INFLAMMATORY BOWEL DISEASE - ACCP

Abbreviations

INFLAMMATORY

BOWEL DISEASE

Jeffrey F. Binkley, Pharm.D., BCNSP

Reviewed by Michelle M. Chapman, Pharm.D., FCCP, BCPS; Joseph T. DiPiro, Pharm.D., FCCP; and

Karen Whalen, R.Ph., BCPS

Learning Objectives

1.

2.

3.

4.

5.

6.

7.

8.

is complex and has not been fully elucidated, both have

distinct and overlapping clinical manifestations and

pathology. These disease processes can have broad social,

economic, and health-related quality of life influences that

significantly impact patients and their families. Treatment

options include medical and surgical interventions, but

results are variable, depending on the type, severity, and

location of disease. This chapter addresses the pathogenesis

and treatment of these two potentially debilitating diseases,

offering guidance to pharmacists who can help patients

achieve optimal pharmacological therapy and improve their

quality of life. Comparisons of UC and CD will be made

throughout the chapter, noting similarities and highlighting

differences in manifestations, diagnosis, and treatment of

these disorders.

Based on a patient¡¯s signs and symptoms, history, and

diagnostic findings, distinguish between the

characteristics of Crohn¡¯s disease (CD) and ulcerative

colitis (UC) and understand how the site and type of

disease can influence treatment options.

Given patient-specific parameters and indicators, assess

a patient¡¯s severity of CD or UC and risk of disease

progression or cancer development.

Based on a patient¡¯s history, symptoms, and type and

site of disease, design and implement the best

pharmacological interventions using antibiotic

drugs, anti-inflammatory drugs, corticosteroids,

immunomodulators, and adjunctive drugs to treat CD

or UC and evaluate the effectiveness of treatment.

Evaluate and justify the appropriate use of infliximab to

treat CD based on the efficacy, toxicity, and

cost-effectiveness.

Design appropriate pharmacological therapies to

maintain remission for patients with inflammatory

bowel disease (IBD).

Given patient-specific information, design appropriate

nutritional interventions for patients with IBD.

Given patient information regarding response to

pharmacotherapy, design appropriate monitoring plans and

evaluate appropriate counseling requirements to optimize

treatment outcomes and prevent treatment failures.

Based on patient-specific needs, recommend resources

for patients with treatment, economic or psychological

challenges due to refractory IBD.

Pathophysiology of IBD

Definitions

Although there are many similarities between UC and

CD, the basic defining differences involve the location of

disease and the extent of inflammation. Ulcerative colitis is

characterized by inflammation limited to the superficial

mucosal layer of the colon and does not affect other areas of

the gastrointestinal tract. Crohn¡¯s disease is characterized by

transmural, or deeper, mucosal inflammation and can be

present throughout the gastrointestinal tract. Other

distinguishing characteristics for UC and CD are listed in

Table 1-1.

For patients with UC, the rectum is almost always

affected, but disease also may extend proximally and

continuously to involve other locations within the large

bowel. When only the rectum is inflamed, the disease is

known as ulcerative proctitis. Distal colitis or

proctosigmoiditis describes disease extending into the

midsigmoid colon. Left-sided UC reaches the splenic

flexure. Disease involving the entire colon, including

Introduction

Inflammatory bowel disease (IBD) is a grouping of two

similar disorders: ulcerative colitis (UC) and Crohn¡¯s

disease (CD). Although the pathogenesis of these disorders

Pharmacotherapy Self-Assessment Program, 5th Edition

69

Inflammatory Bowel Disease

Abbreviations

predominance in CD has been observed in women, but

predominance has been noted in men with UC.

Abbreviations in this

Chapter

CD

IBD

pANCA

Th1

TNF

UC

Etiology

The pathogenesis of IBD is not known; however, three

components have been established as major contributors:

genetic predisposition, environmental factors, and

immunologic influences. Disease development may be a

result of complex interactions of all three of these

influences; however, further investigation is required to

fully understand the intricacies of these interactions.

Crohn¡¯s disease

Inflammatory bowel disease

Perinuclear antineutrophilic

cytoplasmic antibody

Type 1 helper T cell

Tumor necrosis factor

Ulcerative colitis

Genetic Influences

Genetic factors may influence susceptibility to IBD. The

majority of patients with IBD have no family history of

IBD; however, in patients who have a positive family

history, the most common occurrence is in first-degree

relatives. Evidence derived from studies of identical twins

indicates stronger genetic influences for CD than for UC.

Specific genes responsible for the genetic risk of IBD have

not been fully identified; however, multiple genes probably

contribute to the complex IBD phenotype in humans.

Animal models with modified genes have indicated that

colitis may result from alterations in many genes. Many

gene alterations may impact changes in the mucosal

immune system. Animal models with genetic alterations

demonstrated a lack of disease when the animals were

maintained in germ-free environments. This observation

suggests the role of environmental factors in disease

development.

sections beyond the splenic flexure, is described as

pancolitis.

For patients with CD, the severity of mucosal

inflammation may lead to the development of fibrosis,

which may result in obstructive symptoms, which are not

seen in patients with UC. Sinus tracts may burrow and

penetrate the serosa, giving rise to bowel perforations and

fistula formation. Crohn¡¯s disease may involve any area of

the gastrointestinal tract from the mouth to the anus, and

areas of involvement may be patchy and affect multiple,

discontinuous areas. The majority of patients with CD have

some small bowel involvement, usually in the distal ileum;

about 66% of patients with CD exhibit colonic disease.

Crohn¡¯s disease of the colon sometimes spares the rectum,

unlike UC which usually involves the rectum. Fewer

patients have disease involvement in other areas of the

gastrointestinal tract, such as the mouth, esophagus,

stomach, and duodenum. Sometimes interchangeable

terminology is used to describe CD in a specific location,

such as Crohn¡¯s colitis or Crohn¡¯s ileitis. Patients who have

involvement of both the ileum and colon are said to have

ileocolitis.

Remission for IBD defined as the absence of symptoms

of disease without the continued use of significant drugs,

such as corticosteroids. Maintenance therapy is

pharmacological intervention used to maintain remission

and reduce the incidence of disease exacerbation or

recurrence.

Environment Influences

It has been suggested that environmental triggers play a

role in the pathogenesis of IBD. Cigarette smoking, the use

of oral contraceptives, nutritional deficiencies, and the

presence of infectious agents have been suggested as

environmental factors that possibly contribute to disease

progression in susceptible patients. Although several studies

have shown a negative correlation between smoking and

UC, a positive correlation between smoking and CD

recurrence has been demonstrated. A clear association

between oral contraceptive use and IBD incidence has not

been established. No specific causative factor has been

identified in the diets of patients with IBD. In the setting of

an underlying genetic or immune defect, pathogenic

bacteria may play a role in the pathogenesis of IBD.

Although some evidence has linked Mycobacterium species

with CD, no single pathogen has been identified to have a

consistent association with IBD. Microorganisms suggested

as potential IBD pathogens include viruses, mycoplasmata,

Chlamydia, and other bacteria. Limited evidence suggests

that stress can worsen the symptoms of IBD, but the

mechanism underlying this observation is unclear.

Epidemiology

In North America, the incidence for UC ranges from

2.2/100,000 to 14.3/100,000 person-years, and prevalence

ranges from 37/100,000 to 246/100,000 people. The

incidence for CD in North America ranges from

3.1/100,000 to 14.6/100,000 person-years, and prevalence

ranges from 26/100,000 to 199/100,000 people. A higher

incidence of IBD is observed in Jewish and Caucasian

populations, and lower rates are seen in African-American,

Hispanic-American, and Asian-American populations;

however, studies suggest that the incidence of IBD in

African Americans is approaching that of white Americans.

The incidence of IBD is higher in urban areas. Although

IBD can present at any age, peak incidence is observed in

late adolescence and early adulthood; in addition, a second

peak occurs between 50 and 80 years of age. A slight

Inflammatory Bowel Disease

Immunologic Influences

In addition to genetic and environmental factors, altered

immune response has been implicated in the pathogenesis

of both UC and CD. Investigation has revealed two major

areas of immune system involvement: an abnormal

immune system against dietary or microbial antigens and

possible alterations in mucosal barrier function.

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Pharmacotherapy Self-Assessment Program, 5th Edition

Abbreviations

antibodies are directly involved in the development of IBD,

and titers of pANCA are not indicative of disease activity.

An effective mucosal barrier function requires an intact

intestinal epithelium, surface mucus, normal peristalsis, and

the secretion of numerous protective factors. Epithelial cells

provide the first barrier against pathogens crossing the

gastrointestinal tract. Alterations in epithelial cells or in

intestinal mucus, high concentrations of bacteria within

mucus, and increased intestinal permeability may play

contributing roles in the pathogenesis of IBD. Intestinal

growth factors regulate the growth and differentiation of

intestinal epithelial cells and may be involved in IBD

pathogenesis. Excess arachidonic acid and its by-products,

reactive oxygen and nitrogen products, have been

implicated in IBD pathogenesis because of their potential

effects on the mucosal barrier.

Clearly, researchers will continue to investigate the

pathogenesis of IBD; however, the mechanisms of disease

likely involve a matrix of interactions among these genetic,

environmental, and immunologic influences.

Table 1-1. Distinguishing Characteristics of Crohn¡¯s

Disease Versus Ulcerative Colitis

Characteristics

Crohn¡¯s Disease

Ulcerative

Colitis

Pattern

of inflammation

and ulceration

Patchy, ¡°cobblestone¡± Continuous and

appearance

superficial

Histology

Transmural lesions

and granulomas

Nontransmural and

crypt abscesses

Location within

Any location

the gastrointestinal from mouth to anus

tract

Limited to colon

and/or rectum

Presenting

symptoms

Fatigue, diarrhea,

abdominal pain,

and fever

Rectal bleeding

and bloody or

watery diarrhea

Potential

complications

Perineal disease,

abscesses, and

fistula development

Toxic megacolon

Response

to surgery

Variable, not curative

Curative

Clinical Characteristics and Complications

Ulcerative Colitis

Clinical Manifestations of UC

The severity of symptoms associated with UC usually

correlates with the extent of colonic involvement. Initial

presentation often includes an insidious onset of symptoms,

often preceded by a history of self-limited, intermittent

rectal bleeding. Other physical findings include abdominal

tenderness, fever, weight loss, and pallor. In general,

patients can be classified as having mild, moderate, or

severe disease based on their symptoms and diagnostic

studies.

About 33% of patients with UC experience mild disease,

limited to the rectum and sigmoid colon, known as proctitis

or distal colitis. Presentation of mild disease usually

includes intermittent rectal bleeding, passage of mucus, and

development of about four episodes of mild diarrhea daily.

Tenesmus, or difficulty defecating despite urgency, mild

abdominal pain, and periods of constipation are also

common for patients with mild disease.

Patients with moderate UC usually have disease

extending beyond the distal colon. These patients

experience frequent loose bloody stools, mild anemia,

moderate abdominal pain, and low-grade fever.

Patients with severe disease demonstrate extensive

colonic involvement, often pancolitis. In general, these

patients have frequent loose stools (as many as 10 stools/day

or more) with severe abdominal cramping, fever, and

significant bleeding. They also may experience rapid weight

loss and malnutrition. Toxic megacolon is a condition that

may occur in severely ill patients when colonic motility is

impaired, the colon is dilated, and the patient¡¯s bowel

movements decrease or cease. Serious consequences may

result, including colonic perforation, peritonitis, and even

death.

During normal absorptive processes, the intestine has an

effective barrier that uses both innate and acquired immune

systems to discriminate harmless food antigens from

infectious or toxic agents.

The innate immune system provides the initial response

to a foreign antigen exposure and is composed of

phagocytes and natural killer cells. The acquired immune

system involves both humoral and cell-mediated

mechanisms and includes B and T lymphocytes which

provide specific immunity. Humoral immunity is mediated

within the gastrointestinal tract by antibody-secreting B

cells, primarily of the immunoglobulin A class. Cellular

immunity is mediated by T lymphocytes, which include

both CD4+ helper T cells and CD8+ suppressor T cells.

CD4+ helper T cells include both type 1 (Th1) and type 2

(Th2) helper T cells. Inducers of cell-mediated immunity

such as interferon-gamma, tumor necrosis factor-alpha

(TNF-¦Á), interleukin-2, and interleukin-12 are secreted by

Th1 cells. B cell differentiation is regulated by Th2 cells by

secreting interleukin-4, interleukin-5, interleukin-6, and

interleukin-10. Animal studies suggest additional CD4+

subsets, which produce ¡°down-regulatory¡± cytokines.

Studies show abnormally secreted immunoregulatory

and inflammatory cytokines correlate with active IBD.

Secretion of interferon-gamma and TNF-¦Á by Th1 cells has

a significant proinflammatory effect, whereas the secretion

of interleukin-10 by Th2 cells suppresses the Th1-mediated

responses. CD4+ T lymphocytes isolated from patients with

CD secrete large amounts of interferon-gamma and TNF-¦Á,

implicating Th1 cells in the pathogenesis of IBD.

Abnormal B cell regulation may be a factor in IBD

development. An increase in circulating B cells, perinuclear

antineutrophilic cytoplasmic antibodies (pANCAs), and

other autoantibodies have been observed in patients with

IBD. Studies have not shown that production of these

Pharmacotherapy Self-Assessment Program, 5th Edition

Complications of UC

Ulcerative colitis can include both local and

extraintestinal complications. Local complications of UC

include massive hemorrhage, fulminant colitis, toxic

71

Inflammatory Bowel Disease

Abbreviations

Crohn¡¯s Disease

Clinical Manifestations of CD

In contrast to the common features found in patients with

UC, the clinical manifestations of CD may vary greatly

based on the extent of disease. Hallmark characteristics of

CD include fatigue, prolonged diarrhea with abdominal

pain, weight loss, and fever. Bleeding may or may not be

present. Some patients may develop a fistula or abdominal

abscesses.

Diarrhea may result from excessive fluid secretion and

impaired fluid absorption, from bacterial overgrowth, or

from bile salt malabsorption. Abdominal pain often is due to

fibrotic strictures, which may lead to bowel obstruction.

Bleeding may be present in Crohn¡¯s colitis, but typically

is observed less frequently than in UC. Diarrhea without

bleeding, but with other features of IBD such as skin, eye,

or joint problems, or a family history of IBD may aid in

diagnosing CD.

Patients with CD are predisposed to sinus tract formation

with potential bowel wall perforation resulting in acute

peritonitis characterized by fever, abdominal pain and

tenderness, and often a palpable mass. Fistula tracts can

develop at various anatomical locations adjacent to the

diseased bowel, and symptoms may vary accordingly.

Patients with an enterocutaneous fistula have bowel

contents draining to the skin surface. Enteroenteric fistulae

may be asymptomatic or present as a palpable mass on

physical examination. Enterovesical fistulae (bowel to

bladder) lead to recurrent urinary tract infections often

caused by multiple organisms and a complaint of

pneumaturia, or the passage of air in urine. Passage of gas or

feces through the vagina indicates presence of an

enterovaginal fistula.

About 33% of patients with CD develop perianal disease.

Signs and symptoms include perianal pain and drainage

from large skin tags, anal fissures, perirectal abscesses, and

anorectal fistulae.

Systemic symptoms in CD include fatigue, weight loss

and fever. Weight loss often is related to decreased food

intake because patients¡¯ symptoms are lessened when they

do not eat. Weight loss also may result from malabsorption.

Fever may be due to the inflammatory process or due to

bowel infection.

Patients with mild to moderate CD are ambulatory and

able to tolerate an oral diet without dehydration, toxicity,

abdominal tenderness, mass, or obstruction. Patients with

moderate to severe CD exhibit mild to moderate disease or

present with prominent symptoms such as fever, weight

loss, abdominal pain and tenderness, intermittent nausea or

vomiting, or anemia. Patients with severe fulminant disease

have persisting symptoms despite treatment with

corticosteroids or exhibit high fever, persistent vomiting,

intestinal obstruction, rebound tenderness, cachexia, or an

abscess. Patients in remission become asymptomatic either

spontaneously or after medical or surgical intervention.

Patients requiring corticosteroids to remain asymptomatic

are not considered to be in remission.

Table 1-2. Extraintestinal Complications of

Inflammatory Bowel Disease

Eye involvement

Uveitis

Episcleritis

Skin disorders

Erythema nodosum

Pyoderma gangrenosum

Joint disease

Peripheral arthritis (usually involves large joints with no

synovial destruction)

Ankylosing spondylitis (may be the presenting manifestation

of ulcerative colitis)

Sclerosing cholangitis (presents with an elevation in serum

alkaline phosphatase and gamma glutamyltranspeptidase)

Venous and arterial thromboembolism

megacolon, intestinal perforation or stricture, and the

development of colon cancer. Extraintestinal manifestations

of UC can include eye involvement, skin disorders, joint

disease, primary sclerosing cholangitis, and venous and

arterial thromboembolism as described in Table 1-2.

Potential development of colon cancer is a major concern

for patients diagnosed with UC. The risk of colon cancer is

related both to the extent and duration of the disease.

Patients with UC who have proximal disease involvement or

who have a family history of colon cancer are at increased

risk of developing colon cancer. In addition, patients with

UC and primary sclerosing cholangitis may be at increased

risk for colorectal cancer compared to those without primary

sclerosing cholangitis. Compared to an age-matched

population, the risk of colorectal cancer begins to increase

8¨C10 years after the onset of symptoms. The incidence of

colorectal cancer is about 5¨C10% after 20 years and 12¨C20%

after 30 years of disease.

Patients with UC should undergo surveillance

colonoscopy, although the timing and the optimal number

and location of biopsies that should be obtained are

uncertain. Although specific recommendations regarding

screening differ from various professional organizations, all

agree that screening for cancer should occur in patients with

UC who have not had a total colectomy. The timing of these

screenings should be a collaborative decision between the

patient and physician. The American Gastroenterological

Association recommends that surveillance colonoscopy

should begin 8 years after initial diagnosis of pancolitis, and

15 years after initial diagnosis of colitis involving the left

colon. Colonoscopy should then be repeated every

1¨C2 years. The American College of Gastroenterology

recommends annual surveillance colonoscopy beginning

after 8¨C10 years of disease in patients who have not

undergone colectomy. The American Society for

Gastrointestinal Endoscopy recommends that patients with

UC who have pancolitis begin surveillance colonoscopy

after 8 years of disease. Four biopsies should be obtained

every 10 cm from the cecum to the rectum. Suspicious

lesions or masses should be biopsied. Colonoscopy should

be repeated every 1¨C3 years. Colectomy is indicated if

carcinoma, high-grade dysplasia, or dysplasia with lesions

or a mass is found on surveillance.

Inflammatory Bowel Disease

Complications of CD

Crohn¡¯s disease is associated with both local,

extraintestinal, and malabsorption complications. Local

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Abbreviations

increased relative risk of colon cancer in CD, the absolute

number of patients at risk is relatively small because many

patients with extensive colitis undergo colectomy early in

the course of disease. Surveillance guidelines are similar for

CD and UC. The American Gastroenterological Association

concluded that the risk of colorectal cancer associated with

UC and Crohn¡¯s colitis is similar for comparable extent,

duration, and age of onset of inflammatory disease. As a

result, the surveillance strategy previously discussed for UC

also applies for Crohn¡¯s colitis. The American College of

Gastroenterology recognizes the evidence of the

carcinogenic potential of long-standing CD but does not

provide specific guidelines for surveillance. The American

Society for Gastrointestinal Endoscopy also recognizes that

the risk of colorectal cancer is increased in Crohn¡¯s colitis.

Surveillance colonoscopy and biopsy for dysplasia should

be offered to patients with longstanding Crohn¡¯s colitis.

complications include intestinal obstruction, severe

hemorrhage, acute perforation, the development of fistulae

and abscesses and toxic megacolon. Patients with CD may

exhibit extraintestinal manifestations related to

inflammatory bowel disease activity as described in

Table 1-2.

Malabsorption due to CD can have serious consequences,

including weight loss, steatorrhea, calcium oxalate and uric

acid stone formation, and vitamin B12 deficiency. Bile acid

malabsorption can occur in patients with distal ileal CD or

who have had surgical resection of the distal ileum. Milder

degrees of bile acid malabsorption may result in watery

diarrhea, but more profound degrees of bile acid

malabsorption impair micelle formation for fat absorption

and can lead to development of steatorrhea. In addition, bile

acid malabsorption often results in formation of gallstones

because of build up of biliary sludge.

Steatorrhea can lead to severe malnutrition, clotting

abnormalities,

osteomalacia,

osteoporosis,

and

hypocalcemia. Diarrhea and fat malabsorption due to

steatorrhea may ultimately lead to weight loss and a

decrease in absorption of key nutrients, such as fat-soluble

vitamins. Calcium abnormalities lead to clotting disorders,

osteomalacia, and osteoporosis. Primary bone density loss is

related to corticosteroid use; however, alterations in calcium

absorption also can occur in the setting of steatorrhea.

Steatorrhea increases oxalate absorption and results in

hyperoxaluria and can lead to calcium oxalate and uric acid

kidney stone formation. Free calcium binds to fatty acids in

the intestinal lumen, allowing free oxalate to be absorbed.

Exposure to unabsorbed bile salts increases colonic

permeability to small molecules such as oxalate. Volume

depletion and metabolic acidosis can lead to a reduction in

the urinary excretion of citrate, a process that normally

inhibits oxalate stone formation. Dehydration and acidosis

also increases uric acid kidney stone formation because

acidic urine decreases uric acid solubility.

Vitamin B12 is absorbed in the distal ileum; consequently,

severe ileal disease or ileal resections can lead to vitamin

B12 malabsorption and deficiency, which may lead to

pernicious anemia. Serum vitamin B12 concentrations

should be monitored in patients with ileal CD or in patients

with a history of ileal resection.

Other nutrients commonly malabsorbed in patients with

CD are folate, zinc, and iron. Folate deficiency may occur

because of a decreased intake or because of treatment with

sulfasalazine, which interferes with folate absorption. In

general, other water-soluble vitamins are rarely deficient in

CD. Zinc deficiency usually is caused by excessive wasting

in diarrhea or by enteric fistulae. Iron deficiency frequently

can be caused by a decreased intake, by rectal bleeding, and

by decreased absorption in the gastrointestinal tract.

Patients with a long history of CD are at increased risk of

colon cancer, and to a lesser extent small bowel cancer. In a

population-based study from Sweden, the relative risk of

colon cancer was 2.5 overall in patients with CD and 5.6 in

those with only colonic disease. The relative risk was even

greater in patients who were younger than 30 years of age at

the time of diagnosis. Similar to UC, risk is related to the

extent and duration of disease. Colorectal cancer in CD is

observed in a similar time frame as that in UC. Despite the

Pharmacotherapy Self-Assessment Program, 5th Edition

Diagnostic Approach and Tools

The clinical presentations of UC and CD are similar to

many other diseases or conditions as listed in Table 1-3.

Infection or adverse drug reactions must be ruled out both at

diagnosis and during symptomatic periods. About 5¨C15% of

patients are initially diagnosed with ¡°indeterminate¡± colitis,

because neither UC nor CD can be definitively diagnosed.

The diagnosis of IBD involves both subjective and

objective parameters. Clinical history, family history, and

patient physical examination often are as important as

radiographic and endoscopic evaluations. A family history

of IBD is associated with an earlier age of diagnosis in

affected patients. Because of differences in treatment

options, UC must be distinguished from Crohn¡¯s colitis.

Ulcerative colitis usually is diagnosed by characteristic

clinical history, endoscopic mucosal findings, and histology

from colonic biopsy. Presence of family history may aid in

Table 1-3. Differential Diagnosis for Ulcerative Colitis

and Crohn¡¯s Disease

Mild disease

Lactose intolerance

Irritable bowel disease

Colonic disease

Radiation colitis

Ischemic colitis

Diverticular colitis

Infectious disease

Salmonella

Shigella

Campylobacter

Aeromonas

Escherichia coli

Clostridium difficile colitis

Cytomegalovirus

Tuberculosis

Amebiasis

Adverse drug reactions

Antibiotic drugs

Nonsteroidal anti-inflammatory drugs

Retinoic acid

Oral contraceptives

Penicillin-induced segmental hemorrhagic colitis

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