DRUGS IN DISEASE MANAGEMENT

Dis Manage Health Outcomes 2002; 10 (1): 17-39 1173-8790/02/0001-0017/$22.00/0 © Adis International Limited. All rights reserved.

Management of Rheumatoid Arthritis Defining the Role of Etanercept Gillian M. Keating and Blair Jarvis Adis International Limited, Auckland, New Zealand Various sections of the manuscript reviewed by: E. Choy, King’s College Hospital (Dulwich), Academic Department of Rheumatology, London, England; N.J. McGriff, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, USA; L.W. Moreland, University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, Birmingham, Alabama, USA; J.R. O’Dell, University of Nebraska Medical Center, Section of Rheumatology and Immunology, Omaha, Nebraska, USA; M. Østergaard, Hvidovre University Hospital, Department of Rheumatology, Hvidovre, Denmark; D.L. Scott, King’s College Hospital (Dulwich), Academic Department of Rheumatology, London, England. Data Selection Sources: Medical literature published in any language since 1980 on etanercept, identified using Medline, supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). 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 Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.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: AdisBase search terms were ‘rheumatoid-arthritis’ or ‘juvenile-rheumatoid-arthritis’ and (‘guideline’ or ‘guideline-utilisation’ or ‘practice-guideline’ or ‘disease-management-programmes’ or ‘treatment-algorithms’ or ‘reviews-on-treatment’ or ‘drug-evaluations’ or ‘epidemiology’ or ‘cost-of-illness’ or ‘pathogenesis’), or ‘etanercept’ and (‘review’ or ‘clinical-study’). Medline search terms were ‘rheumatoid-arthritis’ or ‘juvenile-rheumatoid-arthritis’ and (‘guidelines’ or ‘decision-making’ or ‘health-policy’ or ‘managed-care-programmes’ or ‘epidemiology’ or ‘outcome-assessment-health-care’ or ‘clinical-protocols’ or ‘guideline in patient’ or ‘practice-guideline in patient’), or ‘etanercept’ and ‘review in patient’. Searches were last updated 23 Nov 2001. Selection: Studies in patients with rheumatoid arthritis 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, pharmacokinetic, pharmacoeconomic and epidemiological data are also included. Index terms: etanercept, rheumatoid arthritis, disease management, review on treatment.

Contents Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Disease Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1 Incidence and Prevalence . . . . . . . . . . . . . . . . . . . 1.2.2 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Cost Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Current Management Strategies . . . . . . . . . . . . . . . . . . . . . . 2.1 Nonpharmacological Interventions . . . . . . . . . . . . . . . . . . 2.2 Pharmacological Interventions . . . . . . . . . . . . . . . . . . . . 2.2.1 DMARDs and Biologic Agents . . . . . . . . . . . . . . . . . . 2.2.2 NSAIDs and Analgesics . . . . . . . . . . . . . . . . . . . . . . 2.2.3 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Potential Role of Etanercept in the Treatment of Rheumatoid Arthritis 3.1 Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1 In Early Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2 In Patients Not Responding to Other DMARDs . . . . . . . . . 3.2 Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2 Injection Site Reactions . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

18 19 19 19 19 20 20 20 21 22 23 23 24 24 25 25 25 27 29 29 30

18

Keating & Jarvis

3.2.3 Other Adverse Events . . . . . . . . . . . . . . . . . 3.3 Health-Related Quality of Life and Cost Considerations 3.3.1 In Early Disease . . . . . . . . . . . . . . . . . . . . 3.3.2 In Patients Not Responding to Other DMARDs . . . 3.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

30 30 30 31 32

Summary Abstract

Rheumatoid arthritis is associated with substantial costs to both the individual and society; costs increase as disease severity worsens. Current thinking is that disease-modifying antirheumatic drug (DMARD) therapy should be started as soon as possible after the diagnosis of rheumatoid arthritis and that patients should be offered the most effective treatment available. Etanercept is a soluble dimeric fusion protein comprising two copies of the extracellular ligand-binding domain of the human p75 receptor for tumour necrosis factor-α (TNFα ) linked to the constant portion of human immunoglobulin G1. TNFα is thought to play an important role in the pathophysiology of rheumatoid arthritis; by binding the cytokine, etanercept blocks its biologic effects. In a 12-month double-blind, randomized study involving patients with early active rheumatoid arthritis, administration of subcutaneous etanercept 25mg twice weekly was associated with a more rapid and significantly greater overall response (assessed using American College of Rheumatology criteria) than oral methotrexate. In addition, compared with methotrexate, etanercept was associated with more rapid slowing of radiographic progression and a more rapid improvement in measures of health-related quality of life. The efficacy of etanercept was maintained at 3 years’ follow-up. Etanercept, alone or in combination with methotrexate, also showed sustained efficacy in three double-blind, randomized, placebo-controlled studies of 3 to 6 months’ duration involving patients with active rheumatoid arthritis who had not responded adequately to previous treatment with DMARDs. Etanercept was generally well tolerated in clinical trials (the most commonly occurring adverse events included injection site reactions, infection, headache, nausea, rhinitis, dizziness, pharyngitis and cough). The high cost of etanercept relative to traditional DMARDs may be justified if it can be shown to reduce long-term outcomes associated with rheumatoid arthritis, thereby reducing disease costs. Conclusion: Etanercept is an important new treatment option in rheumatoid arthritis. It provides a rapid and sustained reduction in disease activity and inhibits the progression of structural damage in patients with early active rheumatoid arthritis, with good tolerability. The improvement in disease activity and slowing of joint damage seen with etanercept was more rapid than that seen with methotrexate. In addition, etanercept, alone or in combination with methotrexate, is effective in the treatment of patients with active rheumatoid arthritis who have not responded adequately to previous DMARD therapy. It is anticipated that etanercept may also improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial economic burden imposed by the disease; however, more long-term data are needed to establish this.

This article reviews the epidemiology and management of rheumatoid arthritis and, in particular, focuses on the role of etanercept in the treatment of this disease. Etanercept is a soluble dimeric fusion protein comprising two copies of the extracellular ligand-binding domain of the human p75 receptor for tumor necrosis factor-α (TNFα) linked to the constant (Fc) portion of human immunoglobulin (Ig) G1. TNFα is thought to play an important role in the pathophysiology of rheumatoid arthritis; by binding the cytokine, etanercept blocks its biologic effects. In the US, etanercept is currently approved for reducing symptoms and signs and inhibiting the progression of structural damage in patients with moderately to severely active rheumatoid arthritis either © Adis International Limited. All rights reserved.

as monotherapy, or in combination with methotrexate in patients who have not responded adequately to methotrexate alone.[1] In the European Union, etanercept is indicated for use in patients with active rheumatoid arthritis who have not responded adequately to disease-modifying antirheumatic drugs (DMARDs).[2] Etanercept is also approved in the US and the European Union for use in juvenile rheumatoid arthritis[3] and has been granted priority review status by the US Food and Drug Administration for use in psoriatic arthritis,[4] but these indications are not discussed in this article. For a more detailed review of the pharmacology and clinical efficacy of etanercept, see Jarvis and Faulds.[5] Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

1. Disease Profile Rheumatoid arthritis is a disease that is commonly associated with progression and disability. Usually, the condition starts with symmetrical involvement of the small joints of the hands, feet, wrists, elbows and ankles, with subsequent progression to the large synovial joints.[6] Early rheumatoid arthritis is characterized by pain and other signs of inflammation (e.g. heat, swelling, loss of function and erythema).[7] If inflammation goes uncontrolled and the disease remains active, patients will eventually experience deformity and instability of the joints.[7] Patients with rheumatoid arthritis may also exhibit extra-articular manifestations. These manifestations include constitutional symptoms (e.g. fever and malaise), rheumatoid nodules, elevated liver enzymes, cardiovascular conditions (e.g. vasculitis and myocarditis), pulmonary conditions (e.g. interstitial fibrosis), ocular conditions (e.g. scleritis), skin conditions (e.g. palmar erythema), neurologic conditions (e.g. compression neuropathy) and hematologic conditions (e.g. anemia).[8]

1.1 Pathophysiology

The etiology of rheumatoid arthritis is unclear although it is evident that it is an immune mediated disease involving complex cellular interactions. Hallmarks of rheumatoid arthritis include infiltration of the synovium by T cells, angiogenesis and synovial proliferation.[9] The synovium is eventually transformed into an aggressive invasive pannus that leads to joint damage.[10] It is a generally held view that the activation of T cells is responsible for the cascade of events leading to rheumatoid arthritis. Supporting this view are several lines of evidence including data from various animal models, the clinical efficacy of certain T celldirected drugs such as cyclosporin and the finding that the major histocompatibility complex class II alleles human leukocyte antigen (HLA)-DRB1*0404 and HLA-DRB1*0401 are linked to rheumatoid arthritis.[11] The role of these HLA molecules is to present antigens to CD4+ T cells, suggesting that rheumatoid arthritis may be triggered by an antigen. The triggering antigen may be exogenous (e.g. viral) or endogenous (e.g. citrullinated protein, human cartilage glycoprotein 39 or heavy chain binding protein).[12] The key cytokines driving inflammation in rheumatoid arthritis appear to be interleukin (IL)-1, IL-6 and TNFα.[12] These cytokines are released by monocytes, macrophages and synovial fibroblasts in response to stimulation by activated CD4+ T cells. In particular, IL-1 and TNFα are thought to have a primary role in the pathogenesis of rheumatoid arthritis. These cytokines promote the expression of endothelial adhesion molecules (e.g. intercellular adhesion molecule 1)[12] leading to the migration of © Adis International Limited. All rights reserved.

19

leukocytes to the site of inflammation.[13] TNFα also stimulates the production of other proinflammatory cytokines (e.g. IL1, IL-6, IL-8 and granulocyte-monocyte colony-stimulating factor).[12,14] As well as causing synovial inflammation, IL-1 and TNFα are potent stimulators of mesenchymal cells (e.g. synovial fibroblasts, osteoclasts and chondrocytes) that release matrix metalloproteinases (e.g. stromelysin and collagenases) which degrade connective tissue matrix.[12] In addition, these cytokines block the production of matrix metalloproteinase inhibitors by synovial fibroblasts.[12] It is thought that the consequence of these actions is joint damage. Studies in animals have also shown that, independently of these cytokines, activated CD4+ T cells may contribute to joint damage by stimulating osteoclastogenesis.[12] Many cytokines are involved in promoting the angiogenesis seen in rheumatoid arthritis, although vascular endothelial growth factor seems to be of particular importance.[15] Platelet derived growth factor and fibroblast growth factor seem to be primarily responsible for the transformation of the synovium into pannus.[15] It has been suggested that the progression of rheumatoid arthritis can be classified into the following five pathogenetic stages:[16] • Stage 0: interaction of initial factors (e.g. genetic, autoimmune, environmental) that may contribute to the development of rheumatoid arthritis • Stage 1: activation of T cells leading to synovial proliferation and the formation of pannus • Stage 2: activation of chondrocytes and invasion of pannus leading to erosions • Stage 3: subchondral, capsular and ligament damage leading to deformity and joint destruction • Stage 4: degenerative changes leading to disability.

1.2 Epidemiology

1.2.1 Incidence and Prevalence

Rheumatoid arthritis is thought to affect approximately 1% of the adult population worldwide.[17] The prevalence of severe disease is lower at around 0.23%.[18] Interestingly, the incidence of severe disease may vary with geographic location. For example, a higher incidence of severe rheumatoid arthritis is seen in northern Europe, compared with Mediterranean countries; it appears that genetic divergence may partly account for this difference.[19] The incidence of rheumatoid arthritis tends to increase with advancing age,[20,21] with disease onset typically occurring between the ages of 40 and 60.[22] More women than men develop the disease (ratio of approximately 3 to 1).[7] Dis Manage Health Outcomes 2002; 10 (1)

20

Keating & Jarvis

1.2.2 Risk Factors

Both environmental and genetic risk factors are thought to contribute to the development of rheumatoid arthritis, although their relative contribution remains to be determined.[23] The observation that rheumatoid arthritis is more common in women than men (section 1.2.1) suggests that female sex hormones may have a role in the pathogenesis of the disease.[24] However, the exact role of such hormones in rheumatoid arthritis is controversial with studies showing conflicting results.[25-33] Other environmental factors found to be associated with an increased risk of rheumatoid arthritis include cigarette smoking,[24,34,35] obesity[35] and a history of prior blood transfusion.[35] Rheumatoid arthritis has been linked with various genetic risk factors; the most well recognized association is with certain HLA-DRB1 alleles (e.g. HLA-DRB1*0101, *0102, *0401, *0404, *0405, *0408, *1001 and *1402).[36] These alleles share a similar amino acid sequence (the shared epitope[37]) in the third hypervariable region of HLA-DRB1 (QKRAA, QRRAA or RRRAA).[36] It is generally thought that the presence of particular HLA-DRB1 alleles is predictive of disease susceptibility and severity, although studies have yielded conflicting results.[38-42] 1.3 Outcome

A link has been shown between joint damage and subsequent disability in rheumatoid arthritis; this link seems to be strongest in late disease (after about 5 to 6 years have elapsed)[43,44] while the disability observed in early disease (in the first 5 to 6 years) appears to be related to the extent of disease activity.[43,44] Radiographic progression and disability can occur quickly in patients with rheumatoid arthritis.[45] In one study, 70% of patients with rheumatoid arthritis (disease duration of <1 year) had evidence of radiographic damage after 3 years’ follow-up despite treatment with traditional DMARDs.[46] In another study involving patients with early rheumatoid arthritis (symptom duration of <2 years) who received DMARD therapy, 8% of patients required major joint replacement and 3% of patients required excision arthroplasty or synovectomy after 5 years’ follow-up.[47] Furthermore, 50% of patients with rheumatoid arthritis will experience some difficulty in performing the usual activities of daily living within 2 years of disease onset, and 60 to 70% of patients aged <65 years who were working when they developed rheumatoid arthritis report work disability within 5 years of disease onset.[48] Approximately 50% of patients with rheumatoid arthritis must stop working within 10 years of diagnosis.[49] The long-term prognosis of rheumatoid arthritis is poor, with approximately 80% of patients experiencing disability within 20 years of disease onset.[50] © Adis International Limited. All rights reserved.

Factors that appear to predict greater disease severity include the following:[42] having large joint involvement, higher overall joint counts or upper extremity disease; being of female gender; being rheumatoid factor positive; and having markers of increased disease activity [e.g. high C-reactive protein (CRP) levels or a high erythrocyte sedimentation rate (ESR)]. Life expectancy is reduced by between 5 and 10 years in patients with rheumatoid arthritis.[51] The 5-year survival rate in patients with rheumatoid arthritis who have >20 involved joints or who can perform <80% of activities of daily living without difficulty is 40 to 60%, similar to that seen in patients with triple vessel coronary artery disease or stage IV Hodgkin’s disease.[52] The mortality rate appears to be lower in patients with rheumatoid arthritis who present early rather than late[53] and patients who respond to treatment appear to have a lower mortality rate than those who do not.[54,55]

1.4 Cost Considerations

Rheumatoid arthritis is associated with substantial costs to both the individual and society.[45] It has been shown that the indirect cost of rheumatoid arthritis to society (e.g. the cost incurred by lost productivity in the workplace) can be reduced by treating the disease with DMARDs.[56] Furthermore, it has been suggested that reducing long-term disability by initiating early, aggressive therapy in rheumatoid arthritis may be associated with substantial cost savings.[57] Interestingly, while the cost of rheumatoid arthritis to the patient is high, the low prevalence of the disease (section 1.2.1) means that the cost of the disease to the healthcare payer may be relatively low.[58] In a US managed health care organization with approximately 160 000 members, 365 patients had rheumatoid arthritis. The average cost of rheumatoid arthritis care was $US2162 per patient-year with a total direct cost of $US703 053 (currency year not stated). In contrast, 10 101 patients had osteoarthritis; while the average cost of osteoarthritis care was only $US543 per patient-year, the total direct cost was $US4 728 425. A systematic review of 14 studies examining the costs associated with rheumatoid arthritis found that the mean annual direct cost was $US5720 per patient (1996 values) and the mean annual indirect cost was $US5822 per patient.[59] Several studies have shown that hospital admissions account for a large proportion of the direct costs associated with rheumatoid arthritis.[57,60-63] A US study examining the direct medical care costs incurred by 1156 patients with rheumatoid arthritis over a 1-year period found that the annual total medical care cost for rheumatoid arthritis averaged $US5919 per patient (medical care costs included those for hospital admissions, physician Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

visits, drugs and ancillary costs for things such as blood tests, urinalysis and x-rays) [1996 values].[61] Hospital admissions accounted for >50% of this total ($US3061) with most of this attributable to the cost of total joint replacement surgery ($US1533). It is interesting to note that although hospital admissions for rheumatoid arthritis dominated direct costs associated with the disease in this study, <10% of patients actually required hospitalization for rheumatoid arthritis during the study period. Following hospital admission, drug costs comprised the next largest component of medical care costs associated with rheumatoid arthritis ($US1552).[61] DMARDs accounted for approximately two-thirds of this cost with NSAIDs responsible for most of the remainder. It should be remembered that costs associated with drug therapy include not only the acquisition cost of the drug, but also other expenditures, including the cost of monitoring patients for potential adverse events and the cost of managing adverse events when they occur.[64] A study modeling the use of hydroxychloroquine, oral gold, injectable gold, azathioprine, penicillamine and methotrexate in rheumatoid arthritis found that medication costs accounted for 25.1 to 45.4% of the total drug cost, monitoring costs accounted for 39 to 62.2% and toxicity costs accounted for 9.3 to 22.8%.[64] In a UK study that used data from a population-based register, 171 patients with rheumatoid arthritis incurred total secondary health service care and second-line drug costs of £338 704 over a 5-year period (1990 to 1991 values) [costs included drug costs, staff costs, capital costs, laboratory costs and overheads].[65] 58% of this cost was accounted for by inpatient costs, 33% by second-line drug costs and 9% by outpatient costs. In terms of the total costs associated with rheumatoid arthritis, studies have shown that indirect costs generally are similar to, or exceed, direct costs.[66] For example, in England in 1992, direct costs (including the use of health services, drug costs, management of toxicity, the cost of aids and adaptations and the cost of adults with disabilities living in communal establishments) associated with rheumatoid arthritis were £604.5 million (1992 values) while indirect costs associated with rheumatoid arthritis were £651.5 million.[66] These high indirect costs are attributable to lost productivity associated with the inability of patients with rheumatoid arthritis to work at full capacity. Interestingly, a German study found that even early rheumatoid arthritis was associated with high indirect costs (mean annual indirect cost of $US11 750 per patient) [costs were converted to US dollars by applying an average of DM1.5 to $US1 for the period 1994 to 1996].[67] In this 3-year study, indirect costs decreased over time by 21%, mainly because of a reduction in costs associated with sick leave. © Adis International Limited. All rights reserved.

21

A US study, in which the total cost of rheumatoid arthritis was $US8.74 billion (1994 values), found that direct costs ($US4.76 billion) exceeded indirect costs ($US3.98 billion).[62] A prospective Canadian study, involving 1063 patients with rheumatoid arthritis who were followed up for 12 years, also found that between 1990 and 1994, mean annual direct costs associated with the condition exceeded mean annual indirect costs ($Can4656 vs $Can1597 per patient) [1994 values].[57] However, this finding may reflect the age distribution of the patients involved in the study (mean age of >60 years). It has also been noted that the direct costs of rheumatoid arthritis are increasing rapidly because of the increasing use of new technologies, expensive surgical procedures and drugs,[68] including new biologic agents. Whether the increase in direct costs associated with these innovations is offset by a reduction in indirect costs remains to be determined. In addition to direct and indirect costs, rheumatoid arthritis is also associated with intangible costs (e.g. costs associated with pain, depression, anxiety and reduced quality of life).[68] Such costs are often assessed using instruments that measure functional status and quality of life. Functional status, as assessed by Health Assessment Questionnaire scores, has been shown to be strongly related to the direct costs associated with rheumatoid arthritis.[61,69] In a US study examining the direct costs incurred by 1156 patients with rheumatoid arthritis over a 1-year period, scores in the fourth quartile of functional status (i.e. patients with the worst functional status) were found to be over 2.5-fold higher than those in the first quartile of functional status ($US9477 vs $US3721) [1996 values].[61] In a subgroup of 272 patients who were followed up for 10 years, cumulative costs were approximately 75% greater among patients in the fourth quartile of functional status at baseline than in those in the first quartile ($US72 448 vs $US41 423). Similar results were seen in a Markov modeling study using data from a cohort of 116 Swedish patients with early rheumatoid arthritis (disease duration of <2 years).[70] Costs increased as the Markov state increased (indicating worsening disability); Markov state 1 was associated with 5-year undiscounted total costs of SEK179 750 per patient (1997 values) and Markov state 6 was associated with 5-year undiscounted total costs of SEK722 368 per patient.

2. Current Management Strategies Given that rheumatoid arthritis is a progressive disease associated with disability and premature death (section 1.3), early diagnosis and the rapid institution of effective treatment is important. However, this aggressive approach to therapy, where early Dis Manage Health Outcomes 2002; 10 (1)

22

Keating & Jarvis

treatment with DMARDs is advocated, is a relatively recent development. Previously, a pyramidal treatment approach was used. This involved starting treatment with rest, joint protection and physical therapy, with the subsequent addition of salicylates followed by NSAIDs and paracetamol [acetaminophen]; treatment with DMARDs was usually added in at a later date.[71] While the ultimate goal of treatment in patients with rheumatoid arthritis is complete remission (defined as the absence of symptoms of inflammatory joint pain, morning stiffness, fatigue, synovitis and radiographic progression and the absence of elevated ESR or CRP levels), this is achieved only rarely. More realistically, goals of treatment are to control disease activity and slow the rate of joint damage, relieve pain, maximize quality of life and enable patients to continue working and performing activities of daily living.[72] As well as undergoing a thorough clinical examination, patients with newly diagnosed rheumatoid arthritis should have their hands and feet x-rayed and a number of laboratory tests performed (including a complete blood count, platelet count, electrolytes, liver and renal function tests, rheumatoid factor measurement, ESR and CRP level).[72] Following diagnosis and the start of treatment, patients must have regular follow-up to monitor disease control and the tolerability of drug therapy.

A multidisciplinary approach is often needed in patients with rheumatoid arthritis, requiring the input of numerous health professionals (e.g. physiotherapists, occupational therapists, podiatrists, pharmacists, orthopedic surgeons, clinical psychologists and vocational rehabilitation staff).[72] An algorithm for the treatment of rheumatoid arthritis, based on US treatment guidelines and consensus recommendations, is shown in figure 1.[72,73] However, it is important to note that treatment should be tailored to the individual patient,[73] as the suggested approach may be too aggressive for some patients and too limited for others.

2.1 Nonpharmacological Interventions

While the mainstay of treatment in patients with rheumatoid arthritis is pharmacological, surgery may be an option in patients with unacceptable pain and/or limited function because of structural joint damage.[72] The most successful surgical procedures performed in patients with rheumatoid arthritis include carpal tunnel release, resection of the metatarsal heads and total hip or knee arthroplasty.[72] However, surgery only resolves the damage and pain at the joint operated on.

Diagnosis and evaluation of rheumatoid arthritis (disease activity, structural damage, functional and psychosocial status)

Start treatment • Start DMARD as soon as possible • Trial NSAID and/or other simple analgesics • Possible use of oral or local coticosteroids • Physical and occupational therapy • Patient education Persistent active disease after an adequate DMARD trial Review treatment • Change/add DMARD/biologics (consider combination therapy or treatment with etanercept or infliximab)

Remission/ satisfactory control

Monitor disease activity

Disease reactivation

Remission/ satisfactory control Disease reactivation

Monitor disease activity

Mechanical joint symptoms Surgical intervention

Fig. 1. Disease management algorithm: management of rheumatoid arthritis.[72,73] Recent consensus recommendations[73] did not advocate the routine first-line use of biologic agents. However, it should be noted that since these recommendations were formulated, etanercept has been approved in the US for first-line use in the treatment of rheumatoid arthritis.[1] DMARD = disease-modifying antirheumatic drug.

© Adis International Limited. All rights reserved.

Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

23

2.2 Pharmacological Interventions

2.2.1 DMARDs and Biologic Agents

DMARD therapy has the potential to prevent or reduce joint damage and preserve joint integrity and function in patients with rheumatoid arthritis.[72] Treatment with a DMARD/biologic agent should commence as soon as possible after the diagnosis of rheumatoid arthritis as studies show that early treatment may prevent or delay functional loss and work disability.[73,74] It also appears that effective treatment reduces mortality in patients with rheumatoid arthritis.[54]

A comparison of some of the characteristics of DMARDs/ biologic agents is shown in table I. The onset of action of the traditional DMARDs (e.g. methotrexate, hydroxychloroquine) is slow relative to that of newer biologic agents such as etanercept and infliximab (1 to 6 months vs 1 to 2 weeks). In addition, laboratory monitoring for specific adverse effects is required during treatment with the traditional DMARDs, but not during therapy with etanercept or infliximab. However, patients receiving the new biologic agent anakinra, a recombinant human IL-1 receptor antagonist recently approved in the US[75] for use in refractory rheumatoid arthritis, must have their neutrophil count assessed

Table I. Overview of some features of biologic agents and DMARDs used in rheumatoid arthritis[5,72,76-83] Drug

Route of administration

Onset of action

Adverse events

Monitoring requirements

1-2wk

Injection site reactions, infections, headache, rhinitis

No specific requirement

1-2wk

Upper respiratory tract infections, headache, infusion-related reactions, nausea

Subcutaneous

NA

Injection site reactions, infections, headache, nausea

No specific monitoring requirements above those required for methotrexate although in the US patients must undergo tuberculin testing before starting therapya Neutrophils

Oral

2-3mo

Biologic agents Etanercept (recombinant Subcutaneous human fusion protein that binds TNFα) Infliximab (chimeric monoclonal Intravenous antibody against TNFα)

Anakinra (recombinant form of the human interleukin-1 receptor antagonist) DMARDsb Azathioprine

GI, flu-like illness, FBC, platelets myelosuppression, elevated LFTs, hepatotoxicity Cyclosporin Oral 2-6mo GI, headaches, paresthesia, Serum creatinine hypertrichosis, gingival hyperplasia, renal toxicity, hypertension, malignancy Hydroxychloroquine Oral 2-4mo GI, rash, retinal toxicity Ophthalmologic examinations Injectable gold salts Intramuscular 3-6mo Stomatitis, rash, proteinuria, FBC, platelets, urine protein myelosuppression, thrombocytopenia Leflunomide Oral 1mo GI, rash, hepatotoxicity, alopecia, FBC, LFTs respiratory infections Methotrexate Oral 1-2mo GI, stomatitis, hepatotoxicity, rash, FBC, platelets, LFTs, albumin, serum alopecia, myelosuppression creatinine Penicillamine Oral 3-6mo Stomatitis, dysgeusia, rash, FBC, urine protein proteinuria, myelosuppression, autoimmune disease Sulfasalazine Oral 1-2mo GI, rash, myelosuppression FBC a In Europe, it is recommended that consideration be given to performing a chest x-ray and tuberculin test prior to starting infliximab therapy, in addition to obtaining a detailed medical history. b Recent consensus recommendations[73] suggest that auranofin and cyclophosphamide should generally be avoided in patients with rheumatoid arthritis, the former because it is not particularly effective and the latter because it does not tend to be well tolerated. DMARD = disease modifying antirheumatic drug; GI = gastrointestinal; FBC = full blood count; LFT = liver function test; NA = not available; TNF = tumor necrosis factor.

© Adis International Limited. All rights reserved.

Dis Manage Health Outcomes 2002; 10 (1)

24

before starting treatment and for regular intervals up to 1 year after starting therapy.[76] Unfortunately there is no simple rule as to the order in which DMARDs/biologics should be administered.[73] US consensus recommendations state that first-line treatment in rheumatoid arthritis should comprise the most effective DMARD and suggest the use of methotrexate or leflunomide. [73] Patients who fail an adequate trial of treatment with methotrexate or leflunomide are unlikely to respond to further treatment with hydroxychloroquine, sulfasalazine, injectable gold or azathioprine (an adequate trial of therapy is generally considered to be 6 months for penicillamine, 5 months for injectable gold, 4 months for hydroxychloroquine and 3 months for other DMARDs). Therefore, rather than successive trials of other DMARDs, the most appropriate step for patients who fail treatment with methotrexate or leflunomide may be to commence triple therapy with methotrexate plus sulfasalazine plus hydroxychloroquine or to start treatment with biologic agents such as etanercept or infliximab. US consensus recommendations[73] also suggest that first-line use of etanercept or infliximab should be considered in patients who have very active disease. The consensus recommendations did not advocate the routine first-line use of biologics in rheumatoid arthritis because limited data existed supporting the efficacy of these agents in this indication at the time that the recommendations were formulated. However, the authors of these recommendations did envisage that the use of biologics in the treatment of early rheumatoid arthritis would expand. Indeed, since the formulation of the recommendations, etanercept has been approved in the US for use in the first-line treatment of rheumatoid arthritis.[1] Several consensus statements have specifically addressed the role of biologics in the treatment of rheumatoid arthritis.[18,84-86] The most recent consensus statement emerged from a World Health Organization Collaborating Centre consensus meeting.[18] The statement noted that while there is good evidence supporting the efficacy of biologics in early rheumatoid arthritis, more long-term data are needed before the broad introduction of first-line therapy with biologics in early disease can be supported. Thus, the consensus statement recommends the use of biologics in patients with active disease who have not responded to an adequate course of DMARD therapy.[18] Unacceptable disease activity was defined as five swollen joints plus an elevated acute phase response (this approximates a disease activity score of >3.2). Older consensus statements[84-86] concur that biologic therapy should be reserved for patients with rheumatoid arthritis who have not responded adequately to DMARD therapy; one of the statements also defines active disease as a 28-joint disease activity score of >3.2.[86] Recent treatment guidelines formulated © Adis International Limited. All rights reserved.

Keating & Jarvis

by the British Society for Rheumatology are more stringent. They recommend that patients should have failed treatment with at least two DMARDs (of which methotrexate must have been one) before treatment with etanercept or infliximab is considered and that patients should have highly active disease (a 28-joint disease activity score of >5.1).[87] Generally, auranofin (an oral gold compound) and cyclophosphamide should be avoided in patients with rheumatoid arthritis, the former because it is not particularly effective and the latter because it does not tend to be well tolerated.[73] Considering the use of combination therapy is of particular importance in patients with severe disease or in patients whose disease is not adequately controlled with DMARD monotherapy. Interest in the use of combination therapy has increased in recent times,[17] with several combination regimens demonstrating clinical efficacy (e.g. methotrexate plus cyclosporin, methotrexate plus sulfasalazine plus hydroxychloroquine, sulfasalazine plus methotrexate plus prednisolone, infliximab plus methotrexate, and etanercept plus methotrexate).[88] In Europe, combination therapy with leflunomide plus methotrexate and/or other potentially hepatotoxic drugs is not advised because of an increased risk of serious hepatic adverse events.[80] 2.2.2 NSAIDs and Analgesics

NSAIDs provide symptomatic relief by reducing joint pain and swelling and improving function and are usually part of the initial treatment regimen in patients with rheumatoid arthritis.[72] However, NSAIDs do not prevent joint destruction or change the course of the disease[72] and use of these agents should not be considered mandatory.[73] Cost, the duration of action and patient preference are the main factors involved in deciding which NSAID to use.[72] Treatment with conventional NSAIDs is commonly associated with dyspepsia and less commonly associated with gastrointestinal bleeding or ulceration. The development of selective cyclo-oxygenase-2 inhibitors such as celecoxib and rofecoxib represents an advance in this regard as these agents are less likely than conventional NSAIDs to be associated with gastric erosions or ulcers.[88] Rarely, NSAIDs may be associated with renal complications.[77] Other opioid and nonopioid analgesics may also provide useful pain control in patients with rheumatoid arthritis. Neither NSAIDs nor other analgesics should be given instead of DMARDs/biologics when control of disease activity is needed.[73] 2.2.3 Corticosteroids

Although low-dose oral corticosteroids provide symptomatic relief in patients with active rheumatoid arthritis,[72] such treatment is associated with numerous adverse effects (e.g. weight gain, hypertension, diabetes mellitus, osteoporosis, cataract Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

formation, increased susceptibility to infection and impaired wound healing).[77] Thus, there is controversy surrounding the optimal role of low-dose oral corticosteroids in the treatment of rheumatoid arthritis,[73] even though it appears that they may slow the rate of joint damage.[72] Intra-articular injection of corticosteroids into individual recalcitrant joints is an effective way of reducing pain and inflammation in patients with active rheumatoid arthritis.[89] Corticosteroids should always be considered an adjunct to DMARD/biologic therapy rather than a substitute for such therapy.[73] 3. Potential Role of Etanercept in the Treatment of Rheumatoid Arthritis Etanercept is produced by recombinant technology in a Chinese hamster ovary cell line[90] and is a soluble dimeric fusion protein comprising two copies of the extracellular ligand-binding domain of the human p75 receptor for TNFα linked to the Fc portion of human IgG1. [91] TNFα binds to the soluble and cell surface TNF receptors p55 and p75.[12] By binding excess TNFα, etanercept blocks the interaction between TNFα and the cell surface receptors p55 and p75, [90] thereby inhibiting the biologic effects of TNFα. Etanercept also binds TNFβ (lymphotoxin-α). The efficiency of etanercept in inactivating TNFα is approximately 1000-fold greater than that of the p75 receptor.[12] Synovial biopsies taken from patients with rheumatoid arthritis revealed that after 1 month’s treatment with etanercept there were statistically significant reductions from baseline in T cell and plasma cell numbers and in the levels of vascular cell adhesion molecule 1 and IL-1.[12] For a detailed review of the pharmacodynamic and pharmacokinetic properties of etanercept, see Jarvis and Faulds.[5] 3.1 Clinical Efficacy

Etanercept provides rapid and sustained reductions in disease activity in both early rheumatoid arthritis and rheumatoid arthritis that is refractory to DMARDs. Prescribing information for etanercept is summarized in table II. Given that 25mg twice weekly is the etanercept dosage approved for clinical use, only results obtained in patients receiving this dosage are presented in section 3. Lower etanercept dosages also showed efficacy in clinical trials, although this tended to be less than with the approved dosage. 3.1.1 In Early Disease

A more rapid improvement in disease activity and more rapid slowing of joint damage was seen with subcutaneous etanercept, compared with oral methotrexate, in patients with early active © Adis International Limited. All rights reserved.

25

rheumatoid arthritis enrolled in a randomized, double-blind, placebocontrolled trial.[92] This study involved 632 patients (mean age 49 to 51 years) who had had rheumatoid arthritis for ≤ 3 years and who had not received previous treatment with methotrexate. Patients were considered to be at high risk of radiographic disease progression (i.e. patients were rheumatoid factor-positive or had ≥3 bone erosions on x-rays of the hands, wrists or feet; had ≥10 swollen joints and ≥12 tender or painful joints; and had an ESR of ≥28 mm/h, a serum CRP level of ≥20 mg/L or morning stiffness that lasted ≥45 minutes). Patients were allowed to continue receiving stable doses of NSAIDs and prednisone during the study, but DMARDs such as hydroxychloroquine and sulfasalazine were discontinued ≥4 weeks prior to the start of the study. Patients were randomized to receive 12 months’ treatment with twice-weekly subcutaneous etanercept 10mg (n = 208) or 25mg (n = 207) or once-weekly oral methotrexate (starting at a dosage of 7.5 mg/week and reaching a maximum dosage of 20 mg/week at week 8) [n = 217]. All patients also received folic acid 1 mg/day in addition to administration of the appropriate placebo. The primary clinical endpoint was the overall response [American College of Rheumatology (ACR)-N] during the first 6 months of treatment [assessed by measuring the area under the curve (AUC) for ACR-N]. The ACR-N was determined by calculating the smallest degree of improvement from baseline in the number of tender joints, the number of swollen joints and the median of the five other ACR response criteria (table III). The primary radiographic endpoint was the change in the total modified Sharp scale score over the 12-month treatment period [46 joints were scored for erosions on a 6-point scale (0 to 5) and 42 joint spaces were scored for narrowing on a 5-point scale (0 to 4) giving a total modified Sharp scale score ranging from 0 (no damage) to 398 (severe joint destruction)]. With regard to clinical efficacy, etanercept had a more rapid onset of action than methotrexate. The differences between recipients of etanercept 25mg and methotrexate in the AUC for ACR-N were significant (p < 0.05) at 3 months (6 vs 3), 6 months (15 vs 11), 9 months (26 vs 20) and 12 months (35 vs 29) [all values estimated from a graph]. ACR 20, 50 and 70 responses were defined as reductions of ≥20, 50 and 70%, respectively, in the tender and swollen joint counts and improvements of ≥20, 50 and 70%, respectively, in ≥3 of the remaining 5 ACR criteria (table III). Etanercept 25mg, compared with methotrexate, recipients had significantly higher (p < 0.05) ACR 20, 50 and 70 response rates at most timepoints during the first 6 months of treatment; thereafter ACR response rates were similar in the two treatment groups. After 12 months’ treatment, an ACR 20 response was seen Dis Manage Health Outcomes 2002; 10 (1)

26

Keating & Jarvis

Table II. Etanercept: prescribing summary[1,2] Approved indications in the US

Approved indications in the European Union

Pharmacokinetics

Dosage Adverse events

Contraindications Precautions

Availability

Reducing the signs and symptoms and inhibiting the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis either as monotherapy, or in combination with methotrexate in patients who do not respond adequately to methotrexate alone Reducing the signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients with an inadequate response to ≥1 disease-modifying antirheumatic drugs Treating active rheumatoid arthritis in adult patients with an inadequate response to disease-modifying antirheumatic drugs, including methotrexate Treating active polyarticular-course juvenile chronic arthritis in pediatric patients aged between 4 and 17 years who do not respond adequately or do not tolerate methotrexate Mean maximum serum concentration of 2.4 mg/L after 6 months’ administration of twice-weekly subcutaneous 25mg doses Mean terminal elimination half-life of 102 hours and clearance of 0.16 L/h after a single subcutaneous 25mg dose Pharmacokinetics in patients with hepatic or renal impairment have not been studied 25mg administered subcutaneously twice weekly Injection site reactions Infection Headache Nausea Rhinitis Sepsis Known hypersensitivity to etanercept or its components Caution needed in patients with a history of recurring infections or with underlying conditions which may predispose them to infection, patients with pre-existing or recent onset CNS demyelinating disorders, patients with a history of significant hematologic abnormalities and the elderly Treatment should not be started in patients with active chronic or localized infections and should be discontinued in patients who develop a serious infection or sepsis Consider treatment discontinuation in patients with confirmed significant hematologic abnormalities Should be used in pregnancy only if clearly needed as etanercept has not been studied in pregnant women Powder for subcutaneous injection

in 72 and 65% of etanercept 25mg and methotrexate recipients, respectively (p = 0.16).[92] Etanercept reduced the rate of radiographic progression in patients with early rheumatoid arthritis.[92] At 6 months, the mean total modified Sharp scale score had increased from baseline by a significantly smaller extent in etanercept 25mg, compared with methotrexate, recipients (+0.57 vs +1.06; p = 0.001). However, at 12 months there was no significant between-group difference in the change from baseline in the mean total modified Sharp scale score (the primary endpoint) [+1 in etanercept 25mg recipients vs +1.59 in methotrexate recipients; p = 0.11]. The mean increase from baseline in the erosion score was significantly smaller in etanercept 25mg, compared with methotrexate, recipients at both 6 months (+0.3 vs +0.68; p = 0.001) and 12 months (+0.47 vs +1.03; p = 0.002). The between-group difference in the change from baseline in the joint space narrowing score at 6 and 12 months was not statistically significant. Among methotrexate recipients, the rate of change in both the total modified Sharp scale score and the erosion score was significantly slower (p ≤ 0.005) in the second 6 months of therapy, compared with the first © Adis International Limited. All rights reserved.

6 months of therapy. During the second 6 months of treatment, the rate of change in erosion scores was similar in etanercept 25mg and methotrexate recipients. In this study, a correlation was seen between reduced disease activity and a lack of radiographic progression (i.e. those patients with the best clinical responses showed the least evidence of radiographic progression). 12 months’ treatment was completed by 85% of etanercept 25mg recipients and 79% of methotrexate recipients. A lack of efficacy was responsible for 5 and 4% of patients in the corresponding treatment groups discontinuing therapy. The study was unblinded after a mean duration of 17.3 months and patients could continue to receive, in a nonblind manner, the treatment to which they had been randomized. Two years of treatment were completed by 154 of the initial 207 recipients of etanercept 25mg (74%) and by 129 of the initial 217 recipients of methotrexate (59%). The results of this 2-year analysis were available as an abstract.[94] At 2 years, the ACR 20 response rate was significantly higher in etanercept, compared with methotrexate, recipients (72 vs 59%; p = 0.005). Readers of x-rays remained blinded to both treatment assignment and the Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

Table III. American College of Rheumatology criteria for measuring improvement in disease activity in patients with rheumatoid arthritis[93]a Criteria Method of assessment A reduction in: Number of swollen joints Assessment of ≥28 joints Number of tender joints Assessment of ≥28 joints Plus an improvement in ≥3 of the following: Patient’s assessment of pain 10cm visual analog scale Physician’s global assessment of 10cm visual analog scale disease status Patient’s global assessment of 10cm visual analog scale disease status Patient’s assessment of disability Use of a validated self-assessment instrument (e.g. the Health Assessment Questionnaire) Acute phase reactants Erythrocyte sedimentation rate or C-reactive protein levels a Minimal clinically significant response is defined as a 20% improvement.

chronological order of the x-rays. At 2 years, etanercept 25mg, compared with methotrexate, recipients had experienced significantly smaller mean changes in both the total modified Sharp scale score (+1.3 vs +3.2; p = 0.001) and the erosion score (+0.7 vs +1.9; p = 0.001). Radiographic progression was prevented in 63 and 51% of etanercept 25mg and methotrexate recipients, respectively (p = 0.017). Patients who completed 2 years’ treatment were eligible to enter a noncomparative extension study in which they received etanercept 25mg twice weekly (patients previously assigned to methotrexate could either continue or discontinue the drug).[95] Results were available in abstract form after a further year of follow-up. In patients initially assigned to methotrexate, the ACR 20 response rate improved from 48% at entry to the extension study to 72% after 1 year of etanercept therapy. After 3 years’ treatment with etanercept 25mg, the ACR 20 response rate was 76%, indicating sustained efficacy. 3.1.2 In Patients Not Responding to Other DMARDs

Several well designed trials have shown the efficacy of etanercept in reducing disease activity in patients with active rheumatoid arthritis who have not responded adequately to prior treatment with a DMARD. These randomized, double-blind, placebocontrolled trials[96-98] involved patients with active rheumatoid arthritis who had an ACR functional class of I to III (table IV) and who had not responded to prior DMARD therapy. In two studies, patients were not permitted to receive DMARDs during the active treatment period[96,97] and in a third study patients continued to receive methotrexate although no other DMARDs © Adis International Limited. All rights reserved.

27

were allowed.[98] Patients were allowed to receive stable dosages of NSAIDs and corticosteroids (prednisone equivalent of ≤10 mg/day). Etanercept Monotherapy

Etanercept monotherapy improved disease activity in a rapid, sustained manner in patients with active rheumatoid arthritis involved in two randomized, double-blind, placebo-controlled studies of 3[96] and 6[97] months’ duration. In the 3-month study, the mean age was 53 years and 77% of patients had a duration of disease of >5 years. In the 6-month study, the mean age ranged from 51 to 53 years and the mean duration of disease ranged from 11 to 13 years. Patients had previously not responded to treatment with between one and four DMARDs; DMARD therapy had to be discontinued at least 4 weeks before study entry. In the 3-month study,[96] 180 patients were randomized to receive twice-weekly subcutaneous etanercept 0.25 mg/m2 (n = 46), 2 mg/m2 (n = 46) or 16 mg/m2 (n = 44) or placebo (n = 44); patients randomized to receive etanercept 16 mg/m2 received dosages ranging from 23 to 30mg twice weekly. In the 6-month study,[97] 234 patients were randomized to receive twice-weekly subcutaneous etanercept 10mg (n = 76) or 25mg (n = 78) or placebo (n = 80). The primary efficacy endpoint in the 3-month study was the percentage change in the swollen joint count, the tender joint count and the total count of swollen and tender joints,[96] and in the 6-month study the primary efficacy outcomes were the ACR 20 and 50 response rates at 3 and 6 months.[97] In the 3-month study,[96] a dose-response relationship was apparent with regard to the primary efficacy endpoint. In etanercept 0.25, 2 and 16 mg/m2 and placebo recipients, the percentage improvement from baseline (calculated as the average of the changes in the individual patients) in the swollen joint count was 16, 32, 58 and 24%, respectively, in the tender joint count was 25, 46, 64 and 28% and in the total count was 22, 40, 61 and 25%. The p value (obtained from an analysis of variance comparTable IV. American College of Rheumatology classification of functional status in rheumatoid arthritis[99] Criteriaa Able to perform usual activities of daily living (self-care, vocational, avocational) Able to perform self-care and vocational activities, but limited in avocational activities Able to perform self-care activities, but limited in vocational and avocational activities Limited in ability to perform self-care, vocational and avocational activities Self-care activities include dressing, feeding, bathing, grooming and toileting; vocational activities include work, educational and/or homemaking activities; avocational activities include recreational and/or leisure activities.

Class I II III IV a

Dis Manage Health Outcomes 2002; 10 (1)

28

Keating & Jarvis

ing all four treatment groups) was < 0.001 for each endpoint. At 3 months, a significantly greater proportion of etanercept 16 mg/m2 recipients than placebo recipients had achieved an ACR 20 response (75 vs 14%; p < 0.001) or an ACR 50 response (57 vs 7%; p < 0.001). In the 6-month study,[97] the ACR 20 response rate at 3 months was 62 and 23% in etanercept 25mg and placebo recipients, respectively (p < 0.001). Moreover, the ACR 50 response rate at 3 months was 41 and 8% in the corresponding treatment groups (p < 0.001) and the ACR 70 response rate at 3 months was 15 and 4% (p = 0.015). At 6 months, etanercept 25mg recipients were significantly more likely than placebo recipients to achieve an ACR 20 response (59 vs 11%; p < 0.001), an ACR 50 response (40 vs 5%; p < 0.001) or an ACR 70 response (15 vs 1%; p = 0.001). Clinical responses were observed within 2 weeks of starting therapy in etanercept 16 mg/m2 recipients in the 3month study[96] and in etanercept 25mg recipients in the 6-month study.[97] In both studies, significantly greater (p ≤ 0.004) improvements in other measures of disease activity (e.g. ESR and CRP levels and duration of morning stiffness) were seen in etanercept than in placebo recipients. Discontinuation because of a lack of efficacy occurred in 5 and 43% of etanercept 16 mg/m2 and placebo recipients, respectively, in the 3-month study,[96] and in 15 and 53% of etanercept 25mg and placebo recipients, respectively, in the 6-month study (p < 0.001).[97] Etanercept Plus Methotrexate

Treatment with etanercept plus methotrexate was more effective than methotrexate alone in a randomized double-blind trial involving 89 patients (mean age 50 years) who had active rheumatoid arthritis, despite receiving methotrexate for at least the previous 6 months (the mean duration of disease was 13 years).[98] Patients were randomized to receive subcutaneous etanercept 25mg twice weekly plus oral or subcutaneous methotrexate (mean dosage 19 mg/week) [n = 59] or oral or subcutaneous methotrexate (mean dosage 18 mg/week) plus placebo (n = 30), for 24 weeks. The primary endpoint was the ACR 20 response rate at 24 weeks. Significantly more etanercept plus methotrexate than methotrexate plus placebo recipients achieved an ACR 20 response at 12 weeks (66 vs 33%; p = 0.003) and at 24 weeks (71 vs 27%; p < 0.001). Similarly, significantly more etanercept plus methotrexate than methotrexate plus placebo recipients achieved an ACR 50 response at 12 weeks (42 vs 0%; p < 0.001) and at 24 weeks (39 vs 3%; p < 0.001) or an ACR 70 response at 12 weeks (15 vs 0%; p = 0.03) and at 24 weeks (15 vs 0%; p = 0.03). Etanercept had a rapid onset of effect and the response was sustained. From week 1 onwards, significantly more etanercept © Adis International Limited. All rights reserved.

plus methotrexate than methotrexate plus placebo recipients achieved an ACR 20 response. At week 24, significantly greater (p ≤ 0.008) improvements from baseline in individual outcome measures (e.g. the numbers of swollen and tender joints, the physician’s and patient’s global assessment of disease status, the duration of morning stiffness and the patient’s assessment of pain and disability) were seen in etanercept plus methotrexate, compared with methotrexate plus placebo, recipients. The median ESR decreased from baseline by a significantly greater extent in etanercept (from 25 to 15 mm/h) than in placebo (from 36 to 30 mm/h) recipients (p = 0.004). Similarly, CRP levels decreased from baseline by a significantly greater extent in etanercept (from 22 to 5 mg/L) than in placebo (from 26 to 16 mg/L) recipients (p < 0.001). 97% of etanercept plus methotrexate recipients completed the 24-week study, compared with 80% of methotrexate plus placebo recipients. Long-Term Therapy

The long-term efficacy of etanercept was evaluated in a noncomparative extension study involving 628 patients with active rheumatoid arthritis who had an inadequate response to previous DMARD therapy and who received etanercept monotherapy in double-blind placebo-controlled trials or nonblind pharmacokinetic or tolerability trials. Follow-up data were available after median durations of etanercept therapy of 25 months[100] and 2.4 years (maximum 4.3 years);[101] the latter analysis[101] was available only as an abstract. An ACR 20, 50 or 70 response was seen in 73, 50 and 26% of patients, respectively, after 30 months’ follow-up[100] and in 69, 50 and 25% of patients, respectively, after 3.5 years’ follow-up.[101] After 30 months’ treatment, 28, 27 and 17% of patients had no tender joints, no swollen joints or no tender or swollen joints, respectively,[100] while after 3.5 years’ treatment, 26 and 24% of patients had no swollen joints and no tender joints, respectively.[101] Corticosteroid dosages were reduced in 55% of patients (by a mean of 70%) and 25% of patients discontinued corticosteroid therapy in the analysis of shorter duration.[100] In the analysis of longer duration,[101] corticosteroid dosages were reduced in 59% of patients (by a mean of 71%) with 29% of patients discontinuing corticosteroid therapy. In the analysis of shorter duration, 9% of patients discontinued treatment because of a lack of efficacy.[100] In addition, long-term data are available from a double-blind, randomized, placebo-controlled study[98] in which patients with active rheumatoid arthritis refractory to previous DMARD therapy received etanercept plus methotrexate or methotrexate plus placebo for 24 weeks. 79 of the patients included in this trial went on to receive etanercept plus methotrexate in a long-term extension study, available in abstract form.[102] After a median duration Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

of follow-up of 32 months, 68% of patients had reduced their methotrexate dosage (by a mean of 63%) and 28% of patients had discontinued methotrexate. In addition, 67% of patients had reduced their corticosteroid dosage (by a mean of 78%) and 42% of patients had discontinued corticosteroid therapy. An ACR 20, 50 or 70 response was seen in 69, 51 and 27% of patients, respectively.

3.2 Tolerability

Etanercept was generally well tolerated in randomized, controlled, double-blind trials of up to 1 year’s duration.[92,96-98] The pooled results[1] of placebo-controlled trials[96-98] in patients with active rheumatoid arthritis who had not responded to previous treatment with DMARDs showed that the most commonly occurring adverse events in etanercept (n = 349) and placebo (n = 152) recipients included injection site reactions (37 vs 10%, respectively), infection (35 vs 32%), headache (17 vs 13%), nausea (9 vs 10%), rhinitis (12 vs 8%), dizziness (7 vs 5%), pharyngitis (7 vs 5%), cough (6 vs 3%), asthenia (5 vs 3), abdominal pain (5 vs 3%), rash (5 vs 3%), peripheral edema (2 vs 3%), respiratory disorders (5 vs 1%), dyspepsia (4 vs 1%) and sinusitis (3 vs 2%). Patients in these studies received subcutaneous twiceweekly etanercept at dosages of 10 or 25mg or 0.25, 2 or 16 mg/m2. In one study patients received etanercept or placebo in combination with methotrexate.[98] The long-term tolerability of etanercept was shown in a noncomparative extension study[100] involving 628 patients with rheumatoid arthritis and an inadequate response to previous DMARD therapy who received etanercept monotherapy in doubleblind placebo-controlled trials or nonblind pharmacokinetic or tolerability trials. The rate of patient withdrawal because of adverse events was 7%. With regard to nonserious adverse events, patients were followed up for a median of 17 months (maximum of 32 months). The adverse event rate per patient-year was 0.46 for upper respiratory tract infection, 0.27 for headache, 0.19 for sinusitis, 0.18 for rash, 0.14 for nausea, 0.14 for skin infection, 0.13 for rhinitis and 0.13 for diarrhea. Serious noninfectious adverse events occurred at a rate of 0.15 per patient-year and death occurred at a rate of 0.01 per patient-year. In a placebo-controlled trial involving patients with early active rheumatoid arthritis (section 3.1.1),[92] etanercept 25mg recipients were significantly more likely than methotrexate recipients (who received placebo injections) to experience injection site reactions (37 vs 7%, respectively; p < 0.001). In contrast, methotrexate recipients were significantly more likely than etanercept 25mg recipients to experience nausea (29 vs 17%; p < 0.05), mouth ulcers (14 vs 5%; p < 0.05), rash (23 vs 12%; p < © Adis International Limited. All rights reserved.

29

0.05) or alopecia (12 vs 6%; p < 0.05). Significantly more methotrexate than etanercept 25mg recipients did not complete the 12-month study because of an adverse event or elevated serum aminotransferase levels (11 vs 5%; p = 0.04). 3.2.1 Infection

Infection was one of the most common adverse events occurring in double-blind randomized controlled trials[92,96-98] examining the use of etanercept. The pooled results of placebocontrolled trials[1] indicate that in etanercept and placebo recipients the rates of overall infection (35 vs 32%, respectively) and non-upper respiratory tract infection (38 vs 32%) were similar, although more etanercept than placebo recipients experienced upper respiratory tract infections (29 vs 16%). However, in patients with early rheumatoid arthritis, the rate of upper respiratory tract infection was similar in etanercept 25mg and methotrexate recipients (35 vs 39%).[92] In a noncomparative extension study[100] examining the long-term use of etanercept in 628 patients with rheumatoid arthritis who had an inadequate response to previous DMARD therapy, potentially serious infections occurred at a rate of 0.048 per patient-year. 34 of the 43 patients who developed potentially serious infections continued to receive etanercept therapy after successful resolution of their infections. In all clinical trials, serious infection (including pyelonephritis, bronchitis, septic arthritis, abdominal abscess, cellulitis, osteomyelitis, wound infection, pneumonia, foot abscess, leg ulcer, diarrhea, sinusitis and sepsis) occurred in 50 of 1197 etanercept recipients (maximum duration of therapy of 36 months).[1] The use of etanercept outside of the clinical trial setting has also been associated with reports of serious infection (e.g. sepsis) including serious infection resulting in death.[1,103] In particular it appears that the use of certain concomitant drugs and the presence of comorbidity may predispose etanercept recipients to serious infection. As of April 2001, 103 000 patients worldwide had received etanercept (the majority of patients had rheumatoid arthritis).[104] Serious infection occurred at a rate of 4.3 per 100 patient-years. Analysis of postmarketing reports of serious infection revealed that 78% of etanercept recipients were receiving corticosteroid therapy at the time that serious infection developed and each patient had, on average, four comorbidities. The use of etanercept is contraindicated in patients with sepsis and the manufacturer advises that caution be exercised when contemplating the use of the drug in patients with a history of recurring infection or in those predisposed to infection.[1] In addition, treatment with etanercept should not be started in patients with active infections and should be discontinued in patients who develop a serious infection or sepsis.[1] Dis Manage Health Outcomes 2002; 10 (1)

30

Keating & Jarvis

As previously mentioned, 103 000 patients worldwide had received etanercept as of April 2001.[105] To date, there have been nine reports of etanercept recipients being diagnosed with tuberculosis while receiving the drug. In addition, 19 patients with a history of tuberculosis and seven patients with a positive tuberculin test have received etanercept in clinical trials (average duration of therapy of 22 months); none of the patients have shown evidence of disease reactivation. 3.2.2 Injection Site Reactions

Injection site reactions occurred more frequently in etanercept than placebo recipients in double-blind, randomized, controlled trials.[96-98] Etanercept 25mg recipients were significantly more likely than placebo recipients to experience this adverse event (49 vs 13%; p < 0.001[97] and 42 vs 7%; p < 0.001[98]). Similarly, in the placebo-controlled trial comparing etanercept with methotrexate,[92] injection site reactions occurred in significantly more patients who received etanercept, compared with methotrexate recipients (who received placebo injections) [37 vs 7%; p < 0.001]. Injection site reactions were of mild severity and were characterized by erythema with or without pain, itching or swelling;[97,98] symptoms lasted a median of 3 days.[97,98] Few patients discontinued etanercept therapy because of injection site reactions.[96-98] Injection site reactions tended to be more common in the first month of treatment.[97] It has been suggested that the injection site reactions seen with etanercept therapy may be an example of a T cell-mediated delayed hypersensitivity reaction.[106] 3.2.3 Other Adverse Events [97,98]

Autoantibodies and non-neutralising antibodies against etanercept[92,96-98] were detected in some etanercept recipients during clinical trials but did not appear to be of clinical significance. Malignancy does not appear to occur in etanercept recipients at a greater rate than that seen in the general population,[1] although more long-term data are needed. In clinical trials involving 1197 patients with rheumatoid arthritis who received etanercept for up to 36 months, 17 malignancies were reported. In one study it was noted that the malignancy rate in etanercept recipients was not higher than the expected rate from the US National Institutes of Health Surveillance, Epidemiology and End Results database.[92] Etanercept therapy has been associated with reports of demyelinating lesions,[1,107,108] although it is not clear that there is a causal relationship. In addition, pancytopenia, including aplastic anemia, has been reported, albeit rarely, in etanercept recipients.[1,108] © Adis International Limited. All rights reserved.

The use of etanercept in pregnant women has not been studied.[1] Similarly, it is not known if etanercept is excreted in human milk or if the drug is absorbed from the gastrointestinal tract following ingestion.[1] 3.3 Health-Related Quality of Life and Cost Considerations

The rapid and beneficial effect of etanercept on health-related quality of life has been shown in numerous studies. Several modeling studies have examined the cost effectiveness of etanercept therapy in rheumatoid arthritis although prospective pharmacoeconomic data are lacking. 3.3.1 In Early Disease

Patients with early active rheumatoid arthritis who received etanercept 25mg experienced more rapid improvement in measures of health-related quality of life than methotrexate recipients in a double-blind, randomized trial involving 632 such patients (section 3.1.1).[92] In this analysis, available as an abstract,[109] average improvements from baseline in Health Assessment Questionnaire and Short-Form 36 physical summary scale scores were more than 2-fold greater in etanercept 25mg, compared with methotrexate, recipients after 2 and 4 weeks of treatment (p < 0.001). By week 52, similar improvements in Health Assessment Questionnaire scores (1 point) and Short-Form 36 physical summary scale scores (10 points) were seen in etanercept 25mg and methotrexate recipients. It also appears that etanercept therapy has beneficial effects on healthcare utilization and employment. A study, available as an abstract,[110] included data obtained from 260 patients with early rheumatoid arthritis involved in a double-blind, randomized trial.[92] While patients initially received etanercept or served as controls, all 260 patients eventually went on to receive etanercept. In the current analysis, patients were interviewed after they had been receiving etanercept for a mean of 882 days (patients initially assigned to etanercept) or 239 days (controls). In the 3 months prior to the interview, patients initially assigned to etanercept, compared with controls, reported 0.88 [95% confidence interval (CI) 0.18 to 1.59] fewer physician visits for rheumatoid arthritis, 0.03 (95% CI 0 to 0.07) fewer outpatient surgeries for rheumatoid arthritis and 0.04 (95% CI 0 to 0.07) fewer hospital admissions for rheumatoid arthritis. Among patients who were still working at the time of diagnosis, including patients who were no longer employed, etanercept recipients worked 125 (95% CI –200 to 450) more hours than controls in the year prior to interview. Among patients who were still working, etanercept recipients worked 237 (95% CI 8 to 466) more hours than controls in the year prior to interview. Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

The magnitude of improvement in Health Assessment Questionnaire disability scores was greater in patients with early rheumatoid arthritis (mean disease duration of 1 year; n = 207) than in patients with long-standing disease (mean disease duration of 12 years; n = 563) who received subcutaneous etanercept 25mg twice weekly for 2 years.[111] Patient characteristics in the two groups were generally similar although patients with long-standing, compared with early, disease had received more DMARDs (mean of 3.3 vs 0.5). Health Assessment Questionnaire disability scores decreased from 1.5 to 0.6 in patients with early disease and from 1.6 to 1 in patients with long-standing disease. Significantly more patients with early disease, compared with late disease, achieved Health Assessment Questionnaire disability scores of 0 (29 vs 14%; p < 0.001). This study was available as an abstract.[111] With regard to the cost effectiveness of etanercept therapy in early rheumatoid arthritis, a decision model analysis was conducted in patients with methotrexate-naive disease.[112] This analysis, available as an abstract, considered four monotherapy options (etanercept, leflunomide, methotrexate and sulfasalazine) and one no treatment group. Costs comprised drug costs, monitoring costs, costs associated with adverse events, surgery costs and costs associated with lost wages. Compared with sulfasalazine, the incremental cost-effectiveness ratio of etanercept was $US41 900 per patient achieving an ACR 20 response over a 6-month period (1999 values). The cost effectiveness of treatment was also considered in a setting where the use of methotrexate and sulfasalazine were contraindicated. Compared with the option of no second-line agent, the incremental cost-effectiveness ratios for the direct costs of leflunomide and etanercept were $US4300 and $US37 900 per patient achieving an ACR 20 response, respectively, and the incremental cost-effectiveness ratios for the total costs were $400 and $US35 500 per patient achieving an ACR 20 response, respectively (base case ACR 20 response estimates were 55 and 68% in the corresponding treatment groups). 3.3.2 In Patients Not Responding to Other DMARDs

In studies involving patients with rheumatoid arthritis who had not responded adequately to previous DMARD therapy, improvements in health-related quality of life were seen in etanercept recipients.[96-98] A double-blind study involved patients with active rheumatoid arthritis who had not responded adequately to prior treatment with methotrexate and who were randomized to receive etanercept plus methotrexate or methotrexate plus placebo for 25 weeks.[98] The median Health Assessment Questionnaire disability index score improved by 47% in etanercept plus methotrexate © Adis International Limited. All rights reserved.

31

recipients (from 1.5 at baseline to 0.8) and by 27% in methotrexate plus placebo recipients (from 1.5 at baseline to 1.1). Similarly, greater improvements in Health Assessment Questionnaire scores were seen in etanercept recipients than in placebo recipients in two double-blind, randomized studies involving patients with active rheumatoid arthritis who had responded inadequately to prior treatment with DMARDs and who received etanercept or placebo for 3[96] or 6[97] months. In the 3-month study,[96] the Health Assessment Questionnaire scores at the end of treatment were 137, 123, 104 and 141 in etanercept 0.25, 2 and 16 mg/m2 and placebo recipients, respectively, where 45 is the best possible score and 245 is the worst [p value (obtained from an analysis of variance comparing all four treatment groups) of < 0.001]. In the 6-month study,[97] a significantly greater (p < 0.05) change from baseline was seen in etanercept 25mg, compared with placebo, recipients in the Health Assessment Questionnaire disability index (+39 vs +2%), general health status (+33 vs –12%) and arthritis specific health status (+44 vs –22%) and the vitality domain from the Short-Form 36 (+25 vs +2%) [positive values indicate improvement and negative values indicate worsening]. In addition, the mental health domain from the Short-Form 36 was improved by a significantly greater extent (p < 0.05) in etanercept 25mg recipients than in placebo recipients (+35 vs +3%). In an additional analysis[113] of the 6-month study,[97] significantly greater (p < 0.05) improvements in etanercept, compared with placebo, recipients were seen for seven of the eight category scores making up the disability index score (arising, dressing, eating, walking, hygiene, reach and activities but not grip). Furthermore, significantly greater improvements were seen in etanercept 25mg recipients, compared with placebo recipients, for scores on the mental health (13.88 vs 4.41; p < 0.01) and energy/vitality (16.35 vs 4.74; p < 0.01) scales of the Medical Outcomes Study. In addition, etanercept 25mg recipients had significantly greater improvements in the Short Form-36 Mental Component Score at months 3 and 6 (p ≤ 0.02) and the Physical Component Score at months 1, 3 and 6 (p ≤ 0.01). However, the Short-Form 36 data should be interpreted with caution as this analysis was implemented after the study was already underway and involved only a subset of patients (n = 48). Interestingly, patients who started etanercept therapy earlier had better functional status than those in whom etanercept therapy was delayed in an analysis of data from 309 patients with rheumatoid arthritis who were involved in randomized controlled trials and who all went on to receive etanercept therapy at the end of these trials.[114] At the time of the present analysis, available as an abstract, the mean duration of etanercept therapy in patients originally assigned to etanercept was 799 days and in patients Dis Manage Health Outcomes 2002; 10 (1)

32

originally assigned to control was 546 days (the mean duration of disease was 15 years). The Health Assessment Questionnaire score was 0.191 points lower in patients who had received etanercept throughout, compared with those who initially served as controls (p = 0.013), indicating significantly better function in the former group of patients. The cost effectiveness of etanercept in patients with rheumatoid arthritis that is refractory to methotrexate was examined in a modified decision analysis modeling study.[115] Direct costs included drug costs, monitoring costs, costs associated with adverse events and surgery costs, and indirect costs were those associated with lost wages. Data were obtained from published literature and official price and tariff lists. Six treatment options were compared: etanercept plus methotrexate, etanercept monotherapy, cyclosporin plus methotrexate, triple therapy with hydroxychloroquine plus sulfasalazine plus methotrexate, methotrexate monotherapy or no second-line agent. When the outcome considered was an ACR 20 response over a 6-month time period, the treatment options of methotrexate monotherapy, cyclosporin plus methotrexate and etanercept monotherapy were dominated and were not considered cost effective [the incremental costeffectiveness ratio of etanercept monotherapy was higher than that of etanercept plus methotrexate (the next most expensive option)]. In contrast, with regard to total costs, the incremental cost-effectiveness ratios of triple therapy and etanercept plus methotrexate were $US1500 and $US42 600, respectively (1999 values). Similarly, when the outcome was the ACR 70 weighted response (a weighted outcome measure of ACR responses relative to a full weight of ACR 70 response), the treatment options of methotrexate monotherapy, cyclosporin plus methotrexate and etanercept monotherapy were dominated. With regard to total costs, the incremental cost effectiveness ratios of triple therapy and etanercept plus methotrexate were $US3100 and $US34 800, respectively. The results of a Dutch decision analysis modeling study[116] revealed that the cost of etanercept therapy in rheumatoid arthritis was substantially lower than that of treatment with infliximab plus methotrexate. The study had a 1-year time horizon and was conducted from the perspective of Dutch society; data were obtained from literature, official price and tariff lists and expert opinion. Patients had rheumatoid arthritis and had failed treatment with one or two DMARDs. Total annual drug costs per patient were similar in etanercept and infliximab recipients [NLG31 334 ($US12 534) vs NLG31 526 ($US12 610); 1999 values]. However, other medical costs were higher in infliximab, compared with etanercept, recipients [NLG12 621 ($US5048) vs NLG269 ($US107)]; this was attributable to the costs of day care and use of methotrexate. Overall, the total cost of treatment with © Adis International Limited. All rights reserved.

Keating & Jarvis

infliximab was 42.7% higher than that with etanercept [NLG45 115 ($US18 046) vs NLG31 621 ($US12 648) per patient]. Sensitivity analysis revealed that the results varied with infliximab dosage and dosing interval. A budgetary impact analysis, conducted from the perspective of the Dutch Ministry of Health, calculated that the total cost of treating the maximum number of potentially eligible patients with rheumatoid arthritis in the Netherlands (n = 4116) with etanercept would be NLG130 153 573 and with infliximab would be NLG185 692 266 (1999 values).[116] Medical costs were NLG130 078 661 and NLG181 708 059 in the corresponding treatment groups. The results of a US decision analysis modeling study, available as an abstract,[117] indicate that etanercept appears to be more cost effective than infliximab plus methotrexate in patients with rheumatoid arthritis who have not responded adequately to previous DMARD therapy. The study had a 1-year time horizon. At 1 year, the ACR 20 response rates (as reported in the literature) were 69% in etanercept 25mg twice weekly recipients, 42% in recipients of infliximab 3 mg/kg every 8 weeks plus methotrexate and 59% in recipients of infliximab 10 mg/kg every 4 or 8 weeks plus methotrexate. The average cost of 1 year of treatment with etanercept was $US12 336, and the average cost of treatment with infliximab plus methotrexate ranged from $US13 958 with infliximab 3 mg/kg every 8 weeks to $US71 041 with infliximab 10 mg/kg every 4 weeks (currency year not stated). When the outcome considered was the ACR 20 response, the average cost of etanercept was $US17 906 per successfully treated patient, and the average cost of infliximab plus methotrexate ranged from $US33 233 per patient successfully treated with infliximab 3 mg/kg every 8 weeks to $US120 409 per patient successfully treated with infliximab 10 mg/kg every 4 weeks. The results of a UK modeling study, available as an abstract,[118] indicate that, compared with placebo, etanercept was cost effective in patients with rheumatoid arthritis who had an inadequate response to prior treatment with two or three DMARDs. When only direct costs were considered, the cost of etanercept was £18 938 ($US27 271) per discounted qualityadjusted life year (QALY) gained (currency year not stated). When indirect costs were included, the cost of etanercept was £8439 ($US12 152) per discounted QALY gained.

3.4 Conclusions

Rheumatoid arthritis is a progressive disease associated with a poor outcome (section 1.3) and substantial costs (section 1.4). While most of the costs are incurred in the latter stages of the disease (e.g. costs associated with the need for joint replacement Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

and work-related costs), the process of joint damage starts much earlier.[46] Results of studies point to links between joint damage and subsequent disability (section 1.3).[43,44] It has been suggested that a therapeutic window exists during the early stage of joint damage and that administering DMARDs at this time may be more effective than offering treatment later on;[119] this hypothesis is supported by data from clinical trials.[120-123] This suggestion carries with it the implication that instituting effective therapy early on in rheumatoid arthritis and preventing or delaying disease progression and disability will reduce the costs associated with the long-term outcomes of the condition. While there has been a move towards the earlier use of DMARDs in rheumatoid arthritis (section 2), there are several problems associated with the use of traditional agents. Many of the traditional DMARDs have a slow onset of action and are associated with a requirement for close patient monitoring in order to minimize adverse events (table I). These adverse events are responsible for a considerable proportion of patients discontinuing treatment.[17] In addition, many patients receiving traditional DMARDs do not maintain a satisfactory response to treatment in the long term.[17] These two factors (i.e. poor tolerability and poor long-term efficacy) account for why many patients do not continue treatment with traditional DMARDs for an extended period of time. [124] One study found that about only 50% of patients continued treatment with injectable gold, hydroxychloroquine, penicillamine or azathioprine for 2 years, while about 20% of patients continued treatment for >5 years. Lower discontinuation rates were seen with methotrexate, with about 75 and 55% of patients still receiving this drug at 2 and 5 years, respectively.[125] Similar results showing low long-term continuation rates have been seen in a large retrospective observational study[126] and in a meta-analysis of both randomized controlled trials and observational studies.[127] The results of a large, well designed study indicate that etanercept therapy is associated with a rapid and sustained reduction in disease activity in patients with early active rheumatoid arthritis (section 3.1.1). [92] The overall ACR response rate was significantly higher in etanercept 25mg recipients, compared with methotrexate recipients, at each 3-month timepoint throughout the 12-month study, indicating a more rapid onset of action with etanercept than with methotrexate. In addition, the response to etanercept therapy was sustained, as at 2 years the ACR 20 response rate was significantly higher in etanercept 25mg recipients, compared with methotrexate recipients (72 vs 59%).[94] Moreover, the ACR 20 response rate was maintained in etanercept recipients after 3 years’ treatment (76%).[95] Similarly, the mean total modified Sharp scale score had increased by a significantly smaller extent in etanercept than in methotrexate recipients at 6 © Adis International Limited. All rights reserved.

33

months and the mean erosion score had increased by a significantly smaller extent in etanercept than in methotrexate recipients at 6 and 12 months. At 2 years’ follow-up, the changes in both the total modified Sharp scale score and the erosion score were significantly smaller in etanercept than in methotrexate recipients. In addition, radiographic progression was prevented in significantly more etanercept, compared with methotrexate, recipients after 2 years’ follow-up (63 vs 51%). These trial results suggest that etanercept may be associated with greater long-term benefit than methotrexate in rheumatoid arthritis. Etanercept therapy was also associated with more rapid improvement in measures of health-related quality of life than methotrexate (section 3.3).

Table V. Formulary considerations: etanercept in patients with rheumatoid arthritis Clinical benefits Reduces disease activity and slows radiographic progression in early active rheumatoid arthritis, and improves disease activity in active rheumatoid arthritis that has not responded adequately to other disease-modifying antirheumatic drugs Rapid onset of action and sustained efficacy Generally well tolerated with no specific requirement for adverse event monitoring Potential concerns Expensive relative to traditional disease-modifying antirheumatic drugs Infrequently associated with serious infection (e.g. sepsis), including serious infection resulting in death Approved indications In the US: reducing symptoms and signs and inhibiting the progression of structural damage in patients with moderately to severely active rheumatoid arthritis either as monotherapy, or in combination with methotrexate in patients with an inadequate response to methotrexate alone. Treatment of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients with an inadequate response to ≥1 disease-modifying antirheumatic drugs In the European Union: treating active rheumatoid arthritis in adult patients with an inadequate response to disease-modifying antirheumatic drugs, including methotrexate. Treating active polyarticular-course juvenile chronic arthritis in pediatric patients aged between 4 and 17 years who do not respond adequately or do not tolerate methotrexate Conclusions Etanercept provides a rapid and sustained reduction in disease activity and inhibits the progression of structural damage in patients with early active rheumatoid arthritis, with good tolerability. The improvement in disease activity and slowing of joint damage seen with etanercept was more rapid than that seen with methotrexate. In addition, etanercept, alone or in combination with methotrexate, is effective in the treatment of patients with active rheumatoid arthritis who have not responded adequately to previous disease-modifying antirheumatic drug therapy. It is anticipated that etanercept may also improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial economic burden imposed by the disease; however, long-term data are needed to confirm this.

Dis Manage Health Outcomes 2002; 10 (1)

34

Thus, while these data suggest that etanercept may improve longterm outcomes in rheumatoid arthritis (e.g. joint deformity, functional and work disability and the need for joint replacement surgery), long-term studies are needed to confirm this. If etanercept proves to be effective in preventing/delaying these long-term outcomes, it is anticipated that this may in turn reduce the substantial economic burden associated with rheumatoid arthritis (section 1.4); again, formal long-term economic evaluation of etanercept is needed to establish this.[17] Based on the results of a recent study[54] showing a reduction in mortality in patients with rheumatoid arthritis who responded to methotrexate therapy, compared with those who did not respond, it is also expected that etanercept therapy may be associated with an improvement in mortality in the long term. An overview of formulary considerations for etanercept is presented in table V. Etanercept has also shown efficacy in patients with active rheumatoid arthritis refractory to DMARDs (section 3.1.2). In 3-[96] and 6-month[97] studies involving patients with rheumatoid arthritis who had not responded to previous DMARD therapy, etanercept 16 mg/m2 recipients[96] and etanercept 25mg recipients[97] achieved significantly higher ACR 20 and 50 response rates, compared with placebo recipients. Similarly, in a 24-week study involving patients with rheumatoid arthritis who had not responded to previous DMARD therapy, significantly more recipients of etanercept plus methotrexate, compared with methotrexate plus placebo, achieved ACR 20, 50 or 70 responses.[98] ACR response rates were maintained after 3.5 years’ treatment in etanercept monotherapy recipients involved in long-term followup.[101] In addition, it appears that etanercept therapy is associated with reduced corticosteroid requirements in the long term.[101] Improvements in health-related quality of life were seen in patients with rheumatoid arthritis who had not responded adequately to DMARDs.[96-98] Interestingly, the magnitude of improvement in Health Assessment Questionnaire disability scores was greater in etanercept 25mg recipients with early rheumatoid arthritis than in those with long-standing disease.[111] This supports the idea that administering etanercept earlier, rather than later, in the course of rheumatoid arthritis is associated with greater benefit. Subcutaneous etanercept was generally well tolerated in double-blind randomized trials (section 3.2). The most commonly reported adverse events in etanercept recipients included injection-site reactions, infection, headache, nausea and rhinitis.[96-98] While there was no significant difference between etanercept and placebo recipients in the rate of overall infection, upper respiratory tract infection occurred more commonly in etanercept than in placebo recipients.[1] Etanercept therapy has also been associated with reports of serious infection (e.g. sepsis), © Adis International Limited. All rights reserved.

Keating & Jarvis

including serious infection associated with death, outside of the clinical trial setting. Consequently, etanercept therapy is contraindicated in patients with sepsis and should be administered with caution to patients with a history of recurring infection or who have an underlying condition that may predispose them to infection.[1] In a study involving patients with early rheumatoid arthritis, fewer etanercept than methotrexate recipients discontinued therapy because of adverse events.[92] Methotrexate recipients were significantly more likely than etanercept 25mg recipients to experience nausea, mouth ulcers, rash or alopecia. Taken together, these data show that etanercept has several potential advantages over traditional DMARDs in the treatment of rheumatoid arthritis. These include a rapid onset of action, sustained efficacy, good tolerability and no need for specific adverse event monitoring (with potential associated cost savings). These advantages were reflected in the discontinuation rates seen in the trial comparing etanercept with methotrexate in patients with early rheumatoid arthritis (2 years of treatment were completed by 74 and 59% of etanercept and methotrexate recipients, respectively).[92] In keeping with the move to offer patients with newly diagnosed rheumatoid arthritis the most effective available treatment, these data support the use of etanercept in the first-line treatment of rheumatoid arthritis. Besides etanercept, infliximab is the only other anti-TNFα agent available for use in the treatment of rheumatoid arthritis. Data from well designed trials comparing etanercept with infliximab in a head-to-head manner are not currently available. Infliximab is a chimeric monoclonal antibody against TNFα that has shown efficacy in the treatment of patients with rheumatoid arthritis refractory to prior treatment with methotrexate.[128,129] Unlike etanercept, infliximab is not approved for first-line use.[82] Moreover, infliximab must be administered in combination with methotrexate in order to avoid the development of human antichimeric antibodies that may interfere with the efficacy of the drug;[45] this means that patients must be monitored for methotrexate-associated adverse events. Patients do not require laboratory monitoring for adverse events associated with infliximab administration during treatment. However, in the US they must undergo tuberculin testing to exclude latent tuberculosis prior to starting infliximab[82] as it appears that there may be an association between infliximab therapy and the development of tuberculosis.[130] Similarly, in Europe it is recommended that consideration be given to performing a chest x-ray and tuberculin test prior to starting infliximab therapy, in addition to obtaining a detailed medical history.[83] While it is not yet clear that this is a class effect,[18] there does not appear to be a relationship between etanercept therapy and the onset of tuberculosis[105] (section 3.2.1). Routine tuberculin testing is not required prior to Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

starting etanercept therapy; however, it is recommended that physicians prescribing etanercept carefully consider each patient’s tuberculosis risk factor profile.[105] Both etanercept and infliximab are relatively costly drugs. Across four US states in June 2000, the acquisition cost of a month’s treatment with methotrexate ranged from $US53 to $US76, whereas the cost of a month’s treatment with etanercept ranged from $US1211 to $US1679.[45] For a patient weighing 67kg, a month’s treatment with infliximab cost between $US870 and $US915 in the first year and between $US580 and $US610 in the second year[45] (the cost of infliximab rises with increasing bodyweight as it is administered on a mg/kg basis). In the UK, a year’s treatment with etanercept, infliximab and methotrexate cost approximately £8450, £10 829 (70kg patient) and £18 to £57, respectively (currency year not stated).[131] There is a current lack of data from prospective pharmacoeconomic studies examining etanercept use. Modeling studies indicate that in terms of achieving an ACR 20 response, treatment with etanercept monotherapy or etanercept plus methotrexate is associated with relatively high incremental cost effectiveness ratios (≈$US40 000; 1999 values) [section 3.3].[112,115] Interestingly, the total cost of treatment with infliximab was higher than that with etanercept [NLG45 115 ($US18 046) vs NLG31 621 ($US12 648) per patient] in a Dutch modeling study in patients with moderate to severe rheumatoid arthritis.[116] In part, this reflects the greater administration costs associated with infliximab (given by intravenous infusion), compared with those associated with etanercept (given subcutaneously and may be self-administered). Similarly, in a US modeling study, etanercept was more cost effective than infliximab.[117] While etanercept therapy is associated with high costs, both in terms of acquisition cost and the cost of achieving an ACR 20 response, this cost may be justified if the rapid onset of action and sustained efficacy associated with etanercept translates into improved long-term outcomes and a reduction in the costs associated with the disease[124] (e.g. reduced need for interventions such as physiotherapy, aids and surgery). Some insurers in the US have placed restrictions on the use of etanercept because of the high cost of the drug. For example, some insurance plan administrators require evidence of methotrexate failure before etanercept therapy can be started.[45] Moreover, in some instances different coverage and reimbursement policies apply to etanercept and infliximab because of their differing routes of administration.[132] For example, some US managed care organizations reimburse infliximab because it is administered by intravenous infusion while etanercept is not reimbursed because is it administered by self injection.[132] These policies limit the access of US patients to etanercept therapy. © Adis International Limited. All rights reserved.

35

Anakinra is another biologic agent that was recently approved in the US[75] for the reduction of the signs and symptoms of moderate to severe rheumatoid arthritis in patients aged ≥18 years who have failed treatment with ≥1 DMARD.[76] Anakinra is a recombinant human IL-1 receptor antagonist and has been shown to improve disease activity and reduce radiologic progression in placebo-controlled, double-blind, randomized trials.[133,134] Importantly, the use of anakinra in combination with etanercept or infliximab should be avoided because of an increased risk of serious infection and neutropenia.[76] While etanercept shows clear evidence of efficacy in both early and long-standing active rheumatoid arthritis, there are outstanding issues regarding the best use of the drug. Questions remain concerning whether or not etanercept should be used routinely prior to methotrexate and whether it should be administered alone or in combination with methotrexate following methotrexate failure.[45] Furthermore, in addition to studies examining the long-term efficacy, tolerability and cost effectiveness of etanercept, there is a need for trials examining different DMARD/ biologic combination regimens.[45] In particular, it may be of interest to examine the use of etanercept in combination with DMARDs, including methotrexate, in early rheumatoid arthritis.[135] In addition, given cost considerations, defining the population of patients with rheumatoid arthritis who are most suitable for etanercept therapy is of particular importance. One possibility may be to restrict the use of etanercept to patients with early rheumatoid arthritis who are considered at high risk of disease progression and disability. While numerous studies have examined factors associated with poor prognosis in patients with rheumatoid arthritis,[136-139] reliably predicting which patients will go on to develop severe disease remains problematic.[140] The double-blind, randomized, placebo-controlled study[92] examining the use of etanercept in early disease enrolled patients considered to be at high risk of radiographic disease progression (i.e. patients were rheumatoid factor-positive or had ≥3 bone erosions on x-rays of the hands, wrists or feet; had ≥10 swollen joints and ≥12 tender or painful joints; and had an ESR of ≥28 mm/h, a serum CRP level of ≥20 mg/L or morning stiffness that lasted ≥45 minutes) [section 3.1.1]. Another approach to selecting suitable candidates for etanercept therapy may be to target young patients with rheumatoid arthritis since they potentially stand to have the greatest economic burden associated with future disability. To date, consensus statements and treatment guidelines have recommended the use of etanercept in patients with active rheumatoid arthritis who have not responded to prior DMARD therapy (section 2.2.1).[18,73,84-87] Interestingly, a recent Scandinavian study[141] applied this recommendation to patients on the Oslo Dis Manage Health Outcomes 2002; 10 (1)

36

Keating & Jarvis

rheumatoid arthritis register in order to determine how many patients would be eligible to receive etanercept therapy (active disease was defined as a 28-tender joint count of ≥6, a 28-swollen joint count of ≥6 and an ESR of ≥28 mm/h or a CRP level of ≥20 mg/L). Of 636 patients on the register who were assessed, 98 (15%) fulfilled the eligibility criteria for etanercept therapy. In conclusion, etanercept is an important new treatment option in rheumatoid arthritis. It provides a rapid and sustained reduction in disease activity and inhibits the progression of structural damage in patients with early active rheumatoid arthritis, with good tolerability. The improvement in disease activity and slowing of joint damage seen with etanercept was more rapid than that seen with methotrexate. In addition, etanercept, alone or in combination with methotrexate, is effective in the treatment of patients with active rheumatoid arthritis who have not responded adequately to previous DMARD therapy. It is anticipated that etanercept may also improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial economic burden imposed by the disease; however, more long-term data are needed to confirm this.

15. 16.

17. 18.

19.

20. 21.

22. 23. 24.

25.

References 1.

2.

3.

4.

5. 6.

7. 8. 9. 10. 11. 12. 13.

14.

Immunex Corporation, Wyeth-Ayerst Pharmaceuticals. Enbrel® (etanercept) prescribing information. Available from http://www.immunex.com [Accessed 2001 Sep 10] European Agency for the Evaluation of Medicinal Products. Etanercept: summary of product characteristics. Available from http://www.emea.eu [Accessed 2001 Oct 1] Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000; 342: 763-9 Wyeth. FDA assigns priority review status to ENBREL® (etanercept) sBLA for treatment of psoriatic arthritis [media release]. Available from http://www.wyeth.com [Accessed 2001 Sep 28] Jarvis B, Faulds D. Etanercept: a review of its use in rheumatoid arthritis. Drugs 1999; 57: 945-66 Nichol MB, Harada ASM. Measuring the effects of medication use on health-related quality of life in patients with rheumatoid arthritis: a review. Pharmacoeconomics 1999; 16: 433-48 Akil M, Amos RS. ABC of rheumatology: rheumatoid arthritis: clinical features and diagnosis. BMJ 1995 Mar 4; 310: 587-90 Grassi W, De Angelis R, Lamanna G, et al. The clinical features of rheumatoid arthritis. Eur J Radiol 1998; 27 (Suppl. 1): 18-24 Buckley CD. Science, medicine and the future: treatment of rheumatoid arthritis. BMJ 1997; 315: 236-8 Pearce GJ, Chikanza IC. Targeting tumour necrosis factor in the treatment of rheumatoid arthritis. Biodrugs 2001; 15 (3): 139-49 Kavanaugh A. An overview of immunomodulatory intervention in rheumatoid arthritis. Drugs Today 1999; 35: 275-86 Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344: 907-16 Schulze-Koops H, Burkhardt H, Kalden JR. What we have learned from trials of immunomodulatory agents in rheumatoid arthritis: future directions. Drugs Today 1999; 35: 327-51 Brennan FM, Maini RN, Feldmann M. Role of pro-inflammatory cytokines in rheumatoid arthritis. Springer Semin Immunpathol 1998; 20: 133-47

© Adis International Limited. All rights reserved.

26.

27. 28.

29. 30.

31. 32. 33. 34. 35.

36.

37.

38.

Arend WP. Cytokine inhibition in the treatment of rheumatic and inflammatory diseases. Jpn J Rheumatol 1998; 8 (4): 333-45 Urbina-Joiro H, Cardiel MH, Alcocer-Varela J. Reclassifying the pathogenesis of rheumatoid arthritis: from the susceptibility to the degenerative stages. Clin Exp Rheumatol 1998; 16: 87-91 Gabriel SE, Coyle D, Moreland LW. Clinical and economic review of diseasemodifying antirheumatic drugs. Pharmacoeconomics 2001; 19 (7): 715-28 Emery P, Reginster JY, Appelboom T, et al. WHO Collaborating Centre consensus meeting on anti-cytokine therapy in rheumatoid arthritis. Rheumatology (Oxford) 2001; 40: 699-702 Balsa A, Minaur NJ, Pascual-Salcedo D, et al. Class II MHC antigens in early rheumatoid arthritis in Bath (UK) and Madrid (Spain). Rheumatology (Oxford) 2000; 39: 844-9 Wiles N, Symmons DP, Harrison B, et al. Estimating the incidence of rheumatoid arthritis: trying to hit a moving target? Arthritis Rheum 1999; 42: 1339-46 Uhlig T, Kvien TK, Glennås A, et al. The incidence and severity of rheumatoid arthritis. Results from a county register in Oslo, Norway. J Rheumatol 1998; 25: 1078-84 Alarcón GS. Epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am 1995; 21: 589-604 Rooney BK, Silman AJ. Epidemiology of the rheumatic diseases. Curr Opin Rheumatol 1999; 11: 91-7 Karlson EW, Lee IM, Cook NR, et al. A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals. Arthritis Rheum 1999; 42: 910-7 Vandenbroucke JP, Valkenburg HA, Boersma JW, et al. Oral contraceptives and rheumatoid arthritis: further evidence for a preventive effect. Lancet 1982; 2: 839-42 van Zeben D, Hazes JM, Vandenbroucke JP, et al. Diminished incidence of severe rheumatoid arthritis associated with oral contraceptive use. Arthritis Rheum 1990; 33: 1462-5 Spector TD, Roman E, Silman AJ. The pill, parity, and rheumatoid arthritis. Arthritis Rheum 1990; 33: 782-9 Romieu I, Hernandez-Avila M, Liang MH. Oral contraceptives and the risk of rheumatoid arthritis: a meta-analysis of a conflicting literature. Br J Rheumatol 1989; 28 Suppl: 13-7 Hernandez-Avila M, Liang MH, Willett WC, et al. Exogenous sex hormones and the risk of rheumatoid arthritis. Arthritis Rheum 1990; 33: 947-53 Barrett JH, Brennan P, Fiddler M, et al. Breast-feeding and postpartum relapse in women with rheumatoid and inflammatory arthritis. Arthritis Rheum 2000; 43: 1010-5 Brun JG, Nilssen S, Kvåle G. Breast feeding, other reproductive factors and rheumatoid arthritis. A prospective study. Br J Rheumatol 1995; 34: 542-6 Hazes JMW, Dijkmans BAC, Vandenbroucke JP, et al. Pregnancy and the risk of developing rheumatoid arthritis. Arthritis Rheum 1990; 33: 1770-5 Heliövaara M, Aho K, Reunanen A, et al. Parity and risk of rheumatoid arthritis in Finnish women. Br J Rheumatol 1995; 34: 625-8 Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Arthritis Rheum 1996; 39: 732-5 Symmons DP, Bankhead CR, Harrison BJ, et al. Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum 1997; 40: 1955-61 Toussirot E, Auge B, Tiberghien P, et al. HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis. J Rheumatol 1999; 26: 1446-51 Gregersen. PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987 Nov; 30 (11): 1205-13 Harrison B, Thomson W, Symmons D, et al. The influence of HLA-DRB1 alleles and rheumatoid factor on disease outcome in an inception cohort of patients with early inflammatory arthritis. Arthritis Rheum 1999; 42: 2174-83

Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

39. Thomson W, Harrison B, Ollier B, et al. Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis. Arthritis Rheum 1999 Apr; 42 (4): 757-62 40. Perdriger A, Guggenbuhl P, Chalès G, et al. Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis. Rheumatology (Oxford) 1999; 38: 448-52 41. Weyand CM, Hicok KC, Conn DL, et al. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med 1992 Nov 15; 117 (10): 801-6 42. Kim JM, Weisman MH. When does rheumatoid arthritis begin and why do we need to know? Arthritis Rheum 2000; 43: 473-84 43. Scott DL, Pugner K, Kaarela K, et al. The links between joint damage and disability in rheumatoid arthritis. Rheumatology (Oxford) 2000; 39: 122-32 44. Welsing PMJ, van Gestel AM, Swinkels HL, et al. The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis Rheum 2001 Sep; 44 (9): 2009-17 45. Kremer JM. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med 2001 Apr 17; 134: 695-706 46. van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis. Arthritis Rheum 1992; 35: 26-34 47. Young A, Dixey J, Cox N, et al. How does functional disability in early rheumatoid arthritis (RA) affect patients and their lives? Results of 5 years follow-up in 732 patients from the Early RA Study (ERAS). Rheumatology (Oxford) 2000: 603-11 48. Pincus T. Long-term outcomes in rheumatoid arthritis. Br J Rheumatol 1995 Nov; 34: 59-73 49. Pope RM. Rheumatoid arthritis: pathogenesis and early recognition. Am J Med 1996 Feb 26; 100 (Suppl. 2A): 3S-9S 50. Scott DL, Symmons DPM, Coulton BL, et al. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1987 May 16; 1: 1108-11 51. Guedes C, Dumont-Fischer D, Leichter-Nakache S, et al. Mortality in rheumatoid arthritis. Rev Rhum - Engl Ed : Joint, Bone, Spine Diseases 1999; 66: 492-8 52. Pincus T. The underestimated long term medical and economic consequences of rheumatoid arthritis. Drugs 1995; 50: 1-14 53. Symmons DPM, Jones MA, Scott DL, et al. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998; 25 (6): 1072-7 54. Krause D, Schleusser B, Herborn G, et al. Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum 2000 Jan; 43 (1): 14-21 55. Wolfe F, Lane NE. RA patients who improve during the first year of rheumatology treatment have decreased long-term mortality [abstract]. Arthritis Rheum 2000 Sep; 43 (Suppl. 9): 183 56. Magnusson S. Treatment of rheumatoid arthritis–does it affect society’s cost for the disease? Br J Rheumatol 1996; 35: 791-5 57. Clarke AE, Zowall H, Levinton C, et al. Direct and indirect medical costs incurred by Canadian patients with rheumatoid arthritis: a 12 year study. J Rheumatol 1997; 24: 1051-60 58. Lanes SF, Lanza LL, Radensky PW, et al. Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting: the importance of drug and surgery costs. Arthritis Rheum 1997; 40: 1475-81 59. Cooper NJ. Economic burden of rheumatoid arthritis: a systematic review. Rheumatology (Oxford) 2000; 39: 28-33 60. Lubeck DP, Spitz PW, Fries JF, et al. A multicenter study of annual health service utilization and costs in rheumatoid arthritis. Arthritis Rheum 1986; 29: 488-93 61. Yelin E, Wanke LA. An assessment of the annual and long-term direct costs of rheumatoid arthritis: the impact of poor function and functional decline. Arthritis Rheum 1999; 42: 1209-18 62. Yelin E. The costs of rheumatoid arthritis: absolute, incremental, and marginal estimates. J Rheumatol 1996; 23: 47-51

© Adis International Limited. All rights reserved.

37

63. Liang MH, Larson M, Thompson M, et al. Costs and outcomes in rheumatoid arthritis and osteoarthritis. Arthritis Rheum 1984; 27: 522-9 64. Prashker MJ, Meenan RF. The total costs of drug therapy for rheumatoid arthritis: a model based on costs of drug, monitoring, and toxicity. Arthritis Rheum 1995; 38: 318-25 65. Cooper NJ, Mugford M, Scott DGI, et al. Secondary health service care and second line drugs costs of early inflammatory polyarthritis in Norfolk, UK. J Rheumatol 2000; 27 (9): 2115-22 66. McIntosh E. The cost of rheumatoid arthritis. Br J Rheumatol 1996; 35: 781-90 67. Merkesdal S, Ruof J, Schöffski O, et al. Indirect medical costs in early rheumatoid arthritis: composition of and changes in indirect costs within the first three years of disease. Arthritis Rheum 2001 Mar; 44 (3): 528-34 68. Allaire SH, Prashker MJ, Meenan RF. The costs of rheumatoid arthritis. Pharmacoeconomics 1994; 6: 513-22 69. van Jaarsveld CH, Jacobs JWG, Schrijvers AJ, et al. Direct cost of rheumatoid arthritis during the first six years: a cost-of-illness study. Br J Rheumatol 1998; 37: 837-47 70. Kobelt G, Eberhardt K, Jonsson L, et al. Economic consequences of the progression of rheumatoid arthritis in Sweden. Arthritis Rheum 1999; 42: 347-56 71. Wolfe F, Rehman Q, Lane NE, et al. Starting a disease modifying antirheumatic drug or a biologic agent in rheumatoid arthritis: standards of practice for RA treatment. J Rheumatol 2001; 28 (7): 1704-11 72. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum 1996 May; 39 (5): 713-22 73. Wolfe F, Cush JJ, O’Dell JR, et al. Consensus recommendations for the assessment and treatment of rheumatoid arthritis. J Rheumatol 2001 Jun; 28: 1423-30 74. Tsakonas E, Fitzgerald AA, Fitzcharles M-A, et al. Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a 3 year follow-up on the hydroxychloroquine in early rheumatoid arthritis (HERA) study. J Rheumatol 2000; 27 (3): 623-9 75. Amgen Inc.. FDA approves KineretTM for the treatment of rheumatoid arthritis. Available from http://www.amgen.com [Accessed 2001 Dec 3] 76. Amgen Inc.. KineretTM (anakinra) prescribing information Available from http://www.amgen.com [Accessed 2001 Dec 3] 77. American College of Rheumatology Ad Hoc Committee On Clinical Guidelines. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 1996; 39: 723-31 78. Markham A, Lamb HM. Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs 2000; 59: 1341-59 79. Prakash A, Jarvis B. Leflunomide: a review of its use in active rheumatoid arthritis. Drugs 1999; 58: 1137-64 80. European Agency for the Evaluation of Medicinal Products. EMEA public statement on leflunomide (Arava) - severe and serious hepatic reactions [media release]. Available from http://www.emea.eu.int [Accessed 2001 Oct 1] 81. European Agency for the Evaluation of Medicinal Products. Leflunomide: summary of product characteristics. Available from http://www.emea.eu.int [Accessed 2001 Nov 19] 82. Centocor I. Remicade® infliximab recombinant for IV injection. Available from http://www.centocor.com [Accessed 2001 Sep 14] 83. European Agency for Evaluation of Medicinal Products. Infliximab: summary of product characteristics. Available from http://www.emea.eu.int [Accessed 2001 Oct 5] 84. Furst DE, Breedveld FC, Burmester GR, et al. Access to disease modifying treatments for rheumatoid arthritis patients. Ann Rheum Dis 1999; 58 (Suppl. 1): 129-30 85. Furst DE, Breedveld FC, Burmester GR, et al. Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis. Ann Rheum Dis 2000 May; 59 (Suppl. 1): 1-2 86. Smolen JS, Breedveld FC, Burmester GR, et al. Consensus statement on the initiation and continuation of tumour necrosis factor blocking therapies in rheumatoid arthritis. Ann Rheum Dis 2000 Jul; 59 (7): 504-5

Dis Manage Health Outcomes 2002; 10 (1)

38

87.

88. 89. 90. 91. 92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103. 104. 105. 106.

107.

108.

Keating & Jarvis

Working Party of the British Society for Rheumatology. Guidelines for prescribing TNF-α blockers in adults with rheumatoid arthritis. Available from http://www.rheumatology.org.uk [Accessed 2001 Sep 5] Moreland LW, Russell AS, Paulus HE. Management of rheumatoid arthritis: the historical context. J Rheumatol 2001; 28 (6): 1431-52 Matteson EL. Current treatment strategies for rheumatoid arthritis. Mayo Clin Proc 2000; 75: 69-74 Richard-Miceli C, Dougados M. Tumour necrosis factor-α blockers in rheumatoid arthritis: review of the clinical experience. Biodrugs 2001; 15 (4): 251-9 Hughes LB, Moreland LW. New therapeutic approaches to the management of rheumatoid arthritis. Biodrugs 2001; 15 (6): 379-93 Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 1586-93 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 Spencer-Green G, Genovese M, Martin RW, et al. Enbrel® (etanercept) vs. methotrexate (MTX) in early rheumatoid arthritis (ERA trial): two-year follow-up [abstract]. J Rheumatol 2001 Jul; 28 Suppl. 63: 106 Genovese M, Martin R, Fleischmann R, et al. Etanercept (Enbrel®) in early erosive rheumatoid arthritis (ERA trial): observations at 3 years [abstract]. Arthritis Rheum 2001 Sep; 44 (Suppl. 9): 78 Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997; 337: 141-7 Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled study. Ann Intern Med 1999; 130: 478-86 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. N Engl J Med 1999; 340: 253-9 Hochberg MC, Chang RW, Dwosh I, et al. American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 1992; 35: 498-502 Moreland LW, Cohen SB, Baumgartner SW, et al. Longterm safety and efficacy of etanercept in patients with rheumatoid arthritis. J Rheumatol 2001 Jun; 28 (6): 1238-44 Baumgartner SW, Moreland LW, Cohen SB, et al. Long-term use of Enbrel® (etanercept) in patients with DMARD-refractory rheumatoid arthritis. J Rheumatol 2001 Jul; 28 (Suppl. 63): 106 Burge D J, Weinblatt M E, Kremer J M, et al. Enbrel® (etanercept) in addition to methotrexate (MTX) in rheumatoid arthritis (RA): long-term observations [abstract]. J Rheumatol 2001 Jul; 28 (Suppl. 63): 106 Baghai M, Osmon DR, Wolk DM, et al. Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept. Mayo Clin Proc 2001 Jun; 76 (6): 653-6 Wallis WJ, Burge DJ, Holman J, et al. Infection reports with etanercept (Enbrel®) therapy [abstract]. Arthritis Rheum 2001 Sep; 44 Suppl. 9: 78 Wallis WJ, Burge DJ, Sabath M, et al. Tuberculosis reports with etanercept (Enbrel®) therapy [abstract]. Arthritis Rheum 2001 Sep; 44 Suppl. 9: 78 Zeltser R, Valle L, Tanck C, et al. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factorα receptor: Fc fusion protein ENG. Arch Dermatol 2001 Jul; 137 (7): 893-9 Mohan N, Edwards ET, Cupps TR, et al. Demyelination diagnosed during etanercept (TNF receptor fusion protein) therapy [abstract]. Arthritis Rheum 2000 Sep; 43: 228 European Agency for the Evaluation of Medicinal Products. Revised EMEA public statement on etanercept (Enbrel) – serious hematological reactions and demyelination disorders. Available from http://www.emea.eu.int [Accessed 2001 Oct 21]

© Adis International Limited. All rights reserved.

109. Bury-Maynard D, Kosinski M, Wanke LA, et al. Comparing the health related quality of life outcomes of treatment for early rheumatoid arthritis [abstract]. Value Health 2000; 3: 97 110. Yelin E, Katz P, Lubeck D, et al. Impact of etanercept (Enbrel®) on health care use and employment in early RA [abstract]. Arthritis Rheum 2001 Sep; 44 (Suppl. 9): 152 111. Baumgartner SW, Fleischmann RM, Moreland LW, et al. Improvement of disability in RA patients with early vs established disease after treatment with Enbrel®. Journal of Rheumatology 2001; 28 Suppl. 63: 106 112. Choi HK, Seeger JD, Kuntz KM. A cost-effectiveness analysis of treatment options for patients with methotrexate [MTX]-naive rheumatoid arthritis [abstract]. Arthritis Rheum 2000 Sep; 43: 389 113. Mathias SD, Colwell HH, Miller DP, et al. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther 2000; 22: 128-39 114. Yelin E, Roepke L, Katz P, et al. Long-term impact of Enbrel on functional status of persons with RA [abstract]. Arthritis Rheum 2000 Sep; 43: 147 115. Choi HK, Seeger JD, Kuntz KM. A cost-effectiveness analysis of treatment options for patients with methotrexate-resistant rheumatoid arthritis. Arthritis Rheum 2000 Oct; 43 (10): 2316-27 116. Nuijten MJC, Engelfriet P, Duijn K, et al. A cost-cost study comparing etanercept with infliximab in rheumatoid arthritis. Pharmacoeconomics 2001; 19 (10): 1051-64 117. Malone DC. Cost-effectiveness analysis of etanercept monotherapy versus infliximab plus methotrexate in the treatment of rheumatoid arthritis [abstract]. Arthritis Rheum 2001 Sep; 44 (Suppl. 9): 322 118. Brennan A, Bansback N, Conway P, et al. Modelling the cost-effectiveness of etanercept in adults with rheumatoid arthritis (RA) in the UK [abstract]. Arthritis Rheum 2001 Sep; 44 (Suppl. 9): 157 119. Fleischmann RM. Early diagnosis and treatment of rheumatoid arthritis for improved outcomes: focus on etanercept, a new biologic response modifier. Clin Ther 1999; 21: 1429-42 120. van der Heide A, Jacobs JWG, Bijlsma JWJ, et al. The effectiveness of early treatment with "second-line" antirheumatic drugs. Ann Intern Med 1996 Apr 15; 124 (8): 699-707 121. Egsmose C, Lund B, Borg G, et al. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study. J Rheumatol 1995; 22 (12): 2208-13 122. Anderson JJ, Wells G, Verhoeven AC, et al. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000; 43: 22-9 123. Albers JMC, Paimela L, Kurki P, et al. Treatment strategy, disease activity, and outcome in four cohorts of patients with early rheumatoid arthritis. Ann Rheum Dis 2001; 60: 453-8 124. Kalden JR. How do the biologics fit into the current DMARD armamentarium? J Rheumatol 2001 Jun; 28 (Suppl. 62): 27-35 125. Pincus T, Marcum SB, Callahan LF. Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone. J Rheumatol 1992; 19 (12): 1885-94 126. Galindo-Rodriguez G, Aviña-Zubieta JA, Russell AS, et al. Disappointing longterm results with disease modifying antirheumatic drugs. A practice based study. J Rheumatol 1999; 26 (11): 2337-43 127. Maetzel A, Wong A, Strand V, et al. Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying antirheumatic drugs. Rheumatology (Oxford) 2000; 39: 975-81 128. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999 Dec 4; 354: 1932-9 129. Lipsky PE, van der Heijde DMFM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000 Nov 30; 343 (22): 1594-602

Dis Manage Health Outcomes 2002; 10 (1)

Etanercept in Rheumatoid Arthritis

130. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factorα -neutralizing agent. N Engl J Med 2001 Oct 11; 345 (15): 1098-104 131. Etanercept and infliximab for rheumatoid arthritis. Drug Ther Bull 2001 Jul; 39 (7): 49-52 132. Gallup E. Coverage inequalities of new therapies for rheumatoid arthritis in a managed care setting. Manag Care Interface 2001 Jul; 14 (7): 52-457869 133. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998 Dec; 41 (12): 2196-204 134. Jiang Y, Genant HK, Watt I, et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 2000 May; 43 (5): 1001-9 135. O’Dell JR. TNF-α inhibition: the need for a tumor necrosis factor thermostat. Mayo Clin Proc 2001 Jun; 76 (6): 573-5 136. Hochberg MC. Early aggressive DMARD therapy: the key to slowing disease progression in rheumatoid arthritis. Scand J Rheumatol 1999; 112 Suppl.: 3-7

© Adis International Limited. All rights reserved.

39

137. Emery P. Early rheumatoid arthritis: therapeutic strategies. Scand J Rheumatol 1994; 23 (Suppl. 100): 3-7 138. van Zeben D, Hazes JMW, Zwinderman AH, et al. Factors predicting outcome of rheumatoid arthritis: results of a followup study. J Rheumatol 1993; 20 (8): 1288-96 139. van Zeben D, Breedveld FC. Prognostic factors in rheumatoid arthritis. J Rheumatol 1996; 23 Suppl. 44: 31-2 140. Young A, van der Heijde DMFM. Can we predict aggressive disease? Baillieres Clin Rheumatol 1997 Feb; 11 (1): 27-48 141. Kvien TK, Uhlig T, Kristiansen IS. Criteria for TNF-targeted therapy in rheumatoid arthritis: estimates of the number of patients potentially eligible. Drugs 2001; 61 (12): 1711-20

Correspondence: Gillian M. Keating, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand. E-mail: [email protected]

Dis Manage Health Outcomes 2002; 10 (1)