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REMICADE and 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.

Epidemiology
Pathophysiology
Clinical Manifestations and Complications
Rheumatoid Arthritis Implications
References

Epidemiology

RA is a chronic autoimmune inflammatory disorder of unknown etiology that:

Occurs in approximately 1% of the population
Is two to three times more prevalent among women than men
Most commonly develops in the third to fifth decades of life; approximately 80% of total cases occur between the ages of 35 and 50
Shortens the life span by three to ten years

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Pathophysiology

RA is a chronic, progressive, and disabling disease. Despite intensive research, the cause of RA remains unknown. The pathogenesis of this disease is likely multifactorial, involving autoimmunity and genetic factors; infectious agents also are suspected of having a role. Further details are provided below.

Genetic factors: Family studies reveal that RA has a genetic component; human leukocyte antigen (HLA) is an important genetic factor, and the risk for RA is thought to be associated with a sequence of amino acids within the genetic code of certain individuals.

Autoimmunity: Macrophage-derived cytokines appear to be involved in the induction and perpetuation of the chronic inflammatory processes of the joints seen in RA. High titers of serum rheumatoid factors, or autoantibodies to the Fc portion of the immunoglobulin G (IgG) molecules, are associated with more severe joint disease and with extra-articular manifestations.

Infectious agents: Viral infections such as rubella, Ross River virus, and parvovirus are associated with the development of acute polyarthritis; Chlamydia pneumoniae has been detected in some individuals with RA. However, cause or connection has not been demonstrated(1).

Although the precise mechanism of bone and cartilage destruction in RA is not completely understood, the cytokines IL-1 and TNF-alpha play an important role. These cytokines:

Are abundant in inflamed joints and promote the influx of inflammatory neutrophils and monocytes into the joints
Stimulate cells in the inflamed synovium to produce proteolytic enzymes, including collagenase and stromelysin, that can degrade tissue
Cause systemic manifestations such as malaise and fatigue

Thus, although the initial cause of RA remains unknown, the maintenance and propagation of the disease appear to be related to immunologically mediated inflammatory processes. Hence, interfering with key steps in the inflammatory process would be expected to provide symptomatic relief and to slow disease progression.

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Clinical Manifestations and Complications

The clinical course of RA can vary considerably. While some patients experience only mild illness of short duration with minimal joint involvement, others experience relentless polyarthritis accompanied by marked joint deformities. The majority of patients follow an intermediate course.

The main presenting symptoms of RA are:

Pain
Marked morning stiffness
Swelling and tenderness of the joints, typically symmetrical
Impaired physical function

Constitutional symptoms of RA include the following:

Fever
Weight loss
Fatigue/malaise

Manifestations/complications of RA include the following:

Joint deformities resulting from cartilage destruction and bone erosion
Rheumatoid nodules
Rheumatoid vasculitis
Pleuropulmonary manifestations, including pulmonary fibrosis
Serositis
Eye inflammation
Osteoporosis
Requirement for surgery to normalize functional capacity and/or range of motion

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Rheumatoid Arthritis Implications

Rheumatoid arthritis is a difficult disease to diagnose. Patients often discount rheumatoid arthritis symptoms as an inevitable part of aging and do not seek relief until significant joint damage has already occurred.

It is important to be aware of the serious and often devastating effects of rheumatoid arthritis, including the following:

Disability: Up to 85% of people with rheumatoid arthritis are unable to work by the 11th year after disease onset(2). Nearly 30% of these patients become disabled within the first three years after onset(2). Physicians are becoming more aggressive in treating rheumatoid arthritis, with the goal of slowing disease progression before disability occurs.

Premature death: The mortality rate for rheumatoid arthritis patients is twice the expected rate in the general population(3), and those with more severe rheumatoid arthritis are five times more likely to die within the next five years than are those with milder rheumatoid arthritis(4).

Direct medical costs: The direct medical costs of rheumatoid arthritis approach $5 billion annually, with nearly 70% of these costs attributable to hospitalizations and home nursing care(5, 6). Rheumatoid arthritis patients make more than 9 million physician visits and account for over 250,000 hospitalizations annually(7). The direct cost to patients is considerable, even with insurance.

Productivity losses: Lost productivity costs due to rheumatoid arthritis approach $20 billion annually, and rheumatoid arthritis patients lose, on average, 50% of potential earnings(8-10). The lifetime indirect costs of rheumatoid arthritis are similar to those for stroke or coronary artery disease(11). Increased absenteeism, disability, and early retirement all contribute to the loss of personal income resulting from rheumatoid arthritis.

Psychological impact: Most people have trouble coping with the physical disabilities caused by rheumatoid arthritis and often will feel anxious, frustrated, and discouraged as a result(12).

Timely diagnosis and aggressive treatment can go far in preventing the downward spiral of pain, stiffness, and disability that can accompany rheumatoid arthritis, and contribute to longer, more satisfying lives for rheumatoid arthritis patients.

Please see Full Prescribing Information and Medication Guide for REMICADE.

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References

Schumacher HR Jr, Gerard HC, Arayssi TK, et al. Lower prevalence of Chlamydia pneumoniae DNA compared with Chlamydia trachomatis DNA in synovial tissue of arthritis patients. Arthritis Rheum. 1992;42:1889-1893.
Mau W, Bornmann M, Weber H et al. Prediction of permanent work disability in a follow-up study of early rheumatoid arthritis: results of a tree structured analysis using RECPAM. Br J Rheumatol. 1996;35:652-659.
Wolfe F. The natural history of rheumatoid arthritis. J Rheumatol. 1996;23(suppl):13-22.
Pincus T. The underestimated long term medical and economic consequences of rheumatoid arthritis. Drugs. 1995;50(suppl):1-14.
Yelin E. The costs of rheumatoid arthritis: absolute, incremental, and marginal estimates. J Rheumatol. 1996;23(suppl):47-51.
Jacobs J, Keyserling JA, Britton M, et al. The total cost of care and the use of pharmaceuticals in the management of rheumatoid arthritis: the Medi-Cal program. J Clin Epidemiol. 1988;41:215-223.
American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum. 1996;39:713-722.
Mitchell JM, Burkhauser RV, Pincus T. The importance of age, education, and comorbidity in the substantial earnings losses of individuals with symmetric polyarthritis. Arthritis Rheum. 1988;31:348-357.
Burkhauser RV, Butler JS, Mitchell JM, Pincus T. Effects of arthritis on wage earnings. J Gerontol. 1986;41:277-281.
Meenan RF, Yelin EH, Nevitt M, Epstein WV. The impact of chronic disease. A sociomedical profile of rheumatoid arthritis. Arthritis Rheum. 1981;24:544-549.
Stone CE. The lifetime economic costs of rheumatoid arthritis. J Rheumatol. 1984;11:819-827.
Moran MG. Psychiatric aspects of rheumatology. Psychiatr Clin N Am. 1996;19:575-587.

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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