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Etanercept

An Updated Review of its Use in Rheumatoid Arthritis, Psoriatic Arthritis and Juvenile Rheumatoid Arthritis

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Summary

Abstract

Etanercept is a subcutaneously administered biological response modifier that binds and inactivates tumour necrosis factor-α, a proinflammatory cytokine.

In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly was associated with a more rapid improvement in disease activity and a significantly greater cumulative response than methotrexate over 12 months of treatment in a randomised, double-blind trial. In addition, etanercept recipients showed a slower rate of radiographic progression and a more rapid improvement in quality of life than methotrexate recipients. The efficacy of etanercept was maintained at 3 years’ follow-up.

Etanercept was also significantly better than placebo at reducing disease activity in patients who had an inadequate response to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in several well controlled trials. At study end (after 3 or 6 months’ treatment), the percentage of patients achieving an American College of Rheumatology 20% (ACR20) response with etanercept (25mg or 16 mg/m2 twice weekly) was 59 to 75% as monotherapy and 71% in combination with methotrexate; corresponding placebo response rates were 11 to 14% and 27%, respectively. Response has been maintained in patients who continued treatment for up to 5 years.

In patients with psoriatic arthritis, etanercept 25mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12-to 24-week trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic arthritis response rates (70 vs 23%) and the median improvement in skin lesions (33 vs 0%) were significantly greater in etanercept than in placebo recipients.

In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept resulted in improvements in all measures of disease activity and was significantly more effective than placebo at reducing disease flare. Eighty percent of patients receiving etanercept achieved a ≥30% reduction in disease activity over 7 months of treatment, and this was maintained for up to 2 years in a trial extension.

Etanercept was generally well tolerated in children and adults in clinical trials; the most commonly occurring adverse effects included injection site reactions, infection, headache, rhinitis and dizziness.

In conclusion, etanercept has emerged as an important new treatment option in inflammatory arthritis. Etanercept provides rapid and sustained improvements in disease activity in patients with early and DMARD-refractory rheumatoid arthritis and has been shown to inhibit radiographic progression in those with early disease. Well controlled studies have also demonstrated the efficacy of etanercept in patients with psoriatic arthritis or polyarticular-course juvenile rheumatoid arthritis.

Pharmacodynamic Properties

Etanercept is a soluble, dimeric, fusion protein consisting of two copies of the extracellular ligand-binding portion of the human tumour necrosis factor (TNF) p75 receptor linked to the constant portion of human immunoglobulin G1. It binds to TNF, thereby blocking its interaction with cell surface receptors and attenuating its pro-inflammatory effects. Etanercept appears to have greater affinity for TNF than infliximab (a monoclonal antibody against TNF).

In mice, etanercept reduced both the incidence and severity of collagen-induced arthritis when administered in prevention and treatment protocols.

In patients with rheumatoid arthritis, etanercept treatment reduced plasma levels of interleukin (IL)-6, matrix metalloproteinase (MMP)-1 and MMP-3 and decreased staining scores for CD3+ T cells, CD38+ plasma cells and vascular cell adhesion molecule-1 and IL-lβ expression; these changes were associated with clinical improvement. Staining scores for CD68+ macrophages and intercellular adhesion molecule-1 expression also decreased, but not to a significant extent.

Etanercept also reduced elevated levels of TNFα-and IL-1-producing peripheral blood mononuclear cells in patients with rheumatoid arthritis receiving long-term, but not short-term, treatment.

In an observational study in patients with rheumatoid arthritis (n = 49), etanercept did not have detrimental effects on global immune function.

Pharmacokinetic Properties

Following a single dose of subcutaneous etanercept 25mg, a mean peak serum concentration (Cmax) of 1.1 mg/L was reached after a mean of 69 hours in patients with rheumatoid arthritis. The Cmax of etanercept increased in patients with rheumatoid arthritis who received long-term treatment (mean Cmax 2.4 mg/L after 6 months’ treatment with etanercept 25mg twice weekly). The bioavailability of etanercept after subcutaneous administration was 58% and the volume of distribution was 17L in healthy volunteers who received two 10mg doses over 30 minutes.

Etanercept is widely distributed throughout the body, including the synovium. The elimination half-life of etanercept was 102 hours and the clearance rate was 0.160 L/h following a single subcutaneous dose of 25mg in patients with rheumatoid arthritis. After binding to TNFα, the etanercept-TNFα complex is believed to be metabolised by proteolytic processes in the body in the same way as other proteins and either recycled or eliminated in the bile and/or urine.

The pharmacokinetics of etanercept in elderly (aged ≥65 years) and paediatric (aged 4 to 17 years) patients were similar to those observed in the general adult population; however, the manufacturer states that clearance of etanercept may be slightly reduced in children aged 4 to 8 years.

Heart failure does not appear to affect the pharmacokinetics of etanercept. No formal studies have been conducted to examine the effects of renal or hepatic impairment on the pharmacokinetics of the drug.

No clinically relevant interactions between etanercept and warfarin or between etanercept and digoxin were seen in two nonblind, crossover studies in healthy volunteers.

Therapeutic Efficacy

Rheumatoid Arthritis: Etanercept, administered subcutaneously, has been investigated in patients with early rheumatoid arthritis and in patients with rheumatoid rthritis who showed an inadequate response to prior therapy with other isease-modifying antirheumatic drugs (DMARDs). Clinical improvement in hese trials was assessed according to American College of Rheumatology (ACR) criteria.

In a recent randomised, double-blind, placebo-controlled trial in 632 patients with early rheumatoid arthritis (≤3 years duration) who had not previously been treated with methotrexate, subcutaneous etanercept (10 or 25mg twice weekly) was at least as effective as oral methotrexate (mean dosage of 19 mg/week) at reducing disease activity and slowing radiographic progression over 12 months’ treatment. Etanercept had a faster onset of action than methotrexate. The area under the curve for ACR response (the primary clinical endpoint) was significantly greater in the etanercept 25mg group than the methotrexate group after 3, 6, 9 and 12 months of treatment. ACR20, ACR50 and ACR70 response rates (improvement in ACR criteria of 20, 50 and 70%) were also greater in etanercept 25mg versus methotrexate recipients at most evaluations over the first 6 months, but no statistically significant between-group differences were observed at the end of the trial. In addition, etanercept 25mg was more effective at slowing radiographic progression than methotrexate over the first 6 months; however, the total increase in Sharp score (primary radiographie endpoint) after 12 months was similar between the two groups (1.00 vs 1.59). The mean increase in erosion score was significantly smaller in the etanercept 25mg than the methotrexate group at both 6 (0.30 vs 0.68) and 12 months (0.47 vs 1.03) of therapy. The etanercept 10mg dose was not as effective as the 25mg dose for any of the clinical or radiographic endpoints.

Response was maintained in patients who continued etanercept 25mg twice weekly in a nonblind extension study, whereas disease control declined in those who continued methotrexate. After a total of 2 years of treatment, patients continuing etanercept had a significantly higher ACR20 response rate (72 vs 59%) and showed a significantly lower mean increase in total Sharp score (1.3 vs 3.2) and erosion score (0.7 vs 1.9) compared with those who continued methotrexate. In an additional noncomparative investigation in which all patients received etanercept 25mg twice weekly for a further year, the ACR20 was 76% in patients who had received etanercept for a total of 3 years.

In this study, improvements in the Health Assessment Questionnaire (HAQ) and the Medical Short-Form 36 Health Survey (SF-36) summary scores and sub-scales occurred more rapidly with etanercept 25mg twice weekly than with methotrexate. By the end of the study, all HAQ and SF-36 measures had improved significantly versus baseline in both treatment groups and there was no significant difference between treatments.

Etanercept (either alone or in combination with methotrexate) also induced significant improvements in disease activity in patients who had failed to respond to previous treatment with one or more other DMARDs in several randomised, placebo-controlled, double-blind investigations. Monotherapy studies (n = 180 to 559) demonstrated a dose-response relationship for etanercept. In patients receiving etanercept 16 mg/m2 or 25mg twice weekly, the ACR20 response rate ranged from 59 to 75% compared with 11 to 14% in the placebo group at study end (after 3 or 6 months’ treatment). In another study in which etanercept 25mg twice weekly or placebo were added to an existing, ineffective methotrexate regimen (n = 89), the ACR20 response rate after 6 months was 71 and 27%, respectively.

Long-term follow-up data from these trials demonstrated the sustained efficacy of etanercept. In addition, patients who were receiving concomitant treatment with corticosteroids or methotrexate at baseline were able to reduce the dosage of, or discontinue, these treatments.

In these trials, etanercept 25mg twice weekly (alone or in combination with methotrexate) was significantly more effective than placebo at improving health-related quality of life: HAQ scores were reduced by 23 to 40% and 2 to 26% in etanercept and placebo recipients, respectively.

The results of studies examining the use of etanercept in patients with rheumatoid arthritis in clinical practice settings tended to mirror those of controlled clinical trials.

Psoriatic Arthritis: Subcutaneous etanercept 25mg twice weekly significantly reduced arthritic disease activity and improved skin lesions in patients with psoriatic arthritis in two placebo-controlled trials of 12 and 24 weeks’ duration. Clinical response in these studies was measured according to two standard criteria: ACR criteria and the psoriatic arthritis response criteria (PsARC). Changes in psoriasis activity were also assessed in patients with plaque psoriasis involvement over ≥3% of their body surface area.

In the 12-week study (n = 60), the PsARC and ACR20 response rates were significantly higher in etanercept versus placebo recipients (87 vs 23% and 73 vs 13%, respectively). In addition, a 75% improvement in the Psoriasis Area and Severity Index score was seen in significantly more etanercept than placebo recipients (26 vs 0%).

Similar results were found in the 24-week study (n = 205): in etanercept and placebo recipients the PsARC response rates were 70 and 23% and the ACR20 response rates were 50 and 13%, respectively (p < 0.05 between-group difference for both endpoints); median improvements in target lesion scores were also higher in etanercept versus placebo recipients (33 vs 0%). Etanercept also induced a significantly greater reduction in HAQ Disability Index score than placebo (54 vs 6.4%). In addition, patients receiving etanercept showed significantly greater improvements in SF-36 summary scale and the EuroQoL Feeling Thermometer scores.

Polyarticular-Course Juvenile Rheumatoid Arthritis: Subcutaneous etanercept 0.4 mg/kg twice weekly showed good disease-reducing activity in paediatric patients (aged between 4 and 17 years) with polyarticular-course juvenile rheumatoid arthritis. The study (n = 69) included a noncomparative phase during which all patients received etanercept for 3 months followed by a double-blind phase in which patients who responded to etanercept in the first part of the trial were randomised to continue etanercept or switch to placebo for up to an additional 4 months.

After the first phase of the trial, 74% of patients experienced a response (defined as an improvement of ≥30% in at least three of a core set of six response variables, with worsening of ≥30% in not more than one variable). In those patients who continued etanercept in the second phase of the trial (n = 25), disease flare (defined as a ≥30% worsening in three of the six core criteria, a minimum of two active joints and an improvement of ≥30% in not more than one of the six core set criteria) occurred significantly less often than it did in those who were randomised to receive placebo (n = 26) [28 vs 81%]. Furthermore, the median time to flare was significantly longer in etanercept than placebo recipients (>116 vs 28 days). Patients who continued or switched to etanercept treatment in a non-comparative extension trial continued to show a good response to therapy. At the 2-year follow-up, the response rate was 81%.

In two small (n = 15 and 22) nonblind studies in patients with polyarticular-course juvenile rheumatoid arthritis (mean age 10.2 and 13.9 years), etanercept showed good disease-reducing activity when added to existing treatment with other DMARDs. In one of these studies, etanercept (0.4 mg/kg twice weekly) and infliximab (3 mg/kg at weeks 0, 2 and 6 then at 4-weekly intervals) showed similar efficacy when added to the regimen of patients with polyarticular-course juvenile rheumatoid arthritis who were refractory to at least two other DMARDs (patients continued to receive low-dose methotrexate).

Pharmacoeconomic Considerations

The pharmacoeconomic impact of instituting etanercept therapy in patients with rheumatoid arthritis has been assessed in several decision-analysis modelling studies.

In a US study evaluating patients with methotrexate-naive rheumatoid arthritis, the incremental cost-effectiveness ratio of etanercept (versus sulfasalazine) was estimated to be $US41 900 per patient achieving an ACR20 response over 6 months of treatment when total (direct plus indirect) costs were considered and $US48 300 per patient achieving an ACR20 response over 6 months of treatment when direct costs were considered (1999 values).

In patients with rheumatoid arthritis failing to respond to treatment with other DMARDs, the incremental cost effectiveness ratio of combined treatment with etanercept and methotrexate (versus triple therapy comprising hydroxychloroquine, sulfasalazine and methotrexate) was estimated at $US42 600 per patient achieving an ACR20 response over 6 months of treatment when total costs were considered and $US43 900 per patient achieving an ACR20 response over 6 months of treatment when direct costs were considered, in another US study (1999 values).

In a UK cost-utility analysis in patients with rheumatoid arthritis who had an inadequate response to prior treatment with two or three DMARDs, the cost of etanercept, compared with placebo, was £18 938 ($US27 271) per discounted quality-adjusted life year (QALY) when direct costs were evaluated (currency year not stated). A higher value was obtained in another UK analysis. If anti-TNF therapy was used last in the sequence of DMARDs, the incremental cost effectiveness ratio of etanercept, compared with not using anti-TNF therapy, was £71 659 per QALY (2000 values). Sensitivity analyses revealed incremental cost effectiveness ratios ranging from £46 612 to £128 283 per QALY.

Treatment with etanercept was also associated with lower costs than infliximab plus methotrexate treatment in patients who had previously been treated with other DMARDs in US and Dutch modelling studies. In addition, etanercept was shown to be more effective than infliximab at reducing the number of days in hospital and improving work capacity in a Swedish study, which assessed a group of 117 patients before and after 1 year of treatment.

Tolerability

Etanercept was generally well tolerated in clinical trials in adults. The most commonly reported adverse events in patients with rheumatoid arthritis receiving etanercept in placebo-controlled (n = 349) or active-controlled (n = 415) trials, respectively, were injection-site reactions (37 and 34%), infections (35 and 64% [upper respiratory infections: 29 and 35%]), headache (17 and 24%) rhinitis (12 and 16%) and nausea (9 and 15%). Approximately 4% of patients receiving etanercept withdrew because of adverse events; this rate was the same as that observed for placebo recipients and lower than that observed for methotrexate recipients in controlled trials. The type and frequency of adverse events occurring in children receiving etanercept were generally similar to those observed in adults.

The rate of serious infection was similar in etanercept and placebo recipients in clinical trials, and no increase in infection rate was observed in patients who continued etanercept treatment for up to 5 years in nonblind extension studies. However, cases of serious infection (e.g. sepsis) and tuberculosis have been reported in patients receiving etanercept during post-marketing experience.

Less than 5% of patients receiving etanercept in clinical trials developed non-neutralising antibodies to the drug. These were not associated with the development of autoimmune disease in clinical trial experience, but there have been anecdotal reports of patients developing additional autoantibodies in connection with rashes or symptoms consistent with systemic lupus erythematosus-like syndrome in post-marketing experience. The long-term impact of etanercept on autoimmune diseases is not known.

Treatment with etanercept and other anti-TNFα agents have also been associated (rarely) with neurological events (exacerbation or new onset of CNS demyelinating disorders and seizures) and haematological events (pancytopenia); however, a causal relationship to etanercept remains unclear.

Dosage and Administration

In the US, etanercept is indicated for use in adults with rheumatoid arthritis and psoriatic arthritis, and in paediatric patients with polyarticular-course juvenile rheumatoid arthritis. Etanercept can be used as monotherapy or in combination with methotrexate; in children, etanercept is only indicated for use in patients who have shown an inadequate response to other DMARDs.

In Europe, etanercept is indicated for use in patients with rheumatoid arthritis or polyarticular-course juvenile rheumatoid arthritis who have shown an inadequate response to other DMARDs.

The recommended dosage of etanercept in adults and paediatric patients aged 4 to 17 years is 25mg and 0.4 mg/kg (maximum of 25mg), respectively, by subcutaneous injection twice weekly.

Treatment with etanercept should not be initiated in patients with active infections (chronic or localised), and caution is advised when considering the use of etanercept in patients with a history of recurring infections or in those with underlying conditions that may predispose them to infections (e.g. poorly controlled or advanced diabetes mellitus). Etanercept is contraindicated in patients with sepsis or risk of sepsis; the drug has not been investigated in patients aged <4 years, pregnant women or nursing mothers. No dosage adjustment is deemed necessary in the elderly. Limited clinical experience indicates that dosage adjustment is not required in patients with renal or hepatic impairment.

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Various sections of the manuscript reviewed by: A. Eigler, Medizinische Klinik Innenstadt, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; R. Fleischmann, Radiant Research-Dallas, Dallas, Texas, USA; G. Jones, Department of Rheumatology, Menzies Centre for Population Health Research, Hobart, Australia; D. Lovell, Pediatric Rheumatology, Children’s Hosptial Medical Center, Cincinnati, Ohio, USA; N.J. McGriff-Lee, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, USA; L.W. Moreland, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA; D.L. Scott, Department of Rheumatology, King’s Healthcare (Dulwich), London, England; W. Taylor, Department of Medicine, Wellington School of Medicine, Wellington, New Zealand.

Data Selection

Sources: Medical literature published in any language since 1980 on Etanercept, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘etanercept’ or ‘TNF 001’ or ‘TNFR FC’. EMBASE search terms were ‘etanercept’. AdisBase search terms were ‘etanercept’ or ‘TNF 001’ or ‘TNFR FC’. Searches were last updated 21 Oct 2002.

Selection: Studies in patients with rheumatoid disorders who received etanercept. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: etanercept, TNF, rheumatoid arthritis, juvenile chronic arthritis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Culy, C.R., Keating, G.M. Etanercept. Drugs 62, 2493–2537 (2002). https://doi.org/10.2165/00003495-200262170-00013

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