Brian A. Hemstreet
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Characterize the pathophysiologic mechanisms underlying inflammatory bowel disease (IBD).
2. Recognize the signs and symptoms of IBD, including major differences between ulcerative colitis (UC) and Crohn’s disease (CD).
3. Identify appropriate therapeutic outcomes for patients with IBD.
4. Describe pharmacologic treatment options for patients with acute or chronic symptoms of UC and CD.
5. Create a patient-specific drug treatment plan based on symptoms, severity, and location of UC or CD.
6. Recommend appropriate monitoring parameters and patient education for selected drug regimens for treatment of IBD.
KEY CONCEPTS
Inflammatory bowel disease (IBD) includes both ulcerative colitis (UC) and Crohn’s disease (CD) and is associated with inflammation of various areas of the GI tract.
Differentiation of UC and CD is based on signs and symptoms as well as characteristic endoscopic findings including the extent, pattern, and depth of inflammation.
Patients may manifest extraintestinal symptoms of IBD, such as arthritis, primary sclerosing cholangitis, erythema nodosum, and pyoderma gangrenosum, among others.
Major treatment goals for patients with IBD include alleviation of signs and symptoms and suppression of inflammation during acute episodes and maintenance of remission thereafter.
When designing a drug regimen for treatment of IBD, several factors should be considered, including the patient’s symptoms, medical history, current medication use, drug allergies, and location and severity of disease.
Antidiarrheal medications that reduce GI motility, such as loperamide, diphenoxylate/atropine, and codeine should be avoided in patients with active IBD due to the risk of precipitating acute colonic dilation (toxic megacolon).
Treatment of acute episodes of UC is dictated by the severity and extent of disease, and first-line therapy of mild to moderate disease involves oral or topical aminosalicylate derivatives.
Maintenance of remission of UC maybe achieved with oral or topical aminosalicylates. Immunosuppressants such as azathioprine, 6-mercaptopurine (6-MP), or infliximab can be used for unresponsive patients or those who develop corticosteroid dependency.
Treatment of active mild to moderate CD involves use of oral or topical aminosalicylate derivatives, whereas moderate to severe disease may require systemic corticosteroid therapy.
Maintenance of remission of CD maybe achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-MP, and methotrexate), or infliximab, adalimumab, certolizumab, or natalizumab.
INTRODUCTION
Inflammatory bowel disease (IBD) encompasses both Crohn’s disease (CD) and ulcerative colitis (UC). Both disorders are associated with inflammation of various regions within the GI tract. Differences exist between UC and CD with regard to the regions of the GI tract that may be affected as well as in the distribution and depth of inflammation. Some patients with IBD may also have inflammation involving organs other than the GI tract, known as extraintestinal manifestations. Symptoms of IBD are associated with significant morbidity, reduction in quality of life, and substantial costs to the health care system. For purposes of this chapter, references made to IBD will include both UC and CD. Significant differences between UC and CD will be discussed separately when applicable.
EPIDEMIOLOGY
IBD is most common in Westernized countries such as the United States. UC affects up to 500,000 people and CD affects up to 480,000 people in the United States.1–5 The age of initial presentation of IBD is bimodal, with patients typically diagnosed between the age ranges of 20 to 40 years or 60 to 80 years.5 The peak incidence of CD occurs in the second and third decades of life, with a smaller peak in the fifth decade.2,5 Peak incidence of UC occurs between the ages of 15 and 25 years.6
Men and women are approximately equally affected by IBD. In general, whites are affected more often than blacks, and persons of Jewish descent also have higher reported incidences of IBD. One of the greatest risk factors for development of IBD is a positive family history of the disease. The incidence of IBD is 10 to 40 times greater in patients with a first-degree relative who has IBD compared to the general population.4,5,7 A positive family history may be more of a contributing factor for development of CD than UC.7–9
ETIOLOGY
The exact cause of IBD is not fully understood. Processes thought to be involved in its development include genetic predisposition, dysregulation of the inflammatory response within the GI tract, or perhaps environmental or antigenic factors.3,4 The fact that a positive family history is a strong predictor of IBD supports the theory that genetic predisposition may be responsible in many cases. Many potential candidate genes have been identified. An example is a gene found on chromosome 16 that encodes for nucleotide oligomerization domain 2 (NOD2). NOD2 is a cytoplasmic protein expressed in macrophages, monocytes, and gut epithelial cells thought to be involved in recognition and degradation of bacterial products by the gut wall. Less is known about genetic alterations that may predispose patients to UC, but UC may share common genetic features with CD.
An alteration in the inflammatory response regulated by intestinal epithelial cells may also contribute to development of IBD. This may involve inappropriate processing of antigens presented to the GI epithelial cells.3,4,10,11 The inflammatory response in IBD may actually be directed at bacteria that normally colonize the GI tract. Products derived from these bacteria may translocate across the mucosal layer of the GI tract and interact with various cells involved in immunologic recognition. The result is T-cell stimulation, excess production of proinflammatory cytokines, and persistent inflammation within the GI tract.
The intestinal mucosa of patients with CD has a preponderance of CD4+ type 1 helper T cells, while patients with UC have more CD4+ lymphocytes with atypical type 2 helper T cells.10 Likewise, drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) that disrupt the integrity of the GI mucosa may facilitate mucosal entry of intestinal antigens and lead to disease flares in patients with IBD.12
The role of antigens derived from dietary intake in the development of IBD is less well defined. There is some speculation that ingestion of large quantities of refined carbohydrates or margarine leads to higher rates of CD. Use of oral contraceptives has been associated with increased development of IBD in some cohort studies, but a strong causal relationship has not been proven.8
Lastly, positive smoking status has been shown to have protective effects in UC, leading to reductions in disease severity. The opposite is true in CD, as smoking may lead to increases in symptoms or worsening of the disease.10
PATHOPHYSIOLOGY
Ulcerative Colitis
The inflammatory response in UC is propagated by atypical type 2 helper T cells that produce proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF).8 As discussed previously, a genetic predisposition to UC may partially explain the development of excessive colonic and rectal inflammation. The finding of positive perinuclear antineutrophil cytoplasmic antibodies (pANCA) in association with the human leukocyte antigen (HLA)-DR2 allele in a large percentage of patients with UC supports this theory.13
The potential role of environmental factors in development of UC implies that the immune response is directed against an unknown antigen. The findings that development and severity of UC are reduced in patients who smoke, or in those with appendectomies, may support the theory that these factors may somehow modify either the genetic component or phenotypic response to immunologic stimuli.12,14
The inflammatory process within the GI tract is limited to the colon and rectum in patients with UC (Fig. 19–1). Most patients with UC have involvement of the rectum (proctitis) or both the rectum and the sigmoid colon (proctosigmoiditis). Inflammation involving the majority of the colon is referred to as pancolitis. Left-sided disease, defined as inflammation extending from the rectum to the splenic flexure, occurs in 30% to 40% of patients.12 A small number of cases of UC involve mild inflammation of the terminal ileum, referred to as “backwash ileitis.”
The pattern of inflammation in UC is continuous and confluent throughout the affected areas of the GI tract. The inflammation is also superficial and does not typically extend below the submucosal layer of the GI tract (Fig. 19–2). Ulceration or erosion of the GI mucosa may be present and varies with disease severity. The formation of crypt abscesses within the mucosal layers of the GI tract is characteristic of UC and may help to distinguish it from CD. Severe inflammation may also result in areas of hypertrophied GI mucosa, which may manifest as pseudopolyps within the colon.13 The inflammatory response may progress in severity, leading to mucosal friability and significant GI bleeding.
FIGURE 19–1. Major Gl landmarks and disease distribution in inflammatory bowel disease.
Crohn’s Disease
As with UC, the immune activation seen in CD involves the release of many proinflammatory cytokines. Cytokines thought to play major roles in CD are derived from T-helper type 1 cells and include interferon-γ, TNF-α, and IL-1, IL-6, and IL-12. TNF-α is a major contributor to the inflammatory process seen in CD. Its physiologic effects include activation of macrophages, procoagulant effects in the vascular endothelium, and increases in production of matrix metalloproteinases in mucosal cells.13,15 Excessive production of both interferon-γ and TNF-α may account for the excessive clinical evidence of granulomatous disease in patients with CD.11 TNF-α is also thought to induce production of nuclear factor κβ, which stimulates further production of TNF-α and other proinflammatory cytokines.3,16
The role of an immune response directed against endogenous bacteria as the initiating factor is more evident in CD, as evidenced by the apparent strong T-helper 1 activation against bacteria seen in animal models of this disease. The role of dietary antigens in the development of CD compared to UC is also another potential initiating factor. Excess ingestion of refined sugars or margarine may be higher in patients who develop CD.8
The distribution of inflammation in CD differs from that seen in UC, as any part of the entire GI tract may be affected in CD. The small intestine is the site most commonly involved. Within the small intestine, the terminal ileum and cecum are almost always affected. Approximately 20% of patients have isolated colonic involvement, whereas inflammation proximal to the small intestine is almost never seen without the presence of small or large intestinal disease.13
FIGURE 19–2. Depth of disease penetration in ulcerative colitis and Crohn’s disease.
In contrast to UC, the pattern of inflammation in CD is described as discontinuous. Areas of inflammation are intermixed with areas of normal GI mucosa, resulting in characteristic “skip lesions.” Superficial aphthous ulcersmay also develop in the GI mucosa. These ulcers may coalesce into larger linear ulcers, resulting in fissure formation as they increase in depth, giving rise to the characteristic “cobblestone” pattern observed upon examination of the mucosa.
Furthermore, the inflammation may be transmural, penetrating to the muscularis or serosal layers of the GI tract (Fig. 19–2). The propensity for transmural involvement may lead to serious complications of CD, such as strictures, fistulae, abscesses, and perforation.13 While rectal inflammation is typically less common in CD than UC, several types of perianal lesions may be observed in patients with CD. These include skin tags, hemorrhoids, fissures, anal ulcers, abscesses, and fistulae.15
CLINICAL PRESENTATION AND DIAGNOSIS
Differentiation between UC and CD is based on signs and symptoms as well as characteristic endoscopic findings, including the extent, pattern, and depth of inflammation (see Clinical Presentation box).
Extraintestinal Manifestations and Complications of IBD
Patients may manifest signs and symptoms of disease in areas outside the GI tract. These extraintestinal manifestations may occur in various body regions.5,13 Painful joint complications associated with IBD include sacroiliitis and ankylosing spondylitis. Ocular involvement with episcleritis, uveitis, or iritis may manifest as blurred vision, eye pain, and photophobia. Associated skin findings include pyoderma gangrenosum (involving papules and vesicles that develop into painful ulcerations) and erythema nodosum (red nodules of varying size typically found on the lower extremities). Nephrolithiasis may also develop at a higher rate in patients with IBD. Oxalate stones are more common in CD, and uric acid-containing stones are more common in UC.13
Clinical Presentation and Diagnosis of IBD
General
• Patients with CD or UC may present with similar symptoms.
• The onset may be insidious and subacute.
• Some patients present with extraintestinal manifestations before Gl symptoms occur.
• In approximately 10% of cases it may not be possible to distinguish between UC and CD. These patients are described as having “indeterminate colitis.”
Symptoms
• Ulcerative colitis: Diarrhea (bloody, watery, or mucopurulent), rectal bleeding, abdominal pain/cramping, weight loss and malnutrition, tenesmus, constipation (with proctitis)
• Crohn’s disease: Diarrhea (less bloody than UC), rectal bleeding (less than UC), abdominal pain/cramping, weight loss and malnutrition (more common than UC), fatigue/malaise
Signs
• Ulcerative colitis: Fever, tachycardia (with severe disease), dehydration, arthritis, hemorrhoids, anal fissures, perirectal abscesses
• Crohn’s disease: Fever, tachycardia (with severe disease), dehydration, arthritis, abdominal mass and tenderness, perianal fissure or fistula
Laboratory Tests
• Ulcerative colitis: Leukocytosis, decreased hematocrit/hemoglobin, elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), guaiac-positive stool, (+) perinuclear antineutrophil cytoplasmic antibodies (pANCA; up to 70% of patients)
• Crohn’s disease: Leukocytosis, decreased hematocrit/hemoglobin, elevated ESR or CRP, guaiac-positive stool, (+) anti-Saccharomyces cerevisiae antibodies (up to 50% of patients), hypoalbuminemia with severe disease
Liver and biliary manifestations of IBD include an increased incidence of gallstone formation in patients with CD and development of sclerosing cholangitis or cholangiocarcinoma in patients with UC. Patients with UC are also at increased risk for development of colorectal cancer. Ongoing inflammation due to active IBD may induce a hypercoagulable state, resulting in higher rates of both arterial and venous thromboembolism. Likewise, inflammation and recurrent blood loss may result in the development of chronic anemia. Patients with IBD also have higher rates of osteopenia, osteoporosis, and fractures, which are most strongly associated with use of corticosteroids.17
A serious complication of UC is toxic megacolon, defined as dilation of the transverse colon of greater than 6 cm (2.4 in.). Patients with toxic megacolon typically manifest systemic signs of severe inflammation such as fever, tachycardia, and abdominal distention.3,13 Surgical intervention, including colonic resection, may be necessary to acutely manage toxic megacolon.
Formation of strictures, abscesses, fistulae, and obstructions in patients with CD is possible. Patients with CD may develop significant weight loss or nutritional deficiencies secondary to malabsorption of nutrients in the small intestine, or as a consequence of multiple small- or large-bowel resections. Common nutritional deficiencies encountered in IBD include vitamin B12 fat-soluble vitamins, zinc, folate, and iron. Malabsorption in children with CD may contribute to significant reductions in growth and development.
Diagnosis
Because patients often present with nonspecific GI symptoms, initial diagnostic evaluation includes methods to characterize the disease and rule out other potential etiologies. This may include stool cultures to examine for infectious causes of diarrhea.
Endoscopic approaches are typically used and may include colonoscopy, proctosigmoidoscopy, or possibly upper GI endoscopy in patients with suspected CD. Endoscopy is useful for determining the disease distribution, pattern and depth of inflammation, and to obtain mucosal biopsy specimens. Supplemental information from imaging procedures, such as CT, abdominal x-ray, abdominal ultrasound, or intestinal barium studies may provide evidence of complications such as obstruction, abscess, perforation, or colonic dilation.3
After the diagnosis is made, the information derived from diagnostic testing and the patient’s medical history and symptoms are used to gauge disease severity. The severity of active UC is generally classified as mild, moderate, severe, or fulminant.1 Mild UC typically involves up to four bloody or watery stools per day without systemic signs of toxicity or elevation of erythrocyte sedimentation rate (ESR). Moderate disease is classified as more than four stools per day with evidence of systemic toxicity. Severe disease is considered more than six stools per day and evidence of anemia, tachycardia, or an elevated ESR or C-reactive protein (CRP). Lastly, fulminant UC may present as more than 10 stools per day with continuous bleeding, signs of systemic toxicity, abdominal distention or tenderness, colonic dilation, or a requirement for blood transfusion.
Patient Encounter 1, Part 1
A 25-year-old Caucasian woman presents to the university student clinic with complaints of intermittent crampy abdominal pain and four to five loose stools per day. She describes some visible mucus and blood in the stool and states that these symptoms have been present for 6 to 8 weeks. She also has intermittent lower back pain, fatigue, fever, and a 4.5-kg (10-lb) weight loss. The back pain started about the same time as her Gl symptoms. She denies any sick contacts and has not eaten any takeout or restaurant food over the last 2 months. She takes nonprescription naproxen as needed for aches and pains. She has been using more naproxen recently because of the back pain. She also takes an oral contraceptive pill once daily. She consumes alcohol socially and currently smokes one-half to one pack of cigarettes per day.
What symptoms are suggestive of IBD in this patient?
Are these symptoms more suggestive ofUC or CD?
What factors may be contributing to her IBD symptoms?
What additional information would you acquire prior to recommending drug therapy?
A similar classification scheme is used to gauge the severity of active CD.2 Patients with mild to moderate CD are typically ambulatory and have no evidence of dehydration; systemic toxicity; loss of body weight; or abdominal tenderness, mass, or obstruction. Moderate to severe disease is considered in patients who fail to respond to treatment for mild to moderate disease, or those with fever, weight loss, abdominal pain or tenderness, vomiting, intestinal obstruction, or significant anemia. Severe to fulminant CD is classified as the presence of persistent symptoms or evidence of systemic toxicity despite outpatient corticosteroid treatment, or presence of cachexia, rebound tenderness, intestinal obstruction, or abscess.
TREATMENT
Desired Outcomes
Pharmacologic interventions for IBD are designed to target the underlying inflammatory response. Treatment goals involve both management of active disease and prevention of disease relapse. Major treatment goals include alleviation of signs and symptoms and suppression of inflammation during acute episodes and maintenance of remission thereafter. Addressing active IBD in a timely and appropriate manner may prevent major complications such as perforation and may reduce the need for hospitalization or surgical intervention. Once control of active disease is obtained, treatment regimens are designed to achieve the following long-term goals: (a) maintenance of remission and prevention of disease relapse; (b) improvement in the patient’s quality of life; (c) prevention of surgical intervention or hospitalization; (d) management of extraintestinal manifestations; (e) prevention of malnutrition; and (f) prevention of treatment-associated adverse effects.
General Approach to Treatment
When designing a drug regimen for treatment of IBD, several factors should be considered, including the patient’s symptoms; medical history; current medication use; drug allergies; and extent, location, and severity of disease.A thorough patient history may also help to identify a family history of IBD or potential exacerbating factors, such as tobacco or NSAID use.
Nonpharmacologic Therapy
No specific dietary restrictions are recommended for patients with IBD, but avoidance of high-residue foods in patients with strictures may help to prevent obstruction. Avoidance of excess fat in the diet may be preferred as well. Nutritional strategies in patients with long-standing IBD may include use of vitamin and mineral supplementation. Administration of vitamin B12 folic acid, fat-soluble vitamins, and iron may be needed to prevent or treat deficiencies. In severe cases, enteral or parenteral nutrition may be needed to achieve adequate caloric intake.
Patients with IBD, particularly those with CD, are also at risk for bone loss. This may be a function of malabsorption or an effect of repeated courses of corticosteroids.17 Risk factors for osteoporosis should be determined, and baseline bone density measurement may be considered.17 Vitamin D and calcium supplementation should be used in all patients receiving long-term corticosteroids. Oral bisphosphonate therapy may also be considered inpatients receiving prolonged courses of corticosteroids or in those with osteopenia or osteoporosis.
Surgical intervention is a potential treatment option in patients with complications such as fistulae or abscesses, or in patients with medically refractory disease. UC is curable with performance of a total colectomy. Patients with UC may opt to have a colectomy to reduce the chance of developing colorectal cancer. Patients with CD may have affected areas of intestine resected. Unfortunately, CD may recur following surgical resection. Repeated surgeries may lead to significant malabsorption of nutrients and drugs consistent with development of short-bowel syndrome.
Pharmacologic Therapy
Several pharmacologic classes are available for the acute treatment and maintenance therapy of IBD. Because there may be differences in the underlying disease process, distribution, and severity between CD and UC, response rates to drugs in the same pharmacologic class may differ between these two diseases. Therefore, initial selection of an appropriate agent for patients with active IBD should be designed to deliver maximum efficacy while minimizing toxicity. Response rates to individual classes of medications for both UC and CD will be discussed within the specific treatment section for each disease.
Symptomatic Interventions
Patients with active IBD often have severe abdominal pain and diarrhea. Medications used to manage these types of symptoms may have adverse consequences in patients with active IBD. Antidiarrheal medications that reduce GI motility, such as loperamide, diphenoxylate/atropine, and codeine should be avoided in patients with active IBD due to the risk of precipitating acute colonic dilation (toxic megacolon).15 Drugs with anticholinergic properties, such as hyoscyamine and dicyclomine, are often used to treat intestinal spasm and pain, but these drugs may also reduce GI motility and should generally be avoided in active IBD.
Patients who have had multiple intestinal resections due to CD may have diarrhea related to the inability to reabsorb bile salts. Cholestyramine has been demonstrated to improve diarrheal symptoms in this population.15 NSAIDs should be avoided for pain management due to their ability to worsen IBD symptoms. Opioid analgesics should be used with caution, as they may significantly reduce GI motility.
Aminosalicylates
The aminosalicylates are among the most commonly used drugs for inducing and maintaining remission in patients with IBD (Table 19–1). These drugs are designed to deliver 5-aminosalicylate (5-ASA, mesalamine) to areas of inflammation within the GI tract. While the mechanism of mesalamine is not fully understood, it appears to have favorable anti-inflammatory effects. The delivery of mesalamine to the affected sites is accomplished by either linking mesalamine to a carrier molecule or altering the formulation to release drug in response to changes in intestinal pH. Topical suppositories and enemas are designed to deliver mesalamine directly to the distal colon and rectum.7,18-21
The prototypical aminosalicylate is sulfasalazine, which is comprised of mesalamine linked by a diazo bond to the carrier molecule sulfapyridine. This linkage prevents premature absorption of mesalamine in the small intestine. Once sulfasalazine is delivered to the colon, bacterial degradation of the diazo bond frees mesalamine from sulfapyridine. Sulfapyridine is then absorbed and excreted renally, while mesalamine acts locally within the GI tract.
Newer mesalamine products utilize nonsulfapyridine methods for drug delivery. Olsalazine uses two mesalamine molecules linked together, while balsalazide uses the inert carrier molecule 4-aminobenzoyl-β-alanine. Both drugs use a diazo bond similar to sulfasalazine. Other mesalamine formulations are pH-dependent formulations that release mesalamine at various points throughout the GI tract. The newest mesalamine products include Lialda, a multimatrix (MMX) formulation with a pH-sensitive coat that releases in the terminal ileum, allowing for once-daily dosing.18 Enteric-coated mesalamine granules that also use a polymer matrix for extended release (Apriso) are also able to be given in a once-daily fashion.
Sulfasalazine is associated with various adverse effects, most of which are thought to be due to the sulfapyridine component. Common adverse effects that may be dose related include headache, dyspepsia, nausea, vomiting, and fatigue.19,21 Idiosyncratic effects include bone marrow suppression, reduction in sperm counts in males, hepatitis, and pulmonitis. Hypersensitivity reactions may occur in patients allergic to sulfonamide-containing medications.
Table 19–1 Aminosalicylates for Treatment of IBD
Table 19–2 Corticosteroids for Treatment of IBD
The use of nonsulfapyridine-based aminosalicylates has led to greater tolerability. Although the adverse effects are similar to those of sulfasalazine, they occur at a much lower rate. Olsalazine, in particular, is associated with a higher incidence of secretory diarrhea. These agents can also be used safely in patients with a reported sulfonamide allergy.
Corticosteroids
Corticosteroids have potent anti-inflammatory properties and are used in active IBD to suppress inflammation rapidly. They may be administered systemically or delivered locally to the site of action by altering the drug formulation (Table 19–2). Because these drugs usually improve symptoms and disease severity rapidly, they should be restricted to short-term management of active disease. Long-term use of systemic corticosteroids is associated with significant adverse effects, including cataracts, skin atrophy, hypertension, hyperglycemia, adrenal suppression, osteoporosis, and increased risk of infection, among others.21–23
Budesonide is a high-potency glucocorticoid used in CD that has low systemic bioavailability when administered orally.24 The formulation releases budesonide in the terminal ileum for treatment of disease involving the ileum or ascending colon. Due to its reduced bioavailability, budesonide may prevent some long-term adverse effects in patients who have steroid-dependent IBD.23,24
Immunosuppressants
Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 19–3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids.23,25 Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.22,23,25 Patients should be tested for activity of thiopurine methyltransferase, the major enzyme responsible for metabolism of azathioprine. Deficiency or reduced activity of thiopurine methyltransferase may result in excess toxicity from azathioprine and 6-MP.
Table 19–3 Immunosuppressant and Biologic Agents for Treatment of IBD
Methotrexate is a folate antagonist used primarily for maintaining remission of CD. It maybe administered orally, subcutaneously, or IV and may result in a steroid-sparing effect in patients with steroid-dependent disease.23,26,27Long-term methotrexate use may result in serious adverse effects, including hepatotoxicity, pulmonary fibrosis, and bone marrow suppression.
Cyclosporine is a cyclic polypeptide immunosuppressant typically used to prevent organ rejection in transplant patients. Its use is restricted to patients with fulminant or refractory symptoms in patients with active IBD. Significant toxicities associated with cyclosporine are nephrotoxicity, risk of infection, seizures, hypertension, and liver function test abnormalities.1,23
Biologic Agents
Several biologic agents targeting TNF-α are used for treatment of IBD (Table 19–3). Reduction in TNF-α activity is associated with improvement in the underlying inflammatory process. Infliximab is the prototypical agent and is used in both UC and CD, whereas the other agents are approved for use only in CD. Due to its chimeric structure (i.e., part human, part mouse) antibodies to infliximab may develop, resulting in loss of efficacy over time. Newer biologic agents are humanized and have a lower propensity for antibody development.28
Disadvantages of anti-TNF biologic therapy include need for parenteral administration, significant drug cost, and potential for serious adverse effects. Adverse effects may include infusion-related reactions such as fever, chest pain, hypotension, and dyspnea. All of the TNF-α inhibitors have also been associated with reactivation of serious infections, particularly intracellular pathogens such as tuberculosis, as well as hepatitis B.16,22 These agents should not be used in patients with current infections, and patients should be screened for tuberculosis prior to initiating therapy. Exacerbation of heart failure is also a potential adverse effect, and biologic agents should be avoided in patients with advanced or decompensated heart failure.16,21,22
Natalizumab is a humanized monoclonal antibody that antagonizes integrin heterodimers, prevents α4-mediated leukocyte adhesion to adhesion molecules, and prevents migration across the endothelium.29 It has been associated with development of progressive multifocal leukoencephalopathy, and its use is restricted to patients with CD who have failed other therapies. Natalizumab should notbe used concomitantly with immunosuppressants or TNF-α inhibitors.
Other Agents
Antibiotics have been studied based on the rationale that they may interrupt the inflammatory response directed against endogenous bacterial flora. Metronidazole and ciprofloxacin have been the two most widely studied agents.30Metronidazole may benefit some patients with pouchitis (inflammation of surgically created intestinal pouches) and patients with CD who have had ileal resection or have perianal fistulas. Ciprofloxacin has shown some efficacy in refractory active CD. Both drugs may cause diarrhea, and long-term use of metronidazole is associated with the development of peripheral neuropathy.
Patient Encounter 1, Part 2: Medical History and Physical Examination
PMH: Tonsillectomy at age 5, fractured right clavicle (sports related)
FH: Both parents alive; father has history of hypertension, type 2 DM, and dyslipidemia; mother has a history of colon cancer with subtotal colectomy; brother with history of “indeterminate colitis”
SH: College student, social alcohol use and one-half to one pack per day tobacco use for 6 years
Allergies: sulfa drugs (rash)
Meds: Naproxen 220 mg orally as needed, Lo-Ovral orally once daily
ROS: (+) Diarrhea, abdominal pain, fatigue, back pain, fever, weight loss
PE:
VS: BP 118/65 mm Hg, P 92 bpm, RR 13/min, T37.9°C (100.2°F)
CV: Tachycardia with normal rhythm. No murmurs, rubs, or gallops
HEENT: Dry mucous membranes
Abd: Soft, nondistended, mild diffuse tenderness, (+) bowel sounds, (-) hepatosplenomegaly, (-) masses, heme (+) stool
MS: Point tenderness over sacral area, (-) erythema, reduced lower back ROM
Labs: Sodium 139 mEq/L (139 mmol/L), potassium 3.2 mEq/L (3.2 mmol/L), chloride 100 mEq/L (100 mmol/L), bicarbonate 27 mEq/L (27 mmol/L), blood urea nitrogen 12 mg/dL (4.3 mmol/L urea), serum creatinine 1.0 mg/dL (88.4 μmol/L), albumin 4.2 g/dL (42 g/L), hemoglobin 11 g/dL (110 g/L or 6.82 mmol/L), hematocrit 33%, white blood cell count 11.0 × 103/mm3 (11 × 109L), platelets 300 × 103mm3(300 × 109L), ESR 120 mm/hour, CRP 12 mg/L
Imaging: Abdominal x-ray: (-) obstruction, perforation, or colonic dilation
Colonoscopy: Patchy “cobblestone” inflammation in the terminal ileum and ascending colon with evidence of recent bleeding, (-) polyps or strictures, biopsy taken
Path: Evidence of disease extension to muscularis with noncaseating granulomas
How is this additional information helpful in determining disease type and severity?
What are your treatment goals for this patient?
What factors should you consider in choosing appropriate therapy for this patient?
Because smoking is associated with reduced symptoms of UC, nicotine has been studied as a potential treatment option. Transdermal nicotine may result in some improvement in mild to moderate UC symptoms and maybe more effective in patients who are ex-smokers.1,31 Daily doses between 15 and 25 mg appear to be most effective.
Probiotics, such as Lactobacillus acidophilus or Bifidobacterium, may offer possible benefit, based on the rationale that modification of the host flora may alter the inflammatory response. Some evidence exists for improvement in disease symptoms, but further well-controlled trials are needed.26
Treatment of UC
Drug and dosing guidelines based on disease severity and location are presented in Table 19–4.
Mild to Moderate Active UC
Treatment of acute episodes of UC is dictated by the severity and extent of disease, and first-line therapy of mild to moderate disease involves oral or topical aminosalicylate derivatives. Topical suppositories and enemas are preferred for active distal UC (left-sided disease and proctitis), as they deliver mesalamine directly to the site of inflammation. Topical mesalamine is superior to both topical corticosteroids and oral aminosalicylates for inducing remission in active mild to moderate UC.1,31-34 Enemas are appropriate for patients with left-sided disease, as the medication will reach the splenic flexure. Suppositories deliver mesalamine up to approximately 20 cm and are most appropriate for treating proctitis.6,7,31
Topical mesalamine products provide a more rapid response than oral preparations. Improvement in symptoms may be seen in as little as 2 days, but up to 4 weeks of treatment may be necessary for maximal response. Oral and topical mesalamine preparations maybe used together to provide maximal effect. Oral mesalamine may also be used for patients who are unwilling to use topical preparations.31,34
Topical corticosteroids are typically reserved for patients who do not respond to topical mesalamine.1,23 Patients should be properly educated regarding appropriate use of topical products. This includes proper administration and adequate retention of topical mesalamine products in order to maximize efficacy.
Table 19–4 Treatment Recommendations for UC
For patients with more extensive disease extending proximal to the splenic flexure, oral sulfasalazine or any of the newer oral mesalamine products is considered first-line therapy.1 Doses should provide 4 to 6 g of sulfasalazine or 4.8 g of mesalamine. While little differences in efficacy exist between mesalamine products, sulfasalazine and olsalazine have a higher incidence of adverse effects.18 Use of the once-daily formulations of mesalamine may improve patient adherence.18,34 Induction of remission may require 4 to 8 weeks of therapy at appropriate treatment doses.
Oral corticosteroids may be used for patients who are unresponsive to sulfasalazine or mesalamine. Prednisone doses of 40 to 60 mg/day (or equivalent) are recommended.1,23 Azathioprine or 6-MP is used for patients unresponsive to corticosteroids or those who become steroid dependent. Infliximab 5 mg/kg may also be used for patients who are unresponsive to conventional oral therapies and may reduce the need for colectomy after 3 months of treatment. Infliximab may also be used in patients who are refractory to or dependent on corticosteroids.35,36
Severe or Fulminant UC
Patients with severe UC symptoms require hospitalization for management of their disease. If the patient is unresponsive to oral or topical mesalamine and oral corticosteroids, then a course of IV corticosteroids should be initiated.1Hydrocortisone 300 mg/day given in three divided doses or methylprednisolone 60 mg daily for 7 to 10 days are the preferred therapies.23
Infliximab 5 mg/kg is also an option for severe UC. Cyclosporine 2 to 4 mg/kg/day given as a continuous IV infusion should be reserved for patients unresponsive to 7 to 10 days of IV corticosteroid therapy.
Patients with fulminant disease are treated similarly, although infliximab is not indicated for this population. Patients with fulminant UC should be assessed for signs of significant systemic toxicity or colonic dilation, which may require earlier surgical intervention.
Maintenance of Remission
Unfortunately, up to 50% of patients receiving oral therapies and up to 70% of untreated patients relapse within 1 year after achieving remission.26 For this reason, patients may require maintenance drug therapy indefinitely to preserve remission.
Maintenance of remission of UC may be achieved with oral or topical aminosalicylates. In patients with proctitis, mesalamine suppositories 1 g daily may prevent relapse in up to 90% of patients.1,7,31Mesalamine enemas are appropriate for left-sided disease and may often be dosed two to three times weekly. Oral mesalamine at lower doses (e.g., 1.2 to 1.6 g/day) maybe combined with topical therapies to maintain remission. Topical or oral corticosteroids are not effective for maintaining remission of distal UC and should be avoided.
Oral sulfasalazine or mesalamine is effective in maintaining remission in patients with more extensive disease.1,26 Lower daily doses (e.g., 2 to 4 g sulfasalazine or 1.6 to 2.4 g mesalamine) may be used for disease maintenance. As with distal UC, oral corticosteroids are not effective for maintaining remission and should be avoided due to the high incidence of adverse effects.
Immunosuppressants such as azathioprine or 6-MP can be used for unresponsive patients or those who develop corticosteroid dependency. Remission may be maintained in up to 58% of patients after 5 years of treatment.1,25Intermittent infliximab dosing (5 mg/kg IV every 8 weeks) may be used to maintain disease remission and reduce the need for corticosteroids in patients with moderate to severe UC. Colectomy is an option for patients with progressive disease who cannot be maintained on drug therapy alone.
Treatment of CD
Drug and dosing guidelines based on disease severity and location are presented in Table 19–5.
Mild to Moderate Active CD
Induction of remission of mild to moderate active CD may be accomplished with oral aminosalicylates or budesonide. Sulfasalazine 4 to 6 g/day is most effective for patients with active colonic or ileocolonic involvement, with response rates of approximately 50%.2,5,37 Mesalamine products have shown more variable results but may be used for patients with ileal, ileocolonic, or colonic CD.2,37 These drugs are typically better tolerated than sulfasalazine at full treatment doses. Induction of remission may require up to 16 weeks of treatment at full doses.37
Budesonide 9 mg orally once daily for up to 8 weeks may be used for mild to moderate active CD in patients with involvement of the terminal ileum or ascending colon, with success expected in 50% to 69% of patients.23,24,37Because the formulation releases budesonide in the terminal ileum, it is not effective in reaching sites distal to the ascending colon.24,37 Conventional oral corticosteroids such as prednisone and methylprednisolone may be used for patients who are unresponsive to aminosalicylates or budesonide.
Patient Encounter 2
A 57-year-old African American man presents to the clinic for follow-up management of UC. He has had left-sided disease for 3 years and has been maintained in remission on maximal doses of oral mesalamine and prednisone 35 mg orally once daily. His provider has attempted several times to taper the prednisone dose, but the patient experiences a reappearance of symptoms if the dose is lowered below this level. Medical history is also significant for hypertension and heart failure. He has no known drug allergies.
What are the risks of long-term corticosteroid use in this patient?
What treatment options are available for reducing corticosteroid dependency in this patient?
What other information is needed before recommending a pharmacologic intervention?
Table 19–5 Treatment Recommendations for CD
Metronidazole or ciprofloxacin can be used in patients who do not respond to oral aminosalicylates. Response rates of up to 50% are reported, but data are conflicting, and these agents should generally not be considered first-line therapy.2,37
Moderate to Severe Active CD
Patients with moderate to severe active CD may be treated with oral corticosteroids, such as prednisone 40 to 60 mg daily.2 Budesonide 9 mg orally once daily may be used for moderate active CD involving the terminal ileum or ascending colon.
Infliximab is an effective alternative to corticosteroid therapy for patients with moderate to severe CD, including patients with fistulizing or perianal disease.14,24,37 The recommended regimen for induction of remission is infliximab 5 mg/kg at weeks 0, 2, and 6; it is effective in inducing remission in approximately 80% of patients at 8 weeks. Complete closure of existing enterocutaneous fistulae occurs in approximately 50% of patients.
Adalimumab is effective in moderate to severe active CD and is used preferably in patients with diminished response to infliximab. The approved adult dose of 160 mg on day 1, 80 mg at 2 weeks, and 40 mg at day 29 resulted in a remission rate of 36% at 4 weeks.16,38
Certolizumab is also effective, with a dose of 400 mg subcutaneously initially, and then at 2 and 4 weeks resulting in a clinical response rate of 37% at 6 weeks.16,38 Natalizumab 300 mg IV every 4 weeks has been reported to induce remission in up to 37% of patients at 10 weeks, which was similar to placebo.16,38
For patients with simple perianal fistulae, antibiotics, infliximab, or adalimumab are appropriate treatment options. Complex perianal fistulae are those associated with multiple openings, abscess, stricture, or penetration into the vaginal wall. These types of perianal fistulae may require surgical intervention but may also be amenable to treatment with antibiotics, infliximab, azathioprine, or 6-MP.2,15,16,23
Severe to Fulminant Active CD
Most patients with severe to fulminant CD require hospitalization for appropriate treatment. Patients should be assessed for possible surgical intervention if abdominal distention, masses, abscess, or obstruction are present. Daily IV doses of corticosteroids equivalent to prednisone 40 to 60 mg are recommended as initial therapy to rapidly suppress severe inflammation.
If there are no contraindications, infliximab 5 mg/kg followed by 5 mg/kg at weeks 2 and 6 may be used for severe active CD. There is no evidence that infliximab is either safe or effective for fulminant disease. Adalimumab or certolizumab are also options for patients with severe CD, particularly those who have lost response to infliximab or those who are nonresponsive to traditional therapies. Natalizumab can be used for severe CD but is reserved for patients failing other available therapies, including TNF-α inhibitors.
Adjunctive therapy with fluid and electrolyte replacement should be initiated. Nutritional support with enteral or parenteral nutrition may be indicated for patients unable to eat for more than 5 to 7 days.2Some evidence suggests that enteral nutrition provides anti-inflammatory effects in patients with active CD.39,40
Limited evidence indicates that cyclosporine, or possibly tacrolimus, may be effective as salvage therapy for patients who fail IV corticosteroid therapy.2,23 Surgical intervention may ultimately be necessary for medically refractory disease.
Maintenance of Remission in CD
Patients with CD are at high risk for disease relapse after induction of remission. Within 2 years, up to 80% of patients suffer a relapse; therefore, most patients should be evaluated for indefinite maintenance therapy. Maintenance of remission of CD may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-MP, and methotrexate), or infliximab, adalimumab, certolizumab, or natalizumab.
In contrast to their use in UC, sulfasalazine and the newer aminosalicylates are marginally effective in preventing CD relapse in patients with medically induced remission, with success rates of only 10% to 20% at 1 year.26Nevertheless, aminosalicylates are routinely used to maintain remission of CD. Some evidence does exist that the aminosalicylates may prevent or delay disease recurrence in patients with surgically induced remisson.2,26
Several other treatment options exist for maintaining remission that may also reduce the need for corticosteroids. Infliximab has been shown to maintain remission in 46% of patients compared to 23% of those treated with placebo over a 54-week period.15,23,38 Adalimumab 40 mg subcutaneously given every other week has been shown to maintain remission in up to 36% of patients at 56 weeks of treatment.15,38Certolizumab 400 mg IV every 4 weeks has also been effective in maintaining remission in up to 61% of patients at 26 weeks.15,38 Patients with a baseline CRP of greater than 10 mg/L may have a more favorable response. Natalizumab may also be used for maintenance in patients unresponsive to anti-TNF-α agents. Up to 40% of patients may maintain remission at 15 months.15,38
Azathioprine and 6-MP in oral doses up to 2.5 mg/kg/day have been shown to maintain remission in 45% of patients for up to 5 years.2,23,25,26 These drugs may be used to prevent disease recurrence after surgically induced remission. Methotrexate in doses ranging from 12.5 to 25 mg/week given orally, intramuscularly, or subcutaneously has resulted in remission rates of up to 52% at 3 years.26,27
Corticosteroids, while effective for inducing remission rapidly, are not effective for maintenance therapy and are associated with significant adverse effects with long-term use. Therefore, systemic or topical corticosteroids should not be used for maintaining remission in patients with IBD. Unfortunately up to 50% of patients treated acutely with corticosteroids become dependent on them to prevent symptoms.2
In place of conventional corticosteroids, budesonide 6 mg orally once daily may be used for up to 3 months after remission induction for mild to moderate CD.
Treatment of IBD in Special Populations (Table 19–6)
Elderly Patients
Approximately 8% to 20% of patients with UC and 7% to 26% of patients with CD are elderly at initial diagnosis.41 In general, IBD presents similarly in elderly patients compared to younger individuals. Elderly patients may have more comorbid diseases, some of which may make the diagnosis of IBD more difficult. Such conditions include ischemic colitis, diverticular disease, and microscopic colitis. Increased age is also associated with a higher incidence of adenomatous polyps, but the onset of IBD at an advanced age does not appear to increase the risk of developing colorectal cancer. Elderly patients may also use more medications, particularly NSAIDs, which may induce or exacerbate colitis.
Treatment of elderly patients with IBD is similar to that for younger patients, but special consideration should be given to some of the medications used. Corticosteroids may worsen diabetes, hypertension, heart failure, or osteoporosis. The TNF-α inhibitors should be used cautiously in patients with heart failure and should be avoided in New York Heart Association Class III or IV disease. Lastly, elderly patients requiring major surgical interventions may be at higher risk for surgical complications or may not meet eligibility criteria for surgery because of comorbid conditions, age-related organ dysfunction, or reduced functional status.
Children and Adolescents
CD occurs in approximately 4.56 per 100,000 pediatric patients, and UC occurs in about 2.14 cases per 100,000.42 A major issue in children with IBD is the risk of growth failure secondary to inadequate nutritional intake. Failure to thrive may be an initial presentation of IBD in this population. Aggressive nutritional interventions may be required to facilitate adequate caloric intake. Chronic corticosteroid therapy may also be associated with reductions in growth and bone demineralization. Exploration of using lower doses in patients who are corticosteroid dependent may result in fewer problems with altered height velocity.43
Table 19–6 Dosing Considerations of IBD Therapies in Special Populations
The aminosalicylates, azathioprine, 6-MP, and infliximab are all viable options for treatment and maintenance of IBD in pediatric patients. Use of immunosuppressive therapy or infliximab may help reduce overall corticosteroid exposure. Adalimumab is approved for use in patients age 4 years or greater with juvenile rheumatoid arthritis. Limited recent information suggests that adalimumab may be effective in pediatric patients with CD.44–46 Certolizumab and natalizumab have only recently been approved for use in adult patients with IBD; therefore, data in children are limited.47
Pregnant Women
Inducing and maintaining remission of IBD prior to conception is the optimal approach in women planning to become pregnant. Active IBD may result in prematurity and low birth weight. Thus, pregnant women with IBD should be monitored closely, particularly during the third trimester.48–50
Patients do not need to discontinue drug therapy for IBD once they become pregnant, but certain adjustments may be required.48–50 The aminosalicylates are considered safe to use in pregnancy, but sulfasalazine is associated with folate malabsorption. Because pregnancy results in a higher folate requirement, pregnant patients treated with sulfasalazine should be supplemented with folic acid 1 mg orally twice daily.48
As with nonpregnant patients, corticosteroids may be used for treatment of active disease but not for maintenance of remission. Generally, corticosteroids confer no additional risk on the mother or fetus and are generally well tolerated. Both azathioprine and 6-MP have been used successfully in pregnant patients and appear to carry minimal risk, despite carrying an FDA pregnancy category D rating.49 Infliximab, adalimumab, and certolizumab are all FDA category B drugs and appear to carry minimal risk in pregnant patients.50 Little is known about excretion of these drugs in breast milk, so benefit versus risk should be considered if they are used during nursing. Natalizumab is a pregnancy category C drug and should be used only when other therapies have been exhausted.
Methotrexate is a known abortifacient and carries an FDA category X pregnancy rating. Thus, it is contraindicated during pregnancy. Metronidazole carries a theoretical risk of mutagenicity in humans, but short courses are safe during pregnancy. Prolonged use of metronidazole should be avoided in pregnant patients due to lack of safety data supporting its use.48 Ciprofloxacin should be avoided in pregnant women. First-trimester use of the antidiarrheal diphenoxylate has been associated with fetal malformations and should be avoided.
OUTCOME EVALUATION
• Monitor for improvement of symptoms in patients with active IBD, such as reduction in the number of daily stools, abdominal pain, fever, and heart rate.
• For patients in remission, assure that proper maintenance doses of medications are used and educate the patient to seek medical attention if symptoms recur or worsen.
• Evaluate patients receiving systemic corticosteroid therapy for improvement in symptoms and opportunities to taper or discontinue corticosteroid therapy. For patients using more than 5 mg daily of prednisone for more than 2 months or for steroid-dependent patients consider the following:
• Central bone mineral density testing to evaluate the need for preventive or therapeutic bisphosphonate therapy;
• Periodic monitoring of blood glucose, lipids, and blood pressure;
• Evaluation for evidence of cushingoid features or signs or symptoms of infection.
• When considering treatment with azathioprine or 6-MP, obtain baseline CBC, liver function tests, and TPMT activity. These tests should be monitored closely (every 2–4 weeks) at the start of therapy and then approximately every 3 months during maintenance therapy.
• With azathioprine and 6-MP, monitor for hypersensitivity reactions, including severe skin rashes and pancreatitis. Educate the patient regarding signs and symptoms of pancreatitis (nausea, vomiting, and abdominal pain).
Patient Care and Monitoring
1. Evaluate the patient’s symptoms to determine if they are consistent with UC or CD. Determine whether the patient has evidence of extraintestinal manifestations or Gl complications related to IBD. Identify any psychosocial problems related to the presence of IBD.
2. If the patient is presenting with an exacerbation of preexisting IBD, determine if the symptoms are similar in type and severity to the patient’s previous episodes.
3. Assess the patient’s medical history for pertinent drug allergies, tobacco use, and current prescription and nonprescription drug therapies. Determine if any of the medications could exacerbate IBD. If applicable, inquire about adherence or recent changes to the patient’s current IBD drug regimen.
4. Use available diagnostic laboratory, endoscopic, and imaging data to gauge the extent and severity of the patient’s disease.
5. Construct a drug treatment plan based on the disease severity and location. Identify potential contraindications or financial barriers to drug therapy. Inquire if the patient has an aversion to or inability to properly use certain drug formulations that you may wish to recommend, such as topical (rectal) products.
6. Assess whether the patient will require maintenance therapy after remission induction. If so, identify the treatment duration. Decide when the patient should receive follow-up care.
7. Outline parameters to evaluate the efficacy and toxicity of the drug regimen you are recommending. Determine whether the patient will need preventive drug therapy or diagnostic testing to prevent or screen for potential drug-related toxicities.
8. Educate the patient on proper use of drug therapy, including when to expect symptom improvement after initiation of treatment and which signs or symptoms to report that might be related to adverse drug effects.
9. Provide patient education on the proper use of aminosalicylate medications and assess regularly for adherence. Include the following:
• Proper use of suppositories and enemas
• The appropriate number of tablets or capsules to take per day. Reinforce that tablets and capsules are delayed-release and should not be crushed, opened, or chewed.
• Appropriate dose titration, particularly with oral sulfasalazine
• The time frame the patient can expect improvement based on drug dose and disease severity
• Signs or symptoms of potential adverse effects
10. Once remission is achieved, evaluate the patient’s drug regimen to determine if dose reductions or changes in frequency of administration are required. Reinforce the need for adherence to drug therapy in order to maximize effectiveness.
11. Educate patients about their disease state. Refer patients to available support groups or IBD organizational resources if they are having difficulty in coping with their disease.
• Prior to initiating methotrexate therapy, obtain complete blood count, serum creatinine, liver function tests, chest x-ray, and pregnancy test (if female). Monitor blood counts weekly for 1 month, then monthly thereafter.
• Prior to initiating infliximab, adalimumab, or certolizumab obtain a tuberculin skin test to rule out latent tuberculosis. Also monitor patients with a prior history of hepatitis B virus infection for signs of liver disease, such as jaundice. Assure that patients do not have a clinically significant systemic infection or New York Heart Association Class III or IV heart failure.
• In patients receiving infliximab, monitor for infusion-related reactions such as hypotension, dyspnea, fever, chills, or chest pain when administering IV doses.
• In patients with fistulae, monitor at every infliximab, adalimumab, or certolizumab dosing interval for evidence of fistula closure and overall reduction in the number of fistulae.
• Obtain a magnetic resonance imaging procedure prior to initiation of natalizumab therapy. Monitor patients for signs of progressive multifocal leukoencephalopathy, such as mental status changes, signs of liver disease (e.g., jaundice), and hypersensitivity reactions following administration.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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