REMICADE and Ulcerative Colitis

REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.

Epidemiology
Pathophysiology
Clinical Manifestations and Complications
Disease Severity
Ulcerative Colitis Implications
Ulcerative Colitis Treatment Options
References

Epidemiology

UC is a chronic inflammatory bowel disease that (1):

• Occurs in approximately 11 out of 100,000 people in the United States
• Most commonly develops between ages 15 and 30
• Is equally prevalent among males and females
• Evidence suggests genetics, exogenous factors, and host factors as predispositions for unregulated intestinal immune system response

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Pathophysiology

UC is considered an immune-mediated inflammatory disease. It displays characteristics of an autoimmune disorder, which results from an immune system attack on self-tissues. The normal intestine contains large numbers of immune cells. During the course of an infection in the normal host, a full immune response occurs, which is then rapidly superseded by downregulation and tissue repair, indicating balance between pro-inflammatory and anti-inflammatory systems in the colonic mucosa. In patients with UC, the balance between the two systems in the mucosa is not regulated, thereby shifting the normal equilibrium toward a chronic inflammatory state. The process of downregulation and tissue repair do not occur in the normal fashion. Once the inflammatory cascade begins, many of the subsequent pathophysiologic events are related to an amplified inflammatory process. Ulcerations and the appearance of lesions occur from the loss of surface epithelial cells and damage to the mucosa. A variety of cellular processes and pro-inflammatory mediators influence the pathogenesis of UC (1, 2, 3).

T-lymphocytes (T-cells)
T-cells are important in the normal regulation of intestinal immune responses and the pathogenesis of UC. The CD4+ T-cells, also known as T-helper cells, regulate key aspects of the immune response. They stimulate proliferation of other T-cells and B-cells, bind with antigens presented by antigen presenting cells (APCs), and secrete cytokines. T-cells are classified as either T-helper 1 (Th1) or T-helper 2 (Th2) cells, based on their function and secretion of certain cytokines. Under normal conditions, antigens derived from food and bacteria in the gut are continually in contact with the intestinal mucosa. In UC, however, downregulation of cytokines does not occur as it normally would, which results in an imbalance of pro-inflammatory and anti-inflammatory mediators (1, 2, 3, 4).

Tumor necrosis factor alpha (TNF-alpha)
Activation of CD4+ T-cells leads to the release of TNF-alpha, an inflammatory cytokine that plays a key role in UC. Produced by macrophages and monocytes, TNF-alpha stimulates production of other pro-inflammatory cytokines. The continuous hyperstimulation and chronic inflammation of the bowel in UC can be attributed in part to the increased production of pro-inflammatory cytokines, such as TNF-alpha. TNF-alpha is present in excess in the mucosa of patients with UC, and increases in TNF-alpha are associated with the release of other pro-inflammatory cytokines (1, 2, 3).

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Clinical Manifestations and Complications

Patients with UC have a spectrum of clinical features. UC is progressive, and the severity of symptoms correlates with the extent of the disease (1).

Symptoms typical of moderately to severely active UC include (5, 6):

• ≥5 or 6 bloody stools per day
  
• Flexible proctosigmoidoscopic findings of marked erythema, absent vascular pattern, friability, erosions
  
• Physician’s global assessment of moderate disease, including:
  • Diarrhea, often bloody
    
• Abdominal pain and tenderness
  
• Low grade fever
  
• Fatigue
  
• Physician’s global assessment of severe disease may also include (6):
• >6 bloody stools per day
  
• Fever (mean evening temperature >37.5° C or >37.5° C on at least 2 of 4 days at any time of day)
  
• Tachycardia (mean pulse rate >90 beats per minute)
• Anemia (hemoglobin of <7.5 g/dL, allowing for recent transfusions)
• Elevated sedimentation rate (>30 mm/hr)

The physician’s global assessment acknowledges three other criteria (stool frequency, rectal bleeding, and findings of flexible proctosigmoidoscopy), the patient’s daily recollection of abdominal discomfort and general sense of well-being, and other observations, such as physician findings and the patient’s performance status (5).

Clinical signs of UC include the following:

• Pallor (4)
  
• Anorexia (7)
  
• Abdominal mass or tenderness (4)
  
• Anemia (7)
  

The severity of the symptoms may be related to the extent of the disease and the length of time the disease has been present (1). The hallmark feature of UC is the progression of uniform and continuous lesions, retrograde from the rectum. Assessment of disease severity in newly diagnosed patients varies as follows (2):

• 54% of patients have mild disease limited to the rectum and sigmoid colon (i.e., proctosigmoidosis)
  
• 27% of patients have moderate disease, typically presenting with abdominal pain, fatigue, and possible low-grade fever
  
• 19% of patients have severe disease, typically presenting with weight loss, anemia, and hypoalbuminemia
  

The severity of disease can be determined by examination of the colonic mucosa. With mild UC, the mucosa is erythematous and has a fine granular surface. With more severe disease, the mucosa becomes ulcerated, swollen, and often hemorrhagic. Severe inflammation may also lead to submucosal edema (2).

In addition to intestinal complications, patients with UC may also have extraintestinal manifestations, which may be dermatologic, rheumatologic, or ocular (1). 

Intestinal complications: Intestinal complications include toxic megacolon, which can cause hemorrhaging and perforation and requires colectomy. It is defined as a transverse colon with a diameter of >5 to 6 cm. Obstructions cased by benign intestinal strictures may also occur, with one-third of the strictures occurring in the rectum. Patients may also develop anal fissures, toxic colitis, or hemorrhoids, but the occurrence of extensive perianal lesions should suggest Crohn’s disease (1).

Extraintestinal manifestations: Extraintestinal complications include erythema nodosum, pyoderma gangrenosum, peripheral arthritis, ankylosing spondylitis, sacroiliitis, anterior uveitis, and hepatobiliary disease (1, 4).

Other sequelae: UC may also be complicated by sequelae related to malabsorption (e.g., anemia and cholelithiasis) (1, 7). In children, there is the risk of retarded growth and development (7).

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Disease Severity

At any given time, patients with UC can be characterized as having mild, moderate, or severe disease or as being in remission. Patients may typically fluctuate between these states throughout the course of their disease. The Mayo Score is one index used to determine disease severity. It calculates severity on a 12-point scale (12 being the most severe) based on four subscores: number of bowel movements above normal, rectal bleeding, endoscopic findings, and physician’s global assessment. Severity is established by these clinical parameters, as well as systemic manifestations, and the global impact of the disease on the patient’s quality of life (4, 5, 7).

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Ulcerative Colitis Implications

Beyond its clinical impact, UC carries significant economic consequences and has a major impact on patients’ quality of life.

Because the disease affects most patients at an early age, it carries with it the prospect of years of medical care, hospitalization, and surgery.

UC disrupts the physical, social, and emotional well-being of patients and has a deleterious impact on patients’ quality of life.

• 55% avoided social engagements due to symptoms
• 74% percent reported they have experienced less sleep than desired
• 41% have avoided intimate situations with a spouse or partner, and 24% reported having trouble maintaining a relationship with a spouse or partner
• Approximately 22% reported having missed an average of 16.8 days of work per year
• Nearly 40% of respondents experienced symptoms at least 180 days a year.

Learn more about the survey

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Ulcerative Colitis Treatment Options

Therapeutic recommendations for UC depend on the disease location, severity, and complications (8). Agents currently used in the treatment of UC include:

• 5-aminosalicylates (5-ASAs): The mainstay of treatment for mild to moderate UC is anti-inflammatory therapy with sulfasalazine and the other 5-ASA agents. These agents are effective at inducing and maintaining remission. While sulfasalazine has shown efficacy in the treatment of mild to moderate UC, its high rate of side effects limits its use. In the United States, the most commonly used 5-ASA drugs besides sulfasalazine are sulfa-free mesalamine formulations (1, 3, 4, 8). Rare hypersensitivity reactions, including pneumonitis, pancreatitis, hepatitis, nephritis, and worsening of colitis, have been reported with mesalamine (1, 8).
  
• Corticosteroids: Corticosteroids, such as prednisone, are effective in patients with moderately to severely active UC. They are indicated primarily for the short-term induction of remission and not as long-term maintenance therapy. Once clinical remission has been induced, corticosteroids should be tapered, normally at a rate of no more than 5 mg per week (1). Classic adverse effects associated with long-term corticosteroid use include adrenal suppression, Cushing’s syndrome, osteoporosis, and growth retardation in children (3, 4, 8). Other side effects include fluid retention, emotional disturbances, and withdrawal symptoms (2).
  

• Immunomodulators: Immunomodulatory drugs are appropriate treatments in some patients with UC (8):
  
  
  • Azathioprine and 6-mercaptopurine (6-MP) are purine analogues commonly employed in the management of glucocorticoid-dependent UC. Azathioprine is rapidly absorbed and converted to 6-MP, which is then metabolized to the active end product, thioinosinic acid, an inhibitor of purine ribonucleotide synthesis and cell proliferation. These agents also inhibit the immune response. Azathioprine and 6-mercaptopurine have been employed successfully as glucocorticoid-sparing agents in some UC patients previously unable to be weaned from glucocorticoids. Although azathioprine and mercaptopurine are usually well tolerated, pancreatitis occurs in 3% to 4% of patients. In addition, both azathoprine and 6-mercaptopurine may cause bone marrow suppression (particularly leukopenia). This complication is dose-related and often delayed, requiring regular monitoring of the complete blood count (1).
    
    
  • Cyclosporine (CSA) is indicated for acute, severe UC, and is effective as a continuous intravenous infusion (8). CSA alters the immune response by acting as a potent inhibitor of T-cell mediated responses (1). In UC, cyclosporine may be effective in as many as 82% of patients hospitalized for severe flares refractory to intravenous corticosteroids (3). Continuous intravenous infusions of cyclosporine have proven effective, but lower-dose oral regimens have not been consistently effective for either inducing or maintaining remission. The primary side effect of cyclosporine is renal dysfunction, manifested as a decrease in glomerular filtration, interstitial nephritis, or both. Other complications include neurotoxic effects and seizures (especially in patients with low serum concentrations), immunosuppression, and opportunistic infections (8).
    
    
  • Methotrexate (MTX) is effective in inducing remission and reducing glucocorticoid dosage in patients with UC (1). Because of the potential for bone marrow suppression and hepatic toxicity, blood counts and liver-enzyme concentrations must be monitored (8).
    
    
• Biological response modifiers: REMICADE is the first example of a biologic response modifier used in the treatment of patients with moderately to severely active UC who have had an inadequate response to conventional therapy (3, 9). REMICADE neutralizes the biological activity of TNF by binding with high affinity to the soluble and transmembrane forms of TNF-alpha and inhibits binding of TNF-alpha to its receptors (4). In clinical studies of REMICADE, patients with UC have achieved clinical response, clinical remission, mucosal healing, and steroid reduction or elimination (9). Serious and sometimes fatal side effects have been reported with REMICADE, including TB and other serious infections and a rare form of T-cell lymphoma. REMICADE is also contraindicated in patients with severe hypersensitivity reactions to REMICADE and certain patients with congestive heart failure.

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Please see Full Prescribing Information and Medication Guide for REMICADE.

References

1. Kaspar DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, eds.  Inflammatory bowel disease. Chapter 276. In: Harrison’s Principles of Internal Medicine, 16th edition. New York:McGraw Hill;2005. 1776-1779.
2. Yamada T, et al. eds. Inflammatory bowel disease. Chapter 81. In: Handbook of Gastroenterology. Lippincott, Williams & Wilkins: Philadelphia, Pa;2005.
3. Sands BE. Therapy of inflammatory bowel disease. Gastroenterology.  2000 Feb;118(Suppl 1):S68-S82.
   
4. Markowitz J, et al. Ulcerative colitis. eMedicine website. 2005. Available at:  http://www.emedicine.com/ped/topic1183.htm. Accessed September 19, 2006.
5. Schroeder K, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study. N Engl J Med. 1987 Dec 24:317(26);1625-1629.
6. Yamada T, et al. eds. Inflammatory bowel disease. Chapter 46. In: Handbook of Gastroenterology. Lippincott, Williams & Wilkins: Philadelphia, Pa;2005.
   
7. Beers MH, Berkow R, eds. Ulcerative colitis. Available at:  http://www.merck.com/mrkshared/mmanual/section3/chapter31/31c.jsp. Accessed September 19, 2006.
8. Hanauer SB. Inflammatory bowel disease. N Engl J Med. 1996 Mar 28;334(13):841-8.
   
9. REMICADE^® (infliximab) Prescribing Information. Centocor, Inc.
   

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