As with Crohn’s disease (CD), the goals of medical therapy in patients with ulcerative colitis (UC) are to (i) induce clinical remission, (ii) maintain clinical remission, (iii) improve the quality of life, and (iv) minimize toxicity from medical therapy. While a host of medications can be used to achieve these goals in patients with UC, several questions should be answered when formulating strategies before treatment is initiated. First, what phase of treatment is being initiated? Medications used to induce remission in UC can differ from those used to maintain remission. Second, what is the patient’s baseline disease severity at the time induction therapy is started? Disease severity can be measured objectively via a variety of validated indices, such as Truelove and Witts classification system discussed in Chapter 4 (1). Practically, however, the physician global assessment is often used to classify a patient’s disease activity into mild, moderate, and severe groups. This differentiation is an important step prior to induction therapy since, for example, the aminosalicylates are unlikely to benefit a patient with severe disease. Third, what is the anatomic extent of the disease? Patients with disease limited to the rectum (ulcerative proctitis or UP) or disease distal to the splenic flexure (left-sided colitis) often respond well to topical aminosalicylates or topical steroid therapy. Lastly, searching for factors either masquerading as or driving forward a UC flare is suggested. Examples include searching for infections, such as Clostridium difficile or cytomegalovirus, assessing for use of nonsteroidal anti-inflammatory drugs, and exclusion of superimposed functional bowel disorders.

The purpose of this chapter will be to focus on both traditional and nontraditional therapies for UC. Use of biologic therapies will be discussed in a separate chapter. A comprehensive discussion, including mechanisms of action and side effects of each agent, is beyond the scope of this review. Instead, we will provide a brief summary of the evidence for the use of each agent as well as highlight challenges associated with the use of specific medications.

The aminosalicylates (5-ASA) have been shown to be highly effective in inducing clinical response in patients with mild to moderate UC, with studies reporting response rates of 40% to 80% (2, 3, 4, 5 and 6). Sulfasalazine (SASP) was the first agent in this class used to induce remission in patients with UC (7). Subsequent 5-ASA formulations have been designed to eliminate the sulfa moiety of SASP, which is associated with many of its side effects (8). Newer formulations release 5-ASA into the intestines through several mechanisms, including pH-release mesalamine (Asacol), timerelease mesalamine (Pentasa), delayed-release mesalamine (Lialda), or release via the action of azoreductases of colonic bacteria on the azo-bond compounds, balsalazide (Colozal) and olsalazine (Dipentum). In general, all of these agents are considered effective in the induction of remission in patients with mild to moderate UC at equivalent doses (9). Some of the major controversies with 5-ASA medications
center on the treatment of patients with left-sided UC and the optimal doses needed to induce remission.

Some experts feel that in patients with left-sided colitis, the 5-ASA azo-bonded compounds will deliver more active drug to the distal colon than the time-released and pH-released formulations. Several studies have compared balsalazide to mesalamine at comparable doses (10, 11 and 12). The impact in the subgroup of patients with left-sided colitis was not a primary endpoint in the studies; in fact, UP patients were excluded from two of the studies (10,11). Green et al. demonstrated that 6.75 g/day of balsalazide was more effective in inducing remission compared to 2.4 g/day of mesalamine after 12 weeks of treatment. In addition, complete remission was more likely in the left-sided colitis group treated with balsalazide compared to those treated with mesalamine (31% vs. 6%, respectively) (10). Similarly, Pruitt et al. showed that balsalazide was more effective in the subgroup of patients with left-sided colitis and more rapidly induced remission compared to mesalamine (11). Levine et al. did not demonstrate significant treatment differences between balsalazide and mesalamine, with the caveat that patients treated with balsalazide had superior improvements in endoscopic scores compared to those given mesalamine (12). Hence, additional studies are needed to determine if significant differences exist in the outcomes of left-sided UC based on the 5-ASA formulation chosen. Perhaps more importantly than the oral 5-ASA formulation selected, the use of topical therapies can be critical for induction of remission in patients with left-sided colitis. Both topical 5-ASA in the form of suppositories and enemas as well as topical steroids have been shown to be effective induction therapies (13, 14 and 15). In general, the 5-ASA products seem to be more effective than their steroid counterparts (16), except for budesonide enemas, which are approximately equivalent (17,18). A prospective study in patients with left-sided UC demonstrated that topical therapy was more effective than oral 5-ASA for induction of remission; importantly, combination therapy was more effective than either topical or oral therapy alone (14). Whether high-dose oral 5-ASA is as effective as combination therapy or topical therapy alone is speculative.

The optimal dose of 5-ASA needed to induce remission in patients with UC is also unclear. Several studies have evaluated the efficacy of increased doses of 5-ASA to induce remission in patients with mild to moderate UC (19, 20, 21 and 22). The results of these studies have not clearly demonstrated a dose response for 5-ASA in the treatment of UC (19, 20, 21 and 22). A recent trial to evaluate an 800-mg pH-released mesalamine formulation demonstrated that 4.8 g/day of 5-ASA resulted in higher rates of treatment success than standard dose (2.4 g/day) in patients with moderately severe disease (23). Therefore, it is reasonable to consider higher-dose 5-ASA to induce remission in patients with moderately severe UC; alternatively, dose escalation can be performed early after initiation if a response has not occurred or is incomplete.

5-ASA products, including topical formulations, are effective at maintaining remission (24, 25, 26 and 27). However, there is no consensus on the optimal dose of oral 5-ASA needed to maintain remission, as the few trials that evaluated different 5-ASA doses have yielded conflicting results (28,29). Historically, the dose of SASP has been reduced by 50% to maintain remission, although this was done primarily to limit side effects from the sulfa moiety, as the 4 g/day dose was shown to be more effective than the 2 g/day dose (30). Dose reduction for maintenance of remission has been advocated by some, whereas others argue that the dose of 5-ASA needed to induce remission should be continued for maintenance of remission. Another factor to consider in deciding whether to “dose reduce” or “dose maintain” includes the patient’s underlying disease severity. d’Albasio et al. found that in frequent relapsers, the combination of oral 5-ASA and 5-ASA enemas was superior to oral 5-ASA alone (31); whether this also applies to high-dose oral 5-ASA compared to low dose is not known.

The appropriate dosing frequency of the oral 5-ASA compounds is unknown. It has been recommended that these agents be given two to four times per day depending on the formulation. However, most providers reduce the interval to no more than twice per day to improve adherence without an apparent decrease in efficacy. A small study from the University of Chicago demonstrated that Asacol could be given once daily with similar effectiveness (32). In 2007, the FDA approved a new sustained-release oral 5-ASA, Lialda. This agent has a novel matrix delivery system (MMX); each capsule contains 1.2 g mesalamine. Mesalamine MMX shows efficacy in the treatment of patients with mild to moderate UC and has been shown to be effective when given once or twice daily (5,6).

Corticosteroids have been demonstrated to be effective for remission induction in patients with moderate to severe UC (33,34). Overall, the remission or improvement rates in patients treated with the equivalent of 40 mg of prednisone per day range from 50% to 70%, with improved efficacy at higher doses (34, 35, 36 and 37). Because of the adverse effect profile, these drugs have traditionally been reserved for patients with more severe disease or those who fail induction therapy with 5-ASA. Two cohort studies have addressed the short- and long-term outcomes after steroid therapy in patients with UC. Munkholm et al. demonstrated that prednisolone at 1 mg/kg/day resulted in complete remission, partial remission, and no response at 30 days in 48%, 32%, and 20% of patients, respectively (37). However, 1 year later only 55% of patients were in remission off corticosteroids (37). Similarly, a study of adult outpatients from Olmstead County, Minnesota, reported both 30-day and 1-year results after the first course of prednisone. Fifty-four percent and 30% of patients experienced a complete or partial remission at 30 days, respectively. However, at 1 year only 49% of patients were in remission off steroids, while the rest of the patients were either steroid dependent or had undergone colectomy (36

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