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Aggressive Treatment of Early Rheumatoid Arthritis: Recognizing the Window of Opportunity and Treating to Target Goals
Beth H. Resman-Targoff, PharmD, FCCP, and Marco P. Cicero, PhD
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Treat to Target: Rheumatoid Arthritis Management in a Value-Based Healthcare System
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Aggressive Treatment of Early Rheumatoid Arthritis: Recognizing the Window of Opportunity and Treating to Target Goals

Beth H. Resman-Targoff, PharmD, FCCP, and Marco P. Cicero, PhD


Evidence supports the use of aggressive therapy for patients with early rheumatoid arthritis (RA). Clinical outcomes in patients with early RA can improve with a treat-to-target approach that sets the goal at disease remission. The current selection of antirheumatic therapies, including conventional and biologic disease-modifying antirheumatic drugs (DMARDs), has made disease remission a realistic target for patients with early RA. The challenge is selecting the optimal antirheumatic drug or combination of drugs for initial and subsequent therapy to balance the clinical benefits, risks, and economic considerations. In some cases, the use of biologic agents as part of the treatment regimen has shown superior results compared with conventional DMARDs alone in halting the progression of disease, especially in reducing radiographic damage. However, the use of biologic agents as initial therapy is challenged by cost-effectiveness analyses, which favor the use of conventional DMARDs. The use of biologic agents may be justified in certain patients with poor prognostic factors or those who experience an inadequate response to conventional DMARDs as a means to slow or halt disease progression and its associated disability. In these cases, the higher cost of treatment with biologic agents may be offset by decreased societal costs, such as lost work productivity, and increased health-related quality of life. Further research is needed to understand optimal strategies for balancing costs, benefits, and risks of antirheumatic drugs. Some key questions are (1) when biologic agents are appropriate for initial therapy, and (2) when to conclude that response to conventional DMARDs is inadequate and biologic agents should be initiated.

(Am J Manag Care. 2010;16:S249-S258)



The management of rheumatoid arthritis (RA) has undergone a paradigm shift in the past 15 to 20 years. Factors contributing to this include changes in treatment strategies and the development of antirheumatic biologic agents that down-regulate aspects of the host inflammatory response. In light of these advancements, recent updates have been made by leading organizations regarding clinical recommendations for the use of conventional and biologic agents for treating RA, and criteria for the classification of early RA.1,2

Contemporary approaches to the diagnosis and management of RA have made disease remission an attainable goal for some patients. Disease remission can prolong the health-related quality of life while reducing the long-term societal costs of RA. However, it is important for clinicians to incorporate economic considerations when deciding management approaches that can help optimize outcomes for patients with RA.

This review discusses the latest evidence-based approaches supporting aggressive treatment of early RA as a means to achieve optimal outcomes and reduce the clinical and economic burden of this disease.

Progression of RA

RA is a heterogeneous disease that can lead to severe joint damage and disability. Disease progression can vary greatly among patients, and predicting outcomes in patients with RA can be critical in selecting optimal management strategies. Studies have attempted to identify prognostic factors for progression of disease, with notable factors including the baseline radiographic score, erythrocyte sedimentation rate, C-reactive protein (CRP), and the presence of rheumatoid factor (RF) and anti-citrullinated protein antibody.3-5 The presence of risk factors can aid clinical decision-making. For patients predicted to be at high risk for rapid radiographic progression of disease, the use of more aggressive initial therapy, followed by a more rapid advancement of their regimen, would be justified.5 Conversely, for patients at lower risk, a less expensive, less rigorous treatment strategy could be considered.

A growing body of evidence is demonstrating that early therapeutic interventions can lead to greater improvement in clinical outcomes and greater reduction in joint damage and disability. Unfortunately, active therapy for early RA is often delayed, which can have long-term consequences in disease progression. A report from the Early Rheumatoid Arthritis Network showed that the median time from onset of symptoms to the start of the first disease-modifying antirheumatic drug (DMARD) was 8 months.6 This delay can have lasting consequences and hinder efforts to prevent permanent damage from RA.

The difficulty in identifying and treating patients with early RA has been a lack of uniform criteria that can differentiate patients who present with undifferentiated arthritis who are likely to progress to RA. In September 2010, the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) jointly published RA classification criteria that focus on features at earlier stages of disease for a "definite RA" classification.2 Although the goal of this classification scheme was primarily to aid recruitment of patients for clinical trials, these criteria can be an important guide to recognize patients who would benefit from early therapeutic intervention. Incorporating these criteria among other diagnostic approaches can be important in identifying patients at early stages of RA who would benefit most from aggressive treatment.

Evidence for a Therapeutic "Window"

The medical literature describes a "window of opportunity" to prevent permanent damage when managing patients with early RA.78 Decreases in HAQ score suggested response to therapy and represented a reversible component; continued elevations in HAQ score suggested irreversible damage. The percentage of the HAQ score that was reversible decreased as the duration of disease increased (Figure 1). Data suggest that early treatment of patients with RA may result in greater benefits than therapy started later in the disease course. Evidence suggests that remission is more likely in patients with early RA than in patients with long-standing disease. Aletaha and colleagues studied the effect of RA duration on reversibility of physical impairment. They compiled data from 6 clinical trials on patients who achieved remission (n = 2763) and compared the disability index of the Health Assessment Questionnaire (HAQ) score at study entry to time of remission and identified reversible and irreversible components of the HAQ score.

Further evidence for this "window of opportunity" was demonstrated in the FIN-RACo (Finnish Rheumatoid Arthritis Combination Therapy) study (described in greater detail later in this paper).9,10 The results from this study showed that early suppression of disease (by 6 months) was associated with maintenance of work capacity at 5 years.11 More aggressive therapy (initial combination therapy with conventional DMARDs vs monotherapy) was associated with a better earlier response that was sustained long term (up to 11 years). Clinicians must be aware of the potential long-term consequences of delaying antirheumatic treatment while recognizing the benefits of early, aggressive approaches.

Contemporary Treatment Strategies

Early Aggressive Therapy

The large amount of data demonstrating the benefits of aggressive treatment of patients with early RA has garnered support for changing management strategies to maximize the possibility of achieving disease remission. A group of practicing rheumatologists in the United Kingdom published a set of treatment principles with the goal of reducing cumulative inflammation in patients with early RA.12 The 4 core principles of management include: (1) detect and refer patients early, even if the diagnosis is uncertain; (2) treat RA immediately; (3) tight control of inflammation in RA improves outcome; and (4) consider the risk-benefit ratio and tailor treatment to each patient.

The latest ACR treatment guidelines (published in 2008) support the use of conventional DMARDs in patients at early stages of RA.1 For patients with a disease duration less than 6 months, conventional DMARDs are favored and recommended, even for patients with low disease activity, and with or without features of poor prognosis. For patients with early RA (disease duration <6 months), biologic agents are recommended only for patients who experience high disease activity for 3 to 6 months, or those with high disease activity for less than 3 months and features of poor prognosis (depending on cost or insurance coverage limitations). Clearly, the use of antirheumatic agents in patients diagnosed with early RA can be important in optimizing patient outcomes, although the selection of an agent or combination of agents must be based on individual factors, such as the duration and severity of disease, the presence of prognostic factors for debilitating disease, and comorbidities.

Treat to Target

Treating to target means using specific parameters to decide whether or not treatment needs to be modified to meet treatment goals (such as remission or low disease activity). It has also been demonstrated that structured patient management that aims to meet defined targets leads to better outcomes than traditional care strategies.13,14 To promote optimal management tactics for treatment and follow-up, an international task force developed a set of recommendations to improve the management of RA by emphasizing treating to target.15 This set of 10 recommendations was developed with the goal of informing patients, rheumatologists, and other stakeholders about strategies to reach desired outcomes in patients with RA (Table 1).

These recommendations do not focus on particular therapeutic choices or take into account the potential for financial constraints and access to therapy. However, it is noted that clinical outcomes for patients with RA can be significantly improved with adherence to treatments that are normally easily accessible and affordable. Remission is the ultimate goal, particularly for patients with early RA. Yet, it is important to note that remission does not mean cure; patients may relapse and some definitions of remission allow residual disease activity. To reach this target of remission, frequent follow-up with the rheumatologist (sometimes every month) and therapy adjustment (at least every 3 months) is recommended until the target goal is reached. In addition to patients and clinicians, these recommendations can be an important reference for payers to assess success of patients being treated for RA and recognize the steps needed to reach this target.

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