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).
| 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 |
| 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 |
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.
| 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.
| 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 |
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.
| 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 |
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.
Infliximab
Infliximab is indicated for the induction and maintenance of remission in adults and in children 6 years of age and older. The initial dose is 5mg/kg intravenously at 0, 2, and 6 weeks. In patients with a clinical response, it is continued at the same dose every 8 weeks. In a Cochrane analysis, at 8 weeks, infliximab was more effective than placebo in inducing clinical remission (odds ratio [OR], 3.22; 95% confidence interval [CI], 2.18 to 4.76); endoscopic remission (OR, 1.88; 95% CI, 1.54 to 2.28) and clinical response (OR, 1.99; 95% CI, 1.65 to 2.41). Patients who do not respond to the first two doses are not likely to respond at all, and a different treatment should be initiated.
Loss of Response
It is known that antibodies can develop in patients receiving anti-TNF-α agents with a loss of response to treatment. The most significant determinant for the formation of anti-infliximab antibodies is episodic treatment with long intervals between infusions. When infliximab treatment is episodic, anti-infliximab antibodies are detected in 30% to 60% of patients, compared with only 7% to 10% when infliximab treatment follows a schedule. Anti-infliximab antibodies are important because patients with high titers have a higher frequency of infusion reactions and/or loss of response. When patients lose response to infliximab, measurement of drug level and antibodies can guide treatment. Some of these patients regain response when the dose of infliximab is increased or when it is administered at shorter intervals. A higher dose or more frequent administration increases the cost of care and decreases patients’ quality of life, and eventually infliximab is discontinued because of adverse effects or lack of response. Anti-infliximab antibodies are directed against the murine portion of the molecule; therefore, a patient in whom response is lost as a result of antibody formation may respond to a different anti-TNF-α agent.
Infusion Reactions
Mild infusion reactions occur in 5% to 13% of patients, but severe infusion reactions requiring infliximab discontinuation occur in 1% or fewer of patients. These reactions can occur while the medication is being infused, within 2 hours of finishing the infusion, or 3 to 12 days after the infusion. The most common immediate infusion reactions include fever, chills, headache, chest tightness, shortness of breath, tachycardia, hypotension or hypertension, and rash. These infusion reactions are not true allergic type 1 IgE-mediated reactions. Mild reactions usually respond to slowing or stopping the infusion, and in most patients the infusion can be completed. When the reaction is more severe, the symptoms usually respond to the administration of an antipyretic agent, an antihistamine, and intravenous steroids. In severe cases, the administration of epinephrine and hospitalization for observation are required. Infusion reactions are anaphylactoid reactions to the murine component of the medication and not true anaphylactic reactions.
Delayed Reactions
Delayed reactions occur 3 to 12 days after the administration of infliximab. These reactions result from the activation of circulating antibody-antigen complexes. There is no change in levels of serum complement, however, so these reactions are better termed “serum sickness–like” reactions. Delayed infusion reactions have been reported in as many as 25% of patients who resume infliximab 2 to 4 years after the last dose, and 60% of reactions are severe.
Adalimumab
Two clinical trials explored the benefit of adalimumab in induction and maintenance of remission in UC. The main differences between the trials were whether or not patients had received infliximab, and in the trial with patients who were biologic naïve, besides the induction regimen of 160 mg/80 mg/40 mg every other week, there was a separate induction arm of 80 mg/40 mg/40 mg. The endpoints were clinical remission at week 8 and week 52. The benefit of treatment was modest; remission at 8 weeks was observed in 21.3% of patients naïve to anti-TNF-α (32/150) and in 9.2% of patients with prior exposure (9/98), compared with 11% (16/145) and 6.9% (7/101) in patients who received placebo. The remission rate at 52 weeks in patients naïve to anti-TNF-α was 22% (33/150), and in patients with prior exposure it was 10.2% (10/98), compared with 12.4% (18/145) and 3% (3/101) in patients who received a placebo.
Golimumab
Golimumab is effective in induction and maintenance of remission in patients with moderate to severely active UC. Published, randomized, double-blind, placebo-controlled studies include a phase II dose range study with 291 patients and a phase III efficacy study with 774 patients. For induction of remission, an initial dose of 200 mg by subcutaneous injection is followed by 100 mg 2 weeks later. At 6 weeks, improvement is observed in about 52% of patients and remission is observed in about 18% of patients. In patients with a clinical response, the maintenance dose is 100 mg every 4 weeks. At 1 year, a sustained clinical response is seen in about half the patients.
How to Choose an Anti-TNF-α Agent
Because no head-to-head studies have been performed to compare infliximab with Humira, and because clinical trials have different endpoints, the decision about which agent to use depends on cost and the patient’s preference. In a single-center long-term follow-up of a cohort of patients treated with adalimumab or infliximab, the response rate as assessed by normalization of bowel movements, absence of rectal bleeding, and cessation of corticosteroid use was similar. The response to the induction regimen for infliximab was 96.4% (27/28), and for adalimumab it was 80.0% (20/25). The efficacy of both agents in maintenance of remission was also comparable; for infliximab it was 77.8%, and for adalimumab it was 70.0%.
Complications
Infections are one of the most common and significant complications related to the use of these medications. Infections can be either a result of reactivation of “latent organisms” or they can be opportunistic infections, particularly those in which the infection is controlled by macrophages. Some of the most significant infections that have been reported include tuberculosis, aspergillosis, histoplasmosis, bacterial infections such as Listeria monocytogenes, and viral infections such as CMV. Other complications that have been reported are optic neuritis, peripheral neuropathy, seizures, and new-onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, liver toxicity, drug-induced lupus, and worsening of congestive heart failure. Treatment with biologic agents is frequently associated with autoimmunity with the formation of antinuclear antibodies (ANAs) and antibodies to double-stranded deoxyribonucleic acid, particularly in women. The development of ANAs is no reason to discontinue therapy. In some patients, use of anti-TNF-α must be discontinued because of a severe psoriasiform reaction characterized by a pruritic and papulosquamous rash.
What to Do Before Starting Anti-TNF-α Therapy
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Confirm the diagnosis.
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Ensure that symptoms are related to active disease through use of C-reactive protein, fecal markers of inflammation, and flexible sigmoidoscopy.
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Exclude infections such a C. difficile and CMV.
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Exclude contraindications such as hepatitis B, hepatitis C, tuberculosis, human immunodeficiency virus, moderate to severe heart failure, history of lymphoma, current malignancy, multiple sclerosis or other demyelinating disease, optic neuritis, and active infections.
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Exclude congenital or acquired immunodeficiency.
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In patients with severe disease, obtain a kidney-ureter-bladder radiograph taken in the upright position.
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Review and update vaccinations. Women between 9 and 26 years of age should receive a human papillomavirus vaccination, a pneumonia vaccine should be administered every 5 years, and a hepatitis B vaccine should be administered. If mumps and rubella vaccines are administered, wait 6 weeks before beginning treatment with an immunosuppressant agent.
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In patients with a history of varicella, herpes zoster, or varicella vaccination, assess antibody titers. If a varicella-zoster virus vaccine is administered, do not start an immunosuppressant agent for 3 weeks.
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Provide the patient with information about the therapy.
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Use combination treatment with a thiopurine. Limit such treatment to less than 2 years in patients younger than 35 years and do not use such treatment in patients older than 65 years.
What to Do Once Treatment with an Anti-TNF-α Agent Is Started
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Remind patients to protect against ultraviolet radiation and to have an annual dermatologic examination.
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Perform a yearly screening for human papillomavirus and cervical dysplasia in women.
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Test for latent tuberculosis and hepatitis B in patients without immunity every 1 to 3 years.
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Administer a flu vaccine annually; do not use nasal attenuated virus.
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Administer a pneumonia vaccine every 5 years.
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Withhold infliximab and adalimumab in the last trimester of pregnancy.
Antiadhesion Molecules
A characteristic of IBD is the abnormal recruitment of leukocytes, particularly T cells, and the retention of these cells at the site of inflammation. Leukocytes circulate in blood vessels, and the endothelial cells serve as a barrier between the leukocytes and the intestinal mucosa. Endothelial cells have various adhesion and homing receptors and ligands (addressins). Mucosal addressin–cell adhesion molecule-I (MAdCAM-I) is an addressin that is primarily expressed in high endothelial venules in the small intestine and in Peyer patches and in the colon. Leukocytes have a variety of transmembrane glycoproteins such as L-selectins and integrins that are integral part of the cytoskeleton of the cell. These integrins are transmembrane receptors that can dynamically alter their adhesive properties and interact with endothelial adhesion receptors. The interaction of α4β7 integrin and MAdCAM-I is believed to contribute to chronic inflammation in the intestine.
Vedolizumab is a humanized IgG1 monoclonal antibody against α4β7 integrin. It blocks lymphocyte transit only in the gut and does not block lymphocyte transit in other tissues; therefore, the effect is “gut specific.” In a phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy of vedolizumab in induction and maintenance of remission, patients with moderately to severely active UC were enrolled who had not responded to either a thiopurine or an anti-TNF-α agent. At week 6, the proportion of patients in clinical remission in the vedolizumab arm was 47% compared with 25% in the placebo arm (95% CI, 11.6 to 31.7; P <.0001). Patients were subsequently enrolled in a maintenance of remission study. At 52 weeks, 42% of patients receiving vedolizumab, 300 mg every 8 weeks, and 45% of patients receiving vedolizumab, 300 mg every 4 weeks, were in clinical remission, compared with only 16% of patients receiving placebo.
Alternative Therapies
Nicotine
Since the initial observation in 1976 by Samuelsson that persons who were smokers were lacking in cohorts of patients with UC, numerous studies of the relationship of cigarette smoking and UC have confirmed that UC is primarily a disease of nonsmokers and ex-smokers. Interesting case reports and remarkably consistent epidemiologic studies have shown that cigarette smoking confers protection from the development of UC. At time of diagnosis, fewer than 20% of patients with UC are smokers, compared with a smoking rate of up to 35% in the U.S. adult population. In a 1989 meta-analysis by Calkins, the pooled odds ratio for UC in smokers versus nonsmokers was 0.41 (95% CI, 0.34 to 0.48), and in former smokers versus nonsmokers it was 1.64 (95% CI, 1.36 to 1.98). Furthermore, the protective effect of nicotine is dose dependent, and current smokers with UC have milder disease with fewer relapses, reduced need for steroid use, and a lower hospitalization rate compared with nonsmokers.
Randomized clinical trials comparing transdermal nicotine versus placebo have shown that the use of transdermal nicotine is superior to placebo for induction of remission in patients with UC. However, most randomized clinical trials were small, and many patients withdrew because of adverse effects. Therefore, until evidence from clinical trials shows that nicotine is effective, transdermal nicotine is not indicated for induction of remission in persons with UC. The only group of patients in whom it is reasonable to use transdermal nicotine as adjuvant treatment is ex-smokers with mild or moderately active UC. With the use of a nicotine patch instead of nicotine gum, the typical adverse effects of “nicotine rush” (i.e., a parched throat, tachycardia, a headache, and nausea) are lessened. Nicotine addiction is not a problem if therapy lasts less than 8 weeks. Maintenance therapy with nicotine patches is not effective. Active smokers with UC should be encouraged to stop smoking and use alternative formulations of nicotine.
Clinical Scenarios
Various common clinical scenarios for patients with UC suggest different treatment strategies; some of these strategies are summarized in Table 35-6 .
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