Disease Pathogenesis

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Rheumathoid Arthritis (RA)

In RA, the enlargement of synovial tissue and the activation of destructive enzymes can lead to damage in and around affected joints.

Mimicking the effect of naturally occurring soluble TNF (tumor necrosis factor) receptors (blue), ENBREL (depicted here as a purple-and-blue dimer) binds to TNF (yellow), inactivating it and keeping it from binding to TNF receptors on the surface of target cells.

RA is characterized by¹:

• Chronic synovial inflammation
• Infiltration of immune and inflammatory cells into the joint

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 RA⁴
• 70% to 93% of RA patients have shown erosion on x-rays within 2 years of the onset of symptoms^5,6

The pivotal role of TNF in the RA disease process

TNF, a proinflammatory cytokine produced by immune system macrophages and T cells, plays a role in causing joint inflammation.¹ 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. In RA, however, soluble TNF receptors cannot adequately regulate the increased levels of TNF being produced.⁴ Exposure to increased levels of TNF at the pannus-cartilage junction activates destructive enzyme production in the joints.⁵

Inhibition of TNF can result in a decrease of synovitis, a delay in the progression of joint damage, and clinical improvement.²

The role of TNF in the JIA disease process

Research indicates that there may be differences in the disease processes of RA and JIA.⁹ 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.⁹

The biological activity of both of these cytokines depends on their ability to bind to cell-surface receptors.² ENBREL inhibits binding of TNF and LTα to cell-surface TNF receptors.²

Ankylosing Spondylitis (AS)

AS is a chronic, systemic, inflammatory disorder involving the axial joints and, to a lesser extent, the peripheral joints.¹⁰ 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.¹¹

While the pathogenesis of AS is not fully understood, immune-mediated mechanisms are thought to play key roles, and may involve^11,12:

• HLA-B27
• Inflammatory cellular infiltrates
• Cytokines such as TNF

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.

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. In severe cases of the disease¹¹:

• Outer annular fibers are replaced by bone and the vertebrae become fused
• Fusion may ascend the spine, forming a long, bony column referred to as "bamboo spine"

The role of TNF in the AS disease process

Research into the pathogenesis of AS is ongoing. However, there is evidence that TNF, a proinflammatory cytokine, plays an important role in the inflammatory cascade of AS.^11,12

TNF is elevated in the serum and joints of AS patients. The inflammatory cascade mediated by TNF is believed to have significance in AS in light of the following research results¹²:

• 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

Psoriatic Arthritis

Psoriatic arthritis is an inflammatory autoimmune disorder that affects the skin, and both proximal and distal joints.⁷

Ongoing research suggests that the pathogenesis of psoriatic arthritis is multifactorial, with the following factors playing important roles⁷:

• Genetic factors
• Environmental factors
• Immunologic factors

Although arthritis occasionally develops before psoriatic lesions are evident, the psoriatic component of psoriatic arthritis commonly precedes the arthritic component. Sometimes the two appear together.¹³

The role of TNF in the psoriatic arthritis disease process

Research into the pathogenesis of psoriatic arthritis is ongoing and the role of TNF is currently under investigation.⁹ TNF causes a number of different effects by stimulating diverse cell types.⁹ 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, inflammatory skin disease that affects an estimated 4.5 million adults in the United States.¹³ The most common form is plaque psoriasis, which is often characterized by thickened, well-demarcated, red-violet 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.¹³

Psoriasis is a serious and potentially debilitating disease.¹³ Up to 42% of patients with psoriasis symptoms actually have psoriatic arthritis, a progressive disease that can lead to severe disability if left untreated.¹³ Because skin symptoms can appear before joint symptoms in 70% of these psoriatic arthritis patients, the dermatologist can play a pivotal role in the early diagnosis of patients with joint involvement and may have the first opportunity to initiate treatment.¹³

The role of TNF in the psoriasis disease process

TNF is a cytokine that plays a key role in initiating the inflammatory process. In psoriasis, the chronic T-cell dependent inflammatory process occurring in the skin is mediated by TNF and other inflammatory cytokines. And 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.

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. Moreland LW. Inhibitors of tumor necrosis factor: new treatment options for rheumatoid arthritis. Cleve Clin J Med. 1999;66:367-374.
5. Bresnihan B. Pathogenesis of joint damage in rheumatoid arthritis. J Rheumatol. 1999:26:717-719.
6. Feldmann M, Brennan FM, Miani RN. Rheumatoid arthritis. Cell. 1996;85:307-310.
7. O'Dell JR. Anticytokine therapy—a new era in the treatment of rheumatoid arthritis? [editorial]. N Engl J Med, 1999;340:310-312.
8. Partsch G, Wagner E, Leeb BF, et al. Upregulation of cytokine receptors sTNF-R55, sTNF-R75, and sIL-2R in psoriatic arthritis synovial fluid. J Rheumatol. 1998;25:105-110.
9. Partsch G, Steiner G, Leeb BF, et al. Highly increased levels of tumor necrosis factor-α and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J Rheumatol. 1997;24:518-523.
10. 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.
11. Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis: an overview. Ann Rheum Dis. 2002;61(suppl III):iii8-iii18.
12. 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.
13. National Psoriasis Foundation website. Resources: statistics. Available at: http://www.psoriasis.org/resources/statistics. Accessed November 18, 2003.