DRUGS IN DISEASE MANAGEMENT

Dis Manage Health Outcomes 2003; 11 (11): 745-765 1173-8790/03/0011-0745/$30.00/0 © Adis Data Information BV 2003. All rights reserved.

Management of Rheumatoid Arthritis Defining the Role of Leflunomide Christopher I. Carswell, Caroline M. Perry and Tim Ibbotson Adis International Inc, Yardley, Pennsylvania, USA Various sections of the manuscript reviewed by: C.M Deighton, Department of Rheumatology, Nottingham City Hospital, Nottingham, England; A. Maetzel, Toronto General Research Institute, Toronto, Ontario, Canada; R. Meenan, Boston University School of Public Health, Boston, Massachusetts, USA; B. Tait, Avenue Consultancy, Christchurch, New Zealand; C. Yazdani, NDC Health, Phoenix, Arizona, USA; E. Yelin, University of California, San Francisco, California, USA. Data Selection Sources: Medical literature published in any language since 1980 on leflunomide, identified using Medline and AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: AdisBase search terms were ‘rheumatoid arthritis’ and (‘guideline’ or ‘guideline-utilization’ or ‘practice-guideline’ or ‘disease-management-programs’ or ‘treatment-algorithms’ or ‘reviews-on-treatment’ or ‘drug-evaluations’ or ‘epidemiology’ or ‘cost-of-illness’ or ‘pathogenesis’), or ‘leflunomide’ and (‘review’ or ‘clinical-study’). Medline search terms were ‘rheumatoid arthritis’ and (‘guidelines’ or ‘decision-making’ or ‘health-policy’ or ‘managed-care-programs’ or ‘epidemiology’ or ‘outcome-assessment-health-care’ or ‘clinical-protocols’ or ‘guideline in pt’ or ‘polic* in ti’ or ‘expert panel’ or ‘utilization review’ or ‘algorithms’ or ‘disease management’ or ‘quality of life’), or ‘leflunomide’ and ‘review in pt’. Searches were last updated 9 Oct 2003. Selection: Studies in patients with rheumatoid arthritis who received leflunomide. 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: Leflunomide, rheumatoid arthritis, disease management, review on treatment.

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746 1. Disease Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747 1.1 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747 1.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748 1.2.1 Incidence and Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748 1.2.2 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748 1.2.3 Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748 1.3 Economic Impact of Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749 1.3.1 Direct Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749 1.3.2 Indirect Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749 1.3.3 Intangible Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750 1.3.4 Costs and Type of Healthcare System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750 2. Current Management Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750 2.1 Nonpharmacological Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751 2.2 Pharmacological Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751 2.2.1 Disease-Modifying Antirheumatic Drugs and Biologic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751 2.2.2 NSAIDs and Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753 2.2.3 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754 3. Role of Leflunomide in the Treatment of Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754 3.1 Clinical Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754 3.1.1 Onset of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754

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3.2

3.3 3.4 3.5

3.1.2 Long-Term Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754 3.1.3 Radiological Progression of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756 3.1.4 Combination Therapy with Leflunomide and Other Antirheumatic Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756 Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757 3.2.1 General Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757 3.2.2 Hepatic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758 Physical Function and Health-Related Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Cost Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761

Abstract

Rheumatoid arthritis is a progressive, disabling disease which can lead to long-term deformity and disability. Leflunomide is a disease-modifying antirheumatic drug (DMARD) approved to reduce signs and symptoms, inhibit structural damage and improve physical function in adults with active rheumatoid arthritis. In clinical trials in patients with active rheumatoid arthritis, leflunomide had a more rapid onset of action than methotrexate, sulfasalazine and placebo. In trials of 24 months’ duration, leflunomide was more effective than sulfasalazine and placebo and at least as effective as methotrexate in reducing rheumatoid arthritis disease activity (assessed using the American College of Rheumatology [ACR] criteria). In addition, leflunomide was as effective as sulfasalazine or methotrexate in decreasing the rate of radiological progression over 24 months. Over 12 months leflunomide was more effective than methotrexate and placebo in reducing the rate of structural damage. Data from a nonblind extension study suggests that the efficacy of leflunomide may be maintained when administered for periods up to 5 years. Leflunomide was significantly more effective than methotrexate, sulfasalazine and placebo in improving physical function measures among patients with active rheumatoid arthritis, and improved physical function was maintained after 2 years of treatment. Few well designed pharmacoeconomic analyses of leflunomide treatment in patients with rheumatoid arthritis exist. Economic studies to date show leflunomide to be either less cost effective or cost neutral compared to methotrexate. In addition, leflunomide has been shown to be a cost effective option compared with etanercept, infliximab and infliximab plus methotrexate. Leflunomide was generally well tolerated in clinical trials. Common adverse events associated with leflunomide treatment include diarrhea, respiratory infections, nausea and headache. Hematological and hepatotoxic adverse events are a concern, particularly in a setting of multiple risk factors such as concomitant hepatotoxins. Liver function monitoring should be adhered to in all patients receiving leflunomide and ACR guidelines should be followed in those receiving concomitant methotrexate. In conclusion, leflunomide is a DMARD which produces a rapid and sustained reduction in disease activity in patients with active rheumatoid arthritis. Leflunomide has a more rapid onset of action than sulfasalazine or methotrexate. Leflunomide is at least as effective as methotrexate and more effective than sulfasalazine in reducing disease activity after 24 months’ treatment. In addition, leflunomide is more effective than both of these agents in improving physical function and health-related quality of life. Thus it is predicted that leflunomide therapy may improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial burden imposed by the disease for patient, healthcare provider and payers. Consequently, leflunomide should be considered as an important treatment option for those patients with active rheumatoid arthritis including those intolerant to methotrexate.

Rheumatoid arthritis is associated with high costs for patients, payers and society in general. Early diagnosis and treatment of this condition is critical to control these costs and provide optimal patient outcomes. Although effective disease management programs would involve a multidisciplinary approach, drug therapy is © Adis Data Information BV 2003. All rights reserved.

an essential component in the management of this condition. Because of its disease-modifying effects, leflunomide has particular potential for improving long-term health outcomes of rheumatoid arthritis (physical, psychological and functional disabilities) and reducing the costs associated with their management. This Dis Manage Health Outcomes 2003; 11 (11)

Leflunomide in the Management of Rheumatoid Arthritis

article overviews rheumatoid arthritis and its implications for various stakeholders (patients, health maintenance organizations [HMOs], Medicaid/Medicare populations, managed-care organizations, care providers), discusses current management strategies and places leflunomide within this context. The pharmacological, pharmacokinetic and therapeutic properties of the drug have been extensively reviewed elsewhere.[1] 1. Disease Profile Rheumatoid arthritis is a progressive, disabling disease with an insidious onset in most cases.[2,3] The high incidence and prevalence of this condition (section 1.2.1), the predominantly chronic nature (section 1.2.3) and the high costs (section 1.3) associated with the disease make rheumatoid arthritis an ideal candidate for disease management. According to the American College of Rheumatology Guidelines,[4] rheumatoid arthritis is defined as the presence of four or more of the following criteria: • soft tissue swelling (arthritis) of three or more joint areas • morning stiffness in and around joints, lasting ≥1 hour before maximal improvement • swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal or wrist joints • symmetric swelling (arthritis) • rheumatoid nodules • the presence of serum rheumatoid factor • radiographic erosions and/or periarticular osteopenia in hand or wrist joints. Rheumatoid arthritis is characterized by symmetrical joint swelling and tenderness. The hands, wrists and feet are most often affected. Joint destruction can occur rapidly with erosive changes seen as early as 4 months after the onset of the disease.[5] Rheumatoid arthritis can damage various parts of the joint including cartilage, bone, tendons and ligaments, and can lead to long-term deformity and disability. Some patients develop extra-articular manifestations including pericarditis, vasculitis and pleuritis.[6] 1.1 Pathophysiology

The etiology of rheumatoid arthritis is unknown; however, genetic and environmental factors are implicated in the pathogenesis of the disease.[7] There is clear evidence that it is an immunemediated disease, and data exist to suggest there may also be an infectious component to rheumatoid arthritis.[8] Both T and B lymphocytes are thought to be involved in the pathogenesis of rheumatoid arthritis,[9] and interleukin (IL)-1 and tumor necrosis factor-α (TNFα) may play a central role in the disease process, especially in the development of synovitis and joint destruction.[2] © Adis Data Information BV 2003. All rights reserved.

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It has been suggested that there are five pathogenic stages in the progression of rheumatoid arthritis:[10] • exposure to risk factors and onset of the disease • activation of T lymphocytes, synovial activation and proliferation • chondrocyte activation and pannus formation • subchondral and ligament damage • degenerative changes. Initially, rheumatoid arthritis is characterized by synovitis and effusion into the joint space; tissue edema and fibrin deposition are prominent.[2,11] At this stage, IL-1β and TNFα activate adhesion molecules which help the migration of CD4+ T cells into the joint.[12] In addition, IL-6 and TNFα mediate the activation of macrophages and the differentiation of monocytes into dendritic cells.[12] Support for this hypothesis includes activation of T lymphocytes during the early course of rheumatoid arthritis, a strong association of rheumatoid arthritis with the alleles of the class II MHC genes, and the success of therapies, such as cyclosporin, that affect T lymphocyte production.[10] Once triggered, synovitis, a cardinal feature of rheumatoid arthritis, becomes self perpetuating.[11] T lymphocytes, monocytes and synoviocytes are activated and secrete cytokines such as IL-1, IL-6, TNFα and interferonγ.[10] The synovium lining soon shows evidence of hyperplasia with proliferation of type A and type B synoviocytes. Other inflammatory mediators implicated in the pathogenesis of synovitis include cyclo-oxygenases, nitric oxide synthase and neutral proteases.[2] The activation of macrophages leads to the secretion of chemokines which both inhibit and promote angiogenesis.[13] Angiogenesis is a prominent feature of rheumatoid arthritis. Within the synovium there are both inducers and inhibitors of angiogenesis; it is postulated that an imbalance between the two gives rise to the proliferation of endothelial cells necessary for angiogenesis.[2] IL-1 and TNFα are both potent inducers of metalloproteinases; high metalloproteinase activity contributes to cartilage and bone degradation. IL-1 is thought to promote an imbalance between metalloproteinases (stromelysin-1 and collagenase) and their inhibitors (tissue inhibitor of metalloproteinase-1 and -2).[2] As the disease progresses, polymorphonuclear leukocytes, lysosomal enzymes and other enzymes derived from neutrophils, macrophages and chondrocytes actively degrade the cartilage.[11] An imbalance between proinflammatory and anti-inflammatory cytokines occurs which can result in a rapid progression of the disease.[10] Adhesion molecules and chemokines play a role in augmenting the inflammatory process by aiding the migration of leukocytes. In addition, the molecular and cellular interactions that occur in patients with rheumatoid arthritis create a synovial microenvironDis Manage Health Outcomes 2003; 11 (11)

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ment that inhibits T cell apoptosis, leading to inappropriate cell survival, cytokine secretion and cell retention.[8] Sustained inflammation of the synovium leads to formation of pannus, a granulation tissue. Pannus subsequently erodes cartilage and eventually begins to erode bone.[11] In addition, angiogenesis is thought to play a role in cartilage and joint damage by increasing the area of endothelium in the pannus. Synovial cell invasion into chondrocytes occurs with subsequent chondrocyte proliferation. These factors lead to subchondral, capsular and ligament damage and eventually degenerative changes.[10] Several modes of action are thought to account for the efficacy of leflunomide in rheumatoid arthritis. Leflunomide is an isoxazole derivative and inhibits de novo pyrimidine synthesis.[14,15] It prevents cell proliferation in activated T lymphocytes, causing cell arrest in the G1 phase of mitosis, by inhibiting dihydro-orotate dehydrogenase activity and protein kinase activity in actively dividing cells.[16-19] It may also attenuate humoral immune responses by inhibiting B cell proliferation.[20] In addition, leflunomide inhibits the production of immunoglobulin (Ig)G, IgM, IL-1β and IL-2[21-23] and has inhibitory effects on cell adhesion.[24] 1.2 Epidemiology

from a recent study indicate genes are of minor importance in the development of rheumatoid arthritis.[37] Predisposition to the disease resides with the epitope in the third hypervariable region of the DRβ1 gene. This epitope can be encoded by DR4 and non-DR4 alleles.[38] HLA-DR4 (HLA-Dw4 and HLA-Dw14) is the main genetic marker associated with the occurrence and severity of rheumatoid arthritis in Whites and HLA-DR1 is associated with other populations.[39] Most patients with rheumatoid arthritis have either or both of these class II alleles. The population differences in genetic markers can go some way to explain geographical variance of the prevalence of rheumatoid arthritis.[34] The development of rheumatoid arthritis has been linked to many environmental factors. Positive associations include low androgen levels[40] and early first pregnancy.[41] Smoking, alcohol consumption, stress and diet have also been suggested as risk factors for developing rheumatoid arthritis.[42-44] In addition, the incidence of rheumatoid arthritis has been positively linked to receiving vaccines and a history of blood transfusion.[45-47] Negative associations include the use of oral contraceptives, living at high altitude and a history of heavy parasitic infections. 1.2.3 Outcome

1.2.1 Incidence and Prevalence

Rheumatoid arthritis is the most common inflammatory polyarthropathy. It is thought to affect ≈ 0.5 – 2% of the adult population worldwide.[25,26] The peak age of onset is in the sixth and seventh decades, with women three times more likely to be affected than men.[25,27,28] Data from the US suggest an overall prevalence of 10 per 1000 population among adults. This equates to ≈600 000 men and 1.5 million women affected by the disease in the US.[29,30] Interestingly, the prevalence of rheumatoid arthritis varies according to geographical location. In Mediterranean countries the prevalence is lower than in northern Europe and North America. The overall prevalence of rheumatoid arthritis in Italy was reported as 0.33%[31] and in a study among the inhabitants of Belgrade, Yugoslavia an overall prevalence of 0.18% was reported.[32] Prevalence among North American Indians has been reported to vary between 2% and 5% in men and between 3.4% and 8.2% in women.[33] It has been suggested that these differences can, in part, be attributed to genetic and environmental factors.[34] 1.2.2 Risk Factors

A knowledge of risk factors predisposing patients to the development of rheumatoid arthritis facilitates the risk stratification of patients within disease management programs. It has been estimated that ≈30% of the total case risk for developing rheumatoid arthritis can be attributed to genetic factors;[35,36] however, data © Adis Data Information BV 2003. All rights reserved.

The course of rheumatoid arthritis can vary. Some patients exhibit only mild or moderate disease with periods of remission and flare-ups; however, in most patients the disease is aggressive and progressive. Permanent damage of joints, including the larger weight-bearing joints, and subsequent disability occurs. Importantly, early treatment with newer disease-modifying antirheumatic drugs (DMARDs) has been shown to prevent some of these long-term manifestations (section 3.1.3).[48] Conversely, a meta analysis of 60 publications conducted prior to the introduction of newer DMARD therapies has shown that disability and joint damage increase with disease duration.[49] During the early years of disease, appreciable physical, functional and psychological disabilities are common. Radiographic evidence of joint damage is observed in many patients with rheumatoid arthritis within the first 2 years of disease.[50] In an 18year North American study, among 823 evaluable patients, work disability was estimated to occur in 25% of patients 6 years after the onset of disease and in 50% of patients 21 years after disease onset.[51] Individuals with recent onset disease (≤1 year) had similar physical and psychological disability to those with established disease in a US study among 609 patients;[52] work disability occurred in 85% of patients during a 9-year period in another US trial.[53] In addition, 68% of patients had lost significant functional capacity and 27% had died. Dis Manage Health Outcomes 2003; 11 (11)

Leflunomide in the Management of Rheumatoid Arthritis

Many patients with rheumatoid arthritis develop extra-articular manifestations or have co-occurring chronic diseases. Among 186 patients with rheumatoid arthritis, 30% had a chronic unrelated disease of which 31% were cardiovascular related.[54] The incidence of extra-articular manifestations of rheumatoid arthritis has been reported as 7.9% among a cohort of Swedish patients.[6] Pleuritis, cutaneous vasculitis and pericarditis occurred the most frequently. Patients with rheumatoid arthritis exhibit premature mortality, with mortality rates increased by at least 2-fold compared with patients without the disease.[55] Life expectancy is thought to be reduced by 4 years in men and 10 years in women.[39] Survival rates are similar to those for Hodgkin’s disease, diabetes mellitus, stroke and three-vessel coronary artery disease.[56] Increases in mortality can be attributed to infection, lymphoproliferative malignancy, rheumatoid arthritis itself, and to a lesser extent gastrointestinal disease.[55] 1.3 Economic Impact of Rheumatoid Arthritis

The economic impact of rheumatoid arthritis is substantial, approximating that of stroke and coronary heart disease.[57] For example, in the US the total costs associated with rheumatoid arthritis were equivalent to 0.3% of gross national product for 1994.[58] Monetary costs are generally divided into two categories; direct and indirect. Intangible costs are also appreciable and are assessed qualitatively and quantitatively. 1.3.1 Direct Costs

Direct costs of rheumatoid arthritis include any expenditure associated with the purchase of medical care. They include hospital, medication and physician costs together with expenditures necessary to adapt the home environment. Importantly, it has been demonstrated that change in disability (measured using the Health Assesment Questionnaire - Disability Index [HAQ-DI]) during the early stages of the disease is a strong predictor of increased future direct costs.[59] An increase of one unit per year in the HAQ-DI over the first 2 years of the disease, resulted in 75% greater disability and 74% greater costs over the following 8 years.[59] Direct costs represent a substantial proportion of the total cost of rheumatoid arthritis in North America. In one study, in which National Health Interview Surveys between 1989 and 1991 were analyzed, direct costs of rheumatoid arthritis were estimated to be $US4.76 billion per year in the US (55% of total costs of rheumatoid arthritis). Hospital costs account for a large proportion of the direct costs of rheumatoid arthritis. In a US study that examined the medical care costs per patient of 1156 people with rheumatoid arthritis, © Adis Data Information BV 2003. All rights reserved.

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hospital costs ($US5250) over a 1-year period (1995–1996) accounted for 62% of direct costs ($US8501), with most attributable to surgical fees.[60] Most of the surgical costs comprised expenditure related to joint replacement procedures (>50%). Patients with recent onset rheumatoid arthritis incurred lower hospital costs than those with more advanced disease. Persons in the worst quartile of function had total hospital costs that were seven times as high as those in the best quartile.[60] Early treatment with a DMARD has the potential to reduce hospitalization costs by preventing the progression of the disease to more advanced stages which require surgery (section 3.1.3). After hospital costs, medication costs were the next largest component of direct costs. In a systematic review of nine studies that investigated direct costs associated with rheumatoid arthritis, medication costs accounted for >25% of direct costs.[61] Medication costs include not only acquisition costs but also expenditures associated with monitoring for and treatment of adverse effects, which can exceed the basic drug cost.[62] A study modeling the use of hydroxychloroquine, oral gold, injectable gold, azathioprine, penicillamine and methotrexate in rheumatoid arthritis found that medication costs accounted for 25.1–45.4% of the total drug cost, monitoring costs accounted for 39–62.2% and treatment for adverse effects accounted for 9.2–22.8%.[63] 1.3.2 Indirect Costs

Indirect costs primarily consist of lost income from work with consequent impact on the patient, their family and society at large. In patients unemployed because of arthritis and musculoskeletal disorders, the presence of rheumatoid arthritis is strongly associated with failure to return to work.[64] Many studies have shown these costs to be substantial and in some cases they exceed direct costs. In addition, existing estimates may well underestimate true indirect costs. The value of work loss of older patients and females is generally underestimated.[65] It has been estimated that approximately a quarter of patients experience income reduction and that after a mean disease duration of 3 years, 42% of patients are registered as work disabled.[66] Indirect costs per patient were 40% higher than direct costs among 150 patients with rheumatoid arthritis of 5.9 ± 2.9 months duration.[67] It was estimated that almost 4 days of usual activity are lost each month because of rheumatoid arthritis. In 1994 dollars, this translated to average indirect costs of $US281 per month compared with direct costs of $US200 per month. Interestingly, the indirect cost per month of patients with a disease duration of <6 months was significantly higher than that of patients with a disease duration of ≥6 months ($US348 vs $US188; p < 0.005).[67] Dis Manage Health Outcomes 2003; 11 (11)

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1.3.3 Intangible Costs

The intangible costs of rheumatoid arthritis include changes in psychological and physical well-being, and functioning of the family.[68] In one study, altered leisure time activity, increased need for daytime rest, and reduced transport mobility were identified in a cohort of 186 patients with early rheumatoid arthritis.[66] In an earlier study, which evaluated the impact of the disease among 142 female homemakers, 75% of participants reported that rheumatoid arthritis had limited their ability to perform functional tasks around the home and 70% reported interference with hobbies or favorite pastimes.[69] To quantify and rate the effect of disease on intangible costs the most common instruments used are the Quality of Well-Being Scale and the HAQ.[70,71] HAQ scores have been shown to be consistently and strongly related to direct costs of rheumatoid arthritis.[60] In one study, direct costs of treating patients with rheumatoid arthritis in the fourth quartile of HAQ scores were ≈2.5-fold greater than those of treating patients in the first quartile.[60] In a subgroup of 272 patients who were followed-up for 10 years, cumulative costs were ≈75% greater among patients in the fourth quartile of functional status at baseline than in those in the first quartile. In a further study, female homemakers with severe disease activity had significantly higher HAQ scores (1.47 vs 0.48), pain scores (3.8 vs 3.17) and general perception of health scores (2.59 vs 2.12) than in those with mild disease activity (p ≤ 0.05 for all three parameters).[72] In a retrospective analysis of 200 rheumatoid arthritic patients, over a period of 12 months, the mean Global Health Assessment score was 45.5mm across the four American College of Rheumatology (ACR) functional classes with significant differences between the classes.[73] 1.3.4 Costs and Type of Healthcare System

Direct costs in a managed-care setting have been reported in a US study that included 365 patients with rheumatoid arthritis.[74] The total direct cost of care, for the year 1993–1994, was $US703 053 with an average individual cost rate of $US2162 per year. Most patients incurred costs of between $US400 and $US3000 per year. Prescribed drug costs accounted for 62% of the total cost with 21% and 16% spent on ambulatory and hospital care, respectively. DMARDs and NSAIDs accounted for 48% and 33% of medication costs, respectively. Hospital care costs decreased after the initiation of DMARD therapy.[74] Several North American studies have investigated the effect of the healthcare system on the costs of rheumatoid arthritis.[67,75-77] Taken together, data from three US studies indicate that costs, healthcare utilization and outcomes were similar between managed-care and fee-for-service settings; however, the US healthcare © Adis Data Information BV 2003. All rights reserved.

system is in constant flux and these results may not apply to the current situation. In the largest study, in which 341 patients were followed-up for 11 years, there was no significant difference between healthcare settings in the number of office visits, outpatient surgical procedures, hospital admissions, and procedures or hospital admissions for non-rheumatoid arthritis reasons.[76] Among 182 patients with rheumatoid arthritis, followed prospectively for a mean of 10.3 years, average global arthritis status scores, pain scores and functional disability scores were similar between healthcare settings,[75] and in a retrospective study in 150 patients, monthly direct costs (1994 values) were similar between healthcare settings over a 6-month period ($US197 vs $US192). In addition, there were no significant differences between patients enrolled in copayment plans and those not required to make copayments with respect to direct costs or healthcare visits.[67] In contrast, a North American study identified lower hospitalization rates in a managed-care setting than in a fee-for-service setting. The relative odds of hospitalization in those receiving fee-forservice care compared with those in prepaid health plans were 3.14 (95% CI 1.05 to 9.37). However, prepaid patients were younger, more frequently male and had a lower disability index.[77] 2. Current Management Strategies Early diagnosis and treatment of rheumatoid arthritis is critical to control the progressive manifestations of the disease and subsequent costs. Initial evaluation of patients with rheumatoid arthritis should include documentation of symptoms of active disease, functional status, objective evidence of disease activity, mechanical joint problems, the presence of extraarticular disease, and the presence of radiographic damage.[78] Other useful assesments may include the presence of comorbidities, a global assesment of disease activity and a quantitative determination of pain. The initial evaluation of patients with rheumatoid arthritis should also include a number of laboratory tests (complete blood count, biochemical profile, urinalysis, serum rheumatoid factor measurement and ESR or C-reactive protein level) and a thorough physical examination together with x-rays of the hands and/or feet.[78,79] The management of rheumatoid arthritis involves both pharmacological and nonpharmacological interventions and is influenced by various stakeholders. Treatment needs to be tailored to the individual patient taking into account the severity of the disease, patient preferences and the physician’s clinical expertise.[25] In addition, providers of healthcare such as HMOs and private health insurers have an influence on the choice of drug therapy. HMOs have an interest to keep drug treatment costs as low as possible and may restrict the use of more expensive agents, such as biologic therapy, on the basis of cost-benefit analyses which were conductDis Manage Health Outcomes 2003; 11 (11)

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ed with the potential benefit more defined by the payer than the patient. Moreover, in some instances, different coverage and reimbursement policies apply to biologics because of their differing routes of administration. For example, some US managed-care organizations reimburse infliximab because it is administered by intravenous infusion while etanercept is not reimbursed because it is administered by self injection.[80] A treatment algorithm for the management of patients with active rheumatoid arthritis, based on US guidelines, is shown in figure 1.[78] Although the ultimate goal of treatment is complete remission, in practice this rarely occurs. A more attainable goal is to prevent or control joint damage, prevent loss of function, and decrease pain.[78] The effective management of rheumatoid arthritis necessitates a multidisciplinary approach with input from physicians, physiotherapists, occupational therapists, podiatrists, orthopedic surgeons, pharmacists, clinical psychologists and vocational rehabilitation staff. This integrated approach, together with a disease management program, has been effective in the care of patients with rheumatoid arthritis.[81] Disease management strategies lend themselves to shared-care settings where disease management plans can be co-ordinated. Presentation of symptoms

Diagnosis and assessment of disease severity. Document disease activity and damage Rheumatoid arthritis confirmed • Provide patient and carer education Periodically Satisfactory • Start treatment with DMARD within 3 months control • Consider NSAIDs or simple analgesics monitor • Consider local or low-dose systemic steroids disease • Provide nonpharmacological intervention activity Treatment failure

Satisfactory control Unsatisfactory control

Change or add DMARD • In MTX-naïve pts consider MTX, another monotherapy DMARD or combination therapy • In pts with suboptimal MTX response, consider combination therapy, another monotherapy DMARD or biologics (mono- or combination treatment).

Treatment failure after multiple DMARDs

Joint damage

Surgery

Fig. 1. Disease management algorithm for rheumatoid arthritis.[78] First-line treatment options for patients (pts) with rheumatoid arthritis include leflunomide, methotrexate (MTX) and other disease-modifying antirheumatic drugs (DMARDs). Combination treatment with leflunomide and MTX (or other hepatotoxic or hemotoxic DMARDs) requires careful monitoring of liver function (see section 3). © Adis Data Information BV 2003. All rights reserved.

2.1 Nonpharmacological Interventions

Patient and carer education,[82,83] physiotherapy[84] and occupational therapy[85] have been shown to improve disease symptoms or outcomes in patients with rheumatoid arthritis. In addition, equivocal evidence exists to demonstrate that the use of footwear and various aids and appliances improves function.[25] Dietary education and supplementation may be of benefit to patients with rheumatoid arthritis. Some evidence exists to suggest that the diet of some patients with rheumatoid arthritis does not meet recommended dietary guidelines.[86] It has been speculated that dairy products, cereals and eggs worsen synovitis and there is evidence to suggest that starvation produces short-term improvement in the activity of rheumatoid arthritis.[39] This has lead to the development of an elimination diet for patients with rheumatoid arthritis. This diet typically consists of rice, carrots and fish followed by graded reintroduction of other foods.[39] A liquid elemental peptide diet has been shown to provide some improvement in symptoms of rheumatoid arthritis.[87] Food supplements claimed to help individuals with rheumatoid arthritis include selenium supplements, fish oil, evening primrose oil and extracts from New Zealand green-lipped mussel.[39] 2.2 Pharmacological Interventions

Historically, pharmacological interventions have involved a step-up approach. Patients were initially treated with NSAIDs together with nonpharmacological intervention. DMARD therapy was added to this regimen if considered necessary or as the disease progressed.[88] However, evidence from studies in the last decade[50] have indicated that joint destruction can occur early in the progression of the disease and hence this approach has given way to a much more aggressive treatment regimen in recent years (figure 1).[25,78] 2.2.1 Disease-Modifying Antirheumatic Drugs and Biologic Agents

A comparison of some of the features of DMARDs/biologic agents is shown in table I. There is good evidence to show that DMARDs are effective agents in the management of rheumatoid arthritis (see figure 1). DMARDs have the potential to reduce or prevent joint damage, preserving the integrity and function of the joint and leading to reduced healthcare costs.[78] It is currently recommended that DMARD therapy be commenced as soon as possible after the disease has been diagnosed, as there are clear benefits with early compared with delayed treatment.[78] DMARDs take from between 1 and 6 months to become effective (table I). According to recent guidelines, the frequent use of hydroxycholoroquine or sulfasalazine is based on safety, cost and conveDis Manage Health Outcomes 2003; 11 (11)

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Table I. Overview of some features of DMARDs/biologic agents used in rheumatoid arthritis[78,91-93] Drug

Route of administration

Onset of action

Monitoring requirements

Adverse effects that may be detected by appropriate monitoring

Oral

2–3mo

CBC, platelets, LFTs

Cholestasis and deterioration of liver function. Reversible on withdrawal of drug

DMARDsa Azathioprine

Dose-related bone marrow suppression most frequently manifests as leukopenia; lymphoproliferative disorders Cyclosporin

Oral

2–6mo

Serum creatinine, periodic CBC potassium, LFTs and monitor blood pressure

Acute nephrotoxicity which resolves to dose reduction. Chronic toxicity may develop with prolonged treatment

Hydroxychloroquine

Oral

2–4mo

Ophthalmologic examinations

Retinal damage

Injectable gold salts

Intramuscular

3–6mo

CBC, platelets, urine protein

Leukopenia, granulocytopenia, thrombocytopenia. Agranulocytosis and aplastic anemia have been reported rarely Proteinuria

Leflunomide

Oral

1mo

CBC, LFTs

Hepatotoxicity Leukopenia, anemia, thrombocytopenia, pancytopenia and agranulocytosis

Methotrexate

Oral

1–2mo

CBC, platelets, LFTs, albumin, serum creatinine

Long-term low-dose treatment associated with portal fibrosis and cirrhosis Dose-related bone marrow suppression most frequently manifested as leukopenia, thrombocytopenia, pancytopenia or agranulocytosis

Penicillamine

Oral

3–6mo

CBC, urine protein

Thrombocytopenia and neutropenia which resolve rapidly after drug withdrawal. Agranulocytosis and aplastic anemia have also been reported Proteinuria

Sulfasalazine

Oral

1–2mo

CBC, LFTs

Hepatitis, agranulocytosis

Etanercept (recombinant human fusion protein)

Subcutaneous

1–2wk

No specific requirementsb

NAc

Infliximab (chimeric human/ murine IgG1 monoclonal antibody)

Intravenous

1–2wk

No specific monitoring requirements above those for methotrexate although patients must undergo tuberculin testing before starting therapyb

NAc

Adalimumab (recombinant human IgG1 monoclonal antibody)

Subcutaneous

1–2wk

No specific requirementsb

Higher incidence of lymphoma in pts receiving adalimumab than in the general populationc

Biologic agents

Continued next page

© Adis Data Information BV 2003. All rights reserved.

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Table I. Contd

Drug

Route of administration

Anakinra (recombinant Subcutaneous human interleukin-1 receptor antagonist)

Onset of action

Monitoring requirements

Adverse effects that may be detected by appropriate monitoring Bacterial infections, neutropeniad

3mo

a

Recent consensus recommendations 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.

b

Patients who develop a new infection while undergoing treatment should be closely monitored.

c

FDA Arthritis Advisory Committee has recommended that all tumor necrosis factor inhibitors should carry a warning of the risk of lymphoma. Rare cases of tuberculosis and other opportunistic infections have also been reported in patients receiving these drugs.[94]

d

A risk/benefit assesment should be performed prior to coadministration of anakinra and etanercept because of the lack of clinical benefit and increased risk of serious infection.

CBC = complete blood count; DMARD = disease-modifying antirheumatic drug; LFT = liver function test; NA = not applicable.

nience considerations; however, methotrexate or combination therapy is preferred in patients with more active disease.[78] In those patients who do not achieve remission or a satisfactory response to their initial DMARD, methotrexate (either a monotherapy or as a component of combination therapy) should be initiated. In those patients in whom methotrexate is contraindicated or who fail to achieve satisfactory disease control, treatment with biologic agents or other DMARDs, (as mono- or combination therapy) is indicated.[78] It is important to ensure patients have had a sufficiently long period of treatment with a DMARD before assessing treatment efficacy. Five months of treatment for injectable gold, 6 months for penicillamine, 4 months for hydroxychloroquine and 3 months for all other DMARDs and biologics has been suggested; however, in some cases an optimal response may take longer to achieve. In addition, a full trial of a DMARD requires an adequate dosage. The usual maintenance dose of methotrexate (oral or injectable) is 7.5–20 mg/week.[78] Should initial DMARD treatment be ineffective, combination treatment with two or three DMARDs or a DMARD with a biologic should be considered.[88] There is good evidence to support the use of the following combinations: methotrexate, sulfasalazine and hydroxychloroquine; methotrexate and cyclosporin; or methotrexate with either infliximab or etanercept.[88,89] Recent evidence also suggests that the combination of leflunomide and methotrexate can be used effectively and safely with careful monitoring of liver function (section 3.2.2).[90] Preliminary evidence exists to suggest leflunomide and infliximab may be an effective combination (section 3.1.4). In the US, etanercept[95] and infliximab[96] are approved for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis and can be used © Adis Data Information BV 2003. All rights reserved.

in combination with methotrexate in patients who have not responded to methotrexate monotherapy. Adalimumab is indicated for reducing signs and symptoms and inhibiting the progression of structural damage in patients with moderately to severely active rheumatoid arthritis.[97] Anakinra is indicated for the reduction of signs and symptoms of moderately to severely active rheumatoid arthritis in patients who have failed 1 or more DMARDs.[98] Thus, these biologics are generally used as second-line therapy in patients with advancing disease who have not responded to standard treatment with DMARDs. Post-marketing experience has shown serious infections leading to hospitalization and death in patients receiving these agents although at this time there is no need for routine laboratory monitoring.[78] It has been suggested, in terms of relative benefit, that biologics may be most effective in patients with mild or moderate disease;[99] however, the cost of these agents will undoubtedly restrict their use to patients with severe disease, refractory to other treatments.[88,100] Current recommendations for the management of rheumatoid arthritis suggest that treatment with biologics should be considered in patients with advancing disease who have failed to respond to treatment with DMARDs.[78] 2.2.2 NSAIDs and Analgesics

NSAIDs and analgesics are primarily used to relieve pain, thereby improving patient comfort. Current US guidelines suggest that NSAIDs and/or simple analgesics are useful for some patients with active rheumatoid arthritis.[88] Nevertheless, they are thought to be only palliative, reducing joint pain and swelling, morning stiffness and inflammation. In contrast to the DMARDs/biologic agents, they do not change the pathophysiology or progression of rheumatoid arthritis.[25,78,79] In addition, many patients, especially the elderly and those prone to gastrointestinal ulceration, are at risk of developing adverse effects to NSAIDs. Treatment with NSAIDs is commonly associated with dyspepsia and less commonly associated with gastrointestinal bleeding and ulceration.[78] Dis Manage Health Outcomes 2003; 11 (11)

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This risk can be somewhat ameliorated with the use of the cyclooxygenase-2 inhibitors such as celecoxib or rofecoxib.[79] Cost, duration of action and patient preference are the main factors involved in deciding which NSAID to use.[78] Combinations of two or more NSAIDs should be avoided and NSAIDs should not be given instead of DMARDs when control of disease activity is needed.[88] 2.2.3 Corticosteroids

Oral corticosteroids (≤10 mg/day long term or short courses of 15–25 mg/day) are frequently used to manage symptoms in patients with poorly controlled rheumatoid arthritis, and may also be beneficial during the induction phase of therapy with DMARDs.[100,101] Although there is evidence to suggest that corticosteroids have some disease-modifying activity,[102] corticosteroid treatment should be limited to a short course, or if maintenance treatment is warranted the use of the lowest possible dosage is recommended.[78] Because of the toxicity of this treatment approach US guidelines suggest that corticosteroid therapy should never be used as monotherapy; it should only be used as an adjunct to DMARD therapy.[88] Local periarticular and intra-articular injections of corticosteroids are considered effective short-term therapy for the local symptoms of inflammatory synovitis. In addition, intramuscular corticosteroids can speed up clinical improvement during initiation of gold therapy or other slow-acting DMARDs.[25] Local and systemic benefits may be seen when injecting one or a few of the most involved joints in a patient early in the course of the disease, allowing patients to participate more fully in rehabilitation programs to restore lost joint function.[78] Triamcinolone or methylprednisolone are usually used for injection of large joints and hydrocortisone or prednisolone are preferable for superficial joints or flexor tendon sheaths.[103] 3. Role of Leflunomide in the Treatment of Rheumatoid Arthritis Leflunomide is an isoxazole derivative and inhibits de novo pyrimidine synthesis.[14,15] It is an immunomodulatory prodrug that is rapidly converted to its active metabolite A77 1726, possibly in the gut wall, plasma and liver.[93,104] Peak plasma A77 1726 concentrations are achieved 6–12 hours after oral administration of leflunomide. As A77 1726 has a long half-life (≈2 weeks) a loading dose of leflunomide is required to quickly attain steadystate concentrations of the active metabolite in the plasma. The current recommended dosage of leflunomide is 100mg once daily for 3 days then 10–20mg once daily thereafter.[93,104] A prescribing summary for leflunomide is presented in table II. © Adis Data Information BV 2003. All rights reserved.

3.1 Clinical Profile

Leflunomide is an effective DMARD that significantly reduces disease activity in patients with active rheumatoid arthritis. Efficacy is apparent after 4 weeks of treatment, and still evident after 5 years of therapy.[105] Most of the clinical trial data have been comprehensively reviewed.[1] The majority of clinical studies discussed in this section were randomized, double-blind, multicenter trials. The primary endpoints included tender and swollen joint counts, and physicians’ and patients’ global assessment of treatment-related change in disease activity. Overall treatment responders were defined according to the ACR 20 criteria.[106] The ACR 20 criteria require ≥20% improvement in tender and swollen joint counts and in three or more of the following five measures: patients’ and physicians’ global assessment of disease activity, patients’ assessment of pain intensity and functional ability, and either CRP levels or ESR. Radiological articular damage was assessed using the methods described by Larsen and Sharp.[107] 3.1.1 Onset of Action

In well designed trials, leflunomide (100 mg/day for 3 days then 20 mg/day) had a significantly quicker onset of action than methotrexate, sulfasalazine and placebo.[108,109] In a placebo-controlled study in 358 evaluable patients, after 4 weeks’ treatment, leflunomide recipients had significantly greater improvement in all primary outcome measures than sulfasalazine recipients (0.5 g/ day during the first week, then 1, 1.5 and 2 g/day during weeks 2, 3 and 4, respectively), including tender (–6.0 vs –3.0) and swollen joint count (–3.6 vs –1.5), and physician’s (–0.78 vs –0.5) and patient’s global assessment (–0.8 vs –0.65) [all values estimated from graphs; p ≤ 0.03]. In addition, significant improvements in all clinical outcome measures occurred sooner with leflunomide than with placebo. The mean time to meet ACR 20 criteria was 7.3 weeks with leflunomide, 10.1 weeks with placebo and 8.3 weeks with sulfasalazine.[108] In a further trial of patients with active disease, 66% of whom had failed ≥1 previous DMARD therapy, (n = 736) the mean time to the first ACR 20 response was significantly shorter in leflunomide than in methotrexate recipients (74 vs 101 days, p < 0.05).[109] 3.1.2 Long-Term Therapy

In well designed clinical trials of 24 months’ duration, leflunomide was at least as effective as methotrexate and more effective than sulfasalazine and placebo in the treatment of rheumatoid arthritis.[109-112] In one such trial, 358 patients received either sulfasalazine, placebo or leflunomide for 6 months. Subsequently, 146 patients elected to complete an 18-month double-blind extension to the study.[110] Six months after the start of treatment, leflunomide (20 mg/day) was as effective as sulfasalazine (2 g/ Dis Manage Health Outcomes 2003; 11 (11)

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Table II. Leflunomide: prescribing summary[93,104] Approved indications Pharmacokinetics

To reduce the signs and symptoms of active rheumatoid arthritis, inhibit structural damage and improve physical function in patients with active rheumatoid arthritis Rapidly converted to the active metabolite A77 1726 Plasma A77 1726 levels are not significantly altered when leflunomide is administered with a high fat meal Terminal elimination half-life for A77 1726 is ≈2 weeks and clearance is ≈0.031 L/h In patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis plasma concentrations of A77 1726 remain unchanged; however, plasma free fraction is higher than that in healthy volunteers

Drug interactions

Following concomitant administration of multiple doses of rifampicin (rifampin) and a single oral dose of leflunomide, peak plasma concentrations of A77 1726 were increased by ≈40% In vitro A77 1726 inhibits cytochrome P450 2C9 and increases the free fraction of diclofenac, ibuprofen and tolbutamide by 13–50%

Dosage (oral)

100 mg/day for 3 days then 20 mg/day thereafter

Adverse events

Diarrhea, elevated liver enzymes (ALT and AST), alopecia, rash, abdominal pain, hypertension, nausea, headache, bronchitis, respiratory infectiona

Contraindications

In women who are or may become pregnant

Warnings and precautions

Leflunomide is not recommended in patients with severe immunodeficiency, bone marrow dysplasia, or severe uncontrolled infections, significant hepatic impairment or evidence of infection with hepatitis B or C When switching to another DMARD, monitoring for hematologic toxicity is advised because of the potential for overlap in the systemic exposure to both agents Monitor liver function before treatment begins then monthly for 6 months then every 6–8 weeks thereafter.b Avoid alcoholic drinks White blood cell count and hemoglobin or hematacrit should be monitored at baseline and monthly for 6 months following initiation of therapy and every 6–8 weeks thereafter Blood pressure should be checked before treatment and periodically thereafter Men wishing to father a child should consider discontinuing leflunomide and undergoing a washout procedure with cholestyramine

Availability

10, 20 and 100mg tablets

a

Occurring in >5% of patients receiving leflunomide regardless of causality in controlled studies at 1 year.

b

For confirmed ALT elevations between 2- and 3-fold ULN, reduce the dose to 10 mg/day. If elevations 2- to 3-fold ULN persist, despite dosage reduction, or if ALT elevations >3-fold ULN exist, leflunomide should be discontinued and cholestyramine or charcoal should be administered as indicated.

DMARD = disease-modifying antirheumatic drug; ULN = upper limit of normal.

day) and more effective than placebo. The number of patients who met the ACR 20 criteria were 29%, 55% and 56% for placebo, leflunomide and sulfasalazine recipients, respectively (p = 0.001 vs placebo for leflunomide and sulfasalazine). After 24 months of treatment, 82% of leflunomide recipients met the ACR 20 criteria compared with 60% of sulfasalazine recipients (p < 0.01). Moreover, significantly more leflunomide recipients met the ACR 50 criteria than patients receiving sulfasalazine (52% vs 25%; p = 0.04). Leflunomide was also significantly more effective than sulfasalazine according to the percentage change from baseline in physician’s (50% vs 32%; p = 0.03) and patient’s global assessment (46% vs 30%; p < 0.001). Leflunomide and sulfasalazine were equally effective in reducing the swollen and tender joint counts at 24 months.[110]

© Adis Data Information BV 2003. All rights reserved.

Taken together, two well-designed trials have shown leflunomide to be at least as effective as methotrexate and more effective than placebo in the treatment of rheumatoid arthritis.[109,111,112] In the larger trial,[109] 999 patients were randomized to receive either leflunomide (20 mg/day) or methotrexate (7.5 to 15 mg/week). After 12 months, 612 patients continued to receive treatment for a further 12 months. At 24 months, although changes from baseline values in the swollen joint count (–10.3 vs –9.1) and physician’s global assessment (–1.4 vs –1.1) were significantly greater with methotrexate than with leflunomide (p < 0.02), there was no statistically significant difference between the two treatment groups in total joint count (–10.5 vs –10.9), patient’s global assessment (–1.2 vs –1.3) or ACR 20 responder rate (64% vs 72%).[109,112] In the subgroup of patients treated for 2 years, ≈90%

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of both treatment groups met the ACR 20 criteria at least once during treatment.[109] In the other trial,[111] 235 patients who entered into the second year of treatment continued to receive methotrexate (7.5–20 mg/week), leflunomide (20 mg/day which could be reduced to 10 mg/day based on tolerability) or placebo as previously randomized at study entry. The results were analyzed using an intent-to-treat approach in which the last observation was carried forward for patients who failed to complete the trial. After 12 months, improvements from baseline values in all primary efficacy parameters were significantly greater with leflunomide and methotrexate treatment groups than with placebo. At 24 months, leflunomide treatment was associated with a significantly higher ACR 20 response rate than methotrexate treatment (79% vs 67%, p = 0.049; 95% CI 0.1–24.4%). The overall response in the year-2 cohort, assessed by an area-under-the-curve analysis of the ACR response rate, revealed that leflunomide was equivalent to methotrexate (77.6% vs 66.4%).[111] There was no decrease in the efficacy of leflunomide in patients who had received the drug for 5 years compared with the efficacy after 1 year of treatment. In a nonblind extension[105] of two phase III studies,[108,109] 214 patients treated with leflunomide for 2 years elected to continue treatment for up to 5.8 years. In total, 76.2% of patients completed treatment to study endpoint (commercial launch of leflunomide) for a mean duration of 4.6 years. Mean disease duration was 4.1 years and 32% of patients had not received DMARD therapy previously. At study endpoint, ACR 20 (69.2% vs 72.9%), 50 (43% vs 48.3%) and 70 (19.6% vs 14.5%) response rates were similar to those reported at the end of the first year of treatment. Because of the nature of the time of endpoint in this study (the commercial availability of leflunomide) a lastobservation carried forward analysis was required. However, as clinical assesments were made every 6 months, these results are a valid indicator of the long-term effectiveness of leflunomide.[105] 3.1.3 Radiological Progression of Disease

Several well designed trials of 24 months’ duration have shown leflunomide to be as effective as sulfasalazine and at least as effective as methotrexate in decreasing the rate of structural damage of rheumatoid arthritis over 24 months.[109-111] In addition, leflunomide was shown to be more effective than placebo in reducing the rate of radiological progression over 12 months. In one trial (n = 358), after 6 months’ treatment, changes in mean Larsen scores were significantly improved in both active treatment groups compared with placebo (0.03 vs 0.09; p < 0.05). After 24 months, similar changes from baseline in mean Larsen scores (–0.07 vs –0.03) and erosive joint counts (–0.92 vs 0.08) were seen between leflunomide (20 mg/day) and sulfasalazine (2 g/day) recipients.[110] In a trial among 482 patients randomized to © Adis Data Information BV 2003. All rights reserved.

receive either leflunomide 20 mg/day, methotrexate 7.5–15 mg/ week or placebo, structural damage (as measured by changes from baseline in the median total Sharp scores) in leflunomide recipients (0.53) was significantly lower than that in methotrexate (0.88; p = 0.05) or placebo (2.16; p ≤ 0.001) recipients after 12 months’ treatment.[113] However, radiological progression was similar between active treatment groups (n = 199) at 24 months, with patients showing little or no progression of structural damage.[111] In the year-2 cohort, 88% and 80% of leflunomide and methotrexate recipients, respectively, had no newly eroded joints during year 2 of treatment. Similar numbers of leflunomide and methotrexate recipients had no change in erosion (72% and 70%) and joint space narrowing scores (73% and 71%) from baseline to 24 months. In a further trial among 999 patients, of whom 612 completed the study, similar degrees of disease progression (as measured by the overall Larsen score) were noted between methotrexate and leflunomide recipients in the first year of treatment. In the year-2 cohort little further progression was seen in leflunomide recipients and a small amount of disease regression was noted in methotrexate recipients (no specific data reported).[109] 3.1.4 Combination Therapy with Leflunomide and Other Antirheumatic Treatments

Combination therapy with leflunomide plus methotrexate is significantly more effective than methotrexate plus placebo in patients with rheumatoid arthritis who had active disease while on methotrexate monotherapy. In this randomized, double-blind study, eligible patients (with active rheumatoid arthritis who had been receiving methotrexate for at least the previous 6 months) were randomized to receive either leflunomide or placebo in addition to their background methotrexate therapy. In total, 263 patients receiving background methotrexate (15–20 mg/week or 10–15 mg/week if this was the maximum tolerated dose for ≥6 months) were randomized to receive either leflunomide (100 mg/ day for 2 days then 10 mg/day [n = 130]) or placebo (n = 133).[114] The primary efficacy endpoint was ACR 20 response rate at 24 weeks. At week 24, significantly more patients receiving leflunomide plus methotrexate met the ACR 20 criteria than those who received placebo plus methotrexate. Leflunomide plus methotrexate therapy was also significantly more effective than placebo plus methotrexate when assessing ACR 50 and 70 response rates (figure 2).[114] Results from a nonblind 24-week extension to the study have recently been reported as an abstract.[115] All patients previously randomized to either placebo or leflunomide were treated with leflunomide (no loading dose of leflunomide was used in those patients previously receiving placebo), in addition to methotrexate, for a further 24 weeks. At the end of this open-label extension phase ACR 20, 50 and 70 responder rates were similar between those who were leflunomide recipients throughout the Dis Manage Health Outcomes 2003; 11 (11)

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Lef + mtx Pla + mtx Lef + mtx / lef + mtx (NBE) Pla + mtx / lef + mtx (NBE)

70 60

Patients (%)

50

*

40 30

*

20

*

10 0 ACR20

ACR50

ACR70

Fig. 2. American College of Rheumatology (ACR) response rates in a 24-week, double-blind study[114] and a 24-week, nonblind extension (NBE) study.[115] At enrolment, patients had active rheumatoid arthritis despite receiving methotrexate (mtx) for at least the previous 6 months. Patients were randomized to receive leflunomide (lef) plus mtx (n = 133) or placebo (pla) plus mtx (n = 130) during the double-blind phase. During the NBE, patients receiving lef + mtx during the double-blind phase continued with the same medication (n = 96), while those receiving pla + mtx during the double-blind phase were switched to lef + mtx (n = 96). Response rates during the NBE were calculated using last observation carried forward. Values are percentage of patients who achieved 20%, 50% or 70% improvement in ACR criteria. * p < 0.001 vs pla + mtx.

entire study and patients who switched from placebo to leflunomide (figure 2).[115] Results from a retrospective, multicenter analysis among 93 patients suggest that the combination of infliximab and leflunomide may be a treatment option in patients with mild to moderate rheumatoid arthritis.[116] Ninety-one percent of patients had previously used methotrexate and had an average disease duration of 126.4 months. After 7.5 months (mean duration of combination therapy) the mean tender joint count decreased by 44% and the mean swollen joint count decreased by 64% compared with baseline (no statistical analyses reported). Efficacy data were not available for all patients. 3.2 Tolerability

Leflunomide 20 mg/day was generally well tolerated in patients with rheumatoid arthritis in three well-designed clinical trials of 24 months’ duration (sections 3.1.1, 3.1.2 and 3.1.3).[109-111] In addition, tolerability data are also available from a double-blind, placebo-controlled trial evaluating the efficacy of leflunomide 10 mg/day in combination with methotrexate 16.7 mg/week (mean dose) [section 3.1.4].[114] 3.2.1 General Adverse Events

The nature and incidence of adverse events in patients receiving leflunomide 20 mg/day were similar to those in recipients of © Adis Data Information BV 2003. All rights reserved.

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sulfasalazine 2 g/day[110] or methotrexate 7.5–20 mg/week.[109,111] Pooled results of placebo-controlled trials among patients treated with leflunomide 20 mg/day show the most common adverse events (>5%) in leflunomide (n = 315) and placebo recipients (n = 210) were diarrhea (27% vs 12%), respiratory infections (21% vs 21%), nausea (13% vs 11%), headache (13% vs 11%), rash (12% vs 7%), abnormal liver enzymes (10% vs 2%), dyspepsia (10% vs 10%), alopecia (9% vs 1%), hypertension (9% vs 4%), injury accident (7% vs 5%), asthenia (6% vs 4%), back pain (6% vs 3%) and abdominal pain (6% vs 4%).[104] A recent nonblind extension of two phase III clinical studies has reported that in 214 patients treated with leflunomide for up to 5 years, adverse effects occurred in 26.2% of individuals.[105] Of these, the most frequent adverse effects were diarrhea (5.6%), hypertension, abnormal findings on liver function tests, rash (each 2.8%) and eczema (2.3%). In total, 4.2% of patients experienced a treatment-related serious adverse event, and 5.6% of patients discontinued study medication because of a primary adverse event. In one trial (n = 358), adverse events were generally of mild to moderate intensity and necessitated drug withdrawal in 14%, 19% and 7% of leflunomide, sulfasalazine and placebo recipients, respectively. At 24 weeks, serious treatment-related adverse events were reported in 5% of patients in the leflunomide and placebo groups and in 7% of patients receiving sulfasalazine.[108] The frequency of adverse events at 24 months was similar to that at 6 months; however, the incidences of diarrhea, alopecia and nausea were reduced in the second year of treatment in both active treatment groups.[110] In another trial (n = 999), serious treatment-related adverse events were reported in 7% and 8% of patients receiving leflunomide and methotrexate, respectively.[109] Severe hypertension was reported in two patients treated with leflunomide and interstitial pneumonitis was reported in five patients treated with methotrexate. Among the cohort treated for a second year, adverse events which necessitated drug withdrawal occurred in 8% of leflunomide and 6% of methotrexate recipients.[109] Similar results were seen in a further trial.[111] Of 263 patients receiving long-term methotrexate (≥ 6 months), 133 were randomized to receive additional leflunomide (100 mg/ day for 2 days then 10 mg/day) and 130 received additional placebo for 24 weeks (section 3.1.4). Treatment-related adverse events were mild to moderate (figure 3).[114] Overall discontinuations from this study were similar between treatment groups: slightly more patients receiving leflunomide discontinued because of an adverse event whereas slightly more patients receiving placebo discontinued because of lack of efficacy. Adverse events leading to the withdrawal of more than one patient in the lefluDis Manage Health Outcomes 2003; 11 (11)

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30

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iz zi n

es s

ci a D

pe Al o

as h R

ch e H

ea

da

se a au N

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ia

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ea

0

Fig. 3. Treatment-related adverse events in patients receiving leflunomide plus methotrexate (n = 133) or placebo plus methotrexate (n = 130) in a 24-week randomized, double blind trial.[114] All patients in this study had been receiving methotrexate treatment for at least 6 months prior to randomization. URTI = upper respiratory tract infections.

nomide group were diarrhea (four patients), abnormal liver function (three patients) and rash (two patients).[114] After an estimated 76 000 patients had been treated with leflunomide (pre-1999), 16 potential cases of pancytopenia and nine cases of serious skin reactions were reported in patients taking leflunomide, based on postmarketing data. Most of the hematological reactions occurred when leflunomide was administered with or immediately after another DMARD, or after treatment with leflunomide had been switched to another DMARD with hematological toxicity such as methotrexate.[117] The incidence of malignancies or lymphoproliferative disorders was similar in leflunomide and placebo recipients in 2-year clinical trials;[109,110] however, long-term exposure in larger numbers of patients are required to accurately assess the risk of these adverse events in leflunomide-treated patients.[104] 3.2.2 Hepatic Effects

Leflunomide has been associated with hepatotoxicity in several clinical trials. Combination therapy with other hepatotoxic agents may increase the risk of liver damage. In placebo-controlled trials of 24 months’ duration,[109-111] similar elevations in liver enzymes were observed in methotrexate, sulfasalazine and leflunomide recipients. In one trial (n = 358) similar small increases in ALT (median increase of 2 and 1 U/l) and AST (median increase of 2 and 3 U/l) were seen in leflunomide (20 mg/day) and sulfasalazine (2 g/day) recipients,[110] respectively, and in a placebo-controlled trial in 508 patients, 12.6% and 10% of leflunomide and methotrexate recipients, respectively, had ALT levels >2 times the upper limit of normal © Adis Data Information BV 2003. All rights reserved.

(ULN). Respective incidences of AST values >2 times the ULN were 8.9% and 7.9%.[111] A further study reported that, in 2 years of treatment, 2% of leflunomide and 4% of methotrexate recipients withdrew from treatment because of persistent elevations in plasma liver enzymes.[109] The American College of Rheumatology has issued an online summary of the findings of the recent FDA safety assessment of leflunomide.[118] According to this report, 2–4% of leflunomide recipients experience a 3-fold elevation in liver enzymes while receiving this treatment compared to 1–2% of placebo recipients, hospitalization for apparent drug-related hepatitis occurred at a rate of approximately 0.02% and no cases of hepatocellular necrosis were observed. Few cases of serious liver injury or acute liver failure have been reported with leflunomide in post-marketing surveillance. However, the majority of these reports were confounded by the concomitant use of agents known to be potential hepatotoxins, co-morbidity affecting the liver or otherwise inadequate case information, As such, no conclusions about the relationship between leflunomide and these reports could be drawn. Thus, while elevations in liver function tests are apparent in 2–4% of patients, serious hepatotoxicity is extremely rare.[118] A recent trial in 263 patients with active rheumatoid arthritis (section 3.1.4), showed some differences in the results of liver function tests between patients receiving combination therapy with methotrexate and leflunomide and those receiving methotrexate plus placebo.[114] In general, more patients receiving leflunomide plus methotrexate showed elevated ALT and AST levels than patients receiving placebo plus methotrexate.[114] For example, 41 (31.5%) and 22 (16.5%) patients receiving leflunomide plus methotrexate showed increases in ALT and AST of >1.2 ULN compared with nine (6.8%) and three (2.3%) patients receiving placebo plus methotrexate.[114] These elevations were generally more common during the first 3 months of treatment and, in patients receiving leflunomide plus methotrexate, all ALT and AST levels which exceeded 1.2 times the ULN had normalized to ≤1.2 ULN by week 24. This normalization was achieved without adjustment of leflunomide dose in 58.5% of patients with elevated ALT levels, and 59% of patients with elevated AST levels.[114] Three patients receiving leflunomide plus methotrexate and two patients receiving placebo plus methotrexate discontinued study medication before week 24 because AST and ALT levels were elevated above the protocol-defined range.[114] During the nonblind extension to this study (section 3.1.4), similar numbers of patients who received leflunomide or placebo during the doubleblind phase showed elevated ALT levels ≥1.2 ULN (10.4% in each group).[115] More patients who initially received leflunomide showed elevated AST levels ≥1.2 ULN than those who recieved placebo (11.5% vs 4.2%).[115] To minimize the risk of hepatoDis Manage Health Outcomes 2003; 11 (11)

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toxicity, monitoring guidelines should be strictly adhered to (table II). 3.3 Physical Function and Health-Related Quality of Life

In placebo-controlled clinical studies, leflunomide was significantly more effective than placebo, methotrexate and sulfasalazine in improving physical function measures among patients with active rheumatoid arthritis at the primary endpoint, and the effect was maintained after 2 years of treatment (section 3.1.2). Furthermore, the addition of leflunomide to methotrexate therapy significantly improved physical function and health-related quality of life compared with adding placebo in patients with active disease receiving methotrexate alone. Functional ability was assessed using the HAQ and the results expressed as mean changes from baseline in a trial that enrolled 358 patients (116 completed the study) randomized to receive leflunomide, sulfasalazine or placebo.[119] After 6 months, leflunomide was significantly more effective than sulfasalazine (–0.5 vs –0.29; p ≤ 0.01) and placebo (–0.5 vs –0.04; p ≤ 0.0001) in improving physical function. The difference between active treatment groups was still evident after 24 months (–0.65 vs –0.36; p = 0.0149). Considering the individual subscales of the HAQ score (dressing and grooming, rising, eating, walking, hygiene, reach, grip and other activities), leflunomide was significantly more effective in improving dressing and arising scores than sulfasalazine after 6 months. Significant improvements in all categories were evident in leflunomide compared with placebo recipients.[119] In addition, significantly greater improvements in the HAQ Disability Index (HAQDI) were seen in leflunomide than in sulfasalazine (–0.56 vs –0.37; p ≤ 0.05) and placebo (–0.56 vs –0.08; p ≤ 0.001) recipients after 6 months of treatment. After 24 months the difference was no longer statistically significant between active treatment groups (–0.73 vs –0.56).[119] At 24 months leflunomide recipients showed statistically greater improvements in health status measures and functional activities than recipients of methotrexate treatment.[111] At 12 months improvements were significantly greater in leflunomide compared with placebo recipients.[120] A study comparing the effects of leflunomide, methotrexate and placebo on patient’s physical function utilized the HAQ, HAQDI, Modified Health Assessment Questionnaire (MHAQ), Problem Elicitation Technique (PET) Weighted Top 5 and the health-related quality of life instrument, the Medical Outcomes Survey Short Form 36 (SF-36). After 12 months, mean improvements from baseline in scores for MHAQ (–0.29 vs –0.15; p < 0.01), HAQDI (–0.45 vs –0.26; p < 0.01), PET Top 5 (–6.91 vs –3.41; p < 0.01) and SF-36 (7.6 vs 4.6; p < 0.01) were greater in leflunomide than methotrexate recipients. In addi© Adis Data Information BV 2003. All rights reserved.

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tion, leflunomide recipients had significantly greater improvement when compared with patients receiving placebo (p < 0.0001 for all four scores).[120] In the year-2 cohort, after 24 months the improvement in HAQDI (–0.6 vs –0.37; p < 0.001), PET Weighted Top 5 (–9.1 vs –4.3; p < 0.01) and SF-36 physical (10.8 vs 8.4; p = 0.195) and mental (4.7 vs 2.67; p = 0.062) component summary scores were greater in leflunomide than in methotrexate recipients, although diferences did not always achieve statistical significance.[111] Utilizing the 12-month SF-36 data, quality-adjusted life-years (QALYs) were calculated by application of the SF-6D instrument and the results reported in an abstract. Treatment with leflunomide resulted in an incremental gain of 0.084 QALYs (p = 0.01).[121] Adding leflunomide to methotrexate therapy significantly improved physical function and health-related quality of life compared with adding placebo, in patients with active rheumatoid arthritis while on methotrexate monotherapy.[114] Patients receiving leflunomide plus methotrexate had greater mean improvements in the HAQDI than placebo plus methotrexate recipients (–0.42 vs –0.09; p ≤ 0.001) after 24 weeks. In addition, the mean change in the SF-36 physical component summary score was significantly greater in patients receiving leflunomide in addition to methotrexate than in those treated with methotrexate and placebo (6.8 vs 0.3; p ≤ 0.001). There was no significant difference in the mental component of the SF-36 between treatment groups.[114] The minimum clinically important difference (MCID) provides an estimate of the amount of improvement that is perceptible to an individual patient and thus considered clinically meaningful.[122] The mean change from baseline in HAQDI in patients receiving leflunomide plus methotrexate was approximately twice the estimated MCID for this scale (-0.19 units).[122] Similarly, these patients showed changes in the SF-36 physical component summary score (6.8 units) which exceeded the MCID for this scale (2.5–5.0 units).[123] Similar changes were not apparent in those patients who received placebo plus methotrexate.[114] 3.4 Cost Considerations

Few well designed cost analyses of leflunomide treatment in patients with rheumatoid arthritis exist. Of the two comparisons so far conducted based on US data, leflunomide has been shown to be more costly than methotrexate and sulfasalazine in one[124] while the other unpublished study showed that there was no difference in cost between leflunomide and methotrexate.[125] In addition, leflunomide has been shown to be less costly than etanercept[126] and infliximab plus methotrexate.[127] The 5-year cost effectiveness of adding leflunomide to a DMARD management protocol, representative of an approach Dis Manage Health Outcomes 2003; 11 (11)

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commonly adopted by Canadian rheumatologists, was examined in a decision analysis framework.[128] Data were obtained from a search of Medline (1996–1999) and separately conducted surveys. Among the costs included were drug acquisition and monitoring costs and costs associated with adverse effects. All costs were calculated in 1999 Canadian dollars and converted to US dollars using 1998 purchasing power parities for healthcare. The addition of leflunomide to a typical DMARD management protocol resulted in therapy-related costs of $US9698 per patient per 5-year period compared with $US8467 in a protocol excluding leflunomide.[128] Patients treated with leflunomide were in a state of response for an extra 36.5 days compared with those who received conventional management. This equated to a cost of $US13 096 per additional year of response. The addition of leflunomide to a typical DMARD management protocol increased the number of QALYs by 0.06 at a cost per QALY of $US54 229 QALYs derived from a rating scale and $US71 988 for QALYs derived using the standard gamble technique.[128] The cost of leflunomide therapy in 480 patients with active rheumatoid arthritis has been compared with that of methotrexate and placebo in a recent Canadian study.[124] Data were collected prospectively alongside a 12-month clinical trial.[111] Healthcare resources, out-of-pocket expenses, loss of working time and time spent on chores were recorded at 2-weekly intervals from weeks 4 to 12 and monthly thereafter. All costs were adjusted to 1999 Canadian dollars. Rating scale and standard gamble utilities were collected at baseline, 6 and 12 months or at study exit. The annualized total cost of treating patients with leflunomide was significantly higher than that of methotrexate and placebo (figure 4; p < 0.0001).[124] There was no significant difference between treatment regimens in rating scale values or standard gamble utilities. When drug acquisition and monitoring costs were excluded from the cost analysis differences in medical care costs between leflunomide and methotrexate recipients were not statistically different from a societal and health plan perspective (figure 4). Mean total costs per person-year of observation (societal perspective), mean direct costs per person-year (Provincial Health Insurance Plan perspective) and resource utilization episodes were similar between treatment groups.[124] Indirect costs were $Can986 and $Can660 for leflunomide and methotrexate recipients, respectively. A recent cost-minimization analysis has compared the rheumatoid arthritis-related treatment costs of 6 months’ therapy with leflunomide with that of etanercept.[126] Included in the analysis were 808 patients who were receiving newly prescribed leflunomide (n = 527) or etanercept (n = 281) in 1998. Patients were identified from a US database and observed for 6 months after the index date. The index date was defined as the date of first prescrip-

Carswell et al.

4000 3000 2000 1000 0 Total costs

Total costs excluding drug acquisition and monitoring costs

Direct costs excluding drug acquisition and monitoring costs

Fig. 4. Comparison of annualized mean costs (1999 values) per person associated with treatment of rheumatoid arthritis with leflunomide 20 mg/ day, methotrexate up to 15 mg/week or placebo; prospective analysis of a 1-year randomized, double-blind multicenter US trial.[128] $Can = Canadian dollars. * p < 0.0001 vs methotrexate and placebo.

tion for either of the two agents. Costs included those associated with hospitalizations, emergency department visits, office and outpatient visits, and pharmacy and laboratory fees. After 6 months, etanercept recipients had significantly higher mean per-person total costs (1998 values) than leflunomide recipients ($US7722 vs $US3302; p < 0.0001).[126] Etanercept treatment was associated with significantly higher pharmacy costs than leflunomide treatment $US5878 ± $US2238 vs $US1877 ± $US1258; p < 0.0001). All other costs were similar between treatment groups. After excluding patients who received the other study drug during the 6-month observation period, results were similar to the intent-to-treat analysis. Leflunomide monotherapy is associated with significantly lower costs than combination therapy with methotrexate and infliximab according to a 1-year Spanish cost-minimization analysis.[127] Two hundred and forty-six clinical trials were located from a systematic review of various databases up to November 2000, of which four were finally included. The direct costs taken into account included acquisition costs, waste material, nursing time in administering the drug, hospitalization and physician costs, and monitoring and laboratory costs. In addition, lost income and costs related to adverse reactions were estimated. Costs are expressed in 1999 Euros (€) and were derived from various specific databases. The cost per patient of a 1 year treatment with leflunomide was €1893 compared with €15 604 for infliximab and methotrexate, giving an incremental cost of €13 711 for the combination therapy.[127] A sensitivity analysis showed the cost data to be robust. Dis Manage Health Outcomes 2003; 11 (11)

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In a managed-care setting, use of leflunomide in patients with rheumatoid arthritis is associated with reduced medication and other healthcare service costs compared with etanercept and infliximab.[129] Data were included from 40 healthcare plans within the US and included patients with at least one claim with a diagnosis of rheumatoid arthritis and one pharmacy or medical claim for leflunomide, etanercept or infliximab. This analysis suggested that 83% of patients treated with leflunomide did not switch to, or add a biologic agent during the first year of treatment and did not have a significantly higher use of other medications or invasive procedures. Thus, the use of leflunomide may be associated with reduced resource utilization and costs relative to etanercept and infliximab by delaying the use of a biologic agent.[129] These conclusions are supported by the results of an economic analysis, (published as an abstract) which also suggests that leflunomide is a cost-effective option compared to the biologics, etanercept and infliximab.[130] In this study mean rheumatoid arthritis direct medical charges for leflunomide, etanercept and infliximab at 1 year were $US8609, $US16 534 and $US20 263, while cost effectiveness ratios per ACR 20 were $US16 556, $US28 024 and $US48 245 and per HAQDI were $US19 131, $US26 668 and $US69 872, respectively.[130] 3.5 Conclusions

Rheumatoid arthritis is a progressive disease that can lead to long-term deformity and disability. Data reviewed in the preceding sections demonstrate that: • genetic and environmental factors are implicated in the pathogenesis of rheumatoid arthritis • patients with rheumatoid arthritis experience appreciable physical, functional and psychological disabilities • mortality rates are increased by at least 2-fold in patients with rheumatoid arthritis • early diagnosis and aggressive treatment of rheumatoid arthritis are critical in order to control the progressive manifestations of the disease • there is good evidence that DMARDs can modify the course of rheumatoid arthritis, improving signs, symptoms and outcomes of the disease. An overview of formulary considerations for leflunomide is presented in table III. Evidence that early treatment with DMARDs can prevent the progressive manifestations of rheumatoid arthritis has resulted in a move toward the earlier use of DMARDs in rheumatoid arthritis; however, there are several problems associated with long-term use of some of the traditional agents. Many have poor efficacy, delayed onset of action and are poorly tolerated in long-term © Adis Data Information BV 2003. All rights reserved.

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Table III. Formulary considerations: leflunomide in patients with rheumatoid arthritis Clinical benefits Reduces disease activity and inhibits radiographic progression in early active rheumatoid arthritis Rapid onset of action Improves physical function to a significantly greater extent than methotrexate or sulfasalazine in placebo-controlled trials Administered once daily Potential concerns Hepatotoxicity, especially when prescribed with methotrexate The need for a washout procedure should there be a need to hasten drug elimination. It may take up to 2 years in some patients for plasma concentrations to fall below detectable levels after discontinuation of treatment Requirement for laboratory monitoring Conclusions Provides a rapid and sustained reduction in disease activity, inhibits the progression of structural damage and improves physical function in patients with active rheumatoid arthritis. The drug is generally well tolerated Onset of action is quicker than that seen with other DMARDs Is more effective than methotrexate and sulfasalazine in improving physical function in placebo-controlled studies Has shown potential in combination with methotrexate or infliximab; however, concerns about potential hepatotoxicity limit its use in combination with methotrexate It is predicted that leflunomide may 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 Considering the available data, leflunomide should be viewed as an important treatment option including patients intolerant or unresponsive to methotrexate DMARDs = disease-modifying antirheumatic drugs.

therapy. A dropout rate of 80% has been observed in patients after 5 years of DMARD therapy and the duration of DMARD monotherapy has been reported as <2 years in most patients (excluding methotrexate).[131] In addition, most DMARD therapy requires the patient to undergo frequent monitoring for adverse effects.[2] Randomized trials in the 1980s demonstrated the efficacy of low-dose weekly methotrexate as monotherapy for rheumatoid arthritis.[132,133] This regimen was a major advance on the traditional DMARDs. Patients demonstrated long-term compliance and several longitudinal studies have shown methotrexate to have acceptable tolerability and good efficacy. Tolerability concerns with methotrexate include hepatotoxicity, life-threatening pulmonary toxicity and lymphoproliferative disorders.[78] MethotrexDis Manage Health Outcomes 2003; 11 (11)

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ate is regarded as the least costly and most effective DMARD,[124,134-136] and as a result methotrexate has emerged as the benchmark agent with which others are compared in clinical trials.[2] So where does leflunomide fit into the management of rheumatoid arthritis? In clinical trials of 24 months’ duration, leflunomide has been shown to be at least as effective as methotrexate and more effective than sulfasalazine in reducing disease activity among patients with active rheumatoid arthritis (section 3.1.2). Leflunomide was also significantly more effective than placebo in reducing disease activity in 12-month clinical trials and was more effective than methotrexate, sulfasalazine and placebo in improving physical function measures in patients with active rheumatoid arthritis (section 3.3). Physical function and quality-of-life measures have often been undervalued by managed-care organizations; however, the consideration of these factors by formulary managers makes economic sense.[80] In clinical practice, physical function measures are often used as a guide to treatment success: ACR response rate is rarely measured. In addition, physical function measures such as the HAQ can predict long-term outcomes of rheumatoid arthritis.[80] Leflunomide has been shown to have a slightly quicker onset of action than methotrexate and sulfasalazine (section 3.1.1). This could be attributable to the dosage regimens of these agents. Sulfasalazine and methotrexate regimens are usually built up from smaller dosages to a therapeutic dosage whereas leflunomide therapy is started with a high loading dosage for 3 days. This feature of leflunomide may encourage future treatment compliance. However, elimination of the loading dose regimen may decrease the risk of adverse events, which may be especially important for patients at increased risk of hematologic or hepatic toxicity, such as those receiving concomitant treatment with methotrexate or other immunosuppresive agents or on such medications in the recent past. Leflunomide is contraindicated in women of childbearing potential and in men who are not using reliable contraception. In addition, patients with hepatic insufficiency should avoid taking leflunomide. The addition of leflunomide to methotrexate has been shown to be significantly more effective than adding placebo in patients who had active disease on methotrexate monotherapy; however, patients treated with this combination should be closely monitored for liver abnormalities (section 3.2.2). The use of combination therapy with leflunomide and infliximab has recently been reported in a retrospective analysis and initial results are promising. In clinical trials of up to 24 months’ duration, leflunomide had a similar tolerability profile to methotrexate (section 3.2). Both methotrexate and leflunomide are associated with liver function abnormalities (section 3.2.2); however, the risk of hepatotoxicity © Adis Data Information BV 2003. All rights reserved.

Carswell et al.

with leflunomide can be minimized by strictly adhering to monitoring guidelines.[93] In the current era of cost containment, cost effectiveness and acquisition costs have a big influence on formularies, whether it be in the hospital setting or in the community. A recent well designed cost analysis has shown methotrexate to be less costly than leflunomide, principally because of the higher acquisition costs associated with leflunomide (section 3.4). Once these fixed costs were excluded both drugs were of equal cost. Also cost analyses conducted to date have shown leflunomide treatment to be less costly than etanercept, infliximab and combination therapy with infliximab plus methotrexate. In conclusion, leflunomide is a DMARD that produces a rapid and sustained reduction in disease activity, inhibits the progression of structural damage and improves physical function in patients with active rheumatoid arthritis. Leflunomide has a more rapid onset of action than sulfasalazine or methotrexate. In addition, leflunomide is more effective than both of these agents in improving physical function in placebo-controlled studies. It is predicted that leflunomide therapy may improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial burden imposed by the disease for patients, healthcare providers and payers; leflunomide is at least as effective as methotrexate and more effective than sulfasalazine in reducing disease activity after 24 months’ treatment. Efficacy with leflunomide remains evident after treatment for 5 years. Thus leflunomide can be considered as an important treatment option for patients with active rheumatoid arthritis including those intolerant or unresponsive to methotrexate.

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