TRIPASS XR تري باس

 

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-

MP and AZA.

33 Most experts and recent guidelines suggest reserving MTX use for

patients with CD intolerant of, or refractory to, 6-MP or AZA treatment.

17,34 Adverse

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.

36 The emergence of

the tumor necrosis factor drugs for IBD has caused CSA use to significantly decline.

ANTITUMOR NECROSIS FACTOR AGENTS

Infliximab

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.

37,38

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

time.

40,41

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.

42

Other Biological Therapies

Success with infliximab in IBD has led scientists to develop and test other biological

therapies designed to either block pro-inflammatory mediators or enhance antiinflammatory mediators in the gut. To date, four other biologic agents are approved

in the United States: the fully humanized anti-TNF-α antibody adalimumab, pegylated

humanized Fab′ fragments against TNF-α (certolizumab pegol), and the humanized

α4

-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.

44

ANTIBIOTICS

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

disease.

3,45,46 Common adverse effects with chronic, high-dose metronidazole include

metallic taste and peripheral neuropathy.

NUTRITIONAL THERAPIES

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

with mild-to-moderate CD.

47,48

SUPPORTIVE THERAPY

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.

49

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

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.

16,17,50

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.

ULCERATIVE COLITIS

Pathophysiology and Clinical Presentation

CASE 24-1

QUESTION 1: A.C., a 24-year-old female college student, has had episodic, watery diarrhea, and colicky

abdominal pain relieved by defecation for the past 9 months. Eight weeks before admission, the diarrhea

increased to 3 to 5 semi-formed stools daily. The frequency of the stools gradually increased to 7 to 10 times a

day 1 week ago. At that time, A.C. noted bright red blood in the stools. Stool frequency has now increased to

12 to 15 per day, although the volume of each stool is estimated to be only “one-half cupful.” She feels a great

urgency to defecate, even though the volume is small. She has not traveled outside the United States, has not

been camping, and has not taken any antibiotics within the past 6 months. She is allergic to sulfa, and takes only

occasional over-the-counter acetaminophen for body aches or headaches.

A.C. complains of anorexia and a 10-lb weight loss during the previous 2 months. For the past 4 months, she

has had intermittent swelling, warmth, and tenderness of the left knee, which is unassociated with trauma. She

denies any skin rashes or any

p. 524

p. 525

difficulties with her vision. A review of other body systems and social and family history are largely

noncontributory.

A.C. appears to be a slightly anxious and tired young woman of normal body habitus. She is 165 cm tall and

weighs 51 kg. Her temperature is 100°F; her pulse rate is 105 beats/minute and regular. Physical examination is

normal, except for evidence of acute arthritis of the left knee and tenderness of the left lower abdomen to

palpation.

Stool examination shows a watery effluent that contains numerous red and white cells with no trophozoites.

Stool cultures and an amebiasis indirect hemagglutination test are negative. Other laboratory values include the

following results:

Hematocrit (Hct), 30%

Hemoglobin (Hgb), 8.1 g/dL

White blood cell (WBC) count, 17,500/μL with 82% PMNs

ESR, 72 mm/hour

Serum albumin, 2.8 g/dL

Alanine aminotransferase (ALT), 33 units/mL

Sigmoidoscopy showed evidence of granular, edematous, and friable mucosa with continuous ulcerations

extending from the anus throughout the colon. What is the most likely cause of A.C.’s diarrheal illness, and

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.

1 Characteristically, the

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.

16 Because the

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

disturbances.

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

exacerbated by malnutrition.

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.

52

Remission Induction

CORTICOSTEROIDS

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

mg/day.

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.

53 Given that

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

or breastfeeding

54

(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 treatment goals for A.C.?

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

movements daily. Stools

p. 525

p. 526

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.

Oral Administration

CASE 24-1, QUESTION 5: A.C. is responding well to methylprednisolone. She is afebrile, her abdominal

pain is reduced (to a score of 4 on a 1–10 scale), and her diarrhea is decreasing. When is the oral route of

corticosteroid administration indicated in UC? What are the most appropriate dosages?

Oral corticosteroids are effective for the initial treatment of mild-to-moderate

acute UC.

25

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

effects.

17

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

morning.

Although corticosteroids are effective for inducing remission in many cases of

IBD, up to 50% of patients may not respond (steroid resistant) or will be steroiddependent at 1 year.

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.

16,17

Topical Administration

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,

foams, and retention enemas, are effective in the management of acute, mild-tomoderate UC that is limited to the distal colon and rectum.

22

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

colon.

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

control mild acute UC.

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.

57 For distal UC, therapy is

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.

22

Adverse Effects

CASE 24-1, QUESTION 7: What particular corticosteroid adverse effects should the clinician monitor in

A.C.?

Corticosteroid side effects and precautions for use often limit the therapeutic

effectiveness of these agents and should never be overlooked.

24 Certain

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

euphoria.

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

concentrations have ranged from 226 to 445 mg/dL (normal, 70–110 mg/dL). Her physician would like to try

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.

4 Sulfasalazine use has

declined significantly since the availability of better-tolerated 5-ASA formulations.

21

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.

61,62

In summary, oral 5-ASA compounds are considered first-line therapy for mild-tomoderate exacerbations of UC, with systemic corticosteroids reserved for more

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.

p. 526

p. 527

Remission Maintenance

MESALAMINE

CASE 24-1, QUESTION 9: A.C. feels much better and claims to be “back to normal.” Her abdominal pain is

gone, and she currently has two formed, non-bloody stools daily. Most of her laboratory parameters have

returned to normal (ESR, 19 mm/hour; blood glucose, 95 mg/dL; WBC, 8,300/μL). She is currently taking

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

in remission.

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.

20,21 Data also

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

remission has occurred.

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.

63

Adverse Effects

CASE 24-1, QUESTION 10: A.C.’s mesalamine has been increased to 1,200 mg TID for UC maintenance

therapy. Several days after starting this higher dose of mesalamine, A.C. experienced anorexia, nausea, and

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

the course of therapy.

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

doses.

62

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

shown in Figure 24-1.

IMMUNOSUPPRESSIVE AND BIOLOGICAL AGENTS

CASE 24-1, QUESTION 11: A.C.’s dose of mesalamine was decreased to 800 mg TID. After 2 weeks,

A.C. continued to have nausea, diarrhea, and headache severe enough to cause her to miss classes and call in

sick from her part-time job. Objectively, she has lost 5 kg (now 46 kg) in the last week as a result of anorexia

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.

Figure 24-1 Treatment algorithm for ulcerative colitis. Pancolitis refers to extensive ulcerative colitis. 5-ASA,

mesalamine products, including mesalamine (e.g., Asacol, Pentasa, Rowasa), olsalazine, and balsalazide (see text

for selection guidelines); IV, intravenous; 6-MP, 6-mercaptopurine; UC, ulcerative colitis.

aFor UC adalimumab is

an alternative option to infliximab. (Source: Bernstein CN et al. World Gastroenterology Organization Practice

Guidelines for the diagnosis and management of IBD in 2010. Inflamm Bowel Dis. 2010;16:112; Carter MJ et al.

Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53(Suppl 5):V1; Kornbluth A et

al. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters

Committee. Am J Gastroenterol. 2010;105:501.)

p. 527

p. 528

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.

65

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.

66

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

taking AZA 2.5 mg/kg/day. Today she presented to her primary health care provider for her annual physical

examination. She asked about receiving the yearly influenza vaccination as well as the pneumococcal

vaccination she has been reading about online. Her primary care provider is unsure whether A.C. is a candidate

for either vaccination. Should A.C. receive both vaccinations? What vaccinations, if any, is A.C. a candidate

for?

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

immunizations.

67 Unfortunately, data exist that immunization strategies are

significantly underutilized in the IBD population.

68 Guidelines recommend that

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

receiving AZA.

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.

69

CROHN’S DISEASE

Pathophysiology and Clinical Presentation

CASE 24-2

QUESTION 1: C.J., a 30-year-old man, was well until 18 days ago when he experienced crampy right lower

quadrant abdominal pain associated with an increased frequency of semiformed stools (4–5/day). The pain was

episodic at first, exacerbated by meals, and somewhat relieved by defecation. During this time, C.J.

experienced anorexia and a 10-pound weight loss. He denied any change in vision, joint pain, or the appearance

of skin rashes. He has not traveled outside the United States or taken antibiotics recently.

Physical examination is essentially normal, except for soft, loose, watery stools that are streaked with fat and

positive for occult blood. The abdomen is tender on palpation of the right lower quadrant. Vital signs include a

temperature of 37.8°C, pulse of 100 beats/minute, and blood pressure of 135/75 mm Hg. He is 180 cm and

weighs 80 kg. Pertinent laboratory values include the following:

Hct, 28%

Hgb, 9 g/dL

WBC count, 14.0 × 10

9

/L

ESR, 60 mm/hour

Results of sigmoidoscopy and rectal biopsy are negative. Stool cultures and toxin studies for C. difficile are

negative, as is the examination for signs of trophozoites. A barium enema shows an edematous ileocecal valve

and a terminal ileum that has a nodular irregularity of the mucosa. Follow-up colonoscopy reveals a

cobblestone-appearing terminal ileum with areas of normal tissue separated by diseased mucosa. Which of

C.J.’s signs, symptoms, and laboratory data are consistent with CD? Describe the pathophysiological basis for

C.J.’s clinical presentation.

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.

70

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

(e.g., pyoderma gangrenosum).

71

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.

72 Other patients may

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.

Remission Induction

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

important determinant

p. 528

p. 529

of therapy. Most investigations evaluating the treatment of acute symptomatic CD

have ignored this factor and are therefore difficult to assess or compare.

CORTICOSTEROIDS

Corticosteroids are the most widely used therapeutic agents for the treatment of

active, symptomatic CD.

16,24 A systematic review of the literature confirms that

steroids have a valuable role in remission induction.

56 Landmark studies have

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

effective in ileal and ileocolonic disease and can induce remission in even moderateto-severe CD. Budesonide is also recommended in current CD guidelines for active

mild-to-moderate ileocolonic CD.

16

5-AMINOSALICYLIC ACID

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.

73

OTHER INDUCTION AGENTS

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.