Aggressive Treatment of Early Rheumatoid Arthritis: Recognizing the Window of Opportunity and Treating to Target Goals

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)

Introduction

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"

Figure 1

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 (). 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

Table 1

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 ().

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.

The TICORA (TIght COntrol for Rheumatoid Arthritis) study demonstrated the benefits of using a treat-to-target approach in early RA.¹⁴ This single-blind, 18-month study compared the effectiveness of routine care (n = 55) with intensive management (n = 55) in patients who had RA for less than 5 years. Intensive management included monthly assessment of disease progression and a protocol-based escalation of DMARDs-monotherapy or combination therapy with sulfasalazine, methotrexate, and/or hydroxychloroquine. Other DMARDs and corticosteroids were used when needed. Patients in routine care were reviewed every 3 months and DMARD monotherapy was given to patients with active synovitis. Failure of treatment in these patients resulted in a change to an alternative monotherapy or combination therapy (2 or 3 agents) at the discretion of the rheumatologist. The mean fall in Disease Activity Score (DAS) was greater in the intensive management group than in the routine care group (-3.5 vs -1.9; P <.0001). Patients in the intensive management group were more likely to attain remission (65% vs 16%; P <.0001). Despite the 65% remission rate in the intensive management group, radiographic analysis of these patients showed a median increase in total Sharp Score of 4.5, which, while significantly better than the routine care group (median increase of 8.5; P = .02), still indicated progression of joint damage. (Scoring was performed by 2 radiologists who compared the radiographs of hands and feet from 0 month and 18 months.)

With respect to disease remission, it is important to note that patients can fall in and out of remission, and the percentages reported in clinical trials typically refer to a particular time point (in this case, at the 18-month assessment). The study concluded that intensive outpatient management of RA can substantially decrease disease activity while improving physical function and quality of life. This study also demonstrated that patients who experience clinical benefits from antirheumatic therapy do not necessarily experience comparable radiographic benefits. A more recent study confirmed the clinical and radiographic benefits of a systematic DAS-driven therapy compared with routine care when treatment is at the discretion of the physician.¹⁶

Therapeutic Options for Early RA

Conventional DMARDs

A good response, including remission, can be achieved in some patients treated with conventional DMARDs. As described earlier, results from the TICORA study demonstrated that an intensive step-up DMARD treatment strategy was superior to routine care for patients with early RA.¹⁴ A follow-up study compared step-up therapy (n = 47; sulfasalazine monotherapy for 3 months, followed by addition of methotrexate, followed by addition of hydroxychloroquine) with parallel triple therapy (n = 49; therapy initiated with the 3-drug combination).¹⁷ Both groups showed significant improvement in disease activity and functional outcome with no significant differences observed between the 2 treatment groups. A separate pilot study of 21 patients with active early RA showed that intensified and tightly controlled COBRA treatment (sulfasalazine, methotrexate, and high-dose step-down prednisolone, intensified by adding hydroxychloroquine and continued low-dose prednisolone) resulted in a remission rate of 90% (19 of 21 patients) after 40 weeks.¹⁸ These studies demonstrate that remission can be achieved with conventional DMARDs when part of an intensive and tightly controlled management plan.

Table 2

In addition to the potential for a good response with conventional DMARDs, remission is often sustained over the long term. The FIN-RACo study compared patients treated with triple DMARD therapy plus prednisolone with those treated with monotherapy for the first 2 years (before unrestricting treatment strategy while still targeting remission).^9,10 Better outcomes were observed with initial combination therapy than with monotherapy, including remission at 2 years and sustained remission (defined as remission at 6, 12, and 24 months) (). At the 11-year follow-up, a higher percentage of patients who received combination therapy experienced minimal disease activity and disease remission.

Although it is generally accepted that combination DMARD therapy is more effective than monotherapy (and triple therapy is more effective than dual combinations), further research is needed to determine the most effective regimens and approaches to utilize these combinations during the course of disease progression.¹⁹ Guidelines for the use of methotrexate for rheumatic disorders recommend the use of methotrexate monotherapy for DMARD-naïve patients. Methotrexate should also be considered the anchor for combination therapy when methotrexate monotherapy does not achieve adequate disease control.²⁰ When used concomitantly with biologic drugs, methotrexate decreases the formation of antibodies against biologics, particularly chimeric drugs.

Glucocorticoids

Glucocorticoids, such as prednisone, are often used in the United States as an adjunct to DMARDs for early and advanced RA to help induce remission or delay progression of disease.²¹ Often, glucocorticoids are used as "bridge" therapy to rapidly control inflammation while awaiting the effects of slower-acting agents. A recent systematic review evaluated the efficacy of glucocorticoids in the management of RA.²² Eleven studies were included in the assessment and the data suggested that the addition of glucocorticoids to conventional DMARD monotherapy or combination therapy produced clinical benefits and inhibited radiographic progression of disease, which may extend for several years. BeSt study results (discussed later in this paper) showed that combination therapy with prednisone was comparable to initial combination therapy with a biologic agent (infliximab) in achieving low disease activity and radiographic progression over 6 years.²³

Additional studies are clearly needed to fully understand the role of glucocorticoids in the management of early RA.

Biologic Agents: Tumor Necrosis Factor Antagonists

Antirheumatic biologic agents are the latest addition to the armamentarium to treat RA and have made disease remission a possibility for a significant percentage of patients. However, because the use of these agents is often limited due to cost constraints, it is important to recognize when a biologic agent offers clear advantages to conventional DMARDs in the management of RA. The first biologic agents were tumor necrosis factor (TNF) antagonists; these include etanercept, infliximab, adalimumab, golimumab, and certolizumab.

The BeSt study demonstrated that biologic agents can play an important role in the treatment of early RA.^24,25 It compared the clinical and radiographic efficacy of 4 treatment strategies: sequential monotherapy (n = 126); step-up combination therapy (n = 121); initial combination therapy with methotrexate, sulfasalazine, and tapered high-dose prednisone (n = 133); and initial combination therapy with methotrexate and infliximab (n = 128). Therapy in all groups was frequently monitored and adjusted as needed. Initial combination therapy with either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year when compared with sequential monotherapy or step-up combination therapy. However, all 4 groups were comparable for several other assessments over time, suggesting that the initial therapeutic approach may not be as important as ensuring that prompt adjustments to therapy are performed when needed.²³ Some patients in each group were eventually able to achieve drug-free remission.

The SWEFOT trial compared triple DMARD therapy with methotrexate plus infliximab in patients with early RA (symptom duration <1 year) who were not previously treated with a DMARD and had moderate disease activity as determined by the DAS in 28 joints ([DAS28] >3.2).²⁶ Patients were first treated with methotrexate (20 mg/week) for 3 to 4 months. Patients who did not achieve a DAS²⁸ less than 3.2 at the end of this period were randomized to additionally receive sulfasalazine plus hydroxychloroquine (n = 130) or infliximab (n = 128). The use of methotrexate as initial therapy was found to be sufficient in approximately one third of the patients. At month 12, 25% of the patients in the triple DMARD group achieved a EULAR good response compared with 39% in the infliximab plus methotrexate group (P = .0160). These results suggest that although a large portion of patients responded well without biologic therapy, the addition of an anti-TNF agent was superior to the addition of conventional DMARDs in patients who fail to respond to methotrexate therapy.

Figure 2

Several studies have compared the use of anti-TNF agents (with or without methotrexate) with methotrexate therapy for early RA. The PREMIER study, a randomized, doubleblind trial, compared adalimumab and methotrexate combination therapy (n = 268) with adalimumab monotherapy (n = 274) or methotrexate monotherapy (n = 257).^27,28 Patients included in the study had active disease (duration <3 years) and were not previously treated with methotrexate. After 2 years, a greater percentage of patients in the combination therapy group achieved ACR20/ACR50/ACR70/ACR90 than those in either monotherapy group (). (ACR20/ACR50/ACR70/ACR90 responses were defined as at least 20%, 50%, 70%, and 90% improvement in tender and swollen joint counts and 3 of 5 parameters [CR P, HAQ Disability Index, pain score, and assessors' and patients' global assessment].) Combination therapy was also associated with significantly less radiographic progression of disease (1.9 increase in Sharp units) compared with methotrexate monotherapy (10.4 increase in Sharp units) and adalimumab monotherapy (5.5 increase in Sharp units).

Table 3

The COMET study-COmbination of Methotrexate and ETanercept in active early rheumatoid arthritis-compared methotrexate plus etanercept combination therapy with methotrexate monotherapy in treatment-naïve patients with confirmed RA.^29,30 Patients in the combination therapy group who completed year 1 of the study were randomized to receive either the same combination therapy or etanercept monotherapy. Patients initially in the methotrexate monotherapy group were randomized to receive either the same monotherapy or combination therapy. After 1 year, combination therapy was associated with significantly better DAS28 remission rates (50% vs 28%; P <.0001). After 2 years, clinical remission rates were significantly higher with both continued and delayed combination therapy compared with continued methotrexate monotherapy (). Radiographic nonprogression was significantly better with continued combination therapy (P <.01).

Remission is a realistic therapeutic goal when combination therapy is initiated during early stages of RA. Etanercept in combination with methotrexate was superior to methotrexate monotherapy in providing clinical remission and radiographic nonprogression of disease. However, methotrexate monotherapy was effective in more than one third of patients (producing disease remission) and halted radiographic progression in two thirds of patients. Delaying the use of etanercept did not seem to reduce the incidence of clinical remission, although an advantage was observed in radiographic nonprogression with early etanercept therapy (comparing etanercept-methotrexate/etanercept-methotrexate vs methotrexate/etanercept-methotrexate). Whether this difference justifies initial use of a biologic agent in early RA must be based on clinical and cost-effectiveness analyses.

Higher remission rates with biologic agents were also observed in the ASPIRE study-Active-controlled Study of Patients receiving Infliximab for the treatment of Rheumatoid arthritis of Early onset. This study compared infliximab plus methotrexate combination therapy with methotrexate monotherapy in patients with early RA (duration ≤3 years) who had not previously received methotrexate.³¹ At week 54, clinical remission, as defined by the simplified disease activity index, occurred more frequently in the combination therapy group-21.3% versus 12.3% (P <.001). This study also showed that with methotrexate monotherapy, joint damage progressed even with low disease activity. Infliximab plus methotrexate more effectively inhibited radiographic progression across all disease activity states.

The approval of golimumab and certolizumab provides additional options for clinicians in the management of RA. Golimumab plus methotrexate showed positive results compared with methotrexate alone in patients with early-onset RA.³² Certolizumab also showed rapid and sustained improvements in clinical efficacy and patient-reported outcomes.^33,34

Biologic Agents: Others

Other biologic agents approved for the treatment of RA inhibit different pathways of inflammation and include abatacept (inhibits T-lymphocyte activation), rituximab (causes depletion of B-lymphocytes), and tocilizumab (inhibits interleukin-6 receptor). Westhovens and colleagues assessed the efficacy of abatacept in methotrexate-naïve patients with early RA and poor prognostic factors in a randomized, double-blind, placebocontrolled study.³⁵ Patients with RA (duration <2 years) were randomized to receive abatacept and methotrexate combination therapy or placebo and methotrexate. Patients were required to be seropositive for RF or anti-cyclic citrullinated peptide antibodies, and have radiographic evidence of joint erosions. After 1 year of therapy, combination therapy with abatacept was associated with a significantly higher percentage of patients achieving disease remission by DAS28 (CRP) criteria (41.4% vs 23.3%; P <.001) and less radiographic progression of disease (as measured by Genant-modified total Sharp Score; mean change = 0.63 vs 1.06; P = .04) than methotrexate and placebo.

The authors concluded that in methotrexate-naïve patients with early RA, abatacept and methotrexate combination therapy results in significantly better clinical and radiographic outcomes compared with methotrexate monotherapy.

Table 4

Published studies with rituximab generally involve patients who had an inadequate response to prior antirheumatic therapy. The SERENE study-Study Evaluating Rituximab's Efficacy in methotrexate iNadequate rEsponders-compared 2 doses of rituximab (2×500 mg and 2×1000 mg) with placebo in patients with inadequate response to methotrexate.³⁶ Patients in all groups continued to receive methotrexate. Both doses of rituximab resulted in a higher percentage of patients achieving ACR20, ACR50, and ACR70 after 24 and 48 weeks (). Rituximab has also been shown to reduce radiographic progression of disease in patients who do not respond to anti-TNF therapy.³⁷

In the AMBITION study, tocilizumab monotherapy was compared with methotrexate monotherapy in patients with moderate to severe RA who had not previously failed methotrexate or biologic therapy.³⁸ Tocilizumab was superior to methotrexate at achieving ACR20 (69.9% vs 52.5%; P <.001) and DAS28 remission (DAS28 <2.6) (33.6% vs 12.1%).

Biologic Agents: Head-to-Head Studies

Table 5

Because of a general lack of randomized clinical trials that compare the efficacy of biologic agents, head-to-head comparisons are largely based on placebo-controlled studies, chart-based retrospective analyses, and registry studies. In the ATTEST study-Abatacept or infliximab versus placebo, a Trial for Tolerability, Efficacy, and Safety in Treating rheumatoid arthritis-the addition of abatacept or infliximab therapy to methotrexate was compared with the addition of placebo to methotrexate in patients with RA who failed to respond to methotrexate therapy.³⁹ At month 6, the mean change in DAS28 scores was significantly greater for both abatacept and infliximab compared with placebo. At month 12, significantly more patients achieved an ACR20 response with abatacept than infliximab ().

A nationwide Danish registry study compared the use of and response to anti-TNF agents as the initial biologic treatment for RA.⁴⁰ In the study, 29% received adalimumab, 22% received etanercept, and 49% received infliximab. Treatment with adalimumab was found to have the highest rates for treatment response and disease remission whereas infliximab had the lowest rates. The drug survival rate was greatest for etanercept and lowest for infliximab. However, in the absence of prospective head-to-head randomized studies, it is difficult to judge whether one agent offers clear advantages over others.

Cost-Effective Approaches to Care

In general, the efficacy of biologic agents is largely comparable when considering broad patient populations, although individual response to treatment can vary greatly. This can be a challenge for payers trying to identify the most cost-effective approaches to managing RA. The 2008 ACR guidelines recommend initiating therapy with conventional DMARDs, which can be more cost-effective than starting therapy with biologic agents.¹ As described previously, although clinical trial results tend to favor biologic agents over conventional DMARDs, a significant portion of patients with early RA (typically ≥30%) will respond to conventional DMARD therapy. Therefore, initial treatment with 1 or more conventional DMARDs may be appropriate, while reserving biologic agents for patients with an inadequate response or with high disease activity.

When a biologic agent is needed, the guidelines recommend concomitant use with a conventional DMARD, such as methotrexate, as evidence suggests better clinical and radiographic results. However, evidence for step-up therapy versus initial combination therapy remains conflicting. As described earlier with the BeST study, an initial combination containing infliximab or prednisone results in earlier functional improvement and less radiographic progression of disease compared with sequential monotherapy or step-up combination therapy with conventional DMARDs.²⁴ However, after 6 years of DAS-steered therapy, the rates of low disease activity and remission were comparable in all 4 treatment groups, and radiographic progression had stabilized during this time.²³ Given these results, choosing a treatment strategy may be more critical than specific choice of drugs in achieving optimal outcomes, as long as an intensive management program is followed with frequent follow-up and therapeutic adjustments. From an economic standpoint, this may lead to fewer hospitalizations and office visits, better quality of life, and maintained work productivity, leading to lower long-term costs.⁴¹

Loss of work productivity can contribute greatly to the overall costs of RA. A cohort from the FIN-RACo study was followed for 5 years to estimate work absence from sickness and income losses due to RA.⁴² An estimated 75% of patients lost work days, and the mean loss of productivity per patient-year was €7217 (2002 euros). There was an inverse correlation with lost productivity and clinical improvement, while lost productivity was directly associated with the number of erosions. Other studies have confirmed the benefits of DMARD therapy, particularly biologic agents, on work productivity, prevention of job loss, work absenteeism, quality of life, and household productivity.^11,43-49

It remains to be seen whether reducing the loss of work productivity can outweigh the higher acquisition costs of biologic agents. The BeSt study showed that initial combination therapy with infliximab resulted in significantly better quality of life at 2 years compared with other less costly treatment strategies.⁵⁰ The results may be different after a longer time period. However, a cost-utility analysis demonstrated that the cost to achieve this difference is generally too high to be considered, especially since the clinical and radiographic benefits with infliximab were not much different from combination therapy with prednisone at various timepoints.⁵⁰

This result was confirmed in a cost-effectiveness analysis model that compared 3 treatment strategies: (1) a "pyramid" strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, and low-dose corticosteroids, with DMARDs given at 1 year for nonresponders; (2) early methotrexate therapy; and (3) early biologic agents plus methotrexate therapy.⁵¹ The model showed that both of the early therapy strategies increased quality-adjusted life-years (QALYs) more than the pyramid strategy and saved long-term costs. The cost of early DMARD therapy versus the pyramid strategy was $4849 per QALY, while the cost for biologic therapy versus the pyramid strategy was substantially higher ($727,894 per QALY). The authors concluded that the use of biologic agents should be reserved for patients with more treatment-resistant disease of longer duration. However, the cost-effectiveness of biologic therapy can be improved if (1) drug prices are lower; (2) the risk of death is permanently reduced with biologic therapy; (3) patients experience drug-free remission; (4) responders can be selected prior to therapy initiation; and (5) effective alternative treatments are available for patients in whom several biologic agents have failed.

When a biologic agent is needed, it is important to recognize if there are differences in the cost-effectiveness among available drugs. One modeling study evaluated the cost-effectiveness of sequential therapy with anti-TNF agents for early RA.⁵² The use of anti-TNF agents as part of the sequential therapy produced a greater number of QALYs gained compared with using conventional DMARDs alone. The use of sequential therapy initiated with adalimumab plus methotrexate resulted in a cost of $47,157 per QALY gained, which was more cost-effective compared with infliximab and etanercept sequences.

Based on available health economic evidence, a systematic review was performed to evaluate economic aspects of treatment options for RA.⁵³ The use of conventional DMARDs at the onset of disease was found to be cost-effective. If therapy fails, escalation with anti-TNF agents is recommended and it is cost-effective when standard dosing regimens are used. If anti-TNF agents fail, rituximab or abatacept are cost-effective options. It is important to note that the authors emphasize that intensive escalation of treatment is justified in patients with RA due to the costly consequences of uncontrolled disease. Tocilizumab, golimumab, and certolizumab were likely too new in the marketplace for evaluation, although tocilizumab was included as a search term. A goal of treatment must include keeping patients productive in the work environment, thus decreasing indirect costs.

It will be important to continue to evaluate the cost-effectiveness of antirheumatic agents as conditions change, including acquisition cost fluctuations, new agent availability, and new clinical trial results with head-to-head comparisons of biologic agents. When choosing among biologic agents, it is also important to consider drug administration, such as the need for intravenous infusion in a clinic versus self-administration of subcutaneous injections at home. The availability of oral biologic agents will also have an impact on management approaches, although it is uncertain whether they will provide any cost advantages over currently available agents. Finally, although not reviewed in this article, it is important to mention that all antirheumatic agents have the potential for adverse events, and it is important to consider patient characteristics and comorbidities when selecting an appropriate agent. Although clinical trials have yet to distinguish differences in efficacy among biologic agents across populations, individual patients will respond differently to each agent. Therefore, treatment must be individualized for each patient and the response must be regularly monitored to determine if therapeutic adjustment is needed. Nonetheless, managed care professionals must make use of the available data to recognize today's environment in RA management and find a balance between achieving clinical targets and minimizing costs.

Author Affiliations: University of Oklahoma College of Pharmacy (BHR -T), Oklahoma City, OK; Vemco MedEd, LLC (MPC), Bridgewater, NJ.

Funding Source: Supported by an educational grant from Genentech and Biogen Idec.

Author Disclosures: The authors (BHR-T, MPC) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (BHR-T, MPC); acquisition of data (BHR-T); analysis and interpretation of data (BHR-T, MPC); drafting of the manuscript (BHR-T, MPC); and critical revision of the manuscript for important intellectual content (BHR-T, MPC).

Address correspondence to: Beth H. Resman-Targoff, PharmD, FCP, University of Oklahoma College of Pharmacy, 1110 N Stonewall Ave, Oklahoma City, OK 73117. E-mail: beth-resman-targoff@ouhsc.edu.

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