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REMICADE and Ankylosing Spondylitis

REMICADE is indicated for reducing signs and symptoms in patients with active AS.

Epidemiology
Pathophysiology
Clinical Manifestations and Complications
Disease Severity
AS Treatment Options
References

Epidemiology

AS is a chronic, progressive, immune-mediated inflammatory disorder that has the following epidemiological characteristics:

The incidence of AS may be underestimated due to unreported cases(1)
Almost 1 million Americans have AS
AS affects approximately 0.1% to 1.4% of the population worldwide(2)
The HLA-B27 gene is associated with AS(3)
The typical age of onset is between 17 and 35(4)
AS is three times more frequent in men than in women(5)

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Pathophysiology

The cause of AS is unknown, but strong HLA-B27 association suggests a disregulated immunity. A pathogenic antigen presented by HLA-B27 to CD8 T-cells may trigger AS(6). Gut bacteria may trigger aberrant immune response in HLA-B27 positive patients. HLA-B27 cross-reacts with antigens found in Klebsiella(7). Specific gut bacteria antigens have been isolated from AS joints(7).

Tumor necrosis factor alpha (TNF-alpha)(8):

TNF-alpha is a naturally occurring cytokine.

It is secreted mainly by macrophages and monocytes
Promotes inflammatory cytokines (IL-1, IL-6, IL-8, and GMCSF)
Stimulates fibroblasts to express adhesion molecules such as intercellular adhesion molecule (ICAM-1)
Increases the transport of leukocytes into the inflammatory site
Triggers the release of enzymes that damage cartilage and promote bone destruction
Plays a role in sustaining the immune response

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Clinical Manifestations and Complications

Clinical features of AS include(4):

Presenting symptoms

Insidious onset of low back pain
Persistent for more than three months
Worsened by inactivity
Improved by exercise

Other constitutional symptoms

Fatigue
Fever, anorexia, or weight loss

Sacroiliitis
Enthesitis

Extra-articular manifestations of AS include(6):

Inflammatory bowel disease
Uveitis
Peripheral arthritis

Pulmonary disease

Restrictive capacity
Pulmonary fibrosis

Atypical symptoms of AS include(5):

In women:

Neck and peripheral joint symptoms may dominate
May be difficult to distinguish from RA

Uveitis may be the first symptoms, before joint pain
Occasionally patients (usually in older age groups) may have predominantly systemic symptoms

Fatigue
Anorexia
Fever
Weight loss
Night sweats

Complications of AS may include(5):

Spinal Fracture

May result from minor trauma
May cause spinal cord injury

Aortic insufficiency
Cardiac conduction disturbances, including third-degree heart block

Incidence increases with prolonged disease

Pulmonary lesions
Prostatitis

More common in men with AS than in men without AS

Amyloidosis (rare)

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Disease Severity

The course of AS varies from mild to severe:

Mild

Some stiffness
Sacroiliitis

Severe

Total spinal fusion
Severe bilateral hip arthritis
Severe peripheral arthritis
Extra-articular symptoms

Click here for more information about defining AS disease severity.

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AS Treatment Options(5, 9)

Currently there is no definitive treatment for AS. Because no therapy has been proven to slow disease progression, the goal has been to maintain functional posture and range of motion. Current treatments for AS include:

Exercise and physical therapy — to prevent fusion and increase flexion
NSAIDs (nonsteroidal anti-inflammatory drugs) — to relieve symptoms and facilitate exercise
Corticosteroids
DMARDs (disease-modifying anti-inflammatory drugs), including sulfasalazine and methotrexate
Pamidronate — a bisphosphonate
Surgery, including hip replacement and other stabilizing procedures
Biologic agents, including REMICADE and Enbrel*

*ENBREL (etanercept) is a registered trademark of Immunex Corp.

Please see Full Prescribing Information and Medication Guide for REMICADE.

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References

Spondylitis Association of America. Statement of Spondylitis Association of America regarding clinical trial for treatment of spondylitis as published in the NEJM. 2002 May. Available at: http://www.scienceblog.com/community/older/2002/C/20025406.html. Accessed December 8, 2004.
Sieper et al. Ankylosing spondylitis: an overview. Ann Rheum Dis. 2002; 61 (suppl 3);iii8-18.
American College of Rheumatology. Ankylosing spondylitis. Fact sheet. 2000. Available at: http://www.rheumatology.org/public/factsheets/as.asp . Accessed December 8, 2004.
Rheumatology Diseases and Therapeutics. Primer of the Rheumatic Diseases, 12 th edition. Arthritis Foundation: 2001.
Kasper DL, et al. Harrison’s Principles of Internal Medicine, 16 th Ed. 2005:1993-1996.
Sieper J. et al. Arthritis Rheum 1995;38:1547-54.
Ebringer A., Wilson C. J Med Microbiol 2000;49:305-11.
Zou JX, et al. Immunological basis for the use of TNF a -blocking agents in ankylosing spondylitis and immunological changes during treatment. Clin Exp Rheumotol. 2002;20(Suppl. 28):S34-S37.
Khan M. Ann Intern Med 2002;136:896-907.

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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

Patients treated with REMICADE^® are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE^® if a patient develops a serious infection or sepsis.

Reported infections include:

Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE^® . ^1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE^®.
Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with REMICADE^® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE^®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

MALIGNANCIES

HEPATOSPLENIC T-CELL LYMPHOMAS

Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE^®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE^® at or prior to diagnosis.

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 patients treated with REMICADE^® 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 infusions of REMICADE^®. 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, optic neuritis, and Guillain-Barré syndrome, 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^®. Provide the Medication Guide to your patients and encourage discussion.

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 latest Centers for Disease Control guidelines and recommendations for latent tuberculosis testing in immunocompromised patients.

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Last Updated: January 19, 2009