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REMICADE and Crohn's Disease in Adults

REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy. REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease.

Epidemiology
Pathophysiology
Clinical Manifestations and Complications
Disease Severity
Crohn's Disease Implications
Crohn's Treatment Options
References

Epidemiology

Crohn's disease is a chronic inflammatory bowel disease that:

Occurs in approximately 0.05% of the U.S. population
Most commonly develops between ages of 15 and 25 years
Is equally prevalent among males and females

Of all cases of Crohn's disease, about 35% involve the ileum, about 45% involve the ileum and colon, and about 20% involve the colon alone(9). Occasionally, the entire small bowel is involved, and rarely, the stomach, duodenum, or esophagus. The perianal region is also affected in one-quarter to one-third of cases.

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Pathophysiology

Under normal conditions, the gut immune response is characterized by a balance between pro-inflammatory and anti-inflammatory factors. In patients with Crohn's disease, the balance between these two systems in the mucosa is dysregulated, thereby shifting the normal equilibrium toward a chronic inflammatory state. Once the inflammatory cascade begins, many of the subsequent pathophysiologic events are related to(5, 9, 10, 11) an amplified inflammatory process. A variety of cellular processes and pro-inflammatory mediators influence the pathogenesis of Crohn's disease.

T-lymphocytes (T-cells)
T-cells are important in the normal regulation of intestinal immune responses and the pathogenesis of Crohn's disease(5, 10, 11). The CD4+ T-cells regulate key aspects of the immune response. These 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. However, the action of cytokines secreted by Th2 cells prevents cell-mediated immune responses to these antigens. In the case of Crohn's disease, however, there is a shift toward pro-inflammatory Th1-secreted cytokines, such as tumor necrosis factor alpha (TNF-alpha).

Tumor necrosis factor alpha (TNF-alpha)
The continuous hyperstimulation and chronic inflammation of the bowel in Crohn's disease can be attributed in part to the increased production of pro-inflammatory cytokines, especially TNF-alpha(5, 10, 11). TNF-alpha is present in excess in the mucosa of patients with Crohn's disease, and increases in TNF-alpha are associated with the release of other pro-inflammatory cytokines, including interleukin 1, 6, and 8(10). Other biological activities attributed to TNF-alpha include enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, as well as tissue-degrading enzymes produced by synoviocytes and/or chondrocytes(1).

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Clinical Manifestations and Complications

Patients with Crohn's disease have a spectrum of clinical features, and great variation in the course of disease(7, 9, 10). There is great variability in the clinical presentation of patients with Crohn's disease according to disease location, severity of inflammation within the involved intestinal segment, and intestinal and extraintestinal complications(10).

The common presenting features are the following(7-9):

Chronic or nocturnal diarrhea and abdominal pain
Weight loss
Fever
Rectal bleeding

These symptoms reflect the underlying inflammatory process of Crohn's disease(8).

Common clinical signs include the following(7,9):

Pallor
Anorexia and cachexia
Abdominal mass or tenderness
Perianal fissures, fistulas, or abscesses

Weight loss, wasting, loss of appetite, and general debility are common clinical signs of Crohn's disease; however, many patients may be first seen with an acute abdomen that simulates acute appendicitis(7,9). The ileum and colon are the most commonly affected sites, usually complicated by intestinal obstruction, inflammatory mass, or abscess(12,13). Perianal manifestations are common and may precede the onset of bowel symptoms(14). In addition to intestinal complications, patients with Crohn's disease may also have extraintestinal complications involving the skin or joints.

Intestinal complications: The most common intestinal complications are intestinal structures and fistulas(10). Approximately 6% of Crohn's disease patients develop fistulas, and 15% develop anal complications (fistula, fissure, abscess) within five years of diagnosis.

Extraintestinal complications: Associated extraintestinal features can include inflammation of the eyes, skin, or joints. Extraintestinal symptoms related to intestinal inflammation include the following(7, 9, 15):

Spondylarthritis (ankylosing spondylitis and sacroiliitis)
Peripheral arthritis
Cutaneous manifestations (erythema nodosum and pyoderma gangrenosum)
Ocular inflammation (uveitis or scleroconjunctivitis)
Primary sclerosing cholangitis
Hypercoagulability associated with altered levels of clotting factors and platelet abnormalities

Other sequelae: Crohn's disease also may be complicated by sequelae related to malabsorption (e.g., anemia, cholelithiasis, nephrolithiasis, or metabolic bone disease)(7, 9). Urinary tract infections can occur with fistulization into the urinary tract, as well as hydroureter and hydronephrosis from ureteral compression. In children, growth retardation and delayed sexual maturation are common(10). Also, Crohn's disease of long duration may be complicated by adenocarcinomas of the gastrointestinal tract and, rarely, lymphoma(16).

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Disease Severity

At any given time, patients with Crohn's disease can be characterized as having mild, moderate, or severe disease or as being in remission(7, 10). Patients typically fluctuate between these states throughout the course of their disease. In the absence of a "gold standard" measure of disease activity, severity is established on clinical parameters, systemic manifestations, and the global impact of the disease on the individual's quality of life(17). The most recent approval for Crohn's disease therapy in the United States is based upon definitions of "clinical improvement" and "clinical remission" supported by the Crohn's Disease Activity Index(17) and "fistula closure."

Click here for more information about defining Crohn's disease severity.

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Crohn's Disease Implications

Beyond its clinical impact, Crohn's disease carries significant economic consequences and has a major impact on patients' quality of life.

Direct/indirect medical costs: Because the disease affects most patients at an early age, it carries with it the prospect of years of medical care, hospitalization, and surgery. The total direct cost of Crohn's disease in the United States in 1990 was estimated at $1.0 to $1.2 billion(18). Indirect costs for lost productivity were estimated to range from $0.4 to $0.8 billion. A recent study found that the average cost of hospitalization, excluding physician fees, was $12,528(19). Surgery accounted for the majority of hospitalizations, and nearly 40% of their total costs.

Quality of life: Crohn's disease disrupts the physical, social, and emotional well-being of patients and has a deleterious impact on patients' quality of life(10, 18).

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Crohn's Treatment Options

Therapeutic recommendations for Crohn's disease depend upon the disease location, severity, and complications(7). Agents currently used in the treatment of Crohn's disease include(7, 9, 10, 11):

5-aminosalicylates (5-ASAs): The 5-ASAs may be roughly divided into sulfa-free agents (e.g., mesalamine) and their parent compound, sulfasalazine.
Antibiotics: Metronidazole, ciprofloxacin
Steroids: Steroids, such as prednisone, help many patients who have moderate to severe Crohn's disease. Unfortunately, prednisone has common, and sometimes severe, side effects. Long-term use has been linked to bone loss and fractures, cataracts, high blood pressure, diabetes mellitus, and other conditions.
Immunomodulators: Cyclosporine, tacrolimus, methotrexate, 6-MP, azathioprine
Biological response modifiers: Therapies specifically focusing on the inflammatory process underlying Crohn's disease have the potential for providing disease modification. Infliximab neutralizes the biological activity of TNF-alpha by binding with high affinity to the soluble and transmembrane forms of TNF-alpha and inhibits binding of TNF-alpha with its receptors (1). In clinical studies of infliximab, patients with Crohn's disease have achieved rapid and sustained reduction in clinical signs and symptoms(2-6).

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Please see Full Prescribing Information and Medication Guide for REMICADE.

References

REMICADE^® (infliximab) Prescribing Information.
d'Haens G, van Deventer S, van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: A European multicenter trial. Gastroenterology. 1999 May;116(5):1029-1034.
Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999 May 6;340(18):1398-1405.
Baert FJ, d'Haens GR, Peeters M, et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. Gastroenterology. 1999 Jan;116(1):22-28.
van Deventer SJ. Review article: targeting TNF alpha as a key cytokine in the inflammatory processes of Crohn's disease-the mechanisms of action of infliximab. Ailment Pharmacol Ther. 1999 Sep;13:3-8.
Rutgeerts PJ. Review article: efficacy of infliximab in Crohn's disease-induction and maintenance of remission. Ailment Pharmacol Ther. 1999 Sep;13CY: 9-15.
Hanauer SB, Meyers S. Management of Crohn's disease in adults. Am J Gastroenterol. 1997 Apr;92(4):559-566.
Fiocchi C. Inflammatory bowel disease: Etiology and pathogenesis. Gastroenterology. 1998;115:182-205.
Merck Manual of Diagnosis and Therapy. 17th ed. Beers MH, Berkow R, eds. Available at: http://www.merck.com/pubs/mmanual/. Accessed 2001 Sep 6.
Hanauer SB, Cohen RD, Becker RV 3rd, Larson LR, Vreeland MG. Advances in the management of Crohn's disease: economic and clinical potential of infliximab. Clin Ther. 1998 Sep;20(5):1009-1028.
Sands BE. Therapy of inflammatory bowel disease. Gastroenterology. 2000 Feb;118(2Suppl 1):S68-S82.
Farmer RG, Whelan G, Fazio VW. Long-term follow-up of patients with Crohn's disease: Relationship between the clinical pattern and prognosis. Gastroenterology. 1985;88:1818-25.
Mekhjian HS, et al. Clinical features and natural history of Crohn's disease. Gastroenterology. 1979;77:898-906.
Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 10-1996. A 36-year-old man with right-lower-quadrant pain of two years' duration (clinical conference). N Engl J Med. 1996;334:849-54.
Wagtmans MJ, et al. Clinical aspects of Crohn's disease of the upper gastrointestinal tract: A comparison with distal Crohn's disease. Am J Gastroenterol. 1997;92:1467-71.
Souto JC, et al. Prothrombotic state and signs of endothelial lesion in plasma of patients with inflammatory bowel disease. Dig Dis Sci. 1995;40:1883-9.
Hanauer SB. Inflammatory bowel disease. N Engl J Med. 1996 Mar 28;334(13):841-8.
Feagan BG. Review article: economic issues in Crohn's disease-assessing the effects of new treatments on health-related quality of life. Ailment Pharmacol Ther. 1999 Sep:29-37.
Cohen RD, Larson LR, Roth JM, Becker RV, Mummert LL. The cost of hospitalization in Crohn's disease. Am J Gastroenterol. 2000 Feb;95(2):524-530.

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Indications

Plaque Psoriasis
REMICADE is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

Rheumatoid Arthritis
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.

Psoriatic Arthritis
REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.

Adult Crohn's Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.

REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease.

Pediatric Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.

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.

Ankylosing Spondylitis
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

IMPORTANT SAFETY INFORMATION

RISK OF INFECTIONS
Tuberculosis (TB) (frequently disseminated or extrapulmonary at clinical presentation), bacterial infections including sepsis, invasive fungal infections, and other opportunistic infections have been observed in patients receiving REMICADE. Some of these infections have led to hospitalizations and death. Patients should be evaluated for TB risk factors and tested for latent TB.^1,2 Treatment of latent TB infection should be initiated prior to therapy with REMICADE. Some patients who received treatment for latent or active TB or who tested negative for latent TB prior to receiving REMICADE have developed active TB. In consultation with a physician with expertise in the treatment of TB, consider anti-TB treatment prior to REMICADE therapy in patients with a history of latent or active TB, when adequate treatment cannot be confirmed, or in patients who have a negative test for latent TB, but have several or highly significant risk factors.³ Monitor all patients receiving REMICADE for signs and symptoms of active TB.

Serious infections have occurred in patients on REMICADE alone or on concomitant immunosuppressive therapy that, in addition to their disease, could predispose them to infections. Cases of pneumonia, histoplasmosis, coccidioidomycosis, listeriosis, and pneumocystosis have been reported. For patients who have resided in regions where histoplasmosis or coccidioidomycosis is endemic, the benefits and risks of REMICADE should be considered before initiation of therapy. REMICADE should not be given to patients with a clinically important, active infection. Use with caution in patients with a history of infection. Monitor and educate patients for infection during or after treatment. Discontinue REMICADE if a patient develops a serious infection.

MALIGNANCIES
HEPATOSPLENIC T-CELL LYMPHOMAS
Rare postmarketing cases of hepatosplenic T-cell lymphoma have been reported in adolescent and young adult patients with Crohn’s disease treated with REMICADE. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. All of these hepatosplenic T-cell lymphomas with REMICADE have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine.

In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE, more cases of other malignancies were observed compared with controls. The rate of these malignancies among REMICADE-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

CONTRAINDICATIONS
REMICADE is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE if new or worsening CHF symptoms appear. REMICADE should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.

HEPATITIS B REACTIVATION
TNF inhibitors, including REMICADE, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating REMICADE. Exercise caution when prescribing REMICADE for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE. Discontinue REMICADE in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE and monitor patients closely.

HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE should be discontinued, and a thorough investigation of the abnormality should be undertaken.

HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some fatal, have been reported. The causal relationship to REMICADE therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE in patients who develop significant hematologic abnormalities.

HYPERSENSITIVITY
REMICADE has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with REMICADE infusions. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.

NEUROLOGIC EVENTS
TNF inhibitors, including REMICADE, have been associated with rare cases of new or exacerbated symptoms of demyelinating disorders including multiple sclerosis and optic neuritis, seizure, and CNS manifestations of systemic vasculitis. Exercise caution when considering REMICADE in all patients with these disorders. Consider discontinuation for significant CNS adverse reactions.

Please see Full Prescribing Information and Medication Guide for REMICADE.

References

American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247.
See Centers for Disease Control for latest guidelines and recommendations for latent tuberculosis testing in immunocompromised patients.
Gardam MA, et al. Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-155

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Last Updated: January 22, 2008