It is well established that the pathology of rheumatoid arthritis is associated with an increase in pro-inflammatory cytokines. Of these tumor necrosis factor is thought to have a highly significant role.
Tumor necrosis factor is known to be increased in the synovial fluid in rheumatoid arthritis. The administration of tumor necrosis factor inhibitors have been shown now to reduce symptoms in patients with rheumatoid arthritis. Tumor necrosis factor itself produces an accelerated release of other pro-inflammatory cytokines from lymphocytes. In addition, it increases adhesion molecules at the endothelium of blood cells and increases the transport of leukocytes to sites of inflammation. The tumor necrosis factor requires receptors on the target cell surface to be active. These cell surface receptors are known as P55 and P75. However in addition it is known that portions of these molecules are in circulation in body fluids. These molecules are known as soluble tumor necrosis factor receptors. They are also noted to be present in the synovium of the joint and the pannus - the inflammatory site of the rheumatoid arthritis affected joint.These receptors are noted to be increased in inflammatory disease. Various methods have been developed to counter the action of tumor necrosis factor. The first to obtain licence from the USA Federal Drug Administration is ENBREL made by Immunex Corporation, which is marketing the product with Wyeth of the USA.
This product consists of recombinant human tumor necrosis factor P75 FC fusion protein. Effectively this provides a therapeutic counter effect to tumor necrosis factor itself. The production of the product was made by encoding the DNA of the soluble portion of human tumor necrosis factor receptor P75, and combining it with the Fc portion of immunoglobulin IgG. The product acts as a competitive inhibitor of tumor necrosis factor and prevents the binding of tumor necrosis factor to the cell surface tumor necrosis factor receptor TNFR.Therefore by binding to the receptor itself, it reduces the effect of circulating tumor necrosis factor. Numerous trials have been done in looking at the administration of tumor necrosis factor receptor P75 Fc fusion protein ENBREL. Most of the original trials consisted of patients who had been unsuccessfully treated with numerous disease modifying drugs i.e. resistant disease. However studies are now in progress on early disease, combination therapeutic regimens such as combination of Methotrexate, and also that of accelerating disease and disease in children.
Efficacy has been shown with significant improvement in measures of disease activity with a dose response response in terms of reduction of swollen or tender joints in those patients receiving tumor necrosis factor receptor FC antibody.Administration is via subcutaneous injections.
In addition to reduction of swelling and tenderness of the joints, measures of disease activity improve in approximately 50-75% of patients, depending on dose. This includes reduction in the ESR and CRP.The drug is generally well tolerated and adverse effects include local injection site reactions of swelling or rash. However upper respiratory tract infections or symptoms have been observed, however these are usually transient, and those symptoms are usually mild. No major abnormalities in haematological or chemistry blood tests are noted and importantly, no antibodies to the actual Enbrel molecule itself have been documented in the trials. It would appear that the lack of development of antibodies to the protein is a distinct advantage to other direct monoclonal antibodies to the tumor necrosis factor. Therefore there is a lower tendency to neutralise the actual drug itself and its long term usefulness is maintained. In addition allergic reactions are less likely.
The effect is usually rapid and sustained with a strong dose response relationship. Stopping the drug is associated with an increase in disease activity, this implies that unfortunately, continued administration of the drug is required to maintain efficacy.The dose of the drug is suggested between 16 and 25 mg subcutaneous twice weekly. Most of the predominant trials have been done by LW Moreland and co workers from the university of Birmingham Alabama in collaboration with centres in Portland, Nebraska, Stonybrook, Wichita and Immunex Corporation itself.
The side effect profile includes injection site reactions in 3% of all injections - all mild to moderate as well as minor upper respiratory tract infections including colds, sinusitis and minor urinary tract infections such as cystitis in 3-4 episodes of the year. Headaches, nausea and rash generally may occur.
There is no evidence that there is an increase in malignancy or other immune disorders.
What about quality of life ?Trials have been done looking at the health assessment questionnaire and FF 36 questionnaire. In addition disability index and assessment of general health vitality and mental health has been done. Again results have shown significant improvement both at 3 and 6 months in patients administered twice weekly dose versus placebo. Improvement in tender joint count vary between 50 and 70% in patients on 10 mg versus 25 mg respectively. Improvements in swollen joint count are approximately 50% - 70% for patients on 10 versus 25 mg. Quality of life measures are shown to be significantly improved in particular assessing disability, vitality and mental health.
What About Laboratory Results and Clinical Measures ?Measurement of disease activity shows significant improvement with ENBREL treatment with significant improvement in disease activity measures ESR, platelet count and haemoglobin value.
There is no doubt that this product represents a effective alternative for those patients with resistant disease. However, early use and those patients who are on combination therapy or Juvenile Arthritis patients are also likely to benefit and trials are in progress for these.Go to Rheumatoid Arthritis page
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