Pharmacology Update


By William T. Elliott, MD and James Chan, PharmD, PhD

Along with drugs that selectively inhibit COX-2, the late 1990s will be remembered for another major breakthrough in the treatment of inflammatory diseases—anti-cytokine therapy. Last month, the FDA approved the first tissue necrosis factor (TNF) antagonist for the treatment of rheumatoid arthritis. Etanercept (Enbrel-Immunex Corporation) is a genetically engineered protein that binds and inhibits the activity of TNF. TNF is a cytokine, which is overproduced in rheumatoid joints and plays an important role in inflammation and joint destruction.2,3 Etanercept consists of the soluble extracellular ligand-binding portion of the human 75 kilodalton (P75) TNF receptor linked to the Fc portion of human IgG1 (TNFR:Fc).1 This protein was produced by recombinant DNA technology using the Chinese Hamster ovary cell system.

Etanercept is only available in parenteral form, as a subcutaneous self injectable that is given twice a week. The drug was developed by Immunex and will be co-marketed with Wyeth-Ayerst.


Etancercept is indicated for reduction in signs and symptoms of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). The drug can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.1


Etanercept is supplied at 25 mg single-use vials. The recommended dose for adult patients is 25 mg administered subcutaneously twice weekly. NSAIDs, corticosteroids, salicylates, and methotrexate may be continued during treatment with etanercept.

Potential Advantages

Etanercept provides a drug with a new mechanism of action for patients with rheumatoid arthritis. Placebo-controlled studies indicate that about 60% patients who had failed with at least one but not more than four DMARDS, when given etanercept, show a 20% improvement in composite symptoms of arthritis defined according to the American College of Rheumatology.1

Potential Disadvantages

Entanercept requires subcutaneous injection twice weekly. Patients can be instructed to self-administer the drug; however, the first injection should be performed under the supervision of a qualified health care professional.1 The most common side effects are local injection site reactions, including erythema, pain, swelling, and/or itching. These reactions, described as mild to moderate,1 generally occur in the first month and subsequently, decrease in frequency. Each reaction lasts an average of 3-5 days.1

The development of antinuclear antibodies occurs in 11% of entanercept patients, compared to 5% of patients on placebo. New positive anti-double stranded DNA antibodies occurred in 15% vs. 4% for placebo.1 The long-term clinical implications of these antibodies are currently not known.

Upper respiratory infections and sinusitis appear to be higher in patients treated with etanercept compared to placebo. The drug group had 0.82 events per patient year compared to 0.68 for the placebo group.1


Tumor necrosis factor is a cytokine produced by macrophages. It is a transmembrane protein, which apparently has a role in normal inflammation and immune response. TNF is overproduced in rheumatoid arthritis with levels elevated by up to 50% in rheumotoid synovial fluid.2-4 TNF appears to be produced near the site of joint destruction and mediates the cytokine cascade causing inflammation tissue destruction. Etanercept is a soluble form of a TNF receptor and inhibits the activity of cytokine TNF by "soaking up" these mediators and reduce binding to receptors on the cell surface.

The safety and efficacy of etanercept was established in two randomized, double-blind, placebo-controlled studies (n = 234). Eligible patients had failed with at least one but no more than four DMARDs, and had at least six tender joints, at least six swollen joints, and either ESR equal to or greater than 28 mm/h, CRP more than 2.0 mg/dL, or morning stiffness for more than 45 minutes. In one study, patients were permitted to be on a stable dose of methotrexate. Primary end point was achievement of a 20% improvement in composite symptoms of arthritis defined according to the American College of Rheumatology (ACR 20). This required a 20% improvement in their tender joint count and swollen joint count plus 20% or greater improvement in at least three of the following criteria: 1) patients pain assessment; 2) patient global assessment; 3) physician global assessment; 4) patients self-assessed disability; and 5) acute-phase reactant (ESR or CRP).5 ACR 20 was achieved in 62% (vs 23% for placebo) of patients at three months and 71% (vs 27%) at six months.1 A 70% response was seen in 15% of patients compared to 1% for placebo patients.1 Response, generally seen within 1-2 weeks, leveled off at three months. Durable responses have been seen for up to 18 months.1

After discontinuation of therapy, symptoms will return within a month.1 Etanercept is generally well tolerated with injection reactions being the most common adverse effect. The study population had an average disease duration of 12 years and had failed an average of three previous DMARDs.7 Neutralizing antibodies with etanercept did not appear to be problematic in the clinical trials but nonneutralizing antibodies were detected in at least one in sera of 16% of RA patients.1

Etanercept is extremely expensive. A six-month course will cost about $6500. Rheumatology consultation may be considered before precribing DMARDs or etanercept.

Clinical Implications

Etanercept represents the second of two new drugs for rheumatoid arthritis following the recent approval of leflunomide. It will offer another second line agent for patients who have severe disease and who have had an inadequate response to one or more disease-modifying drugs, such as methotrexate or leflunomide. It is not clear if etanercept slows disease progression (e.g., structural changes and functional changes) and the long-term effects of inhibition of TNF activity are not known. TNF plays a role in the host defense mechanism in infection and tumor formation.2 In addition, TNF is not the only cytokine implicated in the pathogenesis of bone destruction. Other cytokines such as interleukin 1 also appear to have an important role.8 A phase III trial to assess whether etanercept significantly changes the course of disease will be unblinded in the first half of 1999.6 Immunex has also filed an application for etanercept to treat children and teenagers with moderately to severly active polyarticular course juvenile rheumatoid arthritis (JRA).


1. Enbrel Product Information.

2. Camussi G, et al. Drugs 1998;55(5):613-620.

3. Murray KM, et al. Ann Pharmacother 1997;31: 1355-1358.

4. Cope AP, et al. Arthritis Rheum 1992;35:1160-1169.

5. Felson DT, et al. Arthritis Rheum 1995;6:727.

6. FDC Report. The Pink Sheet. November 2, 1998.

7. FDC Report. The Pink Sheet. September 21, 1998.

8. Choy EHS, et al. Drugs 1997;55(3):337-348.