Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

21. Inflammatory Bowel Disease

Brian A. Hemstreet


KEY CONCEPTS

 Images The exact cause of inflammatory bowel disease (IBD) is unknown. Proposed causes include infectious, genetic, and environmental factors, as well as immune dysregulation.

 Images Ulcerative colitis (UC) is confined to the rectum and colon, causes continuous lesions, and affects primarily the mucosa and the submucosa. Crohn’s disease (CD) can involve any part of the GI tract, often causes discontinuous (skip) lesions, and is a transmural process that can result in fistulas, perforations, or strictures.

 Images Common GI complications of IBD include rectal fissures, fistulas (CD), perirectal abscess (UC), toxic megacolon (UC), and colon cancer. Extraintestinal manifestations include hepatobiliary complications, arthritis, uveitis, skin lesions (including erythema nodosum and pyoderma gangrenosum), osteoporosis, anemia, and aphthous ulcerations of the mouth.

 Images The severity of UC may be assessed by stool frequency, presence of blood in stool, fever, pulse, hemoglobin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), abdominal tenderness, and radiologic or endoscopic findings. The severity of CD can be assessed using similar parameters, in addition to the CD Activity Index, which includes stool frequency, presence of blood in stool, endoscopic appearance, and physician’s global assessment.

 Images The goals of IBD treatment are resolution of acute inflammation and complications, alleviation of systemic manifestations, and maintenance of remission.

 Images The first line of treatment for mild to moderate extensive UC consists of oral aminosalicylates with oral controlled release budesonide as an alternative. Mesalamine or steroid enemas or suppositories may be used for distal disease. Mesalamine is less effective for CD; however, certain delayed-release oral formulations of mesalamine may be used for Crohn’s ileitis. Controlled-release budesonide is preferred as a first-line agent for CD confined to the terminal ileum and/or ascending colon.

 Images Systemic corticosteroids are often required for acute UC or CD. The duration of steroid use should be minimized and the dose tapered gradually over 3 to 4 weeks.

 Images Infliximab or adalimumab is a treatment option for patients with moderate to severe active UC and for those patients with UC who are corticosteroid dependent. Azathioprine or mercaptopurine may be used for maintenance of remission as an alternative to or in combination with infliximab for patients with UC who have failed aminosalicylates and for patients who are corticosteroid dependent.

 Images IV continuous infusion of cyclosporine may be effective in treating severe colitis that is refractory to corticosteroids as an option to delay or prevent the need for surgery.

 Images Aminosalicylates can prevent recurrence of acute UC in many patients, while steroids are ineffective for this purpose.

 Images Other treatments for CD include infliximab, adalimumab, and certolizumab (for moderate to severe or fistulizing disease as both induction and maintenance therapies); methotrexate, azathioprine, or mercaptopurine (for inadequate response or to reduce steroid dosage and in combination with infliximab); metronidazole (for perineal or colonic disease); natalizumab (for patients failing tumor necrosis factor-α [TNF-α] antagonists); and cyclosporine (for refractory disease).


There are two forms of idiopathic inflammatory bowel disease (IBD): (a) ulcerative colitis (UC), a mucosal inflammatory condition confined to the rectum and colon, and (b) Crohn’s disease (CD), a transmural inflammation of the GI tract that can affect any part, from the mouth to the anus.

EPIDEMIOLOGY

IBD is most prevalent in Western countries and in areas of northern latitude.1 Rates of IBD are highest in North America, Northern Europe, and Great Britain.1,2 The incidence of IBD is increasing worldwide.2,3 CD has an incidence of 0.03 to 15.5 cases per 100,000 persons per year and a prevalence of 3.6 to 214 per 100,000 people per year.1,2 The incidence of UC ranges from 1.2 to 20 cases per 100,000 persons per year with a prevalence of 7.6 to 246 per 100,000 persons per year.1 Although most epidemiologic studies combine ulcerative proctitis with UC, 17% to 49% of cases are classified as proctitis.

Both sexes are affected somewhat equally with IBD, although 20% to 30% more women are affected with CD and slightly more males (60%) are affected with UC.2 Both UC and CD have bimodal distributions in age of initial presentation. The peak incidence occurs in the second (CD) or third (UC) decade of life, with a second peak occurring between 60 and 70 years of age.13 A higher incidence of IBD occurs in the Jewish population, while black and Asian populations have a relatively similar, and possibly lower, incidence of IBD.2

ETIOLOGY

Images The exact etiology of UC and CD is unknown; however, there are similar factors believed responsible for both conditions. The major theories behind the cause of IBD involve a combination of infectious, genetic, environmental, and immunologic factors. This may involve abnormal regulation of the innate immune response or a reaction to various antigens.46 The microflora of the GI tract may provide an environmental trigger to activate inflammation and are highly implicated in the development of IBD.5,6

Infectious Factors

Microorganisms are proposed to be a major factor in the initiation of inflammation in IBD. In general, there is thought to be shift toward the presence of more proinflammatory bacteria in the GI tract.4However, no one definitive infectious cause of IBD has been found. Patients with IBD have an increased density of intestinal microbiotica compared with those without IBD, including increased numbers of mucus, mucosal, and intraepithelial bacteria.1,4 The development and composition of the intestinal microbiotica may be influenced by dietary factors.5 The pathogenesis of IBD may involve a loss of tolerance toward normal GI bacterial flora.1 Other supporting evidence for an infectious etiology are that colitis does not appear to occur in genetically altered germ-free animals, intestinal lesions in IBD predominate in areas of highest bacterial exposure, and differences are observed in the makeup of the resident luminal and mucosal bacterial flora in healthy subjects versus those with IBD.7,8

Microorganisms may play a key role in the development of IBD. Suspect infectious agents include viruses, protozoans, mycobacteria such as Mycobacterium paratuberculosis or avium, and other bacteria such as Ruminococcus gnavusRuminococcus torquesListeria monocytogenesChlamydia trachomatis, and Escherichia coli.49 Patients with CD typically have circulating antibodies to Saccharomyces cerevisiae, which demonstrates some immunologic response to intestinal organisms.4 Bacterial gene products may promote alteration of the intestinal barrier while bacterial antigens or ligands may include and propagate the inflammatory response.4,5,10

Genetic Factors

Genetic factors play a significant role in the predisposition to IBD. Studies of monozygotic twins demonstrate a high concordance rate of IBD in both individuals (particularly CD).1,11 First-degree relatives of patients with IBD may have up to a 20-fold increase in the risk of disease.4 Several genetic markers and loci have been identified that occur more frequently in patients with IBD. Genes may not act independently, but rather function in an integrated manner. This is referred to as the “limited pathway model.”4 The nucleotide-binding oligomerization domain protein 2 (NOD2), a key component involved in pathogen recognition in the innate immune system, is the major contributor of genetic predisposition to CD.11,12 Other genes involved in the innate immune system autophagy, such as ATG16L1 and IRGM, as well as genes involved in the interleukin (IL) biologic pathway such as polymorphisms of the IL-23 receptor IL-23R, and IL-12B, STAT3, and CCR6, are strongly associated with CD and possibly UC (IL23R).1,1113 The major genetic region for UC is on chromosome 6p21, in the major histocompatibility region, near human leukocyte antigen (HLA) class II genes.11 Alterations in the genes encoding for IL-10 and the IL-10 receptor have been implicated in UC.11,13 Other possible high-risk loci involved in epithelial barrier function such as ECM1, HNF4A, CDH1, and LAMB1, and Th1 and Th17, involved with helper T-cell types, are implicated in the pathophysiology of UC.1

Immunologic Mechanisms

The immune system plays a critical role in the pathogenesis of IBD. Potential immunologic mechanisms include both autoimmune and nonautoimmune phenomena. The innate immune system largely involves the intestinal wall epithelial barrier and its associated secretions in response to contact with organisms.4 NOD proteins (for recognition of organisms) and toll-like membrane receptors (TLRs) are involved in intestinal surveillance and can lead to release of antibacterial peptides such as defensins, among other functions.4 Reduction in defensin secretion by Paneth cells is thought to be one contributing factor in the loss of effective barrier function.4,10 Consequently, the bowel wall in CD is infiltrated with lymphocytes, plasma cells, mast cells, macrophages, and neutrophils, often leading to formation of granulomas. Similar infiltration has been observed in the colonic mucosal layer in patients with UC. Given that inflammation is limited to the colon in UC, dysfunction of colonocytes is highly implicated.1The colonic mucosal layer in UC may be thinner and less effective in protecting the epithelial cells. This may be due to reduced mucin secretion secondary to defective goblet cell differentiation.4,10,17Autoimmune features may be directed against mucosal epithelial cells or against neutrophil cytoplasmic elements.

Antineutrophil cytoplasmic antibodies are found in a high percentage of patients with UC (70%) and less frequently in CD.6,14 Circulating antibodies to goblet cells and anti-tropomysin are present in UC, although their contribution to the disease process is not fully elucidated.10 Overproduction of circulating IgG1 antibodies in UC may react with epithelium in the eyes, skin, joints, and biliary tract.1Dysfunction or reduced expression of the peroxisome proliferator–activated receptor γ in colonocytes may play a role in this process.1

Dysregulation of cytokines is a key component of IBD. Specifically, Th1 cytokine activity is excessive in CD and increased expression of interferon-γ in the intestinal mucosa and production of IL-12 production are features of the immune response in CD.6,10 In contrast, Th2 cytokine activity is excessive with UC.1,14,15 This is mediated by excess production of IL-13, which contributes to epithelial cell dysfunction by enhancing natural killer T-cell cytotoxicity, and IL-5, which is involved with eosinophil recruitment and activation.1,10,14 Upregulation of the IL-13 receptor-2α occurs as well.1,10,14,15 Activated epithelial cells secrete a variety of substances involved in the recruitment of inflammatory cells. These include IL1β, epithelial neutrophil-activating peptide 78, IL-8, and monocyte chemoattractant protein 1.1Neutrophils produce proteolytic enzymes, such as matrix metalloproteinase-8 and neutrophil elastase, which further contribute to epithelial damage.14

Lastly, tumor necrosis factor-α (TNF-α) is a pivotal proinflammatory cytokine that is increased in the mucosa and intestinal lumen of patients with CD and UC. TNF-α can recruit inflammatory cells to inflamed tissues, activate coagulation, promote the formation of granulomas in patients with CD, and possibly modify epithelial cell apoptosis.1,14,15

Psychological Factors

Mental health changes, particularly stress, appear to possibly correlate with disease flares in IBD, but whether psychological factors are true etiologic factors in the pathophysiologic process is unclear.1618Given the complex nature of the disease process and lack of standard measurement processes, documenting the effects of stress in IBD is difficult.17 Some studies demonstrate that perceived stress and negative mood is significantly different between patients in remission and those experiencing a disease flare.17,18 Mood-related components, such as anxiety and depression, may contribute to exacerbations of CD.19 Approximately 50% of patients with IBD reported some type of significant stress during any 3-month period.20 Additionally, subjects with IBD matched by sex, age, and geographic region to control subjects reported significantly worse psychological well-being and more distress compared with controls.21 Stress-related interventions in another study did not appear to alter disease course for patients with IBD, but may result in improved quality of life (QOL).22 While stress and psychological factors may not be a direct cause of IBD, they may significantly affect QOL. This is compounded by the fact that many patients are young at the time of diagnosis, and may require surgical intervention and temporary or permanent ostomy placement.23

Lifestyle, Dietary, and Drug-Related Causes

Several theories regarding dietary influence on the development of IBD have been proposed. Intake of refined sugars has been associated with development of CD, while increased protein intake has been associated with a higher risk of developing IBD.13 Diet composition may directly influence the makeup of the gut microbiotica, possibly triggering IBD.24,25 The “hygiene hypothesis” proposes that cleaner conditions in more industrialized countries expose patients to fewer microorganisms at an early age. The immune response to these organisms is altered when encountered later in life.13,25 Diets low in fruits and vegetables and high in ω-6 polyunsaturated fats have been suggested to increase the risk of CD.24 Changes in expression of the aryl hydrocarbon receptor, a transcription factor activated by dietary ligands and involved in the maintenance of the innate immune response, may increase development of IBD.26

Smoking plays an important but contrasting role in UC and CD. It appears to be protective for UC and is associated with fewer disease flare-ups and reduced disease severity. The risk of developing UC is increased for 2 to 3 years after smoking cessation in patients without IBD.24 In contrast, smoking is associated with increased frequency and severity of CD, and appears to worsen ileal disease more than colonic.24 Patients with CD who stop smoking have a disease severity that is similar to nonsmokers. Smoking cessation should be offered to all patients. There are data to support transdermal nicotine replacement as an adjunctive therapy in UC.27

Use of nonsteroidal antiinflammatory drugs (NSAIDs) may trigger disease occurrence or lead to disease flares.24,28,29 Inhibition of prostaglandin production through cyclooxygenase inhibition may impair mucosal barrier protective mechanisms. Alteration in platelet function, release of inflammatory mediators, and alteration in the microvascular response to stress are other potential mechanisms of worsening of IBD. Cyclooxygenase-2 inhibitors and cyclooxygenase-1 inhibitors increase risk; however, it is unclear whether cyclooxygenase-2 inhibitors may be safer in select patients with IBD.2 A large cohort study in U.S. women revealed an increase in risk of developing IBD with NSAID use; however, no association was found with use of aspirin.28 Use of NSAIDs may be warranted in some patients with IBD, particularly those with arthritic symptoms, if the benefit outweighs the potential risk of disease flare.

An association with development of IBD following use of antibiotics has been found, but a direct causal relationship remains unclear.24,29 Since antibiotics alter the intestinal flora, this appears to be a viable mechanism; however, delineating antibiotics as a causative factor is difficult given that symptoms may not manifest for several weeks to years following a treatment course. Furthermore, antibiotics may induce Clostridium difficile infection, which is a cause of colitis.24,29 Patients presenting with severe diarrhea for whom a diagnosis of IBD is being entertained should be asked about recent antibiotic use.

Oral contraceptives and isotretinoin have been implicated in the development of IBD as well.25,30

PATHOPHYSIOLOGY

UC and CD differ in two general respects: the extent and distribution of inflammation within the GI tract and depth of involvement within the bowel wall. A small fraction of patients have features of both diseases. Confusion can occur, particularly when the inflammation is limited to the colon. For patients in whom it cannot be determined whether they have UC or CD, they are often classified as indeterminate colitis.1 Table 21-1 compares pathologic and clinical findings of the two diseases.

TABLE 21-1 Comparison of the Clinical and Pathologic Features of Crohn Disease and Ulcerative Colitis

Images

Ulcerative Colitis

Images UC is confined to the rectum and colon and affects the mucosal and the submucosal layers. In some instances, a short segment of terminal ileum may be inflamed; this is referred to as backwash ileitis. Unlike CD, the deeper longitudinal muscular layers, serosa, and regional lymph nodes are not usually involved.1 Fistula, perforation, or obstruction is uncommon because this is a superficial inflammation.

In UC abscess formation in the crypts of the mucosa occurs (crypts of Lieberkuhn) secondary to infiltration of lymphocytes, plasma cells, and granulocytes.1 Crypt abscesses are usually visible only with microscopy but may be visible when coalescence results in ulceration. Reduced crypt density, distorted crypt architecture and atrophy, and depletion of goblet cells are typical findings.1,31 Extension and coalescence of ulcers may surround areas of uninvolved mucosa, causing pseudopolyp formation. Mucosal damage and friability in UC can result in significant diarrhea and bleeding, although a small percentage of patients experience constipation.

Images Complications of UC may be local, including hemorrhoids, anal fissures, or perirectal abscesses, and are more likely to be present during active colitis. Extraintestinal manifestations (not directly associated with the colon) may occur and are discussed later.

A major complication is toxic megacolon, which is a segmental or total colonic distension of greater than 6 cm with acute colitis and signs of systemic toxicity.1,32 It occurs in up to 7.9% of UC patients admitted to hospitals and results in death rates of up to 50%. With toxic megacolon, ulceration extends below the submucosa, sometimes reaching the serosa. Vasculitis, swelling of the vascular endothelium, and thrombosis of small arteries occur. Involvement of the muscularis propria causes loss of colonic tone, leading to dilation and potential perforation. Patients typically have a high fever, tachycardia, distended abdomen, and elevated white blood cell count, and a dilated colon is observed on x-ray.7,31 Colonic perforation may occur with or without toxic megacolon and is a greater risk with the first episode. Another infrequent major complication is massive colonic hemorrhage. Colonic stricture, sometimes with clinical obstruction, may also complicate long-standing UC.

The risk of colonic dysplasia with transition to colorectal carcinoma (CRC) is fivefold greater for patients with chronic UC with colonic involvement compared with the general population.33 Patients with ulcerative proctitis or proctosigmoiditis are generally not considered to be at increased risk.33,34 The cumulative risk of developing CRC in patients with chronic UC may be as high as 20% to 30% at 30 years.1 Risk factors for CRC include young age at onset (<50 years), severe inflammation, a positive family history, and presence of primary sclerosing cholangitis (PSC) or inflammatory polyps.1,33,34Screening colonoscopy with multiple biopsies should be performed at 8 years after onset of symptoms in patients with left-sided or extensive colitis, with subsequent screenings at 1 to 2 years if negative.34Patients with PSC should undergo yearly colonoscopy.34

Crohn’s Disease

CD is characterized as a transmural inflammatory process. The terminal ileum is the most common site of the disorder, but it may occur in any part of the GI tract from mouth to anus.35,36 Patients often have normal bowel separating segments of diseased bowel resulting in discontinuous disease. The mesentery first becomes thickened and edematous, and then fibrotic. Ulcers are typically deep and elongated and extend along the longitudinal axis of the bowel, at least into the submucosa. The “cobblestone” appearance of the bowel wall results from deep mucosal ulceration intermingled with nodular submucosal thickening.

Bowel wall injury is generally extensive and the intestinal lumen is often narrowed. Small bowel stricture and subsequent obstruction is a complication that may require surgery. Fistula formation is also common, occurring much more frequently than with UC, and is reported as a 20% to 40% lifetime risk in CD.35 Fistulas often occur in highly inflamed areas, where loops of bowel become matted together by fibrous adhesions. Fistulas may connect a segment of the GI tract to skin (enterocutaneous), two segments of the GI tract (enteroenteric), or the intestinal tract with the bladder (enterovesicular) or vagina. Fistulae associated with CD frequently require surgical treatment.

Bleeding with CD is usually not as severe as with UC, although patients with CD may develop hypochromic anemia. The risk of carcinoma is increased but not as greatly as with UC.34

Nutritional deficiencies are common with CD.37,38 Frequencies of various nutritional parameters are: weight loss, 40% to 80%, up to 90% reported in children at the time of diagnosis; growth failure in children, 15% to 88%; iron deficiency anemia, 39%; vitamin B12 deficiency, 18.4%; folate deficiency, 19%; hypoalbuminemia, 17% to 76%; hypokalemia, 33%; and osteomalacia, 36%. There are usually decreased fat stores and lean tissue. Growth failure in children may be associated with low zinc levels.

Extraintestinal Manifestations of IBD

Both forms of IBD are associated with development of symptoms and organ involvement outside of the GI tract referred to as extraintestinal manifestations.

Hepatobiliary Complications

Approximately 11% of patients with UC are reported to have hepatobiliary complications with overall frequencies ranging from 5% to 95% for patients with IBD.1,39,40 Hepatic complications include fatty liver, pericholangitis, autoimmune hepatitis, and cirrhosis. Biliary complications include PSC, cholangiocarcinoma, and cholelithiasis.1,20,39

Fatty infiltration of the liver may result from malabsorption, protein-losing enteropathy, or corticosteroid use. Pericholangitis (acute inflammation surrounding the intrahepatic portal venules, bile ducts, and lymphatics) occurs in up to one third of UC patients. PSC is associated with progressive fibrosis of intrahepatic and extrahepatic bile ducts in 3% to 7% of patients with UC.39 Cirrhosis may result from cholangitis or chronic active hepatitis. Often the severity of hepatic disease does not correlate with GI disease activity. Gallstones occur in 13% to 34% of patients with CD (particularly with terminal ileal disease) and are related to bile salt malabsorption.39

Joint Complications

Arthritis in IBD is typically asymmetric (unlike rheumatoid arthritis) and migratory, involving one or a few usually large joints. The severity parallels IBD disease activity.1,39 Arthritis may be peripheral or axial in nature and includes sacroiliitis, ankylosing spondylitis, and IBD-associated spondyloarthropathy. Patients positive for HLA-B27 often exhibit axial arthropathy, such as ankylosing spondylitis. Rheumatoid factors are generally not detected and the arthritis is nondeforming and nondestructive. Patients may exhibit enthesopathy, tenosynovitis, or dactylitis.39

Ocular Complications

Ocular complications including iritis, uveitis, episcleritis, and conjunctivitis occur in up to 2% to 29% of patients with IBD.1,39 Commonly reported symptoms with iritis and uveitis include blurred vision, eye pain, and photophobia. Episcleritis is associated with scleral injection, burning, and increased secretions. These complications may parallel the severity of intestinal disease, and recurrence after colectomy with UC is uncommon.

Dermatologic and Mucocutaneous Complications

Skin and mucosal lesions associated with IBD include erythema nodosum, pyoderma gangrenosum, aphthous ulceration, and Sweet’s syndrome.40 Raised, red, tender nodules on the tibial surfaces of the legs and arms that vary in size from 1 cm to several centimeters are manifestations of erythema nodosum, and may occur in 2% to 20% of patients with IBD.40 These lesions are more commonly observed in CD patients and often correlate with disease severity.

Pyoderma gangrenosum occurs in 0.5% to 2% of patients with IBD and is characterized by discrete skin ulcerations that have a necrotic center and a violaceous color of the surrounding skin.1,40 They can be seen on any part of the body but commonly occur on the lower extremities.

Oral lesions are found in 4% to 20% of patients with IBD.35,40 The most common lesion seen with CD is aphthous stomatitis. The severity of these lesions tends to parallel the disease course. Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, is characterized by tender erythematous skin lesions secondary to dermal neutrophil infiltration, and is often associated with fever and a distribution on the upper trunk, face, neck, and arms.40

Hematologic, Coagulation, and Metabolic Abnormalities

Patients with IBD may develop anemia, with a prevalence reported up to 74%.1,40 The anemia may present as iron deficiency related to chronic blood loss, ongoing inflammation, malnutrition, hemolysis, or bone marrow suppression from drug treatment.40 Alternatively, it may be more characteristic of anemia of chronic disease secondary to chronic inflammation and overproduction of cytokines. Patients with IBD are at a 1.5 to 3.6 times higher risk of venous thromboembolism (VTE) compared with the general population.41 This is secondary to activation of the clotting cascade and platelet activation secondary to inflammation.40,41 Occurrence of VTE is higher during disease flares and occurs more often in peripheral veins.1,41 Patients should be considered for pharmacologic VTE prophylaxis when admitted to the hospital for a disease flare. Patients with IBD may be at increased risk for metabolic bone disease and development of osteoporosis. Osteomalacia is less common in IBD.40,42 Bone disease may be related to a combination of nutritional deficiencies, especially calcium and vitamin D, chronic cytokine-related inflammatory effects on bone, disease-associated hypogonadism, and use of corticosteroids.40,42

CLINICAL PRESENTATION

The patterns of clinical presentation of IBD can vary widely. Patients may have a single acute episode that resolves and does not recur, but most patients experience acute flares with alternating periods of remission.

Ulcerative Colitis

There is a wide range of presentation in UC, ranging from mild abdominal cramping with frequent small-volume bowel movements to profuse diarrhea (Table 21-2). Most patients with UC experience intermittent bouts of illness after varying intervals of remission with symptoms. A small percentage of patients have continuous unremitting symptoms or a single acute attack with no subsequent symptoms.

TABLE 21-2 Clinical Presentation of Ulcerative Colitis

Images

Images While various disease classifications are available for UC, a standard disease severity scoring system is not universally accepted.43 The arbitrary distinctions of mild, moderate, severe, and fulminant disease activity are generally used in treatment guideline recommendations, and are determined largely by clinical signs and symptoms1,31,43:

   1. Mild: Fewer than four stools daily, with or without blood, with no systemic disturbance and a normal erythrocyte sedimentation rate (ESR)

   2. Moderate: More than four stools per day but with minimal systemic disturbance

   3. Severe: More than six stools per day with blood, with evidence of systemic disturbance as shown by fever, tachycardia, anemia, or ESR of greater than 30 mm/h (8.3 μm/s)

   4. Fulminant: More than 10 bowel movements per day with continuous bleeding, toxicity, abdominal tenderness, requirement for transfusion, and colonic dilation

With severe disease, the patient typically has profuse bloody diarrhea with a high fever, leukocytosis, and hypoalbuminemia. The patient may be dehydrated with tachycardia and hypotension. This presentation may have a sudden onset with rapid progression.

Determining disease extent, that is, which sections of the colon are involved, is important. This is accomplished via endoscopy. Patients with “distal” disease have inflammation limited to areas distal to the splenic flexure (also referred to as left-sided disease), while those with “extensive disease” have inflammation extending proximal to the splenic flexure.1,31 Inflammation confined to the rectal area is referred to as proctitis, while disease involving the rectum and sigmoid colon is referred to as proctosigmoiditis.29 Inflammation of the majority of the colon is called pancolitis.

The diagnosis of UC is made on clinical suspicion and confirmed by biopsy, stool examinations, sigmoidoscopy or colonoscopy, or barium radiographic contrast studies. The presence of extracolonic manifestations may also aid in establishing the diagnosis.1,31,40

Crohn’s Disease

As with UC, the presentation of CD is highly variable. The time between the onset of complaints and the initial diagnosis may be as long as 3 years. The patient typically presents with diarrhea and abdominal pain. Hematochezia occurs in about one half of patients with colonic involvement and much less frequently when there is no colonic involvement. A patient may first present with a perirectal or perianal lesion (Table 21-3). The diagnosis should also be suspected in children with growth retardation, especially with abdominal complaints.

TABLE 21-3 Clinical Presentation of Crohn Disease

Images

Much like UC, global classification guidelines for scoring severity of active CD are not available. For patients with luminal nonfistulizing CD, the Crohn’s Disease Activity Index (CDAI) is used most often to gauge response to therapy and determine remission and is employed mostly in the research setting.44 This score system ranges from 0 to 600, with score great than 150 defined as active disease. The Harvey Bradshaw Index (HBI) is another scoring system that is also used for CD, and tends to correlate well with the CDAI.44 A decrease of 3 points in the HBI is defined as a clinical response in the with complete remission defined as a score of <4. Treatment guidelines use the presence of signs and symptoms as their marker for disease activity and severity.35 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 corticosteroid or biologic treatment or presence of cachexia, rebound tenderness, intestinal obstruction, or abscess. Disease activity may be assessed and correlated by evaluation of serum C-reactive protein (CRP) concentrations.

The course of CD is characterized by periods of remission and exacerbation. Patients may be symptom-free for years, while others experience chronic symptoms in spite of medical therapy. As with UC, the diagnosis of CD involves a thorough evaluation using laboratory, endoscopic, and radiologic testing to detect the extent and characteristic features of the disease. Small bowel involvement, strictures detected on radiographs, and presence of fistulae are characteristic of CD.

TREATMENT

Desired Outcomes

Images The clinician must have a clear concept of realistic therapeutic goals for each patient with IBD. Goals may relate to resolution of acute inflammatory processes, resolution of complications (e.g., fistulae and abscesses), alleviation of extraintestinal manifestations, maintenance of remission, or surgical palliation or cure.

When determining goals of therapy and selecting therapeutic regimens, it is important to understand the natural history of IBD.1,13,31,35 Some cases of acute UC are self-limited. With mild to moderate acute colitis without systemic symptoms, 20% of patients may experience spontaneous improvement in their disease within a few weeks; however, a small percentage of patients may go on to experience more serious disease. With severe colitis, improvement without treatment cannot be expected. The response to medical management of toxic megacolon is variable and emergent colectomy may be required. When remission of UC is achieved, it is likely to last at least 1 year with medical therapy; however, long-term sustained remission rates are typically less than 50%.43 In the absence of medical therapy, one half to two thirds of patients relapse within 9 months.31

Approximately 20% of patients with CD will experience a relapse annually.35 Sustained remission is impacted by response to treatment. Patients remaining in remission for 1 year have an 80% chance of remaining in remission the subsequent year, while 70% of patients will continue to have active disease in the year following a 12-month period in which they had active disease.35 Thus, inducing and maintaining remission is an important aspect of treatment to improve outcomes and QOL and reduce complications. There has been recent interest in mucosal healing as a more objective end point or goal for the treatment of IBD.45,46 Mucosal healing is accessed via endoscopy; however, there is not a universal scoring system that has been adopted for either CD or UC. The natural course of the disease may be altered and outcomes improved, such as sustained remission and reduced hospitalization, if mucosal healing is achieved.45,46 Mucosal healing is directly related to the efficacy of drug therapies used in the treatment of IBD and may be used to determine the need for escalation or de-escalation of drug therapy.45,46 At this time mucosal healing is a promising end point; however, as more studies incorporate this end point, it can be better determined if this is achievable in all patients, particularly those with CD whose disease typically penetrates below the mucosal layer.

General Approach to Treatment

Images Treatment of IBD centers on agents used to relieve the inflammatory process and induce disease remission. Aminosalicylates (ASAs), corticosteroids, antimicrobials, immunosuppressive, and biologic agents are commonly used to treat active disease and for some agents to maintain disease remission. The severity and extent of the disease should be taken into account, as this will often dictate the dose, route, frequency, and formulation of drug therapy that will be most effective. Patient preference for different drug formulations and cost of therapies should also be taken into account.

Surgical procedures are sometimes performed when active disease is inadequately controlled with drugs or when the required drug dosages pose an unacceptable risk of adverse effects. Nutritional considerations are also important because many patients may develop malnutrition. A variety of adjunctive therapies may be used to address complications or symptoms of IBD. For example, antidiarrheal agents such as loperamide may be used in some patients with relatively well-controlled disease, although these are generally to be avoided in active moderate to severe IBD because they may contribute to the development of toxic megacolon.

Nonpharmacologic Therapy

Nutritional Support

Proper nutritional support is an important aspect of the treatment of patients with IBD. Specific types of diets are not useful in alleviating the inflammatory conditions; however, patients with moderate to severe disease are often malnourished.37,38,47 Malabsorption or maldigestion may occur secondary to the catabolic effects of the disease process. Elevated activity of IL-6 and TNF-α increases protein turnover, resulting in protein loss and muscle wasting.38Malabsorption and malnutrition may occur more often in the patient with CD with involvement of the small bowel, as this is where many nutrients are absorbed.47 Protein–energy malnutrition and suboptimal weight is reported in up to 85% of patients with CD.47 Patients who have undergone multiple small bowel resections may have reduction in the absorptive surface of the intestine (i.e., “short gut”). Maldigestion with accompanying diarrhea can also occur if there is a bile salt deficiency in the gut.

Many specific diets have been tried to improve nutritional status and symptoms in IBD, but none has gained widespread acceptance. On an individual patient basis, elimination of specific foods that appear to exacerbate symptoms can be tried; however, exclusion diets are generally not endorsed, even in the setting of severe disease.48 If attempted, the elimination process must be conducted cautiously, as patients may exclude a wide range of nutritious products without adequate justification. Some patients with IBD may have lactase deficiency as well; therefore, diarrhea may be associated with intake of dairy products. For these patients, avoidance of dairy products or supplementation with lactase generally improves the patient’s symptoms.48 Patients with small bowel strictures due to CD should avoid excessive high-residue foods, such as citrus fruits and nuts, in order to prevent obstruction.

The nutritional needs of patients with IBD may be adequately addressed with use of enteral supplementation in acute or chronic situations.37,38,47 Use of enteral nutrition has favorable effects on reducing inflammation and intestinal cytokine production.47 This may lead to a greater chance of induction and maintenance of remission as well as facilitation of mucosal healing, particularly in patients with CD.47 No specific enteral formula is recommended, so initiation of polymeric feeds may be tried first.47 Monitoring for efficacy of the enteral feeding is similar to other patient populations receiving enteral nutrition.

Parenteral nutrition has a more limited role in CD or UC. It is generally reserved for patients with severe malnutrition or those who fail enteral therapy or have a contraindication to receiving enteral therapy, such as perforation, protracted vomiting, short-bowel syndrome, or severe intestinal stenosis.47 Parenteral therapy is not preferred as primary therapy for IBD even in the setting of acute disease flares in hospitalized patients.48 Home parenteral nutrition may be necessary for patients requiring long-term therapy, particularly those with short-bowel syndrome. Parenteral nutrition is more costly and is associated with more complications, such as serious infections, compared with enteral nutrition.

Given that the intestinal microbiotica may play a key role in IBD pathogenesis, probiotic administration as an adjunctive treatment of IBD has been explored. Postulated mechanisms for using probiotics in IBD include reestablishment of normal bacterial flora within the gut, reduction in bacterial adhesion and competition for nutrients with pathogenic bacteria, production of antibacterial substances, and promotion of favorable effects on the host immune response.4951 Probiotic preparations often contain various organisms such as nonpathogenic E. coli Nissle, bifidobacteria, lactobacilli, Streptococcus thermophilusor Saccharomyces boulardii. Probiotics have demonstrated some effectiveness in inducing and maintaining remission in some trials for patients with UC; however, differences in methodology, probiotics used, and underlying treatments for IBD make comparison of trials difficult.4954 A formulation of Bifidiobacterium, lactobacilli, and streptococci (VSL #3) is marketed specifically for use in UC as an adjunctive therapy and for patients who have a surgically constructed ileal pouch anal anastomosis (IPAA) to prevent or treat pouchitis.31,4951 Use of probiotics as adjunctive agents to avoid stepping up drug therapy to potentially more toxic agents is another potential use.49 Evidence of probiotic use in the induction and maintenance of CD is less compelling and has led to recommendations not supporting widespread use, but rather further investigation.5254 While probiotics are considered to be generally safe in patients with IBD, the added cost and requirement to often take multiple doses per day should also weigh into the decision to use them in IBD.

Surgery

Despite the availability of medications to treat IBD, many patients will often require surgery. Surgical procedures may involve resection of segments of intestine that are affected, as well as correction of complications (e.g., fistulas) or drainage of abscesses.

Rates of colectomy for UC are 5% to 30%.1,31,55 Colectomy may be necessary when the patient has disease uncontrolled by maximum medical therapy or when there are complications of the disease such as colonic perforation, toxic megacolon, uncontrolled colonic hemorrhage, or colonic strictures.1,31,55 Colectomy may be indicated for patients with long-standing disease (greater than 8 to 10 years), as a prophylactic measure against the development of CRC, and for patients with premalignant changes (severe dysplasia) on surveillance mucosal biopsies.33,34,55 Proctocolectomy, after which the patient is left with a permanent ileostomy, is generally considered curative for UC; however, the decision to perform this should take into account the effects on the patient’s QOL. Restorative proctocolectomy with construction of an IPAA is the most common surgical procedure performed in UC and is typically well tolerated with a reported failure rate of less than 10%.55 Patients may develop inflammation of the IPAA, often referred to as pouchitis.53 The risk from surgery for these patients is relatively low if the operations are performed on a nonemergent basis.

Indications for surgery with CD are not as well established as for UC. Surgery is usually reserved for patients with complications of the disease. A recognized problem with intestinal resection for CD is the high rate of recurrence. Surgery may be appropriate in well-selected patients who have severe or incapacitating disease or obstruction in spite of aggressive medical management. The surgical procedures performed most often include resections of the major intestinal areas of involvement. Patients who undergo multiple resections of the small intestine may develop malabsorption related to short-bowel syndrome. For some patients with severe rectal or perianal disease, particularly abscesses, diversion of the fecal stream is performed with a colostomy. Other indications for surgery include resection of strictures or performance of stricturoplasty, or presence of colon cancer, an inflammatory mass, intestinal perforation, or fistulas.35

Pharmacologic Therapy

Drug therapy plays an integral role in the treatment of IBD. None of the drugs used for IBD are curative; therefore, reasonable goals of drug therapy are resolution of acute disease symptoms and induction of remission. The major types of drug therapy used in IBD include ASAs, corticosteroids, immunosuppressive agents (azathioprine, mercaptopurine [MP], cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit TNF-α (anti–TNF-α antibodies) or leukocyte adhesion and migration (natalizumab).

Sulfasalazine is the prototypical ASA, and is composed of a sulfonamide moiety (sulfapyridine) and mesalamine (5-aminosalicylate acid [5-ASA]) joined by a diazo bond in the same molecule.55,56Sulfasalazine has been used for years to treat IBD but was originally intended to treat arthritis. It is cleaved by gut bacteria in the colon to sulfapyridine (which is mostly absorbed and excreted in the urine) and mesalamine (which mostly remains in the colon and is excreted in stool).5456

The active component of sulfasalazine is mesalamine, which exerts its effects locally in the GI tract; however, the mechanism of action is not completely understood. Beneficial effects of mesalamine may include scavenging of free radicals, inhibition of leukocyte motility, interference with TNF-α, transforming growth factor-β (TGF-β) and nuclear factor κ B (NF-κ β), suppression of IL-1 production, and inhibition of leukotriene and prostaglandin production.5559

Because the effectiveness of sulfasalazine is not related to the sulfapyridine component and since sulfapyridine is believed to be responsible for many of the adverse reactions to sulfasalazine, mesalamine can be administered alone. Given that mesalamine is rapidly and completely absorbed in the small intestine but poorly absorbed in the colon, drug formulations must be designed to deliver mesalamine to the affected areas in the GI while preventing premature absorption.5560 Mesalamine can be used topically as an enema, to treat left-sided disease, or as a suppository for treatment of proctitis (Fig. 21-1). In general, the use of topical mesalamine preparations such as enemas and suppositories is more effective than oral preparations.60 Likewise, these therapies may be used concomitantly with the oral mesalamine preparations, which may result in additive efficacy in patients with UC.61 Oral slow-release formulations will deliver mesalamine to the small intestine and/or colon based on the product design (Table 21-4). Slow-release oral formulations of mesalamine, such as Pentasa, release mesalamine from the duodenum to the ileum, with up to 59% of the drug passing into the colon.57 Some dose forms (Asacol, Asacol HD, Delzicol) utilize a pH-dependent coating that releases in response to intestinal pH.58 Another tablet formulation of mesalamine (Lialda) uses a pH-dependent coating that releases at a pH of 7, in combination with a polymeric matrix core, referred to as the Multi-MatriX (MMX) system, and releases drug evenly throughout the colon also allowing for once-daily dosing.59 A capsule formulation of mesalamine (Apriso) utilizes enteric-coated mesalamine granules in a polymer matrix for delayed and extended delivery of mesalamine to the colon and also allows for once-daily dosing.57,58 Use of once-daily oral mesalamine preparations may enhance adherence, which may help to prevent relapse.57,59 Olsalazine is a dimer of two 5-ASA molecules linked by an azo bond. Mesalamine is released in the colon after colonic bacteria cleave the azo bond.56 Balsalazide is a mesalamine prodrug that couples mesalamine with the inert carrier molecule 4-aminobenzoyl-β-alanine and is also enzymatically cleaved in the colon to release mesalamine.56 The recommended daily doses of the oral mesalamine derivatives are intended to approximate the molar equivalent of mesalamine present in 4 g of sulfasalazine. Because the oral mesalamine formulations are delayed-release coated tablets or granules, they should not be crushed or chewed. Unlike sulfasalazine, all of these agents are safe to use for patients with sulfonamide allergies.

Images

FIGURE 21-1 Site of activity of various agents used to treat inflammatory bowel disease.

TABLE 21-4 Agents for the Treatment of Inflammatory Bowel Disease

Images

Images Corticosteroids are used to suppress acute inflammation in the treatment of IBD, and may be given parenterally, orally, or rectally.62 They modulate the immune system and inhibit production of cytokines and mediators. It is not clear whether the most important steroid effects are systemic or local (mucosal). Budesonide is a corticosteroid that is administered orally in a controlled-release formulation designed to release in the terminal ileum or the colon depending on the product. The drug undergoes extensive first-pass metabolism; so systemic exposure is thought to be minimized.36,62 Immunosuppressive agents such as azathioprine, MP, methotrexate, or cyclosporine are also used for the treatment of IBD (Table 21-4).

Azathioprine and MP are effectively used in long-term treatment of both CD and UC.1,31,35,6365 These agents are generally reserved for patients who fail ASA therapy or are refractory to or dependent on corticosteroids. They may be used in conjunction with mesalamine derivatives, corticosteroids, and TNF-α antagonists, and must be used for extended periods of time, ranging from a few weeks up to 12 months, before benefits may be observed.6365

Cyclosporine has a short-term benefit in the treatment of acute, severe UC to avoid colectomy in patients failing corticosteroids.1,13,31,48,66 It is used initially as a continuous IV infusion of 2 to 4 mg/kg daily.48,67 Cyclosporine poses a risk of nephrotoxicity and neurotoxicity. Studies evaluating tacrolimus for the treatment of IBD suggest a potential role for use for patients with luminal or perianal CD; however, results have been variable with few data to support its routine use.68 Methotrexate 15 to 25 mg given intramuscularly or subcutaneously once weekly is useful for treatment and maintenance of CD and may result in steroid-sparing effects, while data supporting use in UC are lacking.13,35,44,63


Clinical Controversy…

The treatment of CD has traditionally used a “step-up” approach, with use of ASAs and corticosteroids first, followed by azathioprine, MP, methotrexate, or biologic agents. Introducing immunosuppressants or biologic agents earlier in a “top-down” approach has gained interest.36 Use of these agents earlier may significantly alter the disease course; however, these agents are costly and may be associated with significant toxicities. More studies are needed to define the role of the “top-down” approach before it is implemented in a wider range of patients.

Antimicrobial agents, particularly metronidazole and ciprofloxacin, are frequently used as adjunctive therapies in IBD. Metronidazole and ciprofloxacin, often given in combination, have demonstrated some value in both induction of remission and decrease in relapse rates in CD with some data supporting use in UC as well.13,36,44,69 Antibiotics are often used in patients with perineal CD or when fistulas or abscesses are present.5 Rifamycin antibiotics have demonstrated some efficacy in treatment of both UC and CD.69 Risks of long-term antibiotic use include the development of antibiotic resistance, predisposition to C. difficile infection, and adverse effects such as neurotoxicity secondary to metronidazole use.

Biologic agents that target TNF-α have become a key class of agents in the treatment and maintenance of IBD.7072 Infliximab is an IgG1 chimeric monoclonal antibody that is administered IV and binds TNF-α and inhibits its inflammatory effects. In addition, it lyses activated T cells and macrophages and induces T-cell apoptosis.72 Infliximab is useful for moderate to severe active CD and UC disease, as well as steroid-dependent or fistulizing disease, as both an induction and a maintenance therapy. Adalimumab is also an IgG1 antibody to TNF-α; however, this agent, unlike infliximab, is fully humanized and contains no murine sequences. Theoretically, the lack of a murine component in adalimumab reduces antibody development seen with use of infliximab. This agent is administered subcutaneously and is a treatment option for patients with moderate to severe active UC and CD and those previously treated with infliximab who have lost response. Certolizumab pegol is a humanized pegylated Fab fragment directed against TNF-α that is also administered subcutaneously. Both adalimumab and certolizumab inhibit soluble and membrane-bound TNF and can be used as both induction and maintenance therapies.72

Lastly, natalizumab is a novel biologic agent that inhibits leukocyte adhesion and migration by targeting the α4 subunit of integrin.71,72 This agent can be used in the treatment of CD for patients who are unresponsive to other therapies, including corticosteroids and TNF-α inhibitors.


Clinical Controversy…

Use of the combination of anti–TNF-α antagonists and immunosuppressants in patients with CD has gained interest based on recent data.84 This combination appears to be more effective than azathioprine or infliximab alone. Despite this efficacy, controversy remains as to the level of immunosuppression that is needed versus the risk of potential toxicities, such as serious infections or lymphoma.65 Likewise, the timing and approach to de-escalation of one or both therapies and which therapies should be stopped or reduced first remains an unclear area.65,83

Treatment of Ulcerative Colitis

Mild to Moderate Active Disease Most patients with mild to moderate active UC can be managed on an outpatient basis with oral and/or topical ASAs (Fig. 21-2Table 21-5). For patients with extensive disease, oral sulfasalazine or an oral mesalamine derivative is preferred, with rates of induction of remission reported as 36% to 60% in 2 to 4 weeks after initiating therapy.1,31,60,61,73,74 Topical mesalamine in an enema or suppository formulation is more effective than oral mesalamine or topical steroids for distal disease.60,61 The combination of oral and topical mesalamine is more effective than either alone for patients with left-sided or extensive disease; however, patients may be less willing to use these formulations.60,61 Usually 4 to 6 g/day of sulfasalazine given in four divided doses is required to suppress active inflammation.31 There does not appear to be an increased rate of response with dosages over 6 g/day, although adverse effects typically increase.

Images

FIGURE 21-2 Treatment approaches for ulcerative colitis.

TABLE 21-5 Levels of Evidence for Therapeutic Interventions in Inflammatory Bowel Disease

Images

Oral mesalamine derivatives (Table 21-2) are alternatives to sulfasalazine for treatment of mild to moderate UC with similar rates of efficacy. Mesalamine preparations are typically better tolerated than sulfasalazine and thus are often chosen preferentially as first-line therapies. Mesalamine suppositories will only reach to approximately 10 to 20 cm within the lower GI tract and thus are reserved for patients with proctitis.1 Enemas will reach to the splenic flexure and can be used for left-sided disease.60 The various oral mesalamine products generally have similar rates of efficacy and the effective daily dose range is 2.4 to 4.8 g/day. Doses greater than 2.4 g/day generally do not demonstrate significant additional benefit; however, patients with moderate disease may respond better to higher doses.1,13,67,73 The choice of oral formulations may be dictated by patient-specific factors, such as use of a once-daily formulation to help improve patient adherence and reduce pill burden, or use of a generically available product in patients with limited financial resources.5659,75 Controlled release budesonide (Uceris) is an alternative for mild-moderate UC. Oral corticosteroids in doses of 40 to 60 mg/day prednisone equivalent can be used for patients with moderate extensive disease who are refractory to oral ASAs or require more rapid control of symptoms.31,62 Topical corticosteroids, given as foams, enemas, and suppositories, while effective for patients with distal disease, are generally less effective than mesalamine but can be used for patients with tenesmus.31

Moderate to Severe Active Disease Patients with moderate to severe active disease require prompt initiation of therapies to quickly suppress inflammation. Systemic corticosteroids are used in the treatment of moderate to severe active UC regardless of disease location or in those patients who are unresponsive to maximal doses of oral and/or topical mesalamine derivatives.21,31 Oral doses of 40 to 60 mg prednisone equivalent daily are recommended.31

Use of TNF-α inhibitors is an option for patients with moderate to severe disease who are unresponsive to ASAs, corticosteroids, or other immunosuppressive agents and is generally the next step in therapy. Infliximab has demonstrated rates of induction of remission of up to 65% using a 5 mg/kg three-dose induction regimen at day 0, 2 weeks, and 6 weeks.1,13,74 Adalimumab has also demonstrated efficacy in moderate to severe UC with reported rates of remission as 16.5% to 18.5% at 8 weeks using a four-dose regimen of 160 mg on day 1, 80 mg 2 weeks later, and then 40 mg every other week starting 2 weeks later.76,77

Severe or Fulminant Disease Patients with uncontrolled severe colitis or those with incapacitating symptoms require hospitalization for effective management. Under these conditions, patients generally receive nothing by mouth to promote bowel rest. Medications are given by the parenteral route and oral sulfasalazine or mesalamine derivatives are not typically beneficial in this setting because of rapid elimination of these agents from the colon with diarrhea.

Systemic corticosteroids are used in the treatment of severe disease and may allow some patients to avoid colectomy. IV hydrocortisone 300 mg daily in three divided doses or methylprednisolone 60 mg once daily is considered a first-line agent.31,67 Methylprednisolone is typically preferred due to its lesser mineralocorticoid effects. A trial of steroids is warranted in most patients before proceeding to colectomy, unless the condition is grave or rapidly deteriorating. The length of corticosteroid therapy before consideration of surgery is open to debate, with recommendations ranging from 3 to 7 days.1,31,48 Steroids do increase surgical risk, particularly infectious, if an operation is required later.

Images Patients who are unresponsive to parenteral corticosteroids after 3 to 7 days have the option of receiving higher-potency agents such as cyclosporine or infliximab. Seventy-six percent to 85% of hospitalized patients who are unresponsive to corticosteroids will typically respond to IV cyclosporine.66 A continuous IV infusion of cyclosporine 2 to 4 mg/kg/day is the typical dose range utilized and may delay the need for colectomy.1,31,48,66,67 Persistent fever, tachycardia, elevated CRP, hypoalbuminemia, and deep colonic ulcerations may be predictors of failure to respond to cyclosporine.31,66 Patients who are controlled on IV cyclosporine can then be switched to an oral cyclosporine (4 to 8 mg/kg/day) tapered regimen with transition to azathioprine or MP.1,31,48,66,78 Infliximab is an alternative to cyclosporine at a dose of 5 mg/kg and has demonstrated similar results regarding delaying the need for colectomy for patients with severe disease unresponsive to steroids.1,48,66,67 Patients who respond to infliximab should be considered for additional doses at 2 and 6 weeks later.48 The sequential use of cyclosporine and infliximab, or the drugs given in reverse order, is not recommended.48 The adverse effects of both cyclosporine and infliximab are potentially serious and should be taken into consideration when using either therapy for patients with severe disease.66,67


Clinical Controversy…

For patients with severe or fulminant IBD that is unresponsive to corticosteroids, cyclosporine has traditionally been a last-line agent. The use of infliximab for this indication has recently gained interest. Both cyclosporine and infliximab appear to be similar in efficacy; however, data are variable and each may have its own role.66 Each agent is associated with potentially serious adverse effects and the decision to use either should take into account each individual case. Few head-to-head trials exist, and more data are needed to determine if either agent should be preferred over the other.

Maintenance of Remission

Images After remission from active disease is achieved, the goal of therapy is to maintain remission. The major agents used for maintenance of remission are sulfasalazine and the newer mesalamine derivatives, infliximab and adalimumab, and azathioprine or MP.

Oral agents, including sulfasalazine, mesalamine, and balsalazide, are all effective options for maintenance therapy. The optimal dose to prevent relapse is 2 to 2.4 g/day of mesalamine equivalent, with rates of relapse over 6 to 12 months reported as 40%.13,31,71,73,74 The newer mesalamine derivatives are generally better tolerated than sulfasalazine and are associated with fewer adverse effects often making them a preferred choice.31,71 For patients with left-sided disease or proctitis, mesalamine enemas or suppositories are preferred.60 The frequency of administration of topical agents may possibly be lessened to every third night over time.29,39,60,70 The combination of topical and oral mesalamine is superior to either regimen alone for maintenance therapy.60

Corticosteroids do not have a role in the maintenance of remission with UC because they are ineffective and are associated with serious adverse effects with long-term use.1,31 Steroids should be gradually withdrawn after 2 to 4 weeks after induction of remission. For patients who require chronic steroid use and are steroid dependent, there is a strong justification for use of alternative therapies. Azathioprine is effective in preventing relapse of UC for patients who fail ASAs or who are steroid dependent.1,13,63,67 Approximately one third of patients will maintain remission on azathioprine; however, the onset of action is slow and 3 to 6 months may be required before beneficial effects are noted.73 As mentioned earlier, azathioprine is also recommended for patients with severe UC who are transitioned to oral cyclosporine.1,13,31,48,66,78

The TNF-α inhibitors are options for maintenance in patients with moderate to severe UC following induction, and in those who are steroid dependent or have failed azathioprine. Despite their effectiveness in inducing remission, less than half of patients with UC will be able to maintain remission with a TNF-α inhibitor.74 For patients who initially respond to infliximab, continued dosing of 5 mg/kg as maintenance therapy every 8 weeks can be used with a 10% colectomy rate reported at 54 weeks.1,13,31,71,74 Adalimumab is an alternative to infliximab and has rates of remission at week 52 reported as 16% in patients failing corticosteroids or immunosuppressants.77

Crohn’s Disease

Management of CD often proves more difficult than management of UC because of the greater complexity of presentation (Fig. 21-3Table 21-3). There is a greater potential for reliance on drug therapy with CD because resection of involved areas of the GI tract may not be possible. Recurrence of CD is common following surgery with reported rates of endoscopic recurrence reported as up to 75% at 1 year.79

Images

FIGURE 21-3 Treatment approaches for Crohn disease.

The drug treatment of CD involves many of the same agents used for UC. While the treatment strategy for CD has often followed a similar “step-up” pattern as seen with UC, which involves initiating therapy with ASAs first, there has been interest in using higher-potency agents first, such as TNF-α inhibitors in a “top-down” approach in patients with severe disease.36

Mild to Moderate Active Crohn’s Disease

While effective in UC, ASAs have not demonstrated significant efficacy in CD. Sulfasalazine is reported to have marginal efficacy when compared with placebo for patients with mild to moderate CD, while the newer mesalamine derivatives are generally considered to have minimal efficacy.13,35,36,44,71,80 Despite limited and variable effectiveness, the mesalamine derivatives are often tried as an initial therapy for mild to moderate CD given their favorable adverse effect profile. Since CD often involves the small intestine, formulations such as Pentasa, which release in the small intestine, may be used.

Systemic corticosteroids are frequently used for the treatment of moderate to severe active CD; however, controlled-release budesonide (Entocort) at a dose of 9 mg daily is a viable first-line option for patients with mild to moderate ileal or right-sided (ascending colonic) disease.13,13,35,36,44,62 This agent is superior to placebo and has demonstrated superiority to mesalamine with reported remission rates of up to 69% at 8 weeks.13,41,71 Budesonide has a low systemic bioavailability, reported as 10%, so it has less potential for systemic adverse effects compared with conventional corticosteroids.36

Antibiotics may have some roles in the treatment of CD. Metronidazole, given orally as 10 to 20 mg/kg/day in divided doses, has demonstrated variable efficacy but may possibly be useful in some patients with CD, particularly for patients with colonic or ileocolonic involvement, those with perineal disease, or those who are unresponsive to sulfasalazine.13,35,36,69 For patients with colonic or perineal disease, metronidazole can be added to a mesalamine product or steroids as adjunctive therapy when satisfactory control of CD is not gained with first-line agents, or in attempts to reduce steroid dosage.36Ciprofloxacin 1 g/day is another antibiotic used in CD, often in combination with metronidazole for patients with perianal disease or septic complications; however, results have been variable due to differences in study design and patient numbers.35,41,44,69 Other antibiotics such as rifaximin and clofazimine have also been studied with variable efficacy reported.44,69 While there has been some demonstrated efficacy with antibiotics in mild to moderate CD, they are generally not recommended as a first-line therapy.35,36,44,69

Moderate to Severe Active Crohn’s Disease

Patients with moderate to severe active CD require rapid suppression of inflammation for symptom improvement and prevention of complications. Oral corticosteroids, such as prednisone 40 to 60 mg/day, are generally considered first-line therapies for moderate to severe active CD who are unresponsive to ASAs and are effective in inducing remission for up to 70% of patients.13,36,62 Traditional oral systemic steroids have greater efficacy in inducing remission compared with budesonide in patients with moderate disease; however, the potential for adverse effects is greater.62,71 Hospitalized patients with moderate to severe disease who are unable to tolerate oral therapy are candidates for administration of parenteral steroids, with methylprednisolone or hydrocortisone being first-line options.36,48 Systemic steroids do not appear to be effective for treatment of perianal fistulas.36,71

Images Immunomodulators (azathioprine and MP) are not recommended to induce remission in moderate to severe CD; however, they are effective in maintaining steroid-induced remission and are generally limited to use for patients not achieving adequate response to standard medical therapy or in the setting of steroid dependency.13,36,63 The usual doses of azathioprine are 2 to 3 mg/kg/day, and for MP 1 to 1.5 mg/kg/day.71 Starting doses are typically 50 mg/day and increased at 2-week intervals.

Clinical response to MP may be related to whole-blood concentrations of the metabolite 6-thioguanine (6-TGN), while toxicity is correlated with concentrations of another metabolite, 6-methylmercaptopurine.71

Images Although mostly used in the setting of maintenance therapy as an alternative to azathioprine, methotrexate is another option for use as induction and/or maintenance therapy for patients with moderate to severe CD. Use of a weekly intramuscular or subcutaneous injection of 15 to 25 mg has demonstrated efficacy for induction of remission in CD and corticosteroid-sparing effects.13,36,44,63

The TNF-α inhibitors are effective agents in the management of CD. Collectively these agents have demonstrated rates of remission of 28% at 4 to 12 weeks versus 19% with placebo (P <0.001).70 Infliximab is a well-established treatment option for moderate to severe active CD for patients failing immunosuppressive therapy, in those who are corticosteroid dependent, and for treatment of fistulizing disease.13,36,70,81,82 In large trials infliximab has resulted in remission in up to 46% of patients at 10 to 12 weeks.13,70,8183 Following the standard dose regimen of 5 mg/kg at 0, 2, and 6 weeks, 69% of patients with fistulizing disease responded with a 50% reduction in draining fistulae.8183Data comparing infliximab with azathioprine and the combination of infliximab and azathioprine demonstrated significantly greater rates of remission of 57% at week 26 with the combination and infliximab alone (44%) compared with azathioprine alone (30%) in immunomodulator and biologic naive patients with CD.84 Patients with CRP levels greater than 0.8 mg/dL (8 mg/L) and those with mucosal lesions responded better in both groups receiving infliximab. Earlier use of infliximab is efficacious, particularly in patients with luminal disease; however, this has also raised concerns regarding development of serious adverse effects such as infections and lymphoma.64,80,85

Adalimumab is another viable option for moderate to severe CD. It has the advantage of subcutaneous administration and may be considered as an alternate to infliximab as initial therapy or in those patients losing response to infliximab. Trials evaluating treatment with adalimumab for patients with moderate to severe active CD demonstrate rates of remission of approximately 25% at 4 weeks.70 In patients who have lost response to infliximab, adalimumab use has resulted in rates of remission of 21% at 4 weeks.72 Certolizumab has also demonstrated efficacy in moderate to severe CD with patients who have a baseline CRP of greater than 10 mg/dL (100 mg/L) exhibiting the best response rates, reported as 25% to 37% at 6 to 12 weeks.70,83 Natalizumab is reserved for patients who do not respond to steroids or TNF-α inhibitors. Patients who initially responded to natalizumab treatment had rates of sustained response reported as 61% versus 28% for placebo at week 36.71

Severe/Fulminant Active Disease

Patients with severe or fulminant disease require prompt management in the inpatient setting and are often considered for surgical intervention. Parenteral corticosteroids at a dose equivalent of 40 to 60 mg prednisone should be instituted once the presence of abscess has been excluded.36 Unresponsive cyclosporine has been tried at doses of 2 to 4 mg/h via IV infusion with reported in-hospital colectomy rates of 12.5%; however, despite these findings, there are few data to support its use in this setting.13,86 It may also be effective as a last-line option for patients with severe fistulizing disease.86

Maintenance of Remission

Maintaining remission is typically more difficult with CD than with UC. There is minimal evidence that sulfasalazine and oral mesalamine derivatives are effective therapies for maintenance of CD following medically induced remission.35,74 Despite these findings, an attempt to maintain remission with sulfasalazine or oral mesalamine following a medically induced remission may be carried out given the favorable side-effect profile and cost of these drugs compared with those of immunosuppressive and biologic agents. Mesalamine appears to have some efficacy in preventing postsurgical relapse following resection, with absolute risk reductions of approximately 14% for relapse in some studies, and can be considered in patients who do not qualify for or have a contraindication to immunosuppressive therapy.79

Systemic corticosteroids have no place in the prevention of recurrence of CD. These agents do not alter the long-term course of the disease and predispose patients to serious adverse effects with long-term use.36 Budesonide has been studied at maintenance doses of 6 mg/day for up to 52 weeks with minimal efficacy in maintaining remission.13,61,74 Despite this recommendation, use of budesonide as maintenance therapy for up to 1 year can be considered, particularly in patients who have become corticosteroid dependent, for whom switching to budesonide is an option.13

Azathioprine and MP are effective in maintaining remission in CD in up to 70% of patients, particularly in infliximab- or steroid-induced remission, and therefore these drugs are generally considered first-line agents.36,74 Patients who may benefit from these agents include those with quiescent disease who are steroid dependent or refractory, postsurgical patients to prevent recurrence, those with frequent flares requiring steroid bursts, and those with perianal or enteric fistulas.13,63,74 For patients who initially respond to methotrexate, continued dosing at 15 to 25 mg intramuscularly once weekly is also effective in maintaining remission in up to 66% of patients and may be considered as an alternative to azathioprine and MP.13,63,74

All of the currently approved TNF-α inhibitors are viable options for maintenance of remission in CD. Infliximab given at a dose of 5 mg/kg every 8 weeks is more effective than placebo in maintaining remission for patients who initially respond.13 Reported rates of steroid-free remission at 48 to 52 weeks range from 12% to 16%70,74,81 An increase in the dose to 10 mg/kg or shortening of the dosing interval to 6 weeks is possible if loss of efficacy over time is evident.72 Additionally, infliximab is the effective maintenance therapy for fistulizing disease, and may be used in combination with azathioprine or MP.81Adalimumab is also a treatment option for maintenance therapy of CD. Following induction therapy, doses of 40 mg subcutaneously every other week have resulted in clinical remission rates of 40% to 47% after 20 to 30 weeks of therapy.13,70,74 Certolizumab is effective for maintenance of CD, with remission rates for patients who initially responded reported as 48% at 20 to 30 weeks.74 For patients treated with natalizumab who initially respond, maintenance therapy led to significant response rates of 40% at 60 weeks compared with 15% with placebo.70

Selected Complications

Toxic Megacolon

The treatment required for toxic megacolon includes general supportive, consideration for early surgical intervention, and drug therapy.32,36 Perforation is reported in up to 36% of patients and can significantly worsen outcomes.48Aggressive fluid and electrolyte management is required for dehydration. Transfusion may be necessary if significant blood loss has occurred. Opiates and medications with anticholinergic properties should be discontinued because these agents enhance colonic dilation, thereby increasing the risk of bowel perforation.48 Broad-spectrum antimicrobials that include coverage for gram-negative bacilli and intestinal anaerobes should be used as preemptive therapy in the event that perforation occurs.32 If the patient is not receiving corticosteroids, then high-dose IV therapy should be administered to reduce acute inflammation. Emergent surgical intervention, mainly an abdominal colectomy with formation of an ileostomy, is an important consideration for patients with toxic megacolon and prevents death in some patients.48

Extraintestinal Manifestations

For some extraintestinal manifestations of IBD, specific therapies can be instituted, whereas for others the treatment that is used for the GI inflammatory process also addresses the systemic manifestations.

Anemia secondary to blood loss from the GI tract can be treated with oral ferrous sulfate. If the patient is unable to take oral medication and the patient’s hematocrit is sufficiently low, blood transfusions or IV iron infusions may be required.40 Anemia may also be related to malabsorption of vitamin B12 or folic acid, particularly for patients who have had ileal resection, so supplementation may be required. Screening for osteoporosis via dual x-ray absorptiometry is recommended for patients using steroids for >3 months, in postmenopausal females, patients of age over 60, and those who have sustained a low-stress fracture.42 If the patient is deemed high risk for osteoporosis or exhibits a reduced serum vitamin D concentration, vitamin D and calcium should be instituted. If osteoporosis is present, then calcium, vitamin D, and a bisphosphonate or possibly teriparatide are recommended.40,42Corticosteroid use should be avoided or limited, and weight-bearing exercise initiated if possible.

There are no consistently recommended therapies for aphthous ulcers; however, topical viscous lidocaine may provide symptom relief while topical corticosteroids may promote healing.40 Episcleritis or uveitis is often worse during exacerbations of the intestinal disease, and measures improving intestinal disease will improve these systemic manifestations. Cool compresses and topical corticosteroids may provide symptomatic relief, while TNF-αinhibitors when in use may also provide benefit.40 For arthritis associated with IBD, aspirin or another NSAID may be beneficial, as are corticosteroids. However, NSAID use may exacerbate the underlying IBD and predispose patients to GI bleeding. Intraarticular corticosteroids may be tried to limit the adverse effects of systemically administered agents.40 Skin manifestations often require local wound care and use of topical or systemic corticosteroids.40Anti–TNF-α therapies may also improve severe dermatologic manifestations. Although ursodiol may improve liver enzymes in patients with IBD-associated PSC, it has not been demonstrated to have favorable effects on outcomes.39,40 Liver transplantation is being used more frequently for definitive treatment of PSC.

Special Considerations

Pregnancy and Breast-Feeding

The occurrence or consideration of pregnancy may cause significant concerns for the patient with IBD. Patients with IBD have similar infertility rates as the general female population. The rate of normal childbirth is similar to that for healthy populations.87,88 Some studies have noted a greater risk of spontaneous abortion, low birth weight, caesarian section, or congenital abnormalities.87 However, most patients can conceive normally and have a normal pregnancy.8791 There is a small risk of preterm labor or low-gestational-weight infants.87,90,91 Preconception counseling is key for female patients with IBD who are considering becoming pregnant. This includes improving prepregnancy nutrition, implementing supplementation with folate, calcium, and vitamin D, ceasing alcohol and tobacco use, and inducing disease remission if possible.87 Overall, pregnancy appears to have minimal effects on the course of IBD.8690 Likewise, IBD appears to have little effect on the course of pregnancy, particularly if the IBD is quiescent at the time of conception.87,88,90 Patients who are pregnant experience IBD recurrence rates similar to those of nonpregnant females.90 Patients are recommended to wait until their disease is in remission for 3 months prior to conceiving if possible.86 Patients requiring colectomy for UC should preferentially receive rectal-sparing surgery if they are considering conceiving, followed by IPAA after delivery.87

Most classes of medications used in IBD are relatively safe in pregnancy. Sulfasalazine is generally well tolerated; however, it does interfere with folate absorption, so supplementation with folic acid 1 mg twice daily should be used during the pregnancy.87,88 Sulfasalazine causes decreased sperm counts and reduced fertility in males. This effect is reversible on discontinuation of the drug, and it is not reported with mesalamine. Other ASAs can be used as well; however, there are concerns regarding the presence of dibutyl phthalate in the coating of Asacol.87 Mesalamine preparations not containing dibutyl phthalate should be preferentially used. Steroids given systemically do not appear to be detrimental to the fetus, with the exception of dexamethasone.87,90 Maternal cortisol is generally inactivated by placental 11β-hydroxysteroid dehydrogenase type 2; however, dexamethasone is not inactivated by this enzyme and may accumulate in fetal tissue. Therefore, dexamethasone should be avoided in pregnancy.87Immunosuppressive drugs (azathioprine and MP) may be associated with fetal deformities in humans and are classified as pregnancy category D; however, they have been used commonly in IBD without detriment for most patients.87,90 Infliximab, adalimumab, and certolizumab are classified as pregnancy category B drugs and appear to be relatively safe for use in pregnant patients.8791 Use of infliximab should be restricted to the first and second trimesters if possible due to placental transfer of infliximab and the potential for neonatal adverse effects.91 There is a similar concern with adalimumab, although this agent is more difficult to detect in the neonatal bloodstream. Consideration can be given to stopping it 8 to 10 weeks prior to delivery.91 Natalizumab is a pregnancy category C drug and not much is known about its safety in pregnancy, and thus may be used if benefit is thought to outweigh risk.91 Metronidazole may be used for short courses for treatment of trichomoniasis, but prolonged use should be avoided due to potential mutagenic effects.90 Methotrexate should not be used during pregnancy, as it is a known abortifacient (category X).8791 Cyclosporine has been used in pregnant patients with success and therefore is an option for patients with severe disease.87,90

Use of agents in breast-feeding women is also a consideration. Sulfasalazine does pose a small risk of kernicterus, as levels of sulfapyridine in breast milk are low or undetectable, and thus monitoring for this symptom should be implemented.87 Other mesalamine derivatives are considered safe in breast-feeding.87,90 Corticosteroids can be detected in breast milk, with fetal levels approximately 10% to 12% of maternal levels.88 However, breast-feeding is believed to be safe for the infant when doses of prednisone less than 40 mg are used.88 Optimally mothers should wait at least 4 hours after an oral dose of systemic corticosteroids before breast-feeding to limit exposure to the child.87,90 The anti–TNF-α agents are generally considered safe for use in breast-feeding and carry minimal risk of adverse effects.88,91Metronidazole and cyclosporine should not be given to nursing mothers because these agents are excreted into breast milk and may cause adverse effects.8790

Adverse Drug Effects

Drug intolerance often limits the usefulness of agents used to treat IBD. In some cases, adverse effects can be significant and require discontinuation of the therapy. Knowledge of the common or important adverse reactions will assist in avoiding or minimizing their effects.

Compared with mesalamine, sulfasalazine is more often associated with adverse drug effects, and these effects may be classified as either dose related or idiosyncratic (Table 21-6).55 The sulfapyridine portion of the sulfasalazine molecule is believed to be responsible for much of the sulfasalazine toxicity.31 Dose-related side effects usually include GI disturbances such as nausea, vomiting, diarrhea, or anorexia but may also include headache and arthralgia. These adverse reactions tend to occur more commonly on initiation of therapy and decrease in frequency as therapy is continued. Approaches to the management of these adverse effects include discontinuing the agent for a short period and then reinstituting therapy at a reduced dosage with subsequent slower dose escalation, administration with food, or substituting another enteric-coated 5-ASA product. Folic acid absorption is impaired by sulfasalazine, which may lead to anemia, so oral folic acid supplementation should be administered.

TABLE 21-6 Drug Monitoring Guidelines

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Idiosyncratic effects commonly include rash, fever, or hepatotoxicity, as well as relatively uncommon but serious reactions such as bone marrow suppression, thrombocytopenia, pancreatitis, pneumonitis, interstitial nephritis, and hepatitis. For most patients with idiosyncratic reactions, sulfasalazine must be discontinued. In some patients who have experienced allergic reactions to sulfasalazine, a desensitization procedure can be instituted. By gradually increasing sulfasalazine dosage over weeks to months, patient tolerance has been improved.31

Oral mesalamine derivatives may impose a lower frequency of adverse effects as compared with sulfasalazine.31,73 Up to 80% of patients who are intolerant to sulfasalazine will tolerate oral mesalamine derivatives.31 The most commonly encountered adverse effects are nausea, vomiting, and headache.73 However, olsalazine may cause watery diarrhea in up to 25% of patients, often requiring drug discontinuation.

There is a greater potential for adverse effects from corticosteroids when used for the treatment of IBD because there is often a requirement for use of high doses for extended periods of time. Adverse effects of corticosteroids include hyperglycemia, hypertension, osteoporosis, acne, fluid retention, electrolyte disturbances, myopathies, muscle wasting, increased appetite, psychosis, infection, and adrenocortical suppression.31,62 To minimize corticosteroid effects, clinicians have used alternate-day steroid therapy; however, some patients do not do well clinically on the days when no steroid is given. For most patients a single daily corticosteroid dose suffices, and divided daily doses are unnecessary. Adrenal insufficiency after abrupt steroid withdrawal often necessitates gradual tapering of steroid therapy for patients using these agents daily for more than 2 to 3 weeks. Due to its lower bioavailability and lower potential for adverse effects, budesonide may be used as alternate steroid therapy in CD involving the ileum or right colon, or in UC, or may be substituted for prednisone in CD patients who are steroid dependent or require long-term therapy.35,36

Complete blood counts with differential should be monitored every 2 weeks while doses are being titrated. Azathioprine and MP may be associated with serious adverse effects such as lymphomas, pancreatitis, or nephrotoxicity.31,36,65 Adverse events to thiopurines are typically divided into two groups, type A and type B.92,93 Type A are dose related and include malaise, nausea, infectious complications, hepatitis, and myelosuppression. Type B reactions are considered idiosyncratic and include fever, rash, arthralgia, and pancreatitis (3% to 15% of patients).92,93 Predisposition to development of these adverse effects may be related to polymorphisms in the enzyme thiopurine methyltransferase (TPMT), which is partially responsible for activation and metabolism of these drugs. Determination of TPMT activity is recommended prior to initiation of therapy to determine which patients require lower doses of these agents.36,71 Alternatively, evaluating TPMT genotype or phenotype can also assist in assessing a patient’s risk for toxicity.6365,71 Adjusting azathioprine and MP doses by measuring concentrations of metabolites, particularly 6-TGN, may be useful, with higher levels associated with greater remission rates.6365,67

With the advent of coadministration of azathioprine with infliximab, development of hepatosplenic T-cell lymphoma (HSTCL) has become a concern. The overall impact of using both drugs together, the contribution of drug classes to the development of lymphoma, and the risk and effects of both drugs are unclear. Those most at risk appear to be younger male patients.64,85,94 Methotrexate is associated with the development of nausea, vomiting, pulmonary fibrosis, pneumonitis, hepatotoxicity, anemia, and renal dysfunction, and is a known abortifacient. Patients should have baseline liver function tests, serum creatinine, BUN, complete blood count, and chest x-ray prior to use. Female patients should have a negative pregnancy test prior to use. Some patients may require supplementation with folic acid.

Most patients receiving metronidazole for CD tolerate the agent fairly well; however, mild adverse effects occur frequently. They commonly include nausea, metallic taste, urticaria, and glossitis.32,35 More serious effects that occur with long-term use include development of paresthesias and reversible peripheral neuropathy. Other effects include a disulfiram-like reaction if alcohol is ingested in conjunction.

The TNF-α inhibitors may be associated with development of serious adverse effects and carry similar adverse effect profiles for the available agents. Patients who receive infliximab often develop antibodies to infliximab (ATIs), also referred to as antidrug antibodies (ADAs), which can result in increases in the occurrence of serious infusion-related reactions and loss of response to the drug. Up to 10% of patients per year require discontinuation of infliximab due to adverse effects and loss of efficacy related to development of ATIs.71,81,95 Strategies to reduce ATI formation include administration of a second dose within 8 weeks of the first dose, concurrent administration of steroids (hydrocortisone 200 mg IV on the day of the infusion or oral prednisone the day prior), and use of concomitant immunosuppressive agents.71,84 Loss of efficacy may be managed by a dose escalation to 10 mg/kg or reducing the dosing interval.80,84 Delayed hypersensitivity reactions may also occur up to 14 days after administration, with 5 to 7 days being the most common time frame.81,95 Due to administration via the subcutaneous route, adalimumab and certolizumab may be more associated with injection site reactions versus infusion-related reactions. Likewise, development of antibodies to adalimumab appears to be minimal due to its humanized structure.81 Autoimmune phenomena, such as lupus and hemolytic anemia, may also occur during infliximab therapy but are uncommon, as are adverse neurologic events such as optic neuritis and demyelinating syndrome.72,81,95 As mentioned earlier, risk of HSTCL may be increased with use of infliximab, particularly if used in combination with immunomodulators such as azathioprine. For these reasons patients with a history of demyelinating disease, optic neuritis, or lymphoma should avoid use of TNF-α antagonists.95 Infliximab may also cause worsening of heart failure and thus is contraindicated for patients with New York Heart Association Class III or IV heart failure.85 While the mechanism is unclear, it may relate in part to the cytoprotective effects of TNF on ischemic cardiac tissue, increases in production of nitric oxide and increased peripheral perfusion secondary to TNF, or TNF’s role in cardiac remodeling and repair.81

All TNF-α inhibitors predispose patients to development of serious infections, including fungal, bacterial, and viral. Patients with clinically significant active infections should not receive TNF-α inhibitors. While the overall risk of hospitalization for serious infections may be less than previously suspected, development of infection remains a serious concern.96 Reactivation of latent mycobacterial infections may occur because of the inhibition of TNF-protective mechanisms; therefore, patients should receive a tuberculin skin test (purified protein derivative [PPD] test) and a chest x-ray prior to initiating therapy to rule out undiagnosed tuberculosis.81,95 Reactivation of hepatitis B may occur; thus, patients should also be screened for hepatitis B virus infection prior to initiating therapy. Patients should also be screened for hepatitis C infection, although it does not appear that use of TNF-α inhibitors is unsafe or significantly alters the disease course.81 Lastly, use of natalizumab is associated with development of progressive multifocal leukoencephalopathy and is only available via the manufacturer’s TOUCH prescribing program.95 Patients receiving natalizumab should be monitored for development of adverse neurologic events and undergo MRI of the brain should development of progressive multifocal leukoencephalopathy be suspected.

PERSONALIZED PHARMACOTHERAPY

The approach to treatment of IBD should consider all aspects of each individual patient in order to maximize therapy, improve patient symptoms and QOL, and prevent complications. To ensure optimal drug therapy, an assessment of each patient’s health literacy and potential barriers to understanding and adherence should be performed. Involving the patient in the care process will help to keep him or her engaged. For the drug classes that are used in the management of IBD, there are several aspects of individualization that may improve efficacy and safety. Since patients with IBD are often seen by GI specialists or surgeons, ensuring that each provider has a current, accurate, and complete medication list will help to prevent potential medication errors. Female patients of childbearing age should discuss with their providers their goals for becoming pregnant, as this may dictate the choice of drugs used.

For the ASAs picking the appropriate formulation and dose of drug for the disease severity and extent is key. Enemas and suppositories, while generally more effective than oral preparations, may not be as acceptable for use, particularly by younger patients. Therefore, individuating the patient’s preference for a specific formulation should be taken into account when choosing ASA preparations.57 Consideration can be given to the use of once-daily products if there is evidence that multiple-daily dosing is affecting patient adherence.5759 This must be weighed against the higher cost of these preparations. If expense is an issue, use of generically available agents may be preferred.

Patients receiving systemic corticosteroids for extended periods of time should be assessed for risk of bone loss and fracture and the need for vitamin D and calcium supplementation. In addition, a review of the patient’s medical history should be performed to identify other conditions that may be worsened by corticosteroids, such as diabetes or hypertension. Adjustment of medications for these types of conditions may need to be made based on the dose and duration of corticosteroid use.

Patients in whom azathioprine or MP is being considered should undergo TPMT activity testing or have a genotype or phenotype test performed to determine if dose adjustments are required. Since the initial dosing of these agents is weight based, obtaining a current accurate weight for the patient is necessary as well. Obtaining a family history regarding lymphoproliferative disorders or lymphoma is important for determining if the potential risks outweigh the benefits of long-term use. For female patients in whom methotrexate is being considered, a pregnancy test should be obtained and the potential desire to become pregnant in the future should be discussed. Female patients of childbearing age opting to use methotrexate should have a safe and effective method of birth control available that is based on their preference.

For patients receiving TNF-α antagonists, baseline screening for latent infections should be performed. Obtaining an accurate weight will assist in the dosing of infliximab. Likewise use of infliximab requires administration in an observed infusion center or clinic. If patients are unable to afford to get to their appointment, use of a self-administered agent, such as adalimumab or certolizumab, may be preferred. If patients appear to be losing response to infliximab, evaluating for ATIs, if assays are available, in addition to evaluating serum trough concentrations may assist the clinician in determining if dose and frequency need to be altered. In vitro infliximab concentrations of 0.2 to 10 mcg/mL (mg/L) are shown to inhibit TNF-α activity, while the optimal in vivo concentration is not known.72 Targeting trough concentrations of least 12 mcg/mL (mg/L) at 4 weeks is reasonable, as higher concentrations appear to improve disease activity and significantly reduce inflammatory markers such as CRP.72 Patients who lose response may need to be switched to adalimumab or certolizumab.

From a health maintenance standpoint, patients should be evaluated for use of recommended vaccines; however, if patients are receiving immunosuppressants or biologic agents, the use of live or attenuated vaccines may be contraindicated. Patients who currently use tobacco should be encouraged to undergo tobacco cessation, as tobacco use will worsen CD. Since nicotine often improves symptoms in UC, it may be more difficult to cease tobacco use in this patient population. Choice of tobacco cessation products should also be based on current amount and patient preference. Nutritional status of patients should also be routinely assessed, and patient-specific diets or delivery, such as enteral or parenteral nutrition, should be implemented.

EVALUATION OF THERAPEUTIC OUTCOMES

The success of therapeutic regimens to treat IBD can be measured by patient-reported complaints, signs, and symptoms; by direct clinician examination (including endoscopy); by history and physical examination; by selected laboratory tests; and by QOL measures. Evaluation of IBD severity is difficult because much of the assessment is subjective. Disease rating scales, such as the CDAI or other indices, have been created to try and make disease assessment more objective. The CDAI is a commonly used scale for patients with nonfistulizing disease and for evaluation of patients during clinical trials.44 The scale incorporates eight elements: (a) number of stools in the past 7 days, (b) sum of abdominal pain ratings from the past 7 days, (c) rating of general well-being in the past 7 days, (d) use of antidiarrheals, (e) body weight, (f) hematocrit, (g) finding of abdominal mass, and (h) a sum of extraintestinal symptoms present in the past week. Elements of this index provide a guide for those measures that may be useful in assessing the effectiveness of treatment regimens. A decrease in CDAI of 100 points is considered a clinically significant response, with a score of <150 considered to be disease remission.44 A subsequent scale was developed specifically for perianal CD, known as the Perianal CD Activity Index (PDAI).44 The PDAI includes five items: presence of discharge, pain, restriction of sexual activity, type of perianal disease, and degree of induration. The HBI may also be used in place of the CDAI.

Standardized assessment tools have also been constructed for UC.43 Elements in these scales vary and include (a) stool frequency, (b) presence of blood in the stool, (c) mucosal appearance (from endoscopy), and (d) physician’s global assessment based on physical examination, endoscopy, and laboratory data. While these tools are often used for assessment of patients in clinical trials, they are sometimes used in the clinical setting as well.

Additional studies that are often useful include direct endoscopic examination of affected areas and/or radiocontrast studies. As mentioned earlier, mucosal healing is being explored as a major end point for patients with luminal disease.46 For patients with acute disease, assessment of fluid and electrolyte status is important, because these may be lost during diarrheal episodes. Other laboratory tests, such as serum albumin, transferrin, or other markers of visceral protein status as well as markers of inflammation such as ESR or CRP, may be used to monitor disease and drug therapy.

Assessment of the IBD patient must include consideration of adverse drug effects. Because many of the agents used have a relatively high probability of causing adverse effects, particularly corticosteroids and other immunosuppressive agents, patient assessment should include collection of history and physical and laboratory data that are necessary to prevent or recognize adverse drug effects.

Finally, a patient QOL assessment should be performed regularly.43,44 Inquiry should be made regarding patient’s general well-being, emotional function, and social function. Social function may include assessment of the ability to perform routine daily functions and to maintain occupational activities, sexual function, and recreation. The most common tool used to assess QOL is the Inflammatory Bowel Disease Questionnaire (IBDQ), a 32-item questionnaire that covers four disease dimensions: bowel function, emotional status, systemic symptoms, and social function. The IBDQ has shown good correlation with the CDAI.44 The standard short form-36 is often used as a measure of QOL in IBD intervention trials.43,44

ABBREVIATIONS

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