US Pharm
. 2010;35(12):HS21-HS26. 

Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) characterized by diffuse mucosal inflammation that is restricted to the colon. It involves the rectum in approximately 95% of cases, and, depending on the degree of anatomical involvement, the disease may extend proximally in a contiguous pattern to involve the sigmoid colon, the descending colon, or the entire colon.1-3 As a result of the disease, extraintestinal manifestations can occur in addition to an increased risk of developing colorectal cancer.2 Additionally, studies have demonstrated that UC has a significant economic impact on society and the psychological well-being of sufferers. In 2008, the total economic burden of UC was estimated to be between $8.1 and $14.9 billion annually in the United States.4-6 Although there is no cure for the disease, effective treatment relies on accurate and timely diagnosis as well as on patient compliance with the assigned medication regimen. The patient-pharmacist relationship is also critical in encouraging medication adherence and education. This article will concentrate on major published studies of investigational treatment options for UC. 


The prevalence of UC varies according to geographic location, with higher incidences of the disease reported in northern Europe, the United Kingdom, and North America.7,8 In the U.S., UC affects approximately 250,000 to 500,000 individuals, with an incidence of 8 to 12 per 100,000 persons annually, which has remained constant over the past 5 decades. The onset of UC is usually diagnosed in patients between the ages of 15 and 40 years, with a second peak in incidence between 50 and 80 years of age. Furthermore, men and women are affected by UC equally, although some studies demonstrate predominance in women.1,2,9,10 


The precise etiology of UC remains undetermined; however, it is believed that a combination of infectious, genetic, and immunologic factors is responsible for the disease. Additional theories suggest that environmental influences, including smoke exposure and nonsteroidal anti-inflammatory drugs (NSAIDs), may be contributing factors in developing IBD. Moreover, it is likely that a number of factors contribute to the development of mucosal inflammation.7,8,11,12 


The diagnosis of UC should be considered for individuals presenting with persistent bloody diarrhea, rectal urgency, or tenesmus. A colonoscopy or proctosigmoidoscopy and biopsy are the tests of choice in confirming this diagnosis. These procedures yield findings of characteristic mucosal changes demonstrating a loss of typical vascular pattern, granularity, friability, and ulceration, which may extend from the distal rectum to involve all or part of the colon. Laboratory tests such as C-reactive protein and erythrocyte sedimentation rate may be elevated, indicating an inflammatory process.  A stool examination is recommended in addition to diagnostic procedures to rule out the presence of infectious and noninfectious etiologies.1,2,13 


According to the guidelines from the American College of Gastroenterology, the severity and extent of the disease may be classified based on clinical and endoscopic findings.1 The clinical course of UC may be classified as mild, moderate, severe, and fulminant. The Ulcerative Colitis Activity Index (UCAI) is a tool used to assess the severity and extent of UC to guide treatment strategies. Patients with mild disease typically have fewer than four stools daily, with or without blood, no systemic signs or symptoms, and a normal erythrocyte sedimentation rate (ESR). Moderate disease is characterized by more than four stools daily but with minimal signs of systemic toxicity. Severe disease is manifested by more than six bloody stools daily and evidence of fever, tachycardia, anemia, or an elevated ESR. Patients with fulminant disease may have more than 10 stools daily, continuous bleeding, toxicity, abdominal tenderness and distention, blood transfusion requirement, and colonic dilatation on abdominal plain films.1,3,14 

Therapeutic Options for Disease Management

Unfortunately, there is no cure for UC; however, current treatment regimens have shown to be effective in managing the disease. The goals of treatment are to alleviate associated symptoms, resolve acute inflammation, manage complications and systemic manifestations, and achieve remission.1,9 Treatment selection is determined based upon colonic involvement, severity, and presence of extraintestinal complications.15,16 

Aminosalicylates: The aminosalicylates remain the mainstay of therapy for induction and maintenance of remission in mild-to-moderate UC.16-18 These agents contain 5-aminosalicylic acid (5-ASA), or mesalamine, and achieve high luminal concentrations to achieve therapeutic goals. The mechanisms of aminosalicylates include inhibition of prostaglandin and leukotriene synthesis, free-radical scavenging, immunosuppressive activity, and inhibition of cytokine synthesis.16,18 Current treatment therapies represent oral and rectal formulations (TABLE 1).

Other Medications: Other therapies for the management of UC include corticosteroids, immunomodulators (i.e., azathioprine, 6-mercaptopurine), cyclosporine (an immunosuppressant), and infliximab (a monoclonal antibody), which have been shown to be efficacious in achieving therapeutic goals (TABLE 2).13,19,20

Investigational Therapies 

With medical advancements and the development of new treatments, as discussed below, the future looks promising for those living with UC. TABLE 3 provides additional information regarding these agents.

Basiliximab: Basiliximab (Simulect) is a chimeric anti-interleukin (IL)-2 receptor monoclonal antibody currently FDA approved for prophylactic treatment of acute organ rejection in renal transplantation. Basiliximab binds to CD52, which is a type of protein known as a leukocyte antigen. This antigen is expressed on the surface of several types of white blood cells including lymphocytes, macrophages, monocytes, and thymocytes. Basiliximab specifically binds to and blocks the alpha chain of interleukin-2 receptors on the surface of activated T lymphocytes, resulting in the inhibition of T-cell proliferation.21,22 

In an open-label, uncontrolled, 24-week study, basiliximab was found to be effective at inducing remission in steroid-resistant UC. Patients in both the moderate group and the severe group were given a single IV infusion of 40 mg of basiliximab plus corticosteroid treatment. Nine of the 10 patients with steroid-resistant UC achieved complete remission within 8 weeks; however, eight of the nine responders relapsed, but remission was reachieved with further corticosteroids and the addition of azathioprine. After 24 weeks, seven of the 10 patients remained in remission, with the majority requiring no corticosteroid treatment.21 

A recent open-label, pilot trial evaluated the efficacy of basiliximab as a steroid-sensitizing agent in steroid-resistant UC, which produced similar results. In clinical trials, therapy was associated with minimal adverse events but included rash, pyrexia, dyspnea, lethargy, loin pain, herpes zoster, and rectal bleeding. Although basiliximab was well tolerated and no infusion reactions were reported, randomized controlled studies are required for confirmation.22 

Daclizumab: Daclizumab (Zenapax) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that has undergone clinical evaluation for the management of active UC. Currently, daclizumab is FDA approved for prophylaxis of acute organ rejection in patients receiving renal transplants. It is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. The mechanism of action of daclizumab is also directed against the alpha chain of IL-2 receptor CD52.23,24 

In an uncontrolled pilot study, daclizumab demonstrated the potential to be beneficial in patients with active UC. Ten patients with chronically active UC received daclizumab, 1 mg/kg IV twice with a 4-week interval. Patients experienced clinical benefit with signs of endoscopic improvement. There were no serious adverse events reported during the trial, with daclizumab appearing to be well tolerated.23 However, a placebo-controlled, double-blind, phase II clinical trial of daclizumab at IV doses of 1 mg/kg twice with a 4-week interval or 2 mg/kg every second week for a total of four doses in 159 patients with active UC failed to show any efficacy. Patients with moderate UC who were treated with daclizumab were not more likely to be in remission or response at 8 weeks than the placebo group.24 Currently, there are no new trials for daclizumab and its use in UC. 

Vedolizumab: Vedolizumab (MLN-02) is another humanized IgG1 monoclonal antibody undergoing phase III clinical trials for the treatment of UC. The proposed mechanism of action of vedolizumab involves the potential to work against the alpha-4 beta-7 integrin that selectively inhibits leukocyte adhesion in the GI mucosa.25 Alpha-4 beta-7 integrin is primarily involved in the recruitment of leukocytes to the gut and is present on the cell surface of T lymphocytes. The major ligand for alpha-4 beta-7 is selectively expressed on intestinal vasculature and is present in increased concentrations in inflamed tissue; therefore, blockade of this interaction may be effective in treating UC.19,26,27 

A multicenter, double-blind, placebo-controlled trial demonstrated that vedolizumab was more effective than placebo for the induction of clinical and endoscopic remission. The study involved 181 patients who were randomly assigned to receive 0.5 mg/kg of vedolizumab, 2 mg/kg, or an identical-appearing placebo IV on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Clinical remission rates at week 6 were 33%, 32%, and 14% for the group receiving 0.5 mg of vedolizumab, the 2-mg/kg group, and the placebo group, respectively.26 

Alicaforsen: The interaction of lymphocyte-associated alpha-1 beta-2 integrin and its ligand, intercellular adhesion molecule-1 (ICAM-1), is important for the recruitment of leukocytes to inflammatory sites and is thought to be involved in inflammatory bowel diseases.27 Alicaforsen (ISIS 2302), an antisense oligodeoxynucleotide, is designed to down-regulate ICAM-1 messenger RNA levels by generating a substrate for ribonuclease H (RNase H).28-30 

Alicaforsen has been studied in clinical trials as an IV infusion and enema formulation for IBD. The safety and efficacy of the enema formulation of alicaforsen was evaluated in a randomized, placebo-controlled, double-blind study. Alicaforsen enema was shown to be effective for acute and long-term treatment in patients with mild-to-moderate descending UC, which resulted in a significant dose-dependent reduction in disease activity.28 Additionally, a randomized, double-blind, active-controlled trial demonstrated no significant differences between the mesalamine enema (Rowasa) and alicaforsen enema treatment groups, but showed that a higher percentage of alicaforsen-treated subjects remained in clinical remission. In addition, the alicaforsen enema was found to provide a more durable treatment. The enema was well tolerated and demonstrated a similar safety profile to the mesalamine enema.29 A placebo-controlled trial showed similar results of a prolonged reduction in mean percentage disease activity index (DAI).30 Based on the tolerability, safety, and efficacy that alicaforsen demonstrated in clinical trials, the FDA has granted fast-track approval for the treatment of chronic and recurrent pouchitis. 

Delmitide (RDP58): This drug is a novel anti-inflammatory decapeptide that has the ability to block tumor necrosis factor (TNF) production at a posttranscriptional step, and to inhibit production of interferon (IFN)-gamma, IL-2, and IL-12.31 In two 4-week, randomized, double-blind, multicenter trials, patients with mild-to-moderate active UC received an oral solution of RDP58 at 100, 200, or 300 mg, or placebo daily for 28 days.32 Clinical remission was achieved in 71% and 72% of patients in the 200-mg and 300-mg groups, respectively. Although there was no significant difference in sigmoidoscopy score improvements, histology scores improved significantly (P = .002) versus placebo. Treatment success was not significant with RDP58 at 100 mg compared to placebo, 29% versus 46%, respectively. However, there were no differences in adverse events among any of the treatment groups. The lack of adverse events was consistent with no systemic bioavailability, which implies a topical action, similar to 5-ASA, which acts on colonic epithelial cells and does not depend on systemic bioavailability.27,32 

Rosiglitazone: Rosiglitazone (Avandia) has shown to be safe and promising in the treatment of UC. Rosiglitazone is a thiazolidinedione (TZD) antidiabetic agent currently FDA approved for the treatment of type 2 diabetes mellitus, and is also a ligand for the gamma subtype of peroxisome proliferator-activated receptors (PPARs). Studies suggest a potential anti-inflammatory effect of PPAR-gamma ligands, particularly in the colon. Therefore, the stimulation of PPAR ligands by rosiglitazone attenuates inflammatory cytokine production.33,34 

In an open-label clinical trial of combined use of rosiglitazone and 5-ASA for UC, patients received an oral dose of rosiglitazone at 4 mg daily plus 5-ASA at 2 g daily versus the control group, which received only 5-ASA at 2 g daily, for 4 weeks. The treatment group achieved better therapeutic effects than 5-ASA alone without adverse effects. Along with the improvement of DAI, the histologic grade improvement was more significant in the treatment group than in the control group (P <.05).33 

A randomized, placebo-controlled trial showed rosiglitazone to be more effective in achieving remission in mild-to-moderately active UC as compared to placebo. In this trial, 4 mg of rosiglitazone was given twice daily versus placebo twice daily for 12 weeks in 105 patients. The quality of life of patients was significantly improved at week 8, and serious adverse events were rare.34 

A recent study explored the potential of topical treatment with rosiglitazone in patients with UC in efforts to restore PPAR activity. Patients with active distal UC were randomized to either rosiglitazone 4 mg or mesalamine 1 g enema treatment once daily for 14 days. Rosiglitazone enema treatment was well tolerated and demonstrated similar therapeutic effects to the mesalamine enema by reducing the Mayo UC score from 8.9 to 4 (P <.01).35 Although there were no cases of significant congestive heart failure observed, patients with advanced heart failure were excluded from the trials. 


Recent advances in the understanding of the pathogenesis of UC have led to the evolution of new therapies targeted at specific disease mechanisms.16,36 Several of these novel drug therapies are undergoing clinical evaluation for the treatment of the disease and have shown to be promising. Additionally, these investigational drugs have demonstrated the potential to provide more effective and safer treatments for UC in the near future. 


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