Ther Adv Gastroenterol. 2009;2(2):99-108. © 2009 Sage Publications, Inc.
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.
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
Aminosalicylates
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 azoreductases 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 leukotriene 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
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.
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
Aminosalicylates
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 azoreductases 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 leukotriene 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