Chapter 41. Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that affects mainly the gastrointestinal (GI) tract and consists of two major subtypes, ulcerative colitis (UC) and Crohn disease (CD). The incidence of UC in the United States is estimated to be 2 to 7 cases per 100,000 population per year, while CD is reported as approximately 5 cases per 100,000 population per year.1,2 While the underlying pathophysiology of IBD involves an abnormal response directed against the intestinal tract, the true cause of IBD has not been identified.2,3 Both genetic and environmental factors have been implicated as contributors to the development of IBD.4 Inflammatory bowel disease has been observed to occur more commonly in patients who report a positive family history of IBD.5 Another leading theory is that the inflammatory response is induced by the local bacterial flora that inhabit the human GI tract.3-6 Ultimately, the inflammatory response results in injury to the GI tract that may vary in location, depth, severity, and duration.

While both forms of IBD involve inflammation of the GI tract, there are some key differences between UC and CD. Ulcerative colitis is localized to the colon and is characterized by diffuse continuous mucosal inflammation with the absence of granulomatous changes.1,5 The rectal area is involved in 95% of patients with UC.1 In contrast, CD may affect any area of the GI tract, but most frequently involves the ileum or colon.2,4 The inflammation is often observed to be discontinuous in nature, resulting in "skip lesions," and often penetrates much deeper into the intestinal wall compared to UC.5 Inflammation confined to the intestinal wall is referred to as luminal CD, and may progress to fibrostenotic disease with development of strictures and luminal obstruction. Likewise, severe inflammation resulting in fistula formation occurs in 20% to 40% of patients with CD, while patients with UC do not develop fistulae.2

Due to the location and inflammatory nature of the disease, most patients with UC will present with bloody diarrhea, urgency, and tenesmus as their main symptoms.1,4 Patients with CD may exhibit similar symptoms, but most commonly present with diarrhea, abdominal pain, weight loss, fever, perianal lesions, and signs of malnutrition.2 Interestingly, patients with IBD may also develop inflammation in various other organ systems, referred to as extraintestinal symptoms. Examples include arthritis, erythema nodosum, pyoderma gangrenosum, uveitis, episcleritis, and primary sclerosing cholangitis, among others.7

The diagnosis of IBD is based collectively on presenting signs and symptoms, along with radiographic and endoscopic findings. Endoscopy is particularly helpful in characterizing the extent and location of the disease, as well as ruling out other potential causes of intestinal inflammation. Determining where the disease is located also directly impacts selection of drug therapy. Patients with UC can be classified as having "extensive" disease if inflammation extends proximal to the splenic flexure.1 The terms "distal" or "left-sided" disease is used if inflammation is distal to the splenic flexure.1,8 Lastly, ulcerative proctitis denotes inflammation localized to the rectum, while proctosigmoiditis involves both the rectum and sigmoid colon.8 While these terms are used for denoting the subtype of UC based on extent and location of inflammation, the extent and location of CD is also determined via endoscopy in a similar manner.2,6

Disease severity in UC is classified based on various parameters, such as the number and characteristics of stools per day, presence of systemic signs of inflammation, such as fever or elevated erythrocyte sedimentation rate, among others. The designations used for UC are mild, moderate, moderate severe, and fulminant.1 While a validated scoring system, the Crohn Disease Activity Index, may be used to classify disease severity, a similar designation to UC also exists and includes classifications of mild-moderate, moderate-severe, and severe/fulminant disease.2

Once disease extent, location, and severity have been determined, pharmacologic therapies may be instituted to address the underlying inflammation. Major goals of drug therapy are to suppress acute inflammation, improve patient symptoms and quality of life, avoid or minimize toxicities, and prevent complications of the disease. Drug therapies should aim to induce disease remission, and then maintain long-term remission if possible. Extraintestinal manifestations of IBD also need to be managed in conjunction with the GI aspects of the disease. In some instances, patients who are refractory to medical therapy or develop severe complications may require surgical intervention.

An important aspect of drug therapy for IBD is that the choice of drug therapy depends on the disease subtype, as well as the severity and location of the disease. More severe or extensive forms of IBD may require administration of systemic medications, either in oral or parenteral forms. Alternatively, disease that is mild or moderate in nature and is located in areas distal to the splenic flexure may be treated with rectal dosage forms, also referred to as "topical" therapies.1,2,8 Suppositories can be used to treat up to 20 cm of the rectal area and are preferred for patients with proctitis.1,8 Enemas may reach inflammation that extends to the splenic flexure and thus may be used for patients with left-sided disease.8 Oral formulations of some drugs used in the management of IBD are designed to release in specific areas of the small or large intestine and should be chosen based on the target area of inflammation. Systemic and topical therapies may be combined for maximal effectiveness. As many drug therapies for IBD may have serious adverse effects or complicated dosing regimens, counseling to promote patient adherence is key to obtain the optimal outcome.9

Aminosalicylates

The aminosalicylate drug class consists of the prototypical agent sulfasalazine and other agents formulated to deliver mesalamine, also known as 5-aminosalicylate or 5-ASA, the active component of sulfasalazine, to various locations within the GI tract (Table 41-1). Sulfasalazine consists of mesalamine bound to sulfapyridine via a diazo bond.10,11 When administered orally, bacteria located in the colon cleave the diazo bond and release mesalamine which acts locally in the colon. The sulfapyridine component is systemically absorbed. Patients with allergies to sulfonamides should avoid sulfasalazine, as the sulfapyridine component may lead to hypersensitivity reactions. Adverse effects from sulfasalazine are mostly related to the sulfapyridine component and may be dose related or idiosyncratic. Common adverse effects are nausea, diarrhea, headache, and abdominal pain.12

Newer formulations of mesalamine lack the sulfapyridine component and deliver the drug to the GI through various delayed release mechanisms.13 All of these formulations are safe to use in patients with allergies to sulfonamides. Some products use inert carrier molecules in place of sulfapyridine, such as balsalazide (Colazal), while others, such as olsalazine (Dipentum), use two molecules of mesalamine linked via a diazo bond to deliver the drug to the colon. Other formulations use pH-dependent coated tablets (Asacol) or microgranules (Pentasa). The newest formulations of mesalamine use pH-dependent multimatrix tablets (Lialda) or granules with a polymer matrix (Apriso) to allow for once daily dosing and improved patient adherence. Lastly, mesalamine is also available as a suppository or an enema, which are preferred formulations for patients with distal disease.8,14 The nonsulfa-containing aminosalicylates are better tolerated than sulfasalazine and thus are used more often.

The choice of an aminosalicylate is based on the type of disease, as well as the location and severity. The formulation of drug chosen should release or deliver mesalamine to the site of inflammation. The aminosalicylates can be used in UC for both induction and maintenance of remission in patients with both distal or extensive mild to moderate disease.1,8 The aminosalicylates can be also be used in mild to moderate CD, but appear to be less efficacious than in UC. Patients should be instructed to take the appropriate number of tablets or capsules and not to crush or break them. Likewise, proper instruction on use of suppositories and enemas will ensure maximal effectiveness.

Corticosteroids

Corticosteroids have potent anti-inflammatory effects and do have specific roles in the management of IBD. The main role for corticosteroids in IBD is to rapidly suppress inflammation in patients with moderate to severe symptoms or in those patients unresponsive to aminosalicylates.15 There are many different formulations of corticosteroids available including oral, parenteral, and topical agents. In general, short courses (7-10 days) of oral prednisone at doses of 40-60 mg daily are used for moderate to severe UC and CD.1,2 Parenteral hydrocortisone or methylprednisolone can be used for hospitalized patients with severe disease. Budesonide (Entocort), a corticosteroid with limited systemic bioavailability, is formulated to release in the ileum and ascending colon and can be considered a first-line agent in the management of mild-moderate CD in place of an aminosalicylate.2,16 Topical hydrocortisone products, available as enemas or suppositories, can be used for patients with distal disease who do not initially respond to aminosalicylates.8 Corticosteroids are generally ineffective for treatment of fistulae associated with CD.15

Despite their ability to rapidly suppress inflammation, corticosteroids are ineffective as long-term treatments and have no role in the maintenance of remission of IBD.1,2,15,16 The potential for serious adverse effects precludes the long-term use of these agents. Patients who become corticosteroid dependent may develop hypertension, osteoporosis, glucose intolerance, and psychiatric disturbances among others.12 Thus, efforts should be made to limit corticosteroid exposure and to utilize other agents that may have steroid-sparing effects should patients become dependent on steroids for controlling their disease.

Immunomodulators

Immunomodulators, such as azathioprine, 6-mercaptopurine (6-MP), and methotrexate, have potent immunosuppressive effects and are used mostly as maintenance therapy in IBD, particularly for patients who are resistant to or dependent on corticosteroids2,15 (Table 41-2).

Azathioprine is the pro-drug of 6-MP, and requires hepatic activation to 6-MP following absorption. 6-MP is then taken up into the cell and further metabolized by various enzymes, including xanthine oxidase and thiopurine methyltransferase (TPMT).17 Genetic polymorphisms in the TPMT enzyme may predispose patients to toxicity from azathioprine and 6-MP, so patients should have TPMT activity or genotype evaluated prior to initiating therapy.2,17,18

Oral azathioprine 2 to 3 mg/kg/d or 6-MP 1 to 1.5 mg/kg/d are recommended as maintenance therapy, following steroid-induced remission, in patients with moderate to severe IBD or in those who have failed corticosteroids or aminosalicylates.1,2,15,16 Recent data also suggest that azathioprine in combination with infliximab is better than either drug alone in biologic or immunomodulator naïve patients with CD.19 Both azathioprine and 6-MP have delayed effects and often take >3 to 4 months to work.15,17 Toxicities associated with azathioprine and 6-MP include bone marrow suppression, hepatitis, pancreatitis, rash, fever, arthralgia, lymphoma, and diarrhea.12 Patients should have complete blood cell counts and liver transaminases monitored regularly during treatment.2

Methotrexate is a folate antagonist that is used mostly in CD as a maintenance therapy. Like azathioprine and 6-MP, methotrexate has a slow onset of action and thus is not used as an induction therapy in patients with active disease. Methotrexate has steroid sparing effects in patients with steroid dependence and can be also used in patients who are steroid refractory.2,15,16 Weekly intramuscular or subcutaneous doses of 15 to 25 mg are recommended for patients with CD.2 Potential toxicities associated with methotrexate therapy include nausea, abdominal pain, diarrhea, bone marrow suppression, pneumonitis, and hepatotoxicity.12 Methotrexate is teratogenic and should be avoided in women of child-bearing age. If therapy is deemed necessary, then reliable forms of contraception should be used.20

Biologic Therapies

Several biologic agents have now been approved for both the treatment of acute, active IBD and for maintaining remission (Table 41-2). The most widely used biologic agents are designed to antagonize the effects of tumor necrosis factor alpha (TNF-α) and include infliximab, adalimumab, and certolizumab.21 These agents are typically indicated for patients with moderate to severe disease as an alternative to corticosteroids, for patients who are steroid dependent, or those that have failed other therapies. The TNF-α antagonists are the drugs of choice for patients with fistulizing CD.22 All of the TNF-α antagonists require parenteral administration and are very costly compared to the available oral therapies.

Infliximab is a chimeric antibody that is given intravenously and is indicated in both moderate to severe UC and CD, with specific indications in pediatric and fistulizing CD. Doses of 5 mg/kg intravenously given at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks are typically used.2,15 Due to it chimeric structure, antibodies to infliximab may develop over time, which may lead to subsequent loss of efficacy.23 Adalimumab is a fully humanized antibody to TNF-α that is approved only for moderate to severe CD. Adalimumab is given subcutaneously at dose of 160 mg on day 1, then 80 mg on day 15 of therapy, followed by 40 mg subcutaneously every other week starting on day 29 of therapy. Since it is a humanized molecule, it may be used in patients who develop loss of efficacy to infliximab due to antibody development or as a first line biologic agent.23 Certolizumab is a pegylated, humanized, antigen-binding fragment with complementary determining regions derived from a murine source.21 Certolizumab is given subcutaneously at a dose of 400 mg initially, and then at 2 and 4 weeks followed by 400 mg subcutaneously every 4 weeks if an initial response is achieved.24 Patients with initial C-reactive protein concentrations >10 mg/dL tend to respond better to certolizumab compared to those with concentrations <10 mg/dL.23,24

All of the TNF-α antagonists carry a risk of serious potential adverse effects, particularly predisposition to infections. Prior to initiating therapy with a TNF-α antagonist, patients should be evaluated for latent tuberculosis.25 Patients being evaluated for possible TNF-α therapy should not have a current serious infection or sepsis. Heart failure may be precipitated or worsened, so use should be avoided in patients with advanced heart failure. Infliximab may cause infusion-related reactions, such as urticaria, erythema, dizziness, and nausea, which can be managed by slowing the infusion or premedicating with acetaminophen and diphenhydramine.2,12,15 Delayed infusion reactions may also occur, ranging from 3 to 14 days after the injection, and may consist of myalgia, fever, rash, urticaria, and pruritis.2 Due to their administration as subcutaneous injections, adalimumab and certolizumab carry a lower risk of injection-related adverse effects. Other less common adverse effects of TNF-α antagonists include a lupus-like syndrome, lymphoma, and nerve demyelination.15

In addition to the TNF-α antagonists, natalizumab is the only other biologic agent approved for IBD. Natalizumab is a humanized monoclonal antibody that prevents leukocyte α-4 mediated adhesion, preventing transmigration across endothelial cells.23 It is indicated for the induction and maintenance of remission of moderate to severely active CD in patients who have failed other therapies, including TNF-α antagonists. It is administered intravenously at a dose of 300 mg initially, and then 300 mg intravenously every 4 weeks. An important aspects of natalizumab therapy is that patients who do not respond within 12 weeks of treatment have little chance of experiencing efficacy and should have therapy discontinued.23,26 Natalizumab also carries a risk of progressive multifocal leukoencephalopathy and is only available by registering through the manufacturer's prescribing program. Patients should be monitored for any signs of neurologic abnormality while receiving natalizumab. Infusion-related reactions and hepatotoxicity have also been reported.12

Antibiotics

Given that bacteria may play a role in the pathogenesis of IBD, antibiotics have been observed to have some roles in IBD treatment. Metronidazole and ciprofloxacin are the two most-studied antimicrobial agents used in IBD therapy.27 These two agents are recommended in patients with UC who develop pouchitis following ileoanal pouch anastamosis.1 In patients with CD, metronidazole alone or in combination with ciprofloxacin has the most favorable effects as short-term adjunctive therapy in patients with colonic, perianal, or fistulizing disease.2,22,25,27 Common adverse effects of metronidazole include nausea, diarrhea, and metallic taste. Long-term use is associated with the development of peripheral neuropathy and should be avoided if possible.2,12,22 Ciprofloxacin may be associated with diarrhea, particularly overgrowth of Clostridium difficile, and may also precipitate tendon rupture in rare instances.12

Special Considerations

Patients with active IBD may be at risk for development of acute colonic dilation, also known as toxic megacolon, particularly if medications are used that decrease intestinal motility. Patients with active disease should have drugs such as loperamide, narcotics, and anticholinergic agents discontinued.28 Patients who receive prolonged courses of corticosteroids may require calcium and vitamin D supplementation for prevention of bone loss and possible use of a bisphosphonate as preventative therapy.1,29 Patients who smoke have a higher risk of steroid dependence, so efforts should be made to institute smoking cessation techniques or therapies, particularly in patients with CD.2 Nicotine replacement therapy, typically with a patch, is a viable adjunctive treatment option in UC, and appears to be most efficacious in ex-smokers.1,8 Lastly, patients who undergo multiple surgeries for IBD may require long-term parenteral or enteral nutrition, particularly if they develop short bowel syndrome.1,2,25

• IBD consists of both UC and CD and is considered an inflammatory disorder with no known definitive cause.
• Differences exist between UC and CD in regards to disease location, depth and pattern of inflammation, and presenting signs and symptoms.
• Patients may also manifest extraintestinal symptoms of IBD, such as arthritis.
• Choice of drug therapy for active IBD should be based on the subtype of IBD, the disease location and severity, and considerations of potential contraindications to therapy.
• Aminosalicylates are generally first-line agents for UC and CD and should be chosen based on the formulation that will deliver the active component, mesalamine, to the site of inflammation.
• Topical mesalamine products are preferred for patients with distal disease.
• Corticosteroids are used short-term in the setting of active IBD and should not be used as maintenance therapy.
• Immunomodulators, such as azathioprine and methotrexate, are used for long-term maintenance therapy, particularly for patients who are steroid dependent.
• Biologic agents that antagonize TNF-α can be used as first-line therapies for moderate to severe IBD and are the drugs of choice for fistulizing CD.
• TNF-α antagonist use predisposes patients to the development of serious infections.
• Antibiotics are considered adjunctive therapies in patients with fistulizing or perianal CD.