Medical Treatment of Ulcerative Colitis and Other Colitides

Ulcerative Colitis

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease that affects the mucosa of the colon. Even though the cause of the disease is unknown, certain risk factors such as cigarette smoking cessation, use of nonsteroidal antiinflammatory drugs (NSAIDs), and infections have been identified. The incidence of UC in the United States is 12 cases per 100,000 persons. The disease can present at any age. The incidence is similar in men and women and does not vary significantly by race. The most typical presenting features are rectal bleeding and diarrhea, but urgency to have bowel movements, tenesmus, abdominal pain, and extraintestinal manifestations are common.

The inflammatory process in UC begins in the rectum and extends proximally in a continuous distribution. The extent of disease is the single most important determinant of both prognosis and response to medical therapy. In a series of 1116 patients followed up for at least 5 years, 46% of patients presented with proctosigmoiditis, 17% had left-sided disease (to the splenic flexure), and 37% had pancolitis. Patients with pancolitis were more likely to experience toxic megacolon, refractory symptoms, malignancy, extraintestinal manifestations and to require surgery. The extent of the presentation often changes during the course of the disease, with 56% of patients who initially presented with limited disease experiencing a proximal extension of the inflammation. About 5% to 10% of patients with extensive UC have a mild inflammatory process of the terminal ileum, termed “backwash ileitis.” Patients with limited disease may have inflammatory changes in the peri-appendiceal area that are referred to as a “cecal patch.” This condition should not be confused with a skip lesion characteristic of Crohn disease.

The choice of treatment depends on the extent and severity of the disease. Most of the indices of disease severity are based on that developed in 1955 by Truelove and Witts ( Table 35-1 ). The “Montreal Classification” of 2005 is also useful ( Table 35-2 ). In this classification the parameters of disease severity are labeled as S1 (mild), S2 (moderate), and S3 (severe). S0 denotes quiescent disease, and extent of disease is represented as E1 (proctitis), E2 (left-sided or distal UC), and E3 (pancolitis).

TABLE 35-1

Truelove and Witts Classification of Disease Severity

Criteria	Mild Activity (S1)	Moderate Activity (S2)	Severe Activity (S3)
Bowel movements/day	≤4	≥4	≥6
Blood in stool	Small amounts	> 50%	Visible blood
Mean evening temperature	<37.5°C	≤37.5°C	≥37.5°C
Temperature 2 out of 4 days	<37.5°C	≤37.8°C	≥37.8°C
Pulse	<90 bpm	≤90 bpm	≥90 bpm
Sedimentation rate	<20 mm/hr	≤30 mm/hr	≥30 mm/hr
Hemoglobin	>11.5 g/dL	≥10.5 g/dL	≤10.5 g/dL

TABLE 35-2

Montreal Classification of the Extent and Severity of Ulcerative Colitis

Classification	Type of Disease	Description
E1	Ulcerative proctitis	Involvement limited to the rectum (proximal extent of inflammation is distal to the rectosigmoid junction)
E2	Left-sided UC (distal UC)	Involvement limited to a portion of the colorectum distal to the splenic flexure
E3	Extensive UC (pancolitis)	Involvement extends proximal to the splenic flexure

UC, Ulcerative colitis.

Clinically, a patient with mild disease is ambulatory and does not have systemic symptoms. These patients have fewer than four bowel movements per day, with or without the presence of blood. Moderate disease is associated with more than four bowel movements a day with minimal systemic manifestations. The simplest clinical measure to distinguish mild from moderately active colitis is the presence of mucosal friability (i.e., bleeding upon light contact with the rectal mucosa at sigmoidoscopy). Patients with severe disease are often bed bound, have more than six bowel movements a day with visible blood, and also have systemic symptoms. Although most acute flares of UC are mild and manageable on an outpatient basis, 15% of patients require hospitalization because they have more severe disease.

Diagnosis

The diagnosis of UC is based on typical endoscopic features (superficial ulcerations, granularity, and distorted mucosal vascular pattern extending from the rectum proximally in a continuous distribution), negative stool cultures, and exclusion of all reasonable alternatives in the differential diagnosis. The differential diagnosis of UC is presented in Table 35-3 . Ischemic bowel disease and diverticulitis are especially important diagnoses to exclude in the patient with UC who is initially diagnosed when he or she is older than 50 years.

TABLE 35-3

Differential Diagnosis of Ulcerative Colitis

Disease	Risk Factor	Evaluation
Amebic dysentery	Travel to high-risk areas	Antiamebic antibodies, fresh stool ova and parasites; typical punched-out ulcers on colonoscopy
Bacterial infection	Always a possibility; history	Stool culture, including Escherichia coli O157:H7
Clostridium difficile	Highest risk antibiotic use, immunosuppression, but may occur in any person	C. difficile toxin A & B Pseudomembranes on colonoscopy
Crohn disease	Always in the differential	Clinical history, patchy, longitudinal ulcers on colonoscopy + biopsy, small bowel imaging
Ischemic colitis	Hypotension, low-flow state	Limited distribution, patchy wide ulceration on colonoscopy and biopsy
Microscopic colitis	Suspect when a patient has nonbloody stool or a history of celiac sprue	Normal colon on colonoscopy; diagnosed with a biopsy
Viral or parasite	Travel history, epidemic, immunocompromised	Colonoscopy + biopsy, stool tests
Radiation colitis	Clinical history	Endoscopy + biopsy
Diverticular colitis	Age	Endoscopy + biopsy

Treatment

The goals of treatment in persons with UC are to induce remission, maintain remission, decrease complications of the disease, improve quality of life, and decrease the need for hospitalizations or surgery ( Table 35-4 ). Medical treatment for UC may be divided into conventional and alternative therapies. Conventional agents are those approved in the United States for use in persons with UC. Alternative therapies are treatments approved for other indications that are used to treat patients with UC. The treatment is divided in two phases: induction of remission and maintenance of remission.

TABLE 35-4

Medications Used in the Treatment of Ulcerative Colitis

Medication	Indication: Induction of Remission	Evidence Rating	Indication: Maintenance of Remission	Evidence Rating
5-ASA	Mild to moderate disease	A	Remission induced by 5-ASA	A
Corticosteroids	Moderate to severe disease	B	Not indicated
Anti-TNF-α	Moderate to severe disease	A	Indicated	A
Thiopurine	Not indicated		Indicated	B
Cell adhesion molecule inhibitor	Indicated		Indicated

A = Consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series.

5-ASA , 5-aminosalicylic acid; TNF, tumor necrosis factor.

Diet

Even though UC is considered a disease of the gastrointestinal tract, the role that diet plays in the cause and treatment of the disease is debatable. Some studies show that a diet high in refined sugar, meat, and fat increases the risk of UC. Conversely, a high intake of fruits and vegetables is associated with a decreased risk of UC. However, once a patient has UC, diet has not been shown to play a role in induction or maintenance of remission. During an acute exacerbation, it is important to maintain adequate nutrition. Anecdotally, patients with active UC appear to best tolerate a low-fiber diet, likely because of lower ingestion of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (the FODMAP diet). Complete bowel rest with total parenteral nutrition is not effective in patients with UC; the only situations in which nothing by mouth status is required are when the patient has toxic colitis or toxic dilatation of the colon or when the patient is being prepared for surgery.

5-Aminosalycilic Acid

Mild to Moderate Ulcerative Colitis

The first-line treatment of patients with mild to moderately active UC is 5-aminosalycilic acid (5-ASA), also known as mesalamine or mesalazine. The antiinflammatory action of 5-ASA is mostly topical and involves inhibition of cyclooxygenase, lipoxygenase, B cells, and several key inflammatory cytokines. 5-ASA also activates selective peroxisome proliferator–activated receptor ligand–γ. This nuclear receptor controls cell proliferation and apoptosis and modulates the inflammatory response of macrophages and monocytes. 5-ASA is more effective in the treatment of UC than of Crohn disease, likely because of the interaction of 5-ASA with the damaged epithelium. Because Crohn disease is transmural, a medication that works on the mucosa can be expected to have little effect on the course of the disease.

Sulfasalazine was the first 5-ASA compound used in the treatment of UC. It was synthesized in 1938 by Nanna Svartz and was first used for the treatment of “rheumatic polyarthritis.” Its effectiveness in treating UC was discovered soon after. Sulfasalazine is composed of a molecule of 5-ASA linked by a diazo bond to sulfapyridine. In the colon, bacterial azoreductases cleave the diazo bond, and the sulfapyridine that is responsible for most of the adverse effects of this medication is absorbed. Only a small fraction of the 5-ASA that is the active moiety responsible for the therapeutic effect is absorbed. This aspect is relevant because to be effective, 5-ASA needs to be in contact with the colonic mucosa.

The usual dose of sulfasalazine for induction of remission is 4 g per day; however, patients who are rapid acetylators require a higher dose of up to 6 g per day. Some investigators recommend decreasing the dose of mesalamine to 2 g daily for maintenance of remission. However, patients with frequent recurrence of symptoms when taking a lower dose and patients with more aggressive disease require higher doses of 5-ASA to maintain remission.

When 5-ASA is administered without a carrier, it is readily absorbed in the small intestine. Different preparations were developed to prevent this phenomenon. Alternative drugs are more costly, but they are also better tolerated, and a Cochrane systematic review showed a slight trend in benefit compared with sulfasalazine. However, if sulfasalazine is tolerated, it is the drug of choice because it is less expensive than other 5-ASA compounds. The 5-ASA compounds available in the United States are olsalazine (Dipentum), mesalamine (Asacol, Delzicol, Pentasa, Lialda, and Apriso), and balsalazide (Colazal; Table 35-5 ). Olsalazine is composed of two 5-ASA molecules linked by a diazo bond. Although olsalazine is effective, it is rarely prescribed because a profound secretory diarrhea occurs in more than 10% of patients. Asacol and Delzicol are delayed-release formulations that consist of 5-ASA in a pH-sensitive capsule. When the pH approaches 7 in the terminal ileum, the capsule dissolves and 5-ASA is released. Asacol can be taken with or without food, but Delzicol should be taken 1 hour before or 2 hours after meals. Balsalazide is 5-ASA linked by a diazo bond to an inert carrier molecule. Colonic bacterial cleavage of the diazo bond is required to release the 5-ASA. Therefore, balsalazide is effective only for colonic inflammation. Pentasa consists of 5-ASA packaged in a time-release ethylcellulose compound, releasing 5-ASA evenly throughout the small and large bowel. Two newer formulations that improve compliance because they are taken once daily, Lialda and Apriso, are available. Lialda is a proprietary delivery system based on Multi Matrix Technology. The formulation is composed of 5-ASA with hydrophilic and lipophilic excipients enclosed within a gastro-resistant, pH-dependent coating that releases in the terminal ileum. Apriso is mesalamine in a delivery system with the proprietary name Intellicor, which is a delayed and extended-release preparation. This preparation begins releasing mesalamine in the distal terminal ileum at a pH of 6 or greater and gradually distributes it throughout the colon.

TABLE 35-5

5-Aminosalicylic Acid Preparations Available in the United States and the Sites of Maximal Effect in the Gastrointestinal Tract

Medication	Unit Dose	Dose	Indication
Sulfasalazine	500 mg	2 to 4 g/day (3 divided doses)	Induction and maintenance of remission
Pentasa	250 mg; 500 mg ^∗	2 to 4 g/day (4 divided doses; 500 mg, two po qid)	Induction and maintenance of remission
Asacol HD Delzicol	800 mg 400 mg	800 mg 3 times daily 800 mg 3 times daily	Induction of remission Maintenance of remission
Balsalazide	750 mg	750 mg to 2.25 g 3 times daily	Induction of remission
Lialda	1200 mg	2.4 to 4.8 once daily	Maintenance of remission
Apriso	375 mg	1.5 g once daily	Induction of remission
Rowasa enemas	4 g	4 g once daily	Induction of remission, distal ulcerative colitis
Canasa suppositories	1 g	1 g/day	Induction and maintenance of remission

∗ 500 mg is the more commonly used unit dose.

The most common adverse effects of sulfasalazine are nausea, vomiting, dyspepsia, and headache. Sulfasalazine is also associated with decreased male fertility because of reversible sperm abnormalities caused by sulfapyridine. Sulfasalazine is a competitive inhibitor of folic acid absorption, and thus folate-binding proteins should be overwhelmed with an oral supplement of folic acid. Severe adverse effects including aplastic anemia and fibrosing alveolitis have been reported. Before starting sulfasalazine, it is recommended that a complete blood cell count (CBC) be performed, and a CBC should then be performed every 2 weeks for the first 3 months. After starting sulfasalazine, it is recommended that serum creatinine be monitored every 3 to 6 months for the first year and then annually. Adverse effects of mesalamine include headache, diarrhea, abdominal pain, pancreatitis, interstitial nephritis, dizziness, Stevens-Johnson syndrome, hypersensitivity reactions, and hair loss.

Proctitis and Left-Sided Ulcerative Colitis

Rectally administered 5-ASA preparations are the first-line treatment for ulcerative proctitis. These preparations are more effective than oral 5-ASA or topical steroids, which are used as second-line treatment in patients who are intolerant of topical 5-ASA. Rectally administered 5-ASA improves symptoms faster than orally administered 5-ASA, and except for rectal discomfort and cramps, it has fewer adverse effects because it is poorly absorbed. Some patients with proctitis have urgency related to decreased rectal compliance and cannot retain suppositories or enemas. A hydrocortisone foam formulation that is available in the United States is better retained and better tolerated than the liquid enema. When topical treatment is not tolerated, patients are treated with an oral 5-ASA.

Left-Sided Disease

Left-sided UC is disease that extends proximal to the rectum but stops distal to the splenic flexure. Patients with left-sided disease are best treated with an oral 5-ASA with or without rectally administered 5-ASA. In some patients with left-sided disease, the most significant symptoms are related to proctitis. In these patients, the combination of oral and rectal mesalamine is more effective than either therapy alone. In patients with mild to moderately severe disease, response rates are between 40% and 70%, and remission rates are 15% to 20%. Patients who do not respond to 5-ASA within 2 to 4 weeks, and patients whose symptoms worsen, should be treated with systemic steroids. 5-ASA is effective in maintenance of remission in patients with a first flare requiring treatment with steroids.

Extensive Disease

Similar to patients with left-sided disease, patients with extensive disease are best treated with oral 5-ASA with or without rectally administered 5-ASA. If there is no response to treatment, then oral corticosteroids are added to the treatment. If remission is not maintained as the steroids are tapered, or if the patient has frequent exacerbations, then administration of a thiopurine or a biologic agent is initiated.

Lack of Response to 5-Aminosalycilic Acid

In patients with mild or moderately active UC that does not respond to conventional treatment, it is important to exclude confounding factors such as cytomegalovirus (CMV) infection, Clostridium difficile infection, mesalamine-induced diarrhea, Crohn disease, NSAID use, and rare diseases such as Behçet disease, as well as common variable immunodeficiency. It is also important to question compliance with treatment regimens, particularly in single young college students and in patients treated with suppositories or enemas.

Oral Budesonide

Budesonide is a potent antiinflammatory corticosteroid with high glucocorticoid effect and minimal mineralocorticoid effect. An advantage of budesonide compared with conventional corticosteroids is that it has minimal adverse effects; however, it is very expensive. After absorption it is subject to high first-pass metabolism (80% to 90%) and is biotransformed to metabolites with negligible (<1/100) glucocorticoid effect. Therefore, to be effective, budesonide needs to be delivered to the colon to exert a therapeutic effect. Budesonide MMX is an oral preparation that uses Multi Matrix Technology to deliver the medication to the entire colon. It is indicated for induction of remission in patients with mild to moderately active UC. At a dose of 9 mg daily, clinical and endoscopic improvement is seen in 43% of patients, clinical remission occurs in 24%, and histologic healing occurs in 17%. Budesonide is not indicated for maintenance of remission. An enema preparation is available in Canada but not in the United States.

Corticosteroids

Severe Ulcerative Colitis

Severe UC is potentially life threatening. In patients with severe UC, oral or intravenous corticosteroids are effective in inducing remission. In patients with proctosigmoiditis, hydrocortisone enemas may be used; however, patients with severe proctitis tolerate foam formulations better than liquid enemas. The mode of action of corticosteroids is through inhibition of phospholipase A ₂ , causing a decrease in prostaglandin and leukotriene levels. Ambulatory patients who do not have signs of toxicity can be treated initially with oral corticosteroids. The dose of oral prednisone to achieve maximal effect with the fewest adverse effects is 0.75 to 1 mg/kg/day. The most commonly used dose is 40 to 60 mg/day. A dose higher than 60 mg/day has not shown to improve response and has more side effects. The dose of 0.75 to 1 mg/kg has been used in clinical trials and for a 60 kg person is 40-60 mg. A significant improvement is expected in the first 2 weeks of treatment, and the dose is then tapered. No trials of different tapering regimens have been performed. The most common recommendation is to taper the total daily dose of prednisone by 5 to 10 mg per week.

If a significant improvement is not seen after 3 to 5 days or if symptoms worsen, the patient should be admitted to the hospital for treatment with intravenous steroids. The most commonly used intravenous steroids are hydrocortisone, 100 mg three times a day or four times a day, or methylprednisolone, 20 mg three times a day; higher doses do not have a higher efficacy and should not be used.

Corticosteroids should be used with caution because significant adverse effects are associated with short- and long-term use. Principal adverse effects include infections, glucose intolerance, acne, moon face, insomnia, weight gain, fat deposition (particularly increased fatty tissue in the face, supraclavicular area, upper trunk, and back), psychosis, headache, hypertension, hyperlipidemia, hirsutism, striae, avascular necrosis, and myopathy.

Patients with severely active disease and signs of toxicity such as tachycardia, dehydration, fever, and continuous abdominal pain and those with electrolyte abnormalities are too sick to be managed on an outpatient basis. 5-ASA agents are not effective in this setting, and oral prednisone often is not effective. If symptoms do not improve within the first 72 hours of starting an intravenously administered steroid, then this treatment is discontinued and an alternative treatment is recommended. Surgery is often the best option in these patients, but salvage therapy with an anti–tumor necrosis factor–α agent, or intravenous cyclosporine, can be considered as long as the patient has no evidence of toxic colitis and the colon is not dilated. In a clinical trial of patients who did not respond to intravenously administered steroids, 17 of 24 patients (71%) improved and avoided a colectomy after a single dose of infliximab, 5 mg/kg. If no improvement occurs after one dose of infliximab, or if the patient does not respond to cyclosporine within 14 days (response is usually within the first 7 days), then surgery should be recommended. Patients with severe disease require close monitoring, including a daily plain radiograph of the abdomen. If at any moment evidence of impending perforation or worsening clinical status is noted, patients should undergo surgery. If cyclosporine induces remission, patients will need a thiopurine to maintain remission. If a patient responds to infliximab, use of this agent can be continued to maintain remission.

Cyclosporine

Cyclosporine, an 11–amino acid cyclic polypeptide, is used as an immunosuppressant in organ transplantation. It reversibly inhibits interleukin-2 (IL-2) gene transcription, which in turn reduces proliferation and activation of T-helper lymphocytes. Cyclosporine is 80% bound to lipoproteins, and because it is secreted in the bile, it requires an intact enterohepatic circulation to maintain levels. It is metabolized and inactivated by the hepatic cytochrome p450 system and by drugs that induce cytochrome p450 affect levels.

In a randomized clinical trial by Lichtiger et al, 20 patients with severely active UC who were refractory to intravenously administered steroids received intravenous cyclosporine, 4 mg/kg/day, or placebo. By day seven, 9 of 11 patients (82%) treated with cyclosporine had a clinical response compared with none of the 9 patients treated with placebo. The trial was terminated early because of ethical considerations. Patients who responded to intravenous cyclosporine were discharged with a prescription for oral cyclosporine. It is important to note that 6 of the original 11 patients (55%) had a colectomy within 6 months of discharge.

In 2013, Chang et al published a systemic review and meta-analysis of studies comparing cyclosporine and infliximab as rescue therapy in patients with steroid-refractory UC. Six studies with a total of 456 patients met the criteria for analysis. Data were available for 321 patients—142 treated with cyclosporine and 179 treated with infliximab. The colectomy rate for patients treated with cyclosporine and infliximab was similar at 3 and 12 months. At 3 months, 30% taking cyclosporine and 32% taking infliximab had a colectomy. At 12 months, colectomy rates were 45% for patients treated with cyclosporine and 42% for patients treated with infliximab. The studies included in the meta-analysis had a great variation in the colectomy rate at 3 months. For cyclosporine, the range was 6% to 63%, and for infliximab, it was 17% to 40%. The complication rate, including adverse drug reactions, postoperative complications, and deaths, was similar. In spite of the limitations of the meta-analysis, it appears that the short-term response to cyclosporine and to infliximab in patients with severe steroid-refractory UC who do not need urgent surgery is similar. When deciding on treatment, it is important to keep in mind that whereas infliximab is also effective in maintenance of remission, cyclosporine is effective only for induction of remission. In patients who do not require hospitalization, the bioavailability of oral microemulsion is similar to that of intravenous cyclosporine. Because cyclosporine has many drug interactions and adverse effects and drug levels need to be monitored, it should be prescribed only by physicians familiar with this medication, and usually in tertiary care centers. Nephrotoxicity, hepatotoxicity, hypertrichosis, gingival hyperplasia, tremors, paresthesia, seizures, and lymphoproliferative disorders are the most common adverse effects of cyclosporine.

Azathioprine and 6-Mercaptopurine

The purine analog 6-mercaptopurine (6-MP) causes chromosome breaks and has antiproliferative effects on activated lymphocytes. Because these medications are slow acting and an effect is usually not seen for 2 to 3 months, they are indicated for maintenance of remission and steroid sparing, and in some patients they improve and prolong the response of anti-TNF-α agents. The bioavailability of oral azathioprine (27% to 83%) is better than that of 6-MP (5% to 37%). After absorption, azathioprine undergoes a rapid nonenzymatic conversion to 6-MP. Subsequently there are three metabolic pathways that result in one active and two inactive metabolites. The active metabolite is 6-thioguanine nucleotide (6-TG), which has antiproliferative effects on activated lymphocytes and bone marrow. Its level is associated with the clinical response. The pathways of 6-MP to inactive metabolites are via thiopurine methyltransferase (TPMT) to 6-methylmercaptopurine (6-MMP), and via xanthine-oxidase to 6-thiouric acid. TPMT activity is determined by a genetic polymorphism. Approximately 10% of Caucasians and African Americans inherit one nonfunctional TPMT allele (heterozygous) and have intermediate TPMT activity, and 0.3% inherit two nonfunctional TPMT alleles (homozygous) and have low or absent TPMT activity. Nonfunctional alleles are less common in Asians. Low TPMT activity is associated with higher 6-TG levels and an increased risk of bone marrow toxicity.

Because one of the pathways of metabolism of these medications is via the xanthine oxidase system, in patients receiving allopurinol, a lower dose is used to decrease the risk of bone marrow toxicity. In patients with normal TPMT enzyme activity, the dose of azathioprine is 2 to 2.5 mg/kg/day, and for 6-MP it is 1 to 1.5 mg/kg/day. Regardless of the TPMT enzyme activity, blood tests are indicated in all patients. When the treatment is initiated, it is recommended that a CBC with differential be obtained once a week for 4 weeks, then every other week for 4 weeks, then once a month for 6 to 9 months, and every 3 months thereafter. Liver enzyme tests are performed 4 weeks after initiation of treatment and then every 3 months. Whenever the dose is adjusted, it is important to monitor the CBC every other week and liver tests every 4 to 12 weeks until a stable dose is achieved. It has been suggested that the dose of immunosuppressant be increased until mild leukopenia develops. However, 6-TG and 6-MMP can be measured, and it appears that the efficacy and safety are improved by following the blood level. In persons with Crohn disease, clinical remission is correlated with an erythrocyte 6-TG level greater than 230 pmol/8 × 10 ⁸ red blood cells (RBCs). In UC the data are lacking, but the therapeutic level is likely similar. In patients who respond to treatment, the value of measuring metabolites is debatable, because it increases the cost of care and is not likely to improve outcomes. However, in patients who do not respond to treatment, monitoring metabolite levels to ensure a therapeutic 6-TG level of 235 to 400 pmol/8 × 10 ⁸ RBC helps determine whether the lack of response is due to poor compliance, absorption problems, or problems metabolizing the medication. If the 6-TG level is low, as long as the white blood cell count is greater than 3, results of liver tests are normal, and the 6-MMP is not greater than 5600, the dose can be adjusted.

Azathioprine and 6-MP have a more favorable adverse effect profile than do corticosteroids. As with all immunosuppressive agents, the risk of infections is increased. In approximately 2% of patients the drugs will need to be discontinued as a result of bone marrow suppression; in addition, 3% will experience acute pancreatitis and 2% will experience an allergy characterized by abdominal pain, high fever, joint stiffness, and rash. According to population-based studies and a meta-analysis, patients have a two- to fourfold increased risk of lymphoma and of nonmelanoma skin cancers. It is important to advise patients to use sunscreen cream and to see a dermatologist on a yearly basis for a skin examination.

Biologic Agents

The advent of biologic agents is one of the most significant advances in the treatment of inflammatory bowel disease (IBD). The two classes of biologic agents used in UC are anti-TNF-α and antiadhesion molecules. Infliximab was approved for induction and maintenance of remission in UC in 2005, followed by adalimumab in 2012 and golimumab in 2013. The antiadhesion molecule vedolizumab was approved in 2014. Given this timeline, there is vast experience with the use of anti-TNF-α agents in UC, but the information on the clinical use of antiadhesion molecules is limited. Infliximab is administered intravenously, whereas adalimumab and golimumab are administered by subcutaneous injection. The three agents are monoclonal antibodies against TNF-α. Infliximab is a chimeric monoclonal antibody consisting of 75% human immunoglobulin (Ig)G and 25% murine components that actively bind membrane-bound and membrane-soluble TNF-α. Adalimumab and golimumab are subcutaneous recombinant humanized monoclonal IgG1 TNF-α antibodies that have only human peptide sequences. Similar to infliximab, adalimumab and golimumab bind TNF-α with high affinity and neutralize its activity by blocking the interaction between this cytokine and the cell surface receptors. The efficacy of anti-TNF-α agents in induction of remission is similar to that of glucocorticoids.

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