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Therap Adv Gastroenterol. 2009 March; 2(2): 99–108.
PMCID: PMC3002512

Ulcerative Colitis: Current Treatment Strategies and Future Prospects

Abstract

Ulcerative colitis (UC) is a disease of unknown etiology characterized by inflammation of the mucosa and occasionally the submucosa of the colon. Conventional drug therapy for UC involves use of aminosalicylates, corticosteroids, azathioprine/6-mercaptopurine, cyclosporine and anti-tumor necrosis factor therapy. Alternative therapies include probiotics, nicotine and fish oil. Drugs like tacrolimus, rosiglitazone and Trichuris suis ova are being evaluated for use in UC patients. With the new biologic agents, new treatment options for UC continue to evolve. In this article we will discuss the conventional drugs, the alternative therapies and the management strategies according to the severity and extent of UC.

Keywords: ulcerative colitis, tumor necrosis factor alpha inhibitors, adalimumab, certolizumab pegol, sagramostin

Introduction

Ulcerative colitis (UC) is a disease of unknown etiology characterized by inflammation of the mucosa and occasionally the submucosa of the colon. A persistent and inappropriate immunologic response to gut luminal antigens is thought to be the reason for this inflammation. Absence of enteric parasites in the developed world and defective mucosal defence mechanisms are some of the hypotheses behind the pathogenesis. The incidence of UC in North America ranges from 2.2 to 14.3 cases per 100,000 person years. The prevalence of UC ranges from 37 to 246 per 100,000 persons [Loftus, 2004]. UC can present at any age, although the peak incidence occurs between the ages of 15 and 30 years.

The following terms are used to describe the degree of involvement of the colon and management depends on the extent and severity of the disease:

  • Ulcerative proctitis refers to disease limited to the rectum.
  • Distal colitis or proctosigmoiditis refers to disease extending to the mid-sigmoid colon, usually reachable by a 60 cm flexible sigmoidoscope.
  • Left-sided colitis refers to disease extending to but not beyond the splenic flexure.
  • Extensive colitis is defined as disease that extends beyond the splenic flexure but not as far as the cecum.
  • Pancolitis is used when the inflammatory process extends to the cecum.

Patients can also be classified as having mild, moderate or severe disease as follows:

  • Mild disease: Patients with mild disease usually present with intermittent rectal bleeding associated with the passage of mucus, and mild diarrhea with fewer than four small loose stools per day. Mild crampy pain, tenesmus, and periods of constipation are also common. Severe abdominal pain, profuse bleeding, fever, and weight loss are not the symptoms and signs of mild disease.
  • Moderate disease: characterized by frequent loose, bloody stools (up to 10 per day), mild anemia not requiring blood transfusions, abdominal pain that is not severe, and low-grade fever.
  • Severe disease: These patients present with frequent loose stools (>10 per day), severe cramps, high-grade fever and bleeding often requiring blood transfusion. They may also have rapid weight loss.

In this article, we will discuss conventional drugs, alternative therapies and management strategies according to the severity and extent of UC.

Conventional drug therapy

AminosaUcylates

Sulfasalazine, the original agent in this class of drugs, consists of 5-aminosalicylic acid (5-ASA) and sulfapyridine, which are bound together by an azo bond. It has both anti-inflammatory (5-ASA) and antibacterial (sulfapyridine) properties. The drug sulfasalazine is partially absorbed in jejunum. When it reaches the colon the bacterial azor-eductases in the colon cleave the azo bond. This leads to release of the metabolites, 5-ASA and sulfapyridine. The 5-ASA moiety is responsible for the efficacy of the drug in UC. 5-ASA if given orally alone would be absorbed in the jejunum and hence would not be effective in distal small intestinal and colonic disease. When 5-ASA is given in combination with sulfapyridine, most of the 5-ASA stays in the colon as only a limited amount of 5-ASA is absorbed in jejunum. Sulfapyridine is absorbed then metabolized by the liver and undergoes renal excretion. Sulfapyridine causes most of the side-effects of the drug.

This class of drugs has been shown to induce remission in 40% to 80% of patients [Riley et al. 1988; Dick et al. 1964; Baron et al. 1962]. The effective dose ranges between 2 and 4 g per day. Continued therapy maintains remission in 60-80% of these patients [Mulder et al. 1988; Dissanayake and Truelove, 1973].

The mechanisms of action of aminosalicylates include inhibition of prostaglandin and leuko-triene synthesis, free-radical scavenging, immunosuppressive activity, impairment of white cell adhesion and function, and inhibition of cytokine synthesis [Shanahan et al. 1990; Craven et al. 1987; Neal et al. 1987; Hawkey et al. 1985].

To reduce the side-effects associated with sulfapyridine, newer drugs contain 5-ASA alone or attached to an inert carrier by an azo bond. Mesalamine preparations Asacol® and Salofalk® have 5-ASA coated with a pH-sensitive acrylic polymer which dissolves at pH greater than 6. This helps release the 5-ASA in the terminal ileum and the colon. Another mesalamine preparation, Pentasa®, has 5-ASA encapsulated in ethylcellulose microgranules that releases 5-ASA throughout the gastrointestinal tract. Olsalazine has two 5-ASA molecules joined by an azo bond. Balsalazide contains a 5-ASA molecule joined to an inert carrier. Both these drugs require colonic bacteria to cleave the azo bond to release 5-ASA. A new formulation, marketed as Lialda®, contains mesalamine in a multimatrix delivery system. Once-daily dosing and sustained release of the drug throughout the colon are the potential advantages of Lialda. A new preparation of mesalamine called Apriso®, which has a once-daily dosing schedule, has been recently approved for maintenance of remission in UC.

In addition to oral preparations, topical preparations of aminosalicylates are also used, mainly to treat distal disease. Mesalamine suppositories (Canasa®) reach the rectum and the distal sigmoid colon. Mesalamine enemas (Rowasa®) reach the proximal sigmoid colon and foams reach the midsigmoid region. Topical preparations have fewer side effects than oral preparations.

Side effects of sulfasalazine such as nausea and headache are dose dependent while others like fever and rash are due to a hypersensitivity reaction to the drug. Side-effects occur in about 20% of patients. Most patients tolerate doses of 2-4 g/ day. Agranulocytosis is a rare side-effect of sulfasalazine and usually occurs in the first 8 weeks of therapy. Patients recover 1-2 weeks after stopping the drug. Male infertility by reversible reduction in sperm function and number can also occur. Common side-effects of mesalamine include fever and rash. Watery diarrhea can occur with 5-ASA preparations and particularly with olsalazine in 15% of patients. Olsalazine promotes ileal secretion of water and electrolytes and hence causes the diarrhea. It occurs at the start of the therapy and resolves in 4-8 weeks. Hypersensitivity reactions like pancreatitis, pneumonitis, pericarditis, hepatitis and nephritis can occur with both sulfasalazine and other 5-ASA preparations but are rare. One review suggested that the incidence of acute interstitial nephritis with 5-ASA preparations was 1 in 500 [World et al. 1996]. Sulfasalazine and other 5-ASA preparations (oral and rectal) can be continued in pregnancy. The incidence of low birth weight, prematurity, spontaneous abortion, stillbirths, or birth defects is similar to that in the general population [Mogadam et al. 1981].

Corticosteroids

Corticosteroids can induce remission in UC flares but do not maintain remission. Their mechanism of action is unclear but is thought to be from inhibition of cytokine release by inactivation of NFKß. This leads to decreased lymphocyte recruitment, reduced vascular permeability and inhibition of cytokine-mediated tissue necrosis. Oral, topical and intravenous forms can be used.

There is no difference in the rates of remission induction with oral or parenteral steroids. Parenteral steroids (methylprednisone 20 mg every 8 hours, prednisolone 30 mg every 12 hours, or hydrocortisone 100 mg every 8 hours) are used in severe disease or in patients who cannot tolerate oral intake. They can either be given as bolus or as continuous infusion. In a recent study of patients with severe attacks of UC, methylprednisolone given as a continuous infusion was no better than bolus administration in terms of efficacy and safety [Bossa et al. 2007]. Oral prednisone in doses of 30-60 mg daily can be used to induce remission. Doses higher than this don't provide additional benefit. Side-effects often occur at doses greater than 40 mg daily. Steroids induce remission in about 50% of the patients and response in 80% of the patients. If steroids are used for more than 2 weeks, then the dose should be tapered slowly to prevent hypoadrenalism. Major adverse effects of long-term steroids include hypertension, diabetes, weight gain, psychiatric disorders and infections. Depending on the population studied, the prevalence of osteoporosis has thus been variably reported to range from 12% to 42% in patients with inflammatory bowel disease (IBD) [Van Hogezand and Hamdy, 2006]. Steroids also can cause osteoporosis. Use of steroids in these patients places them at an increased risk for vertebral fractures. If patients are on steroids, they should be given calcium 1200mg/day and vitamin D 800 IU/day.

Azathioprine/6-mereaptopurine

Azathioprine (AZA) is a prodrug and is converted to 6-mercaptopurine (6-MP) in a nonenzymatic reaction in red blood cells and other tissues. AZA/6MP inhibit purine synthesis and ultimately DNA and RNA synthesis. They also inhibit T- and B-lymphocyte proliferation. However the exact mechanism of action in UC is unknown. Both can be used to induce and maintain remission in UC with efficacy rates of 60–70%. They can be used to decrease the dose or completely stop steroids in patients who have improved with steroids and in patients with chronic active disease not fully controlled with steroids. 6-MP is metabolized by three enzymes. Thiopurine-S-methyltransferase (TPMT) methylates it to 6-methylmercaptopurine (6-MMP). Hypoxanthine-guanine-phosphoribosyl transfer-ase transforms 6-MP into 6-thioguanine (6-TG), which is the active metabolite. Xanthine oxidase catalyses 6-MP to inactive thiourate. Absorption of AZA in healthy subjects ranges from 16% to 50%. It may be lower than this in UC patients due to increased intestinal motility during acute UC exacerbations.

Measurement of TPMT genotypes before instituting AZA or 6-MP may help prevent toxicity by identifying individuals with low or absent TPMT enzyme activity. Patients with normal phenotype can be given a standard weight-based dose. Those who are heterozygous will have half the enzyme levels and would need reduced initial doses of the drug. Patients who are homozygous deficient have very low levels of the enzyme and hence the drug should be avoided in them. The usual weight-based maximum dose for AZA is 2.5 mg/kg while that for 6-MP is 1.0–1.5 mg/kg. A dosage conversion factor of 50% exists between AZA and 6MP. Serious adverse events are rare at doses of AZA less than 2.5 mg/kg/day and for 6MP less than 1.5 mg/kg/day. Mesalamine reduces TPMT activity and hence 6-TG levels can rise with concurrent use of mesalamine. Allopurinol blocks the enzyme xanthine oxidase and can increase the levels of 6TG. In patients taking allopurinol, these drugs should be started at half the usual dose. As long as the treatment with AZA/6-MP is well tolerated it should be continued indefinitely in patients who have achieved remission. Once therapy is tolerated and remission is maintained, there is no convincing reason to reduce the dose. There is no evidence that a dose reduction prevents long-term side-effects. Furthermore, a dose reduction may put the patient at risk for relapse.

Studies have shown that AZA/6MP maintain remission in approximately 40–70% of the patients. In steroid-dependant patients they decrease steroid requirements in about 70% of patients [Timmer et al. 2007]. These drugs are not effective in acute flares of UC because they take 3–6 months to take effect. Usually effects are seen by 3 months and it can take up to 6 months in some patients. Intravenous administration has not been shown to produce rapid effects.

Side-effects occur in 10-15% of the patients. Less than 10% patients discontinue the drug due to side effects. Nausea, vomiting and malaise are the most common ones. Bone marrow suppression (2%) and liver toxicity (0.3%) are dose-dependant adverse events. Complete blood count should be monitored every 1-2 weeks and liver function tests should be monitored frequently for the first month or till the patient is on a stable maintenance dose. If the white blood cell count is less than 4 × 109/l or the platelet count is less than 120 × 109/l, the dose should be reduced until they normalize. If the white blood cell count decreases below 3 × 109/l or the platelet count decreases below 80 × 109/l, the drug should be discontinued until these cell counts normalize [Cuffari et al. 2001; Tanis, 1998]. If the liver enzymes increase to more than 50% of the upper limit of normal, the drugs should be discontinued and reintroduced later at a lower dose when the enzymes normalize. Labs should be monitored every 3 months for the duration of therapy once the patients are on a stable maintenance dose. Bone marrow suppression and hepatotoxicity can occur suddenly even with regular monitoring.

Hypersensitivity occurs in 10% of the patients. Two small reports had suggested that 6MP might be used safely in patients who are intolerant to AZA. A likely explanation for this is that the hypersensitivity reaction to AZA is mostly from the nitroimidazole moiety which is absent in 6-MP. The percentage of patients who develop hypersensitivity reaction to AZA who would tolerate 6-MP is not known exactly. However, as a general rule, patients who develop hypersensitivity reactions to either AZA or 6-MP should not receive these drugs. A meta-analysis has suggested an increased risk of lymphoma with the use of AZA/6-MP. However, the benefits of these drugs in UC usually outweigh the risks of developing lymphoma.

Cyclosporine

Patients with severe or fulminant colitis who do not respond to steroids are candidates for cyclosporine therapy. Cyclosporine may be especially useful in new-onset UC patients presenting with severe or fulminant colitis who are not psychologically prepared for colectomy In a controlled trial in 11 patients given cyclosporine, 9 responded within a mean of 7 days versus none of the 9 in the placebo group [Lichtiger et al. 1994]. In a study looking at the long-term effects of cyclosporine, 62% out of a total of 42 patients avoided colectomy at the end of 5.5 years [Cohen et al. 1999].

Cyclosporine is a lipophilic peptide of 11 amino acids. It binds to a family of cytoplasmic proteins known as cyclophilins. Cyclosporine together with cyclophilins binds to and inhibits calcineurin. This leads to decreased transcription of cytokine genes such as interleukin (IL)-2 and tumor necrosis factor (TNF) alpha [Wiederrecht et al. 1993].

In some studies, the dose of cyclosporine used for UC patients with an acute flare was 4 mg/kg/day with a stable trough ranging between 300 and 400ng/ml [Kornbluth et al. 1997]. However, two studies have shown that a dose of 2 mg/kg/ day with a trough ranging between 150 and 250 ng/ml has similar efficacy and may have less side-effects [Rayner et al. 2003; Van Assche et al. 2003]. Blood trough levels of cyclosporine should be monitored during the therapy. We use the monoclonal assay from Abbott® at our institution. However, other assays like polyclonal assay or high pressure liquid chromatography (HPLC) assay may be available at other institutions. Also, cholesterol levels should be checked before starting the therapy as low cholesterol levels can predispose to seizure.

For patients who respond to cyclosporine and who are not on AZA/6-MP, oral cyclosporine should be continued for 3-4 months and AZA/ 6-MP should be introduced. For patients already on AZA/6-MP, this should be continued during the cyclosporine treatment. The dose of oral cyclosporine usually used is 8 mg/kg/day. Blood level checking should be continued during oral cyclosporine therapy and the trough should range between 150 and 300 ng/ml.

Cyclosporine is metabolized by hepatic cytochrome P450 3A enzymes. Many drugs metabolized by the same enzyme affect levels of cyclosporine. Drugs such as diltiazem, ketoconazole and erythromycin increase cyclosporine levels, while phenytoin, carbamazepine, nafcillin and octreotide decrease cyclosporine levels.

Nephrotoxicity can occur with cyclosporine. Acute renal insufficiency with cyclosporine is usually reversible with decreasing the dose while chronic renal insufficiency is irreversible. Hypertension can occur due to renal vasoconstriction and sodium retention. It may respond to dose reduction, although antihypertensive medications might sometimes be needed. Calcium channel blockers are the drugs of choice to reduce blood pressure. As mentioned above, they can increase the blood levels of cyclosporine and hence their use can allow a decreasing of the dose and therefore a reduction in the total cost of cyclosporine therapy. Cyclosporine-associated neurotoxicity is manifested as severe headache, visual abnormalities and seizures. Squamous cell skin cancers and benign or malignant lymphoproliferative disorders can also occur. Patients are at risk of developing Pneumocystis carinii pneumonia and hence should receive prophylaxis against it. In a study in pregnant women with organ transplant on cyclosporine, growth restriction and prematurity occurred in 40% of the neonates but no congenital defects were seen [Armenti et al. 1994; Cockburn et al. 1989]. Other side-effects include gingival hyperplasia, hirsutism, anorexia, nausea, vomiting, diarrhea and abdominal discomfort [Sternthal et al. 2008].

Anti-tumor necrosis factor therapy

Infliximab (Remicade®) is a chimeric monoclonal antibody directed against tumor TNF-alpha. It can be used for remission induction in moderate-to-severe UC patients who are either refractory to or intolerant of mesalazine (5-ASA) products and immunomodulators. Also it can be used for maintenance of remission in UC patients who have failed mesalamine and immunomodulators. The role of infliximab in UC patients who are dependant on steroids is unclear. Infliximab can be used in acute steroid-resistant UC patients who are reluctant to undergo surgery.

The two major trials of infliximab are ACT 1 and ACT 2. Both had 364 UC patients. ACT 1 had patients with active UC treated with steroids or 6-MP or AZA. ACT 2 had UC patients refractory to at least one standard therapy including 5-ASA, corticosteroids or immunosuppressants. Patients were randomly assigned to infliximab at a dose of 5 or 10 mg/kg or placebo at week 0, 2, and 6 and every 8 weeks through week 46 (in ACT 1) or week 22 (in ACT 2) [Rutgeerts et al. 2005]. Patients were followed through week 54 in ACT 1 and week 30 in ACT 2. Clinical response was higher in both treatment groups than placebo group at week 8 in ACT 1 but similar in drug and placebo groups in ACT 2. At week 30, both studies showed increased clinical response in the infliximab group. Clinical remission was higher in infliximab group at all time points in both studies. Case reports have shown limited benefit of infliximab in chronic pouchitis [Arnott et al. 2001].

Data on adverse effects of infliximab in UC patients are limited. Injection site reactions are common but not serious. Acute (within 524 hours) and delayed (1–14 days) infusion reactions can occur with infliximab. Premedication with diphenhydramine or antihistamines and prednisone and using test dose of infliximab can be tried to prevent infusion reactions. Infectious complications like bacterial pneumonia, tuberculosis and opportunistic infections can also occur. Owing to the increased risk of tuberculosis, a chest radiograph and PPD (purified protein derivative) skin testing should be performed before starting the therapy. Patients with evidence of latent tuberculosis should be given prophylactic antitubercular therapy. Risk of reactivation of hepatitis B is also increased. Although there is a speculation about increased risk of or worsening of a demyelinating disease with infliximab, there is no data to conclusively prove this. Studies done in rheumatoid arthritis patients have shown an increased risk of lymphoma with infliximab [Geborek et al. 2005]. Cases of hepatosplenic lymphoma have been reported in younger patients on infliximab who were on concomitant immunosuppressive agents [Shale et al. 2008; Mackey et al. 2007].

Antibiotics

Luminal bacteria are thought to have an important role in the pathogenesis of IBD. The benefits of antibiotic therapy in UC are mediated by different mechanisms like decreasing the concentration of luminal bacteria, altering the composition of gut microflora, decreasing bacterial tissue invasion, and decreasing bacterial translocation and systemic dissemination. Many of the clinical studies of antibiotics in IBD have been performed in CD patients. Studies in UC have not demonstrated consistent benefit. One randomized placebo controlled study of 83 patients showed that the addition of ciprofloxacin improved the results of conventional therapy [Turunen et al. 1998]. An indication of antibiotic use in UC is in fulminant colitis where they can prevent life-threatening infection.

Methotrexate

The role of methotrexate in the treatment of ulcerative colitis is unclear. Although uncontrolled studies have suggested low-dose methotrexate to be beneficial [Mate-Jimenez et al. 2000; Kozarek et al. 1989], the single controlled trial of methotrexatre in UC patients showed no benefit [Oren et al. 1996].

Alternative therapies

Probiotics

Probiotics modulate the immune system in the gut by inducing protective cytokines and suppressing proinflammatory cytokines. Trials have shown their benefit in preventing relapse in UC. E. coli 1917 Nissle was as effective as 5-ASA in preventing relapse [Rembacken et al. 1999]. A combination of eight species of bacteria called VSL#3, in combination with balsalazide, was slightly more effective than balsalazide or mesalamine alone in mild-to-moderate UC [Tursi et al. 2004]. Lactobacillus GG was shown to be more effective then mesalamine in prolonging relapse free time in UC [Zocco et al. 2006].

Fish oil

Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa. Eicosapentaenoic acid (EPA) derived from fish oil inhibits leukotriene activity. One study showed that fish oil dietary supplementation results in clinical improvement of active mild-to-moderate UC but is not associated with a significant reduction in mucosal leukotriene B4 production, compared with placebo therapy [Aslan and Triadafilopoulos, 1992]. A doubleblind placebo controlled crossover trial of 24 patients with active UC showed reductions in rectal dialysate leukotriene B4 levels, improvements in histologic findings, and weight gain [Seidner et al. 2005; Stenson et al. 1992]. Another randomized controlled trial showed that a fish oil-enriched oral supplement significantly decreased the dose of prednisone required to control clinical symptoms [Seidner et al. 2005]. The dose of fish oil (0.18 g EPA/capsule) is 15–18 capsules per day. The large number of capsules as well as the development of a fishy odor in the breath might reduce patient compliance.

Nicotine

Epidemiologic studies have shown UC to be a disease mainly of nonsmokers. Two trials have shown that transdermal nicotine is beneficial in mild active UC [Sandborn et al. 1997; Pullan et al. 1994]. Another trial showed that it is not effective in maintaining remission [Thomas et al. 1995].

Future prospective therapies

Tacrolimus

A placebo-controlled trial showed that tacrolimus induces remission in refractory UC patients. The dose of tacrolimus which achieved remission resulted in a serum concentration of 10–15 ng/ml. However the incidence of side-effects in the tacrolimus group was significantly higher than that of the placebo group [Ogata et al. 2006]. Another systematic review of 23 reported experiences of tacrolimus use in 286 patients with inflammatory bowel disease showed promising results in unresponsive cases of UC [GonzalezLama et al. 2006].

Trichuris suis

UC is rare in developing countries. A higher rate of helminth infections and colonization is thought to be a potential reason for this. Chronic helminthic infections cause persistent immune activation that results in hyporesponsiveness and anergy [Borkow et al. 2000]. This impaired immune function may diminish the capacity of these individuals to mount an immune response and hence decrease the risk of UC. One study looked at 54 patients with active UC who were randomly assigned to ingestion of Trichuris suis ova or placebo for 12 weeks. Improvement in disease activity occurred in 43.3% patients with ova treatment compared with 16.7% patients given placebo [Summers et al. 2005]. Additional studies are needed to further evaluate this option.

Rosiglitazone

Rosiglitazone, a thiazolidinedione used to treat diabetes mellitus, was more effective than placebo in achieving remission in mild to moderately active UC in a placebo-controlled trial [Lewis et al. 2008]. The stimulation of perixisome proliferatoractivated ligands by rosiglitazone attenuates inflammatory cytokine production.

Visilizumab

Visilizumab is a humanized anti-CD3 monoclonal antibody. It has been studied in a phase I study in severe steroid-refractory UC. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission, and 44% achieved endoscopic remission [Plevy et al. 2007]. However, the phase III study was suspended in 2007 when interim analysis showed no benefit. It is no longer an option for UC therapy.

Management strategies according to the severity and extent of UC

Proctitis and proctosigmoiditis

The initial treatment for proctitis is 5-ASA suppositories or steroid foams or suppositories. For patients with proctosigmoiditis, mesalamine enemas or steroid enemas should be considered. 5-ASA preparations are preferred over topical steroids since they have proven effectiveness in long-term maintenance therapy. Patients can be started on mesalamine 1g suppository once at bedtime. Response is usually seen within 3 weeks. If the patient has mild symptoms and rapid response to therapy, maintenance therapy is not required. Otherwise the same dose of mesa-lamine suppository that is used to achieve remission can be continued for maintenance therapy. The frequency of use can be decreased to every other night. Patients with proctosigmoiditis have more extensive disease than patients with proctitis and need maintenance therapy in the form of enemas or oral treatment. Steroid foams can be used for achieving remission; however, there is no evidence that they can prevent relapse of symptoms and maintain remission. Patients who have anal irritation from topical therapy can be switched to sulfasalazine or other oral 5-ASA preparations.

Left-sided colitis

These patients usually need a combination of oral and rectal therapy. The combination of an oral 5-ASA drug with 5-ASA enemas may be more effective than either alone. Sulfasalazine, mesalamine, olsalazine and balsalazide and Lialda have proven effective in active UC [Rao et al. 1989; Fleig et al. 1988]. It should be ensured that patients are tried on the maximum dosage of these agents before labeling them as treatment failures. Sulfasalazine can be gradually increased to a maximum of 4g/day, mesalamine to 4.8g/day, and olsalazine to 3 g/day. These agents are usually given 3–4 times daily in divided doses but can be given twice a day to improve compliance. Lialda can be given once a day. They often require 3–6 weeks to show any effect. Once remission is achieved, the drug should be continued at the same dose for maintenance therapy. As mentioned previously, the new mesalamine preparation called Apriso, which has a once-daily dosing schedule, has been recently approved for maintenance of remission in UC. Folic acid supplementation (1mg/day) is recommended for patients on long-term sulfasalazine since it can inhibit the absorption of dietary folate. Prednisone should be considered in patients with more severe disease or patients who do not respond to 5-ASA agents. Prednisone can be started at 40–60 mg daily. It takes about 10–14 days to show effect; after that the dose should be gradually tapered down, usually by 5mg/week. As mentioned in mild disease, steroids are not helpful in maintenance therapy.

Extensive and pancolitis

Patients with mild-to-moderate symptoms can be treated with oral 5-ASA agents. If rectal symptoms dominate the clinical picture, concomitant topical therapy with either 5-ASA or steroid enemas should be considered. In patients who do not respond to this regimen and patients with severe disease, oral steroids should be used. Once remission is achieved, maintenance doses of oral 5-ASA agents should be used. Topical 5-ASA can be added if the patient had significant distal disease. AZA/6-MP can be used as maintenance therapy in patients who have steroid-dependant disease and in patients who have failed 5-ASA therapy.

Oral iron therapy might be necessary, as these patients tend to have iron deficiency anemia due to chronic blood loss. Antidiarrheal agents might be useful in patients who have persistent diarrhea. However they should not be used in acutely ill patients as they can precipitate toxic megacolon.

Severe or fulminant colitis

Severe colitis patients present with weight loss, fever, and dehydration and anemia. Fulminant colitis patients have toxic symptoms including fever, abdominal pain, anorexia and bloody diarrhea. Fulminant colitis can be complicated by toxic megacolon and bowel perforation. These patients need to be hospitalized and supportive treatment includes bowel rest, nutrition and parenteral steroids. Hydrocortisone (100 mg i.v. q8h), prednisolone (30 mg i.v. q12h), and methylprednisone (16–20 i.v. q8h) are the steroid preparations commonly used. In patients with significant rectal symptoms, 5-ASA or steroid enemas can be used in addition to the therapy above. Broad-spectrum antibiotics should be started in patients who have high-grade fever, leucocytosis, and signs of peritonitis or megacolon. Patients with intestinal dilation should get a naso-gastric tube and may need a rectal tube for decompression. Patients with toxic megacolon who don't respond to therapy within 72 hours should be considered for colectomy. Intravenous cyclosporine is another option for patients with severe colitis, especially if they are not psychologically prepared for surgery.

Anti-TNF (infliximab) therapy can be used in acute steroid-resistant UC patients who are reluctant to undergo surgery and in whom cyclosporine is contraindicated or has failed. Infliximab has been tested in clinical trials in active UC patients. In severe UC patients infliximab reduces the risk of colectomy at 90 days by 50% [Jarnerot et al. 2005].

Pouchitis

The most frequently observed long-term complication of ileal pouch anal anastomosis (IPAA) is acute and/or chronic inflammation of the ileal reservoir, called pouchitis. Antibiotics such as metronidazole can be used to treat pouchitis [Sandborn, 1994]. Oral metronidazole 1–2 g/day for 7 days can be given. One double-blind crossover trial randomly assigned patients with chronic unremitting pouchitis to metronidazole (400mg three times daily for 7 days) or placebo [Madden et al. 1994]. Metronidazole was associated with a significant reduction in stool frequency by three movements per day (versus an increase of one per day with placebo) but there was not change in the endoscopic or histologic grade of inflammation. Patients resistant to metronidazole can be treated with other antibacterial agents such as ciprofloxacin, doxycycline or ampicillin. The probiotic VSL#3 has been shown to be effective for primary and secondary prevention of pouchitis.

Conclusion

Although the above-mentioned drugs and treatment strategies have been fairly effective, there are still UC patients who do not respond to them and who require a colectomy. With new biologic agents, new treatment options for UC continue to evolve. Anti-TNF therapies such as the fully humanized monoclonal antibody adalimumab, PEGylated humanized Fab fragment certolizumab pegol, anti-IL-12 antibody and the granulocyte-macrophage colony stimulating factor sagramostim have been shown to be effective in CD. Randomized controlled trials of these drugs need to be conducted in UC patients. Several other molecules are being tested. Anti-cell adhesion molecule MLN02 is a humanized antibody targeted against the α4β7 integrin. A double-blind, randomized, placebo-controlled trial in active UC patients MLN-02 was significantly better than placebo in inducing remission.

Conflict of interest statement

Dr Peppercorn is on the Speaker bureau for Procter and Gamble and Abbott Pharmaceuticals.

Contributor Information

Sagar Garud, Dept of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA ; ude.dravrah.cmdib@durags.

Mark A. Peppercorn, Dept of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

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