, rates of mucosal healing with these drugs are
less than those with other modalities.
56 This combined with the significant adverse
effects of corticosteroids (e.g., hyperglycemia, osteoporosis) argue against their
long-term use in IBD, as reflected in current practice guidelines.
CASE 24-1, QUESTION 6: What if A.C.’s UC was limited to the distal colon or rectum? Would topical
corticosteroids be indicated? When should other topical agents be considered for A.C.?
Topically administered 5-ASA and corticosteroids, in the form of suppositories,
The desired outcome for medications administered via this topical route is to
provide a higher concentration of drug to the diseased mucosal area, exerting a local
anti-inflammatory effect, while minimizing systemic side effects. Unfortunately,
variable but significant systemic absorption (up to 90%) and adrenal suppression
occur from the topical administration of corticosteroid to the rectum and distal
57 Therefore, the beneficial effects produced by topical use of these agents may
accrue from both systemic and local effects. The relatively low incidence of
corticosteroid side effects associated with topical administration may be related to
both the low doses and the infrequent administration (daily to twice daily) needed to
5-ASA suppositories and enemas are preferred over topical corticosteroids for the
treatment of distal UC and proctitis because they produce higher remission rates in
proctitis and effectively maintain remission of distal UC.
initiated with a nightly enema (4 g of mesalamine), and the response should be
evaluated in 3 to 4 weeks. For mild acute proctitis, administering one suppository of
5-ASA twice daily for 3 to 6 weeks is generally sufficient to induce disease
remission. Improvement should be seen in 2 to 3 weeks, and therapy should be
maintained until complete remission is achieved. If remission is attained, therapy can
then be tapered to one suppository or enema, 2 to 3 times weekly. Therapy with oral
plus topical mesalamine showed greater efficacy than either alone in achieving
remission of distal UC or proctitis.
Corticosteroid side effects and precautions for use often limit the therapeutic
effectiveness of these agents and should never be overlooked.
glucocorticoid adverse effects are of particular importance in patients with IBD in
that they may mimic, mask, or intensify symptoms and complications of this disease.
For example, the symptoms of peritonitis, one of the major complications of intestinal
perforation, may be masked by corticosteroids. Other deleterious effects of
corticosteroids include hyperglycemia, avascular necrosis, cataract formation, and
central nervous system effects, including mood disorders, insomnia, psychoses, and
Patients with IBD are at risk for decreased bone mineral density, which is
exacerbated by prolonged use of corticosteroids.
58,59 This is an often-overlooked side
effect of these drugs. One study suggested that even budesonide, with its low overall
bioavailability, causes this adverse effect.
60 Thus, calcium, vitamin D supplements,
and possibly bisphosphonates are recommended to minimize metabolic
demineralization in all IBD patients taking corticosteroids for longer than 3 months.
Given the patient’s family history (mother with osteoporosis) and her high risk of
bone loss, alendronate 35 mg weekly with 1,500 mg daily of calcium and 800
international units of vitamin D intake should be initiated.
SULFASALAZINE AND 5-AMINOSALICYLIC ACID
CASE 24-1, QUESTION 8: A.C. is still responding well to oral prednisone; however, her blood glucose
another modality for active treatment. What other drugs could be used for remission induction?
Previously, sulfasalazine was considered the drug of choice in UC exacerbation
because of its demonstrated efficacy and reduced toxicity when compared with
corticosteroids. However, controlled trials have shown that corticosteroids may act
more promptly than sulfasalazine alone for severe acute UC.
declined significantly since the availability of better-tolerated 5-ASA formulations.
Additionally, as in the case of A.C., patients with a sulfa allergy should avoid
sulfasalazine. Clinical improvement or remission of mild-to-moderate UC can be
attained in 40% to 74% of patients treated with oral 5-ASA in doses ranging from
1.5 to 4.8 g/day with further improved response at dosages greater than 2 g/day.
severe active UC or refractory disease. Because A.C. has improved symptomatically
and is suffering significant adverse effects from corticosteroid treatment, switching to
oral mesalamine is a reasonable option at this time.
mesalamine 800 mg PO TID. What drug regimen should be used to maintain disease remission in A.C.?
5-ASA agents significantly reduce the incidence of relapse in UC patients who are
17,19 At 12 months, 65% to 70% of patients remain relatively symptomfree compared with placebo.
63 As discussed previously, the anatomic site of disease
is an important consideration in the selection of a 5-ASA preparation.
suggest that, if tolerated, higher doses have higher rates of treatment success. In
contrast, oral and topical corticosteroids do not prevent relapse of UC once
On the basis of this information, A.C.’s mesalamine should be titrated to a total
dose of 4.8 g in divided doses. If she experiences a relapse, a course of oral
corticosteroids may be needed to re-achieve remission. Prophylactic therapy should
be continued indefinitely unless intolerable adverse effects develop. This is
especially true in light of data that suggest that long-term mesalamine may be
chemoprotective against colon cancer.
CASE 24-1, QUESTION 10: A.C.’s mesalamine has been increased to 1,200 mg TID for UC maintenance
epigastric pain. What is the possible cause of A.C.’s symptoms? How can they be minimized?
A.C. appears to be experiencing adverse effects of mesalamine. Although usually
better tolerated than sulfasalazine, unwanted adverse effects occur in 10% to 45% of
patients. Most 5-ASA adverse reactions are dose related and tend to occur early in
Dose-related 5-ASA adverse effects can be minimized by initiating the patient on a
low dosage (1–2 g/day) and gradually increasing the amount to tolerated therapeutic
If dose-related reactions do occur, the drug should be discontinued until the
symptoms subside, then it may be reinstituted at a lower dosage. A.C.’s symptoms
are probably dose-related adverse reactions to mesalamine. The dosage should be
decreased, or the drug temporarily withheld. If tolerated, the dosage can be increased
slowly as necessary, or she can be switched to another agent to maintain disease
remission, such as an immunomodulator. An algorithm depicting treatment for UC is
IMMUNOSUPPRESSIVE AND BIOLOGICAL AGENTS
CASE 24-1, QUESTION 11: A.C.’s dose of mesalamine was decreased to 800 mg TID. After 2 weeks,
and nausea. What alternative therapies should be considered at this point?
The results of several trials suggest AZA and 6-MP are appropriate alternatives
for patients with active UC that have not responded to systemic steroids, although
their actual level of effectiveness is debated.
64,65 These drugs are also used to
maintain remission, although they are probably used more in CD than UC for this
purpose (see Case 24-2, Question 3).
Infliximab, adalimumab, and vedolizumab are approved in the United States for
moderate-to-severe UC (both for induction therapy and for maintenance of
remission). Because of significant costs and adverse effects, they should be reserved
for patients with refractory disease.
for selection guidelines); IV, intravenous; 6-MP, 6-mercaptopurine; UC, ulcerative colitis.
Committee. Am J Gastroenterol. 2010;105:501.)
Cyclosporine (CSA) has also been used to treat active UC. In one retrospective
review, IV CSA had a roughly 50% response rate even 2 years after acute therapy.
Many drug interactions and adverse effects are associated with CSA. Hypertension,
gingival hyperplasia, hypertrichosis, paresthesias, tremors, headaches, electrolyte
disturbances, and nephrotoxicity are common. In A.C., a reasonable choice would be
AZA 115 mg (approximately 2.5 mg/kg/day). Monthly monitoring of WBC counts and
liver function testing as well as periodic assessment for any signs and symptoms of
pancreatitis would be appropriate.
Vaccinations in the IBD Patient
CASE 24-1, QUESTION 12: One year has passed since A.C. last had an acute attack of UC. She has been
examination. She asked about receiving the yearly influenza vaccination as well as the pneumococcal
Immunomodulators and biologic drugs are the mainstay of IBD treatment.
However, one of the most important adverse effects are infectious complications. As
mentioned above, serious and sometimes fatal infections have been reported with
drugs such as AZA and infliximab.
42 Some of these infections are preventable with
67 Unfortunately, data exist that immunization strategies are
significantly underutilized in the IBD population.
standard immunization schedules (see Chapter 64, Vaccinations) be adhered to; that
serologic testing for varicella be performed on IBD patients without a clear history
of chickenpox, and if negative, such patients should be vaccinated against this virus;
and that live virus vaccinations should be avoided in patients, such as A.C., who are
68 Specifically, concerning A.C., she should receive the seasonal
influenza vaccine as well as the 23-valent pneumococcal polysaccharide vaccine and
hepatitis B vaccine. Many patients with IBD would also be candidates for the human
papilloma virus vaccine, and given the increased incidence of abnormal
Papanicolaou tests in this population, this would be a reasonable strategy.
Pathophysiology and Clinical Presentation
episodic at first, exacerbated by meals, and somewhat relieved by defecation. During this time, C.J.
of skin rashes. He has not traveled outside the United States or taken antibiotics recently.
weighs 80 kg. Pertinent laboratory values include the following:
and a terminal ileum that has a nodular irregularity of the mucosa. Follow-up colonoscopy reveals a
C.J., like most patients with CD, presents with the classic symptom triad of
abdominal pain, diarrhea, and weight loss.
11 His most frequent symptom is right
lower quadrant abdominal pain, which is secondary to an indolent inflammatory
process in the ileocecal area. Diarrhea is also a characteristic symptom; however, in
contrast to UC, the stools are usually partly formed, and gross blood is generally not
visible. If the disease is limited to the colon, the diarrhea may be of the same quality
and quantity as that associated with UC. If the disease is limited to the ileum, as it
appears to be with C.J., the diarrhea is generally moderate, with four to six stools
daily. If ileal involvement is significant, bile salt malabsorption may occur, resulting
in steatorrhea. Weight loss may be pronounced in patients with long-standing CD
because of anorexia and malabsorption. Additionally, vitamin deficiencies, including
vitamin B12 and vitamin D, are more common in CD patients than control subjects.
Rectal bleeding often occurs in patients with CD, particularly those with colonic
involvement, although it is not as common as that associated with UC. Slow blood
loss may occur in patients with disease limited to the small intestine, which may
cause occult blood-positive feces and, eventually, anemia, as illustrated by C.J.
Massive hemorrhage is usually a late complication of CD and is generally caused by
transmural ulceration and subsequent erosion into a major blood vessel.
C.J.’s leukocytosis and increased ESR demonstrate that, like UC, CD is a systemic
disease. Extraintestinal manifestations such as arthritis, liver disease, and skin rash
occur in CD with the same frequency as UC. However, some types of extraintestinal
disease appear to be more common in UC (e.g., primary biliary cirrhosis) than CD
Most patients with CD have recurrent, symptomatic episodes of pain and diarrhea
with gradual progression of their disease to shorter and shorter asymptomatic
periods. Although the clinical course is generally progressive, 10% of patients will
remain essentially asymptomatic after a few acute episodes.
only manifest a slight fever for years until a late complication of the disease, such as
fistula formation, develops. Alternatively, CD may be rapidly progressive.
CASE 24-2, QUESTION 2: What agents can be used to induce a remission of C.J.’s CD?
Because the clinical course of CD varies among patients, the management of this
disease must be individualized. The anatomic location of the disease is also an
of therapy. Most investigations evaluating the treatment of acute symptomatic CD
have ignored this factor and are therefore difficult to assess or compare.
Corticosteroids are the most widely used therapeutic agents for the treatment of
16,24 A systematic review of the literature confirms that
steroids have a valuable role in remission induction.
demonstrated that approximately 60% to 80% of patients with active CD will
respond to a course of corticosteroids.
24 These agents seem to be particularly
mild-to-moderate ileocolonic CD.
Although previously used extensively for mild-to-moderate CD, current trial data and
expert opinion have limited the role of 5-ASA drugs to mild active colonic CD. A
large meta-analysis comparing 5-ASA (Pentasa) versus placebo found a small and
probably clinically insignificant treatment benefit.
The immunomodulators AZA, 6-MP, and MTX have an onset of action of weeks to
months and are not usually appropriate monotherapy for treatment of a CD flare.
Infliximab is effective for both active and quiescent disease.
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