Treatment of Very Early Rheumatoid Arthritis With Symptomatic Therapy, Disease-Modifying Antirheumatic Drugs, or Biologic Agents

Context It remains unclear whether the optimal treatment strategy for early rheumatoid arthritis (RA) is to step care from nonsteroidal anti-inflammatory drugs and other symptomatic treatments to glucocorticoids and then to disease-modifying antirheumatic drugs (DMARDs) only after 1 year, or to use more aggressive therapy early after diagnosis. Contribution The investigators used available data to estimate the cost-effectiveness of initial treatment strategies for RA. Compared with stepped care, early DMARDs or early biologic agents seem to improve outcomes, but only DMARDs do so at a cost per year of life saved that society typically considers acceptable. Caution Assumptions were based on limited data on early RA treatment with DMARDs and biologics. The Editors The treatment of rheumatoid arthritis (RA) has changed dramatically in the past decade with the introduction of new biologic therapies, particularly tumor necrosis factor inhibitors. Growing evidence suggests a benefit of aggressive treatment very early in the course of the disease and the existence of a critical therapeutic window of opportunity within which antirheumatic therapy is more effective and has a more durable effect than later in the course of the disease (1, 2). Very early initiation of disease-modifying antirheumatic drug (DMARD) or biologic therapy has a demonstrated prolonged benefit on RA progression and may permanently modify the disease to a milder course (1, 3). Emerging data also suggest that if RA is detected and treated very early, long-term control or remission may be possible and continuing treatment may not be necessary (46). Although antirheumatic therapy should be initiated as early as possible after disease onset, the optimal strategy has not been determined. Early treatment with biologics seems to be superior to treatment with conventional DMARDs in terms of hard outcomes, such as radiographic structural joint damage, but not necessarily in terms of disease activity (7). Biologics are generally prescribed only after therapy with 1 or more conventional DMARDs has failed. However, randomized, controlled trials (RCTs) have demonstrated improved efficacy of biologics in early disease (811), and the pharmaceutical industry promotes early initiation of biologic therapy for RA. Because early therapy may change the natural course of the disease (4), biologics could be most useful in early RA (4, 12, 13). Although evidence supports the cost-effectiveness of biologic therapy in DMARD-resistant severe RA (14, 15), its long-term cost-effectiveness in very early RA is unknown. The diagnosis of RA can be problematic very early in the course of disease (16). An early diagnosis carries the risk for prescribing expensive and potentially toxic drugs to patients who might have spontaneous remission. Patients may incur time lost from work because of treatment or drug-related toxicities or may die because of treatment (13). In addition, early antirheumatic therapy increases treatment costs; in particular, biologics cost up to 10 times more than conventional DMARDs. However, patients may benefit from early therapy, endure fewer disability days, have less productivity loss, require fewer days in the hospital, and need fewer subsequent joint replacements (13). It is therefore important to consider the total long-term costs associated with various therapeutic strategies. Health policy analyses use the incremental cost effectiveness ratio (ICER) to compare a particular treatment or strategy with competing treatment strategies to inform the allocation of health care resources (17). To determine whether the increased costs of treatment strategies that involve biologics in very early RA are warranted by health gains, we assessed the cost-effectiveness of major therapeutic strategies by examining different scenarios based on emerging data. Methods Decision Model Structure Our base-case analysis considers adults with very early RA, operationally defined as symptoms of less than 3 months in durationa definition commonly used in the literature for very early RA (18, 19). The classification criteria for RA require that signs and symptoms be present for at least 6 weeks (20), and studies of patients with early RA suggest a median duration of illness of 11 to 23 weeks at diagnosis (21, 22). However, RA cannot be reliably diagnosed at an early stage in all patients with inflammatory polyarthritis. A significant proportion of patients with undifferentiated arthritis will have spontaneous remission or receive diagnoses of other conditions (23, 24). Evolving diagnostic techniques, such as biomarkers (25) or improved clinical prediction rules for identifying which patients who present with undifferentiated polyarthritis will progress to RA, enable individualized decisions about initiation of treatment with DMARDs (23, 26). We used an individual sampling model (27) to track the course of disease over time, with changes in important variables (principally radiographic joint damage and functional disability) at time points at which events (toxicities, treatment initiation, treatment discontinuation, or death) occur. We estimated the expected lifetime costs and benefits for U.S. patients, expressed as quality-adjusted life-years (QALYs), from both a health care provider and a societal perspective. Our models explore 5 conceivable strategies, but we focus on the 3 most plausible and clinically relevant strategies for very early RA. Although these may vary in actual practice, we simplified the choices to model the problem. In the pyramid strategy, initial nonsteroidal anti-inflammatory drugs, patient education, joint protection and therapeutic exercise, pain management, and low-dose glucocorticoids are administered as needed, followed by DMARDs at 1 year for nonresponders. This is still the most common pattern of therapy because of delayed consultation and diagnosis (2830). In the early DMARD strategy, conventional DMARDs (such agents as leflunomide, sulfasalazine, hydroxychloroquine, or methotrexate) are given within 12 weeks of symptom onset. Methotrexate is the current standard of care in U.S. rheumatology (30) and also has the most evidence for its effectiveness in very early RA (6). The early biologic strategy involves very early use of biologics, defined as use of 3 sequential tumor necrosis factor inhibitors, in combination with methotrexate. In the first 2 strategies, patients initially receive conventional DMARDs; those who do not respond to therapy with 3 conventional DMARDs, alone or in combination, then receive agents from the third strategy. We modified a published model (31) for this analysis. We tracked hypothetical patient cohorts through the model, one at a time, in 6-month cycles from symptom onset until death. The exact route a simulated patient takes through the model depends on the therapeutic strategy used and the patient's disease characteristics (type of disease progression, age, sex, education level, race, income, duration of disease, comorbid conditions, baseline and current Health Assessment Questionnaire [HAQ] Disability Index score, and type and number of previously received DMARDs). Figure 1 shows model pathways. Figure 1. Model schematic. Patients can change disease state every 6 months, depending on the underlying disease type and the treatment strategy received. The time spent in a particular disease state determines the probability of transition and the ultimate outcome. DMARD = disease-modifying antirheumatic drug; HAQ = Health Assessment Questionnaire; RA = rheumatoid arthritis. * See Appendix for discussion of this strategy. Appendix. Technical Appendix We assume that patients follow 1 of 3 disease courses: drug-free remission, a mild course with slow disease progression, or rapid disease progression. At presentation, we assume that a patient's future course cannot be predicted. The patients' disease characteristics are representative of the U.S. population with RA (32). The model synthesizes data from RCTs (33); the National Data Bank for Rheumatic Diseases (NDB), a longitudinal database of semi-annual, self-reported patient data (32); and other literature. Details on disease progression, treatment effect, estimates for QALYs, and costs are provided in the following sections. Table 1 (3445) describes input variables, and the Appendix details our methods. We used R project statistical software (www.R-project.org) for all decision analyses. Table 1. Key Model Parameters and Assumptions Disease Progression We modeled the course of the disease by using functional disability and radiographic evidence of structural joint damage. Functional disability, measured by the HAQ (46), is a primary outcome in most RA clinical studies. Structural joint damage can be assessed by several radiographic scoring methods. We used the percentage of the maximum score of each measure to include all sources of information (39). We applied the rate of disease progression to each disease course pattern. Because these rates are often unknown over an extended period, we first assumed that all patients present with a HAQ score of 1 and no radiographic damage. We then used the literature as a guide for the mean progression rates in each disease course. Finally, we calibrated the overall progression for all disease courses. We calibrated the HAQ with data from the NDB that show increases during early disease to an annual HAQ score progression of around 0.03 in patients with established disease, similar to previous estimates (47). We assumed that radiographic damage increased linearly over time and calibrated it with rates of approximately 2% per year (48). We computed the relationship between radiographic damage and HAQ score. Estimates indicate that a 1percentage point change in radiographic progression is equivalent to a 0.04 change in HAQ score (38). However, the effect of radiographic progression on functional disability in early phases of disease is only expe