Intercepting TNF-alpha With Etanercept to Treat Rheumatoid Arthritis

 

[Drug & Ther Perspect 14(10):1-5, 1999. © 1999 Adis International Limited]

 

In Brief

Etanercept is the first specific anticytokine therapy approved for use in rheumatoid arthritis. Significant reductions in disease activity occurred within 2 weeks of the introduction of etanercept in adults with active rheumatoid arthritis who were refractory to or intolerant of disease modifying antirheumatic drugs. These improvements were sustained for at least 6 months when etanercept was administered alone or in combination with methotrexate. The drug was also effective in paediatric patients with polyarticular juvenile rheumatoid arthritis.

Etanercept is contraindicated in patients with sepsis. Injection site reactions, which tend to occur during the first month of treatment, were reported by </=49% of patients treated with the drug.

 

Introduction

Rheumatoid arthritis is a chronic, progressive, inflammatory disease for which there is no cure. The current treatment paradigm for the condition involves early intervention with disease modifying antirheumatic drugs (DMARDs) for the purpose of limiting joint damage and preserving joint function. Unfortunately, a satisfactory response to DMARDs is not obtained in all patients with active rheumatoid arthritis. Most patients do not achieve remission, many are unsatisfied with their response to treatment and others become treatment resistant after an initial satisfactory experience. Furthermore adverse events prompt the discontinuation of DMARDs in a considerable proportion of patients. Thus, many patients might benefit from an effective, alternative therapeutic strategy.[1,2]

 

Cytokines Mediate Inflammation

Rheumatoid arthritis is known to result from an inappropriate inflammatory response. The clinical features of rheumatoid arthritis derive, in part, from an imbalance in the cytokines that mediate inflammation. Among cytokines, tumour necrosis factor-alpha (TNF-alpha) may be pivotal in the pathogenesis of the disease. The soluble, extracellular, ligand-binding portion of TNF-alpha receptors (sTNF-R) are frequently shed by cells and are functional antagonists of TNF-alpha. Indeed, sTNF-R is an important, natural, homeostatic regulator of TNF-alpha and the degree of TNF-alpha-mediated inflammatory activity depends, in part, on the balance between TNF-alpha and sTNF-R. Etanercept † is a fusion protein consisting of the extracellular ligand-binding domain of the 75kD human receptor for TNF-alpha and the constant portion of human immunoglobulin (IgG1). This drug is the first specific anticytokine therapy approved for rheumatoid arthritis.[3-5]

 

Etanercept Provides Rapid Relief

In contrast to DMARDs which have a slow onset of effect, etanercept had a rapid onset of action and provided sustained relief when administered twice weekly by subcutaneous injection in clinical trials.

As Monotherapy...

In patients with active rheumatoid arthritis who had failed to respond to previous treatment with >/=1 DMARD, etanercept 25mg twice weekly produced rapid improvements in the signs and symptoms of arthritis [the American College of Rheumatology (ACR) core set of disease activity measures; see table 1]. Within 2 weeks of the start of treatment a significantly greater proportion of etanercept-(32%) than placebo-treated patients (1%) experienced clinically significant improvement (>/=20% improvement in ACR criteria; ACR 20). Importantly, this proportion increased over time such that after 6 months of treatment 59% of etanercept recipients, but only 11% of placebo-treated patients, achieved the ACR 20 criteria (see figure 1).[8] An additional group of patients in this study were randomised to receive etanercept 10mg twice weekly but this dosage tended to be less effective than 25mg twice weekly.

fig1 Figure 1. Improvement in American College of Rheumatology (ACR) criteria after 3 and 6 months' treatment with etanercept. Proportion of patients with active rheumatoid arthritis achieving <20%, 20 to 49%, 50 to 69% or >/=70% improvement in ACR criteria after 3 and 6 months' treatment with subcutaneous etanercept 25mg (n = 78) or placebo (n = 80) twice weekly in a multicentre, double-blind, randomised study.[8] Disease modifying antirheumatic drugs were not allowed during the trial. Significantly more patients treated with etanercept than placebo achieved the ACR 20, 50 and 70 criteria after 3 and 6 months. Abbreviations: ACR 20 = >/=20% improvement; ACR 50 = >/=50% improvement; ACR 70 = >/=70% improvement in ACR criteria.

Limited evidence suggests that the therapeutic effects of etanercept are maintained for up to 2 years. Tender or swollen joint counts were reduced by >/=84% in 51 patients who received 2 years of continuous treatment with etanercept 25mg twice weekly.[5,9]

...Or Combined With Methotrexate

Etanercept was effective in patients with active disease despite ongoing treatment with methotrexate. Within 1 week, the ACR 20 criteria were achieved by a significantly greater proportion of patients treated with etanercept 25mg twice weekly plus oral or subcutaneous methotrexate 10 to 25mg per week than placebo plus methotrexate. The magnitude of effect did not decrease during the study. At the end of the 24-week trial, 71% of etanercept plus methotrexate recipients experienced at least a 20% improvement in ACR criteria compared with 27% of those treated with placebo plus methotrexate (see figure 2).[10]

fig2

Figure 2. Improvement in patients with persistent rheumatoid arthritis treated with etanercept plus methotrexate. Percentage of patients with at least 20 (ACR 20), 50 (ACR 50) and 70% (ACR 70) improvement in American College of Rheumatology criteria after 24 weeks' treatment with subcutaneous etanercept 25mg twice weekly (n = 59) or placebo (n = 30) in a multicentre, randomised, double-blind study.[10] All patients received oral or subcutaneous methotrexate 10 to 25 mg/week. Symbols: *p < 0.05 vs placebo; **p < 0.001 vs placebo.

†Etanercept has been launched in the US and European launch is expected, although this drug is already available under special conditions in some European countries (e.g. The Netherlands).

 

Effective in Children With JRA

 

Etanercept reduced disease activity in children with juvenile rheumatoid arthritis (JRA). After 90 days of nonblind treatment, 51 of 69 children aged >/=4 years with polyarticular JRA refractory or intolerant to methotrexate experienced clinically significant improvement with etanercept 0.4 mg/kg twice weekly. A clinically significant response was defined as a >/=30% improvement in >/=3 of 6 core JRA response variables and </=1 variable worsening by >/=30%. The response variables include the number of active joints, loss of motion plus pain and tenderness, assessments by physician and patient, childhood health assessment questionnaire and erythrocyte sedimentation rate.[11]

 

Contraindicated in Sepsis

 

Etanercept should not be initiated in patients with active infections, including those with chronic or localised infections. Furthermore, the drug should be discontinued in patients who develop sepsis or other serious infections during treatment. These warnings were issued because 30 etanercept-treated patients, a number of whom had coexisting medical conditions which predisposed them to infections, developed serious infections including at least 6 fatalities during the first 5 months after the drug's approval in the US.[12] Approximately 25 000 patients were receiving the drug during this period.

The overall frequency of infection was similar in etanercept and placebo recipients during clinical trials. Nonetheless, upper respiratory tract infections were more common in patients treated with etanercept (29%) than placebo (16%). Serious infections were rare and no more common in etanercept (0.9%) than placebo recipients (1.3%) in these studies.[5]

Injection Site Reactions Common...

As with cytokines, injection site reactions were common with etanercept in clinical trials. Injection site reactions occurred more frequently in etanercept- (</=49%) than placebo-treated patients (</=13%). The reactions tended to occur during the first month of treatment, manifested as erythema, alone or in conjunction with itching, pain or swelling and lasted for a median duration of 3 days. Importantly, these reactions prompted few patients to withdraw from trials (<1%) and did not appear to bias the results of any study.[5]

...But Otherwise Well Tolerated

The frequency of adverse effects was not dose-related, no dose-limiting adverse effects were identified and withdrawal rates because of adverse events were similar in etanercept and placebo recipients in randomised trials. Approximately twice as many etanercept- (11%) than placebo-treated patients (5%) became positive for anti- nuclear antibodies during treatment; however, no patients developed new connective tissue disorders, including systemic lupus erythematosus.[5]

 

Dosage and Administration

 

In the US, etanercept is approved for use in patients with moderate or severe active rheumatoid arthritis, including those with polyarticular JRA, who have had an inadequate response to 1 or more DMARDs. The drug may be used in combination with methotrexate in patients who have not responded adequately to methotrexate monotherapy.[13]

The recommended dosage of etanercept in adult patients is 25mg twice weekly by subcutaneous injection. In paediatric patients aged 4 to 17 years with JRA the approved dosage is 0.4 mg/kg twice weekly by subcutaneous injection. The drug has not been studied in patients aged <4 years.[13]

Prior to initiating therapy with etanercept, it is recommended that the immunisation status of paediatric patients should be brought up to date.

 

Prescribing and Formulary Considerations

 

Specific anticytokine therapy with etanercept is a novel therapeutic strategy in patients with rheumatoid arthritis refractory to DMARDs, a group for which there are few alternatives. In patients who had failed to respond to as many as 4 DMARDs, etanercept produced clinically significant improvements in ACR criteria which were evident within 2 weeks and that were maintained for at least 6 months. Preliminary data suggest that tolerance to the therapeutic effect of etanercept does not develop with long-term treatment. However, it remains to be determined whether etanercept can reduce the need for other antirheumatic drugs such as NSAIDs, corticosteroids and DMARDs. If so, this might result in significant reductions in drug-related morbidity. The effect of etanercept on the progression of joint damage is also of interest and is being addressed in ongoing trials.[5]

In conclusion, etanercept appears to be particularly well suited for use in patients with rheumatoid arthritis who fail to respond to treatment with DMARDs. Nonetheless, the cost of the drug ($US125-137.50 per 25mg vial) will ultimately determine how many patients benefit from this therapeutic advance.

 

Table 1. American College of Rheumatology core set of disease activity measures in rheumatoid arthritis[6]a

  • Swollen jointsb
  • Tender jointsb
  • Patient's assessment of painc
  • Physician's assessment of disease statusc
  • Patient's assessment of disease statusc
  • Patient's assessment of disabilityd
  • Acute phase reactant (either erythrocyte sedimentation rate or C-reactive protein levels)

 

a Clinically significant improvement is defined as a 20% reduction in the number of swollen joints, a 20% reduction in the number of tender joints, plus a 20% improvement in >/=3 of the 5 remaining criteria (ACR 20).[7]
b Based on an assessment of >/=28 joints.
c Assessed with a 10cm visual analogue scale.
d Assessed by a validated instrument (e.g. the Health Assessment Questionnaire).

 

Adis Evaluation

 

Key points in the overall evaluation of etanercept in the treatment of rheumatoid arthritis Clinical Benefits

  • Effective in patients with active rheumatoid arthritis refractory or intolerant to disease modifying antirheumatic drugs
  • Rapid onset (improvement may be seen within 2 weeks)
  • Effective in children with polyarticular juvenile rheumatoid arthritis

 

Potential Limitations

  • Administered by subcutaneous injection
  • Long-term efficacy and tolerability unknown
  • Contraindicated in sepsis

 

References

  1. American College of Rheumatology Ad Hoc Committee On Clinical Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum 1996; 39: 713-22
  2. Pincus T. Long term outcomes in rheumatoid arthritis. Br J Rheumatol 1995; Nov; 34 Suppl. 2: 59-73
  3. Starkebaum G. Role of cytokines in rheumatoid arthritis. Sci Med 1998 Mar-Apr; 5: 6-15
  4. Cope AP. Regulation of autoimmunity by proinflammatory cytokines. Curr Opin Immunol 1998; 10: 669-76
  5. Jarvis B, Faulds D. Etanercept: a review of its use in rheumatoid arthritis. Drugs 1999 Jun; 57: 945-66
  6. Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 1993; 36: 729-40
  7. Felson Dt, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727-35
  8. Moreland LW, Schiff MH, Baumgartner SW et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled study. Ann Intern Med 1999; 130: 478-86
  9. Moreland LW, Baumgartner SW, Tindall EA, et al. Long term safety and efficacy of Etanercept (Enbrel) in DMARD refractory rheumatoid arthritis (RA) [abstract]. XIV European League Against rheumatism (EULAR) Congress; 1999 Jun 6-11; Glasgow
  10. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein in patients with rheumatoid arthritis receiving methotrexate. New Engl J Med 1999 Jan 28; 340: 253-9
  11. Lovell DJ, Giannini EH, Whitmore JB, et al. Safety and efficacy of tumor necrosis factor receptor p75 FC fusion protein (TNFR:FC; Enbrel) in polyarticular course juvenile rheumatoid arthritis [abstract no. 584]. Arthritis Rheum 1998; 41 Suppl; S130
  12. U.S. Food and Drug Administration. Dear Healthcare Professional Letter. http://www.fda.gov/medwatch/safety/1999/enbrel.html
  13. Enbrel Prescribing Information. Immunex Corporation, Seattle, Washington, USA, May 1999. Available at http://www.immunex.com/products/html/prescribe/enbrelpre.html

 

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