Disease Pathogenesis

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The pivotal role of TNF in immune-mediated diseases

Tumor necrosis factor (TNF), a proinflammatory cytokine produced by immune system macrophages and T cells, plays a role in initiating the inflammatory process of the immune system.^1,2 Once released, TNF binds to naturally occurring TNF receptors located on cell surfaces.² Stimulation of these cells has been shown to induce inflammation by³:

• Increasing the production of proinflammatory cytokines
• Increasing cell migration by activating cellular adhesion molecules
• Increasing tissue destruction by matrix-degrading proteinases

In the healthy immune system, soluble TNF receptors appear to serve as a natural counterbalance to TNF. However, in rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), psoriatic arthritis, and plaque psoriasis, elevated levels of TNF are found. In patients with these diseases, it has been suggested that soluble TNF receptors cannot adequately regulate the increased levels of TNF being produced.⁴

Rheumatoid Arthritis (RA)

RA is characterized by chronic synovial inflammation caused by infiltration of immune and inflammatory cells into the joint.¹

In RA, exposure to increased levels of TNF at the pannus-cartilage junction activates destructive enzyme production in the joints.⁵ The enlargement of synovial tissue and the activation of destructive enzymes can lead to damage in and around affected joints.

Enlarged synovial tissue, called pannus, can cause^2,3:

• Damage to the adjacent articular structures of the joint, cartilage, and bone
• Damage to ligaments and tendons

Joint damage may occur early in the disease process:

• Destructive enzymes associated with cartilage and bone erosion are present at the onset of RA⁶
• 70% to 93% of RA patients have shown erosion on x-rays within 2 years of the onset of symptoms^5,7

Juvenile Idiopathic Arthritis (JIA)

JIA is a persistent arthritis in one or more joints that begins before age 16. Research indicates that there may be differences in the disease processes of RA and JIA.⁸ TNF has been observed in the synovium of both RA and JIA patients^2,3 and elevated levels of TNF play a major role in the inflammatory processes of both. However, another cytokine closely related to TNF—lymphotoxin alpha (LTα)—is prominent in the synovium of JIA patients.⁸

The biological activity of both of these cytokines depends on their ability to bind to cell-surface receptors.²

Ankylosing Spondylitis (AS)

AS is a chronic, systemic, inflammatory disorder involving the axial joints and, to a lesser extent, the peripheral joints.⁹ It is characterized by persistent lower back pain that occurs especially at night, loss of spinal mobility, potential extra-articular manifestations, and, in severe cases, fusion of the spinal vertebrae.¹⁰

Research into the pathogenesis of AS is ongoing. While the pathogenesis of AS is not fully understood, immune-mediated mechanisms are thought to play key roles, and may involve^10,11:

• HLA-B27. The high prevalence of HLA-B27 in patients with AS is the disease's most striking genetic feature, suggesting an immunologic basis for its development.
• Inflammatory cellular infiltrates. Chronic inflammation leads to infiltration of subchondral tissues by plasma cells, lymphocytes, mast cells, macrophages, and chondrocytes. Affected joints show irregular erosion and sclerosis, with tissue gradually replaced by fibrocartilage that becomes ossified.
• Cytokines such as TNF. There is evidence that TNF plays an important role in the inflammatory cascade of AS.^10,11 TNF is elevated in the serum and joints of AS patients. Significantly higher levels of TNF are found in the serum of patients with AS than in patients with non-inflammatory back pain. High amounts of TNF, messenger RNA, and protein have been detected in sacroiliac joint tissue of patients with AS.¹¹

Psoriatic Arthritis

Psoriatic arthritis is an inflammatory disorder that affects the skin, and both proximal and distal joints.¹² Although arthritis occasionally develops before psoriatic lesions are evident, the skin lesions commonly precede the arthritic component. Sometimes the two appear together.¹³

Ongoing research suggests that the pathogenesis of psoriatic arthritis is multifactorial, with the following factors playing important roles¹²:

• Genetic factors
• Environmental factors
• Immunologic factors

The role of TNF in the pathogenesis of psoriatic arthritis is currently under investigation.⁸ TNF causes a number of different effects by stimulating diverse cell types.⁸ Of particular relevance to the pathogenesis of psoriatic arthritis, TNF can either directly or indirectly:

• Increase migration of leukocytes into inflamed sites²
• Stimulate production of other proinflammatory cytokines²
• Promote cartilage destruction²

Plaque Psoriasis

Psoriasis is an immune-mediated disease that affects up to 7.5 million Americans.¹³ The most common form is plaque psoriasis, which is often characterized by thickened, well-demarcated, red lesions covered by silvery scales. These scales may occur on the body as a few small plaques or in the form of more generalized lesions. They can be painful and itchy, and may bleed.¹⁴

Plaque psoriasis is a serious and potentially debilitating disease.¹⁴ Up to 42% of patients with psoriasis actually have psoriatic arthritis, a progressive disease that can lead to severe disability if left untreated.¹⁴ Because skin symptoms can appear before joint symptoms in up to 85% of these psoriatic arthritis patients, the dermatologist can play a pivotal role in early diagnosis and may have the first opportunity to initiate treatment.¹⁵

In psoriasis, the chronic T-cell dependent inflammatory process occurring in the skin is mediated by TNF and other inflammatory cytokines. TNF levels are elevated in the plaques of psoriasis patients. As a result of this inflammatory process, epidermal thickening occurs and the red scaly plaque typical of psoriasis appears.

ENBREL can help reduce TNF levels

Enbrel^® (etanercept) is a dimeric soluble form of a 75 kilodalton protein TNF receptor.² By mimicking the effect of naturally occurring soluble TNF receptors, ENBREL binds to TNF. This keeps TNF from binding to TNF receptors on the surface of target cells. Reducing active TNF can result in the clinical improvement of signs and symptoms for RA, JIA, AS, psoriatic arthritis, and plaque psoriasis.²

ENBREL is an immunomodulatory agent and therefore may suppress a patient's ability to fight infection. Please see Important Safety Information below and be sure to read the full Prescribing Information.

References

1. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med. 1999:130:478-486.
2. Enbrel^® (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
3. Moreland LW, Koopman WJ, Biologic agents as potential therapies for autoimmune diseases. In: Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology. Vol 1. 13th ed. Baltimore, Md: Williams & Wilkins; 1997:777-809.
4. Hehlgans T, Pfeffer K. The intriguing biology of the tumor necrosis factor/tumor necrosis factor receptor superfamily: players, rules and the games. Immunology. 2005: 115: 1-20.
5. Bresnihan B. Pathogenesis of joint damage in rheumatoid arthritis. J Rheumatol. 1999:26:717-719.
6. Moreland LW. Inhibitors of tumor necrosis factor: new treatment options for rheumatoid arthritis. Cleve Clin J Med. 1999;66:367-374.
7. Feldmann M, Brennan FM, Miani RN. Rheumatoid arthritis. Cell. 1996;85:307-310.
8. Partsch G, Steiner G, Leeb BF, et al. Highly increased levels of tumor necrosis factor-a and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J Rheumatol. 1997;24:518-523.
9. Williams IR, Rich BE, Kupper TS. Cytokines and chemokines. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick's Dermatology in General Medicine. Vol 1. 5th ed. New York, NY: McGraw-Hill; 1999:384-399.
10. Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis: an overview. Ann Rheum Dis. 2002;61(suppl III):iii8-iii18.
11. Braun J, Sieper J, Breban M, et al. Anti-tumour necrosis factor a therapy for ankylosing spondylitis: international experience. Ann Rheum Dis. 2002;61(suppl III):iii51-iii60.
12. O'Dell JR. Anticytokine therapy—a new era in the treatment of rheumatoid arthritis? [editorial]. N Engl J Med, 1999;340:310-312.
13. National Psoriasis Foundation website. About psoriasis:statistics. Available at http://www.psoriasis.org/about/stats. Accessed March 22, 2007.
14. National Psoriasis Foundation website. About psoriasis FAQ. Available at http://www.psoriasis.org/about/faq. Accessed March 22, 2007.
15. National Psoriasis Foundation website. About psoriatic arthritis: diagnosis. Available at http://www.psoriasis.org/about/psa/diagnosis. Accessed March 22, 2007.