TNF and Anti-TNFα therapy for arthritis

Introduction: 

TNF (tumor necrosis factor) is one of many natural inflammatory mediators that can cause disease when it is not regulated.  Anti-TNFα therapy for arthritis can cause suppression of inflammatory disease processes and improve clinical outcomes.  The goal in anti-TNFα therapy in arthritis patients is to control excess TNF, while limiting associated risks.   

What is TNF? 

TNF is made throughout your body.  It is a proinflammatory cytokine derived from cells called macrophages.  TNF, like other cytokines, is a chemical messenger that mediates messages between cells and provokes an inflammatory response.

TNF was first isolated over 10 years ago, on the basis of its ability to kill tumor cells in vitro and to cause hemorrhagic necrosis of tumors.  Although at first it was thought that TNF could be useful for treating cancer, it actually proved to be highly toxic not only to the cancer (neoplastic) cells, but also to the humans who received it.  Several studies subsequently addressed its potent inflammatory effects and suggested its possible role in chronic inflammatory diseases. 

            TNF is one of 10 known members of a family of ligands that activate a family of structurally related receptors.  These receptors initiate signals for cell proliferation and apoptosis, present on almost all cells throughout the body.  If released systemically, TNF activates neutrophils and the release of other inflammatory cytokines.  The problem arises with excess signaling that can cause severe inflammatory reactions, tissue injury and shock. 

There are 2 types of TNF, TNF-α and TNF-β. There are also numerous TNF ligands and receptors. The functions of these ligands and receptors were unknown for several years until it was discovered that mutation of the ligands or their receptors caused disease in animals and humans.  Both mice and humans who have mutations in one of the TNF-family genes have lymphadenopathy, splenomegaly and signs of autoimmunity at an early age. 

TNF is known to have three important functions:

1. Immunoregulation – TNF-α stimulates an immune response by co-stimulating signals for B and T cells
2. Apoptosis – Programmed cell death
3. Bone metabolism

What is anti-TNFα?

Anti-TNFα is a biologic agent that blocks TNF-α action at TNF receptors 1 and 2.  Blocking TNF-α has the effect of limiting tissue destruction.  When anti-TNFα binds to the receptors, it prevents TNF from binding to the receptor and initiating an inflammatory response. 

Why is anti-TNFα believed to be useful for arthritis? 

Anti-TNFα is useful in arthritis because it prevents the inflammatory response from progressing to tissue damage.  Anti-TNFα is used in arthritis conditions where the inflammatory response by TNFα in the synovium and joints is unchecked.  Many patients with arthritis produce excess TNF.  Anti-TNFα can bind the excess TNF and reduce the inflammatory response.

What types of arthritis does it help? 

Anti-TNFα therapy has several approved indications, which continue to increase in number.  These include rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile chronic arthritis. 

What does the FDA approve TNF-α for? 

What does the research say about anti-TNFα therapeutic efficacy? 

Clinical research studies support anti-TNFα therapy as effective treatment for arthritis. The ASPIRE trial was a double-blind active control study, which evaluated infliximab with methotrexate vs methotrexate alone.  The study included 1,049 patients with early rheumatoid arthritis (RA).  The study demonstrated that more than 55 percent of RA patients treated with infliximab with methotrexate vs 26.8 percent of methotrexate alone achieved an improvement in bone erosion scores, indicating improved joint function. 

Another study, the TEMPO trial, evaluated 682 rheumatoid arthritis patients over two years.  There were 231 patients treated with etanercept and methotrexate, 223 patients received etanercept alone and 228 patients were treated with methotrexate alone.  The study demonstrated a clinical remission for 40% of the patients treated with etanercept and methotrexate.  In comparison, the patients treated with etanercept alone had a 23.3% clinical remission of RA and 15.8% for patients receiving methotrexate alone.  This two year study supports the early treatment of RA for improved clinical outcomes.   

The ASPIRE and TEMPO studies also reported some associated risks with anti-TNFα therapy.  As mentioned before, the risks with anti-TNFα therapy include infection, malignancy and hypersensitivity.  The benefits and risk assessment for arthritis therapy needs to be evaluated for each patient.  Some newer studies indicate that early treatment may be preferable.  Early therapy prevents joint damage, thereby preventing joint deformities.  Arthritis is a chronic and debilitating condition that can compromise the quality of life for many patients.  Anti-TNFα therapy is a unique treatment in that its effect is not just symptom control.  Patients get relief of symptoms over time and improved function of joints. 

How expensive is it?

Anti-TNFα is prohibitively expensive in comparison to traditional arthritis therapies.  The cost of using anti-TNFα agents is well over ten thousand dollars a year.  Medical insurance coverage can vary depending on the drug.  Also, Medicare coverage varies from agent to agent, with reimbursement for infliximab but not etanercept.  The self-injected biologics seem to have broader acceptance into insurance plans.  The socio-economic impact regarding access to these biologics has a profound effect on disability outcomes for those patients who do not have access.  Individuals afflicted with diseases such as RA are at risk for serious and debilitating clinical outcomes without early access to anti-TNFα therapy. 

Authors:  Ana Maria Blanco, B.A., New York College of Osteopathic Medicine, Old Westbury, New York

    Ana Bracilovic, M.D., New York-Presbyterian Hospital, The University Hospital of Columbia and Cornell, New York, NY

REFERENCES

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Lipsky PE. Rheumatoid arthritis. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's principles of Internal Medicine. 15th edn. New York: Mc Graw Hill; 2000, p.1928-36.      

Shanahan JC, Moreland LW, Carter RH. Upcoming biologic agents for the treatment of rheumatic diseases. Curr Opin Rheumatol 2003;15:226-36.

Smolen JS, Emery P, Bathon J, et al. Treatment of early rheumatoid arthritis with infliximab plus methotrexate or methotrexate alone: preliminary results of the ASPIRE trial. (Abstr OP0001) Presented at the Annual European Congress of Rheumatology, Jun 2003, Lisbon

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