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Benefits of Anti-TNF Therapy in Rheumatoid Arthritis


Tim Casey

St. Louis—As the costs associated with rheumatoid arthritis (RA) rise, health plans and providers must enhance RA management and understand the need for early and aggressive treatment of the disease, 4 speakers said during a satellite symposium at the AMCP meeting. The symposium was titled Is It Possible to Significantly Limit or Halt the Damage from Rheumatoid Arthritis? The Benefits of Anti-TNF Therapy in Managed Care. Maria Lopes, MD, MS, began the session by discussing RA’s prevalence, incidence, mortality, and economic burden as well as providing suggestions to treat the disease effectively. RA is a disabling autoimmune disease that can lead to irreversible joint damage, extra-articular manifestations, physical impairment, fatigue, depression, and decreased quality of life. At 5 years, 30% of RA patients are disabled; at 10 years, 50% of RA patients are disabled; and at 30 years, 90% of RA patients are disabled. Dr. Lopes cited data from the Rochester Epidemiology Project that indicated 1.3 million adults in the United States had RA in 2005, the most recent data available. The prevalence of RA was 0.72 per 100,000 population, including 0.98 per 100,000 females and 0.41 per 100,000 males. After declining for the previous 4 decades, the incidence and prevalence of RA increased from 1995 to 2005. Dr. Lopes said the reasons for the increase are unknown, although possible explanations include cigarette smoking, vitamin D deficiency, infections, obesity, and socioeconomic status. Studies have shown overall survival in patients with RA is significantly reduced compared with the general population. In addition, people with RA have high work disability costs, with overall indirect costs resulting from lost productivity exceeding direct healthcare costs in some cases. Compared with the costs associated with other chronic diseases, the expenditure associated with RA is relatively small: $13,530 annually per patient, including $8478 for medical services and $5053 for medication. Dr. Lopes said early treatment with disease-modifying antirheumatic drugs (DMARDs) is associated with improved physical function, less fatigue, and better emotional and mental health. Studies have also shown that TNF (tumor necrosis factor) antagonists decrease excess mortality, particularly mortality caused by cardiovascular disease. Anti-TNF agents may inhibit RA-related inflammation. As the treatment of RA evolves, Dr. Lopes said providers and payers face challenges. Providers must deal with revised treatment guidelines emphasizing early and aggressive treatment, safety concerns associated with long-term use of DMARDs and biologics, and the decision to use single-agent or combinations of DMARDs and biologics. There are also several new biologic agents on the market, including novel anti-TNF agents (certolizumab pegol and golimumab), T-cell activation inhibitors (abatacept), B-cell–targeted agents (rituximab), and anti–interleukin-6 receptor blockers (tocilizumab). Meanwhile, payers have to determine the appropriate use of the drugs as well as cost, access, and reimbursement. To adapt to the new treatments, Dr. Lopes suggested identifying patients who would benefit from early intervention, initiate therapy with the appropriate agents, and implement programs to ensure adherence to prescribed therapies. She also recommended ways to enhance RA management, including employing an integrated multidisciplinary team, adopting national guidelines for the diagnosis and treatment of RA, and encouraging the patient and provider to take accountability for treatment outcomes. Clinical and Financial Implications James T. Kenney, Jr, RPh, MBA, was the next speaker and titled his presentation Benefits of Treating to RA Remission: Clinical and Financial Implications for Managed Care. Dr. Kenney said RA progresses rapidly and cited data supporting his belief that early and aggressive treatment of RA is necessary. For instance, the rate of progression is more rapid in the first year than in subsequent years. Most patients who have had RA for <2 years have radiographic abnormalities, and erosions can be detected within months of onset. If patients with RA are treated early and aggressively, they see improved clinical outcomes and reductions in the accrual of joint damage and disability. Mr. Kenney discussed several trials, including the TICORA (Tight Control for Rheumatoid Arthritis) study that included 111 patients with RA duration <5 years. They received routine or intensive treatment and were assessed by the following criteria: American College of Rheumatology (ACR) 20, defined as ≥20% improvement in tender and swollen joint counts and ≥20% improvement in 3 of 5 other core set measures (patient’s global assessment, physician’s global assessment, physical disability score, acute reactant value, and patient’s assessment of pain); ACR 50; ACR 70; and remission. In the TICORA study, 91% of patients in the intensive treatment group and 64% in the routine treatment group achieved ACR 20; 84% of patients in the intensive treatment group and 40% in the routine treatment group achieved ACR 50; 71% of patients in the intensive treatment group and 18% in the routine treatment group achieved ACR 70; and 65% of patients in the intensive treatment group and 16% in the routine treatment group went into remission. In 2008, the ACR revised its recommendations for optimizing RA outcomes. The guidelines include choosing a treatment algorithm based on treatment history, disease duration, and response to prior treatment; frequently assessing disease activity; encouraging the use of traditional and biologic DMARDs; providing recommendations on specific biologics; and targeting remission as the treatment outcome. The ACR recommendations include the following traditional DMARDs: hydroxychloroquine, leflunomide, methotrexate (MTX), minocycline, and sulfasalazine. The guidelines also include the following biologic DMARDs: abatacept, adalimumab, etanercept, infliximab, rifuximab, certolizumab pegol, golimumab, and tocilizumab. “One of the challenges we’ve seen in the newer areas concerns safety,” Mr. Kenney said. “When you’ve got 10, 12, 15 years [with the older drugs], you know the safety risks.” Mr. Kenney mentioned low disease activity and remission as the 2 targets in treating RA. He said early DMARD and/or biologic therapy may permanently modify the disease activity and possibly lead to remission, which could improve the patient’s quality of life, decrease productivity losses, physical disability and joint replacements, and cause fewer hospitalizations. Disease Activity and Remission Neal S. Birnbaum, MD, followed Mr. Kenney and discussed disease activity in RA, patients who may benefit from aggressive RA treatment, and therapeutic strategies that minimize disease activity. His presentation was titled Correlations of Disease Activity and Remission in Rheumatoid Arthritis. Patients with high disease activity have the following characteristics: poor functional status, hand-joint involvement, earlier age at disease onset, symmetric arthritis, joint symptoms for ≥12 months, high titer of rheumatoid factor or anti-cyclic citrullinated peptide, elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), swelling of >3 joints, radiographic evidence of erosions or cartilage loss, and extra-articular manifestations such as nodules, scleritis, pericarditis, and vasculitis. There are several ways to assess disease activity, including physical examination, functional status, extra-articular findings, imaging techniques, and laboratory tests. Dr. Birnbaum mentioned several measures of RA activity and/or responses to therapy, among them ACR 20, ACR 50, ACR 70, Disease Activity Score (DAS 28), and Health Assessment Questionnaire (HAQ). The DAS 28 includes an assessment of 28 joints for tenderness and swelling, measurement of ESR or CRP, and a patient global disease assessment. Meanwhile, the HAQ score is a robust predictor of remission, according to Dr. Birnbaum. It demonstrates a close connection with the rate of disability and functional status, pain, mortality, and healthcare costs. Dr. Birnbaum also spoke about the ACR guidelines for managing RA. The organization recommends immediately initiating aggressive inflammation control after confirming diagnosis of RA; employing structured protocols and regularly reviewing progress toward treatment goals; and incorporating disease duration (<6 months, 6-24 months, >24 months), disease activity (low, moderate, high), and features of poor prognosis in treatment decisions. Dr. Birnbaum said remission is the treatment goal, and he recommended early treatment. Common nonbiologic DMARDs intended to treat RA (azathioprine, corticosteroids, hydroxychloroquine, leflunomide, MTX, minocycline, and sulfasalazine) have limitations, according to Dr. Birnbaum. There is a lack of efficacy in some patients, the drugs may not slow radiographic progression, and there are some tolerability and toxicity concerns. The US Food and Drug Administration has also approved the following biologic therapies to treat RA: etanercept, infliximab, adalimumab, golimumab, and certolizumab (all 5 are TNF inhibitors), as well as anakinra, abatacept, rituximab, and tocilizumab. RA Remission Robert J. Lipsy, PharmD, FASHP, BCPS, was the final speaker and titled his presentation Practical Approaches to Achieve RA Remission in Managed Care. According to Dr. Lipsy, there are 17,738 hospitalizations per year for primary diagnosis of RA. Patients stay in the hospital an average of 4.2 days at an average cost of $34,544, which is more expensive than treating asthma, diabetes, and hypertension. RA drugs represent 26.8% of specialty drug costs. “We need to have clear patient expectations,” Dr. Lipsy said. “Do people want a reasonable amount of time before switching therapies? We need to have realistic expectations on what patients have to pay.” Dr. Lipsy said aggressive treatment leads to lower total costs, with incremental cost- effectiveness ratios per quality of life year ranging from $50,000 to $89,772, which is well within the acceptable limits. He also said remission rates can lead to remission. Several factors affect remission, among them severity and duration of disease, prognostic factors, current drugs, duration of therapy, and previous therapy. In treatment-naïve patients, remission rates are between 25% and 45%. In patients with early RA and good prognostic factors, remission rates are as high as 59%. In patients with early RA treated with a biologic DMARD, remission rates are 41%, while patients with RA treated with a nonbiologic DMARD have a 23% remission rate. After switching to adalimumab, patients have a remission rate between 5% and 33%. And after switching to tocilizumab, remission rates are between 12% and 30%. Dr. Lipsy also spoke about the International Task Force Goals for RA, which target remission as the ultimate goal and low disease activity (LDA) as secondary. The guidelines also include eliminating signs and symptoms, adjusting therapy every 3 months if necessary, measuring active disease every 1 to 3 months and LDA or remission every 3 to 6 months, using validated composite scores, measuring structural changes and function, maintaining the desired target, modifying the target based on patient factors, and having a rheumatologist inform patients and plan their treatment. To manage RA, the European League Against Rheumatism recommends starting treatment as soon as the RA diagnosis is made, adjusting treatment every 1 to 3 months, including MTX as part of the first treatment, and considering leflunomide or sulfasalazine if MTX is contraindicated. The recommendations also include considering DMARD monotherapy versus DMARD combinations in DMARD-naïve patients; considering glucocorticoids plus DMARD monotherapy as initial short-term therapy; considering adding a biologic DMARD if the target is not achieved and when poor prognostic factors are present; adding a DMARD to MTX if there is an insufficient response to MTX and/or other synthetic DMARDs; switching to another TNF inhibitor, abatacept, rituximab, or tocilizumab if anti-TNF therapy fails; considering azathioprine or cyclosporin A in patients with refractory or severe RA when biologics are contraindicated; considering intensive medication strategies in every patient; considering tapering biologics if patients achieve persistent remission; considering titration of synthetic DMARD in cases of sustained long-term remission; considering combined MTX and a biologic in DMARD-naïve patients with poor prognostic markers; and considering progression of structural damage, comorbidities, and safety concerns when adjusting treatment. Implementing guidelines can improve outcomes, according to Dr. Lipsy, who said 7 studies of clinical, functional, and structural outcomes of targeted treatment demonstrated clinical improvement. In addition, 2 of 4 studies demonstrated radiographic benefit. Dr. Lipsy concluded his presentation by saying RA is an excellent candidate for structured care, remission can be achieved through aggressive treatment and monitoring, clinical practice guidelines are robust, disease activity can be assessed using validated instruments that impose little burden on providers, quality indicators have been developed, and nonrheumatologist physicians and physician extenders positively impact RA outcomes. “All the ingredients are there for drug utilization and improved patient outcomes,” Dr. Lipsy added.¬—Tim Casey

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