Comparative Effectiveness of Current Treatments for Rheumatoid Arthritis

Supplements and Featured Publications, Improving Clinical and Managed Care Outcomes in Rheumatoid arthritis: a Focus on Comparative Effecti, Volume 18, Issue 13 Suppl

An optimal treatment approach to rheumatoid arthritis (RA) is guided by the American College of Rheumatology (ACR) 2012 recommendations. RA should be diagnosed early in the disease process and treatment should be commensurate with the degree of disease activity and the presence or absence of predictors of poor prognosis. The Agency for Healthcare Research and Quality (AHRQ) has recently provided a comparative review of medication for RA. The treatment of RA with conventional disease-modifying antirheumatic drugs and biologic agents, including tumor necrosis factor (TNF) inhibitors and non-TNF biologics (abatacept, rituximab, tocilizumab) will be discussed in the context of the ACR recommendations and the AHRQ review.

(Am J Manag Care. 2012;18:S303-S314)Rheumatoid arthritis (RA) is the most common inflammatory disease involving the joints.1 According to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria, patients with at least 1 joint with clinical synovitis, not explained by another disease, should be scored according to 4 domains (required score at least 6 out of a possible 10). Scoring is based on the number and type of joints involved, the presence or absence of antibodies (rheumatoid factor [RF] or anti-citrullinated protein antibody [ACPA]), the presence or absence of acute-phase reactants (C-reactive protein or erythrocyte sedimentation rate [ESR]), and duration of symptoms (<6 weeks vs >6 weeks).2 The scoring system reflects the underlying pathophysiology, which is characterized by autoantibody production, systemic inflammation, synovial infiltration, joint swelling, and bony erosions.3 In addition to articular involvement, extraarticular involvement affects various organ systems in a widespread manner and leads to an increased risk of death compared with the general population.3 The purpose of this article is to review the goals of treatment, approach to treatment, and monitoring of outcomes in patients with RA with currently available therapies. Special focus will be placed on the role of newer biologic agents and their comparative data. Clinical scenarios reviewed will include management of early disease and disease refractory to current therapy.

Goals of Therapy

The underlying systemic inflammatory disease process of RA results in joint damage, disability, fatigue, reduced quality of life, and increased mortality.1 Treatment goals have historically focused on reduction in pain and joint symptoms, with control of inflammation being a secondary goal. The development of newer medications, discussed in the next section, have resulted in greater control of disease progression.1 This, in turn, has resulted in revision of the disease classification criteria, which are now focused on earlier identification of RA to prevent long-term complications.2 Validated indices used for monitoring disease activity in clinical trials4 have been proposed for wider use in clinical practice.5 The commonly used disease-monitoring indices are summarized in Table 1.5 They characterize RA according to whether there is low disease activity (LDA), moderate disease activity (MDA), high disease activity (HDA), or remission. The development of these reliable and robust validated indices has resulted in the concept of a treat-to-target strategy in RA.6 Identification of those features associated with poor prognosis allows the clinician to “titrate” the aggressiveness of pharmacologic interventions. Poor prognosis is associated with any of the following features of disease: functional limitation on standardized health questionnaires, extra-articular disease, positive RF, positive ACPA, or bony erosions documented by radiograph.5 Current goals are to attain remission or LDA to prevent joint damage, disability, and long-term disease complications (eg, cardiovascular disease).1

Treatment Options

EULAR has identified 3 overarching principles in the treatment of RA.7 The first is that rheumatologists are specialists who should primarily care for patients with RA. The second principle states that the treatment of patients with RA should aim at the best care, and must be based on a shared decision between the patient and the rheumatologist. The third principle acknowledges that RA is expensive in regard to medical costs and productivity costs, both of which should be considered by the treating rheumatologist.7 The 2012 update of the 2008 ACR recommendations for medication management of RA provides a written framework, based on best evidence, for handling clinical scenarios commonly experienced in the care of patients with RA.5

Supportive Therapy

Historically, treatment of RA focused on symptom control with pain management and nonsteroidal anti-inflammatory agents. While this approach helped reduce symptoms, it did not prevent bone or cartilage damage.6 Alternative and complementary therapies have inconsistently demonstrated benefit for symptom management of RA.8 Occupational therapy, hydrotherapy, and dynamic exercise may be useful adjuncts to pharmacologic therapy.1 While glucocorticoids improve symptoms of RA (eg, morning stiffness),5 they are generally not considered disease-modifying agents (when used as monotherapy). In early disease, however, some experts have argued that corticosteroids may indeed have disease-modifying effects.9 Their impact on disease progression will be discussed in more detail in the section on combination therapy.9-11

Disease-Modifying Anti-Rheumatic Drugs: Efficacy and Safety

Because supportive therapies fail to alter disease progression, research has been centered on the development of biologic therapies that may alter disease progression. Currently available medications are summarized in Table 2, including a summary of a comparative review recently conducted by the Agency for Healthcare Research and Quality (AHRQ).5,6,12-14 Agents target the underlying pathophysiology of RA, including suppression of immune activation, antigen presentation, and pro-inflammatory cytokine production. There are 9 biologic agents available, 5 with presumed similar mechanisms of action, and 4 with different mechanisms of action. The primary nonbiologic conventional disease-modifying anti-rheumatic drugs (DMARDs) include leflunomide, methotrexate, and sulfasalazine. Patients’ ability to remain on long-term therapy (ie, persistence) was improved with methotrexate compared with sulfasalazine.14 Methotrexate is considered the “anchor” DMARD, because of the extensive positive clinical and published experience accumulated with this agent.

Based on comparative effectiveness data,14 anakinra was the least effective and the least well tolerated biologic agent. These data are consistent with results from a Cochrane metaanalysis,15 which concluded, through indirect comparison, that the biologic agents had similar efficacy for attaining an ACR 50% (ACR50) responder index. Anakinra was less effective than etanercept with an odds ratio (OR) of 0.34 (95% confidence interval [CI], 0.14-0.81; P = .015) and adalimumab was more efficacious than anakinra (OR, 2.20; 95% CI, 1.01-4.75; P = .046). In terms of safety, the Cochrane review concluded that adalimumab was more likely to lead to drug discontinuations compared with etanercept (OR, 1.89; 95% CI, 1.18-3.04; P = .009); anakinra more likely than etanercept (OR, 2.05; 95% CI, 1.27-3.29; P = .003); and etanercept less likely than infliximab (OR, 0.37; 95% CI, 0.19-0.70; P = .002).15 Another Cochrane review focused on the adverse effects of the biologic agents compared with placebo.16

The overall risk of adverse events was higher with biologics (OR, 1.28; 95% CI, 1.09-1.5), including increased risk of withdrawals due to adverse effects (OR, 1.47; 95% CI, 1.2- 1.86) and serious infections (OR, 1.37; 95% CI, 1.04-1.82). Certolizumab (OR, 4.75; 95% CI, 1.52-18.65) and anakinra (OR, 4.05; 95% CI, 1.22-16.84) resulted in a statistically higher infection rate than placebo.16 Infliximab was associated with a statistically higher risk of total adverse events (OR, 1.55; 95% CI, 1.01-2.35) and drug discontinuations due to adverse events (OR, 2.34; 95% CI, 1.4-4.14) than placebo.

A meta-analysis conducted by Aaltonen and colleagues recently examined tumor necrosis factor (TNF) inhibitors (eg, adalimumab, certolizumab, etanercept, golimumab, infliximab) with regard to efficacy and safety.17 The metaanalysis demonstrated that the overall ACR50 response to TNF inhibitor monotherapy at 6 months was greater than with placebo (risk ratio [RR], 4.07; 95% CI, 2.7-6.13), which was statistically improved relative to placebo by the individual agents adalimumab, etanercept, and certolizumab, but not infliximab or golimumab. Additionally, TNF inhibitor combination therapy with methotrexate was more effective than methotrexate alone (RR, 4.7; 95% CI, 3.07-7.19) or a TNF inhibitor alone (RR, 1.53; 95% CI, 1.08-2.17). Interestingly, high doses (relative to normal doses) of TNF inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab) did not improve ACR50 (RR, 1.02; 95% CI, 0.9-1.15). For the safety analysis, defined by discontinuation of therapy, TNF inhibitors did not differ from placebo (RR, 1.26; 95% CI, 0.93-1.71). However, patients receiving infliximab (RR, 3.22; 95% CI, 1.76-5.91), adalimumab (RR, 1.59; 95% CI, 1.13-2.23), and certolizumab (RR, 2.72; 95% CI, 1.23-6.01) had an increased risk of drug discontinuation; those receiving etanercept (RR, 0.71; 95% CI, 0.54-0.92) had a decreased risk. When TNF inhibitor monotherapy was compared with methotrexate alone, there was no difference in adverse events, with the exception of more infusion or injection reactions with TNF therapy. When TNF inhibitors were combined with methotrexate and compared with methotrexate alone, the risk of drug discontinuation was greater with the combination (RR, 1.37; 95% CI, 1.01-1.87).17

In addition to the AHRQ summary14 and available metaanalyses,15-17 several real-life comparisons of biologic therapy have been recently published.18-23 Yonemoto and colleagues retrospectively compared infliximab, etanercept, adalimumab, and tocilizumab in 147 Japanese patients who were all biologic naïve and started therapy at about the same time. At 12 months, the therapy continuation rate was 86% for infliximab, 78% for etanercept, 73% for adalimumab, and 91% for tocilizumab.18 In the Swedish Biologics Register, infliximab, adalimumab, and etanercept were compared for drug discontinuation over time. Infliximab had a higher discontinuation rate than adalimumab or etanercept, while adalimumab had a higher discontinuation rate than etanercept.19 In an Italian database study, when infliximab, etanercept, and adalimumab were compared, etanercept had a lower discontinuation rate than infliximab, primarily due to a lower discontinuation rate for lack of efficacy. The discontinuation rate for adalimumab was between those of the aforementioned DMARDs, but it was not statistically different.20 Similar findings were noted in a Hong Kong registry.21 Another registry analysis sought to determine time to response and efficacy in 526 treatment courses between abatacept, adalimumab, etanercept, infliximab, and rituximab. Efficacy, defined by a reduction of at least 3.6 points in the RAPID3 ([Routine Assessment of Patient Index Data 3], a patient survey score designed for routine care) score, was achieved in a greater percentage of patients receiving abatacept (66%) versus adalimumab (63%), etanercept (61%), infliximab (43%), and rituximab (41%). Time to response in the first 6 months was not statistically different.22 In a prospective cohort of 617 patients with RA treated with etanercept (n = 250), infliximab (n = 206), or adalimumab (n = 161), “good response” was assessed using EULAR criteria. All comparisons yielded similar results ([etanercept vs adalimumab, OR, 0.97; 95% CI, 0.55-1.71], [etanercept vs infliximab, OR, 1.25; 95% CI, 0.74-2.12], [infliximab vs adalimumab, OR, 0.8; 95% CI, 0.47-1.36]). Better educational background, defined as the number of years of formal education, was associated with a better treatment response, and smoking, presence of ACPA, glucocorticoid use, and worse baseline disease activity were associated with reduced likelihood of response.23 Thus, real-world efficacy and safety outcomes in patients with RA receiving biologic agents tend to mirror clinical trial-based meta-analysis results.

Early RA

In a landmark study, the Early Rheumatoid Arthritis (ERA) trial, Bathon and colleagues compared etanercept with methotrexate in 632 patients with early RA.24 At 6 months, etanercept resulted in 20%, 50%, and 70% improvement in disease activity compared with methotrexate (P <.05 for each assessment). The erosion score increased 0.3 in the etanercept group and 0.68 in the methotrexate group at 6 months (P <.001), and 0.47 and 1.03 (P = .002) at 12 months, respectively.24 A 2-year follow-up of the trial demonstrated that the erosion scores were 0.66 in the etanercept group and 1.86 in the methotrexate group (P = .001), and more patients in the etanercept group (55%) had a 0.5 unit or greater increase in the Health Assessment Questionnaire than those in the methotrexate group (37%, P <.001).25 The meta-analysis by Aaltonen and colleagues also determined that the ACR50 response in patients with early disease (defined as a duration <2 years) was greater with TNF inhibitor monotherapy compared with placebo (RR, 1.36; 95% CI, 1.14-1.62).17 However, by current standards, having symptoms for 2 years before initiating therapy is considered delayed. Emery and colleagues reported that in a post hoc analysis of data from the Combination or Methotrexate and Etanercept (COMET) study, very early (<4 months) versus early (>4 months but <2 years) initiation of combination therapy (etanercept and methotrexate) resulted in improvements in LDA and remission. Very early combination therapy resulted in improvements in LDA relative to early therapy (79% vs 62%, P <.05) and remission (70% vs 48%, P <.05). In patients receiving methotrexate alone, similar results were not observed for very early initiation versus early initiation (LDA, 47% vs 47%; remission, 35% vs 32%). No radiographic evidence of progression was observed in 80% of the combination therapy group, regardless of duration of RA; however, a larger portion of patients who initiated treatment very early with methotrexate alone had no radiographic progression, relative to those in the early group (73.9% vs 50%, P <.01).26,27 These results add to the existing body of literature that supports early initiation of aggressive treatment for RA.28-31 It is important to note that the AHRQ publication supported a similar clinical response between methotrexate and TNF inhibitors (as a class),14 but it is known that the conventional DMARDs are relatively slow to achieve the desired therapeutic effect. The historical name for these agents was SAARDs, or slowly acting antirheumatic drugs, suggesting that the timing of measured outcome is critical in the assessment of overall effectiveness.12

As evidenced by a change in the classification criteria, there is now a great deal of interest in the early diagnosis of RA.2 Early initiation of effective treatment is a predictor of good clinical response, and it can prevent disease progression.32 The ACR has proposed an algorithm for the management of early RA (Figure 1).5 The treatment algorithm suggests that DMARD monotherapy (hydroxychloroquine, leflunomide, methotrexate, minocycline, or sulfasalazine) may be sufficient for patients with LDA or MDA without features of poor prognosis. Combination DMARD therapy (double or triple agent) is recommended for patients with MDA who have features of poor prognosis. Patients with HDA without features of poor prognosis are recommended to receive DMARD monotherapy or hydroxychloroquine plus methotrexate. Patients with HDA and features of poor prognosis are recommended to receive a TNF inhibitor with or without methotrexate, or double or triple non-biologic DMARD therapy.5 This approach is generally supported by the AHRQ findings, in which 2 or 3 DMARDs plus prednisone were more effective in improving ACR50 response and radiographic progression than DMARD monotherapy. The AHRQ document noted that the addition of oral prednisone to any oral non-biologic DMARD resulted in less radiographic progression and fewer eroded joints than an oral DMARD alone. Additionally, the AHRQ identified LDA, radiographic progression, and better quality of life with the combinations of methotrexate, sulfasalazine, and tapered prednisone or methotrexate and infliximab compared with sequential DMARD monotherapy or a step-up combination. However, at 2 years, there was no difference in quality of life, and at 4 years, no difference in remission.14 Importantly, the AHRQ analysis did not stratify treatments based on risk; however, it is appropriate to administer only DMARD monotherapy (methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine) to the lowest risk group.14

Combination non-biologic DMARD therapy has been studied in early RA with promising results.33-35 A recent study, the TEAR (Treatment of Early Aggressive RA) trial, partially validated the approach recommended by the ACR for early RA to control disease activity.5,35 Patients were randomly assigned to 1 of 4 treatment arms: immediate treatment with methotrexate plus etanercept, immediate oral triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine), or step-up from methotrexate monotherapy to one of the combination therapies (methotrexate plus etanercept or methotrexate plus sulfasalazine plus hydroxychloroquine) at week 24 if the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) score was 3.2 or higher. Approximately 43% of patients were taking corticosteroids at baseline. At week 24, the combination regimens demonstrated similar reductions in DAS28-ESR scores, but greater reductions than in the methotrexate monotherapy arm. For weeks 48 to 102, the DAS28-ESR scores were similar between stepped-up and initial combination therapy (3.2 in both groups). There was no significant difference in DAS28-ESR scores between oral triple therapy or methotrexate plus etanercept (3.1 vs 3.2). However, by week 102, there was significant radiographic improvement with methotrexate plus etanercept versus oral triple therapy (0.64 vs 1.69, P = .047).35 The consequences of progression in radiographic changes in the triple combination group are uncertain. The enrolled patients tended to have HDA based on a DAS28-ESR score of 5.8, and also appeared to have a poor prognosis, since 87% to 92% of patients (depending on the assigned group) were positive for RF. HDA and poor prognosis would have made these patients candidates for TNF inhibitor therapy in the current treatment paradigm.5 Given that response to treatment is very heterogeneous in RA, the step-up recommendations of the ACR algorithm are appropriate. However, TNF inhibitors may be better as initial therapy for the highest risk patients to reduce the likelihood of radiographic progression.6

DMARD or Biologic Failure

The ACR recommendations also provide a framework for treating established RA (Figure 2).5 Based on the observed response to treatment, the regimen algorithm is very dynamic, and patients may segregate into different parts of the algorithm, based on response to treatment. The goal is for patients to achieve LDA. Similar to the approach for early RA, Figure 2 demonstrates that treatment for established RA is based on assessment of disease activity and prognosis. Once a therapy is started, it should be reassessed at least every 3 months using the definitions of disease activity in Table 1. LDA without poor prognosis may be managed with step-up therapy from DMARD monotherapy to a second DMARD agent initially, and then to either TNF inhibitor monotherapy or the addition of a TNF inhibitor. Upon reassessment, more serious disease or poor prognosis may be treated by adding or switching to another DMARD, changing to TNF inhibitor monotherapy or adding a TNF inhibitor to the existing regimen, or adding or switching to abatacept, rituximab, or tocilizumab. Once patients are receiving biologic agents, they should be assessed for serious adverse events, and reassessed for efficacy at least every 3 months. If serious adverse events related to TNF inhibitor therapy occur, patients can be switched to a different class of biologic agent.5

The AHRQ summary supports the combination of biologic therapy with methotrexate over biologic therapy alone, methotrexate alone, or a biologic with other non-methotrexate DMARDs for improvement in disease activity, radiographic progression, quality of life, and functional capacity. If patients cannot take methotrexate, biologic therapy alone is preferred over combining a biologic with a non-methotrexate DMARD.14 The addition of sulfasalazine to methotrexate did not improve disease response or functional capacity compared with sulfasalazine or methotrexate alone. The addition of oral prednisone to any oral DMARD resulted in less radiographic progression and greater functional capacity than a DMARD alone. Of significance, the use of a combination of biologic agents is contraindicated.

In the DRAG RACE study, patients with RA for approximately 10 years who failed DMARD therapy and never received a biologic agent (ie, were biologic naïve) were given infliximab, etanercept (25 mg or 50 mg per week), or adalimumab in addition to methotrexate. The study demonstrated that there was no difference among the 3 groups with respect to disease activity by a number of validated index scales at 4 to 6 weeks of treatment.36 ATTEST (Abatacept or infliximab vs placebo, a Trial for Tolerability, Efficacy and Safety in Treating rheumatoid arthritis) was a randomized, placebo-controlled study of infliximab and abatacept in patients with an inadequate response to methotrexate. Both infliximab and abatacept improved DAS28-ESR relative to placebo at 6 months. At 1 year, disease responses were numerically greater for abatacept than for infliximab, adverse effects were numerically less with abatacept than infliximab, and abatacept improved the physical component scale score of the health-related quality of life assessment to a greater degree than infliximab (difference in improvement score, 1.93; 95% CI, 0.2-3.84).37 In another study, abatacept was compared with adalimumab, both given subcutaneously.38 At 1 year, 86.2% of abatacept-treated patients and 82% of adalimumab-treated patients remained on therapy; 64.8% and 63.4% were considered ACR20 responders, respectively. Rates of ACR50 and ACR70 response, kinetics of response, radiographic progression, and total adverse effects were also similar. Compared with patients receiving adalimumab, those receiving abatacept had fewer injection site reactions (9.1% vs 3.8%, respectively; mean difference, —5.37; 95% CI –9.13 to –1.62), discontinuations due to adverse events (6.1% vs 3.5%), and discontinuations due to the number of serious infections (5 vs 0), but they had a higher number of autoimmune adverse effects (3 vs 10 events).38 These results support results from other studies which document the benefit of biologic therapy in combination with methotrexate when non-biologic DMARDs fail.39,40

A meta-analysis compared biologic therapies in patients with an inadequate response to 1 or more TNF inhibitors. 41 The meta-analysis included data from 4 trials with 24 weeks’ follow-up in patients receiving abatacept, golimumab, rituximab, or tocilizumab. All agents increased ACR 20% improvement (ACR20), ACR50, and ACR 70% improvement (ACR70) compared with placebo, and did not demonstrate an increased risk of adverse events versus placebo. Indirect comparison of the agents showed similar ACR50 and ACR70 responses, but a lower chance of achieving an ACR20 response with golimumab (OR, 0.56-0.59). Golimumab was also associated with fewer adverse effects (risk difference, 0.13-0.18). It was noted that efficacy after 1 versus multiple TNF failures did not differ between the agents. The authors concluded that abatacept, golimumab, rituximab, and tocilizumab had similar efficacy with a favorable safety profile in patients refractory to 1 or more TNF inhibitors.41 In an open-label extension of the ATTEST trial, patients who received infliximab were eligible to cross over to abatacept at 1 year. At years 1 and 2, 19.7% and 26.1% of abatacept-treated patients achieved remission (defined by a DAS28 score of <2.6) respectively, and 13.3% and 28.6% of those who switched from infliximab to abatacept achieved remission.42 In another study, abatacept and tocilizumab were compared in patients who failed to respond to rituximab.43 The small, single-center study demonstrated that tocilizumab improved DAS28-ESR at 6 months to a greater degree than abatacept. Recently presented data have confirmed the effectiveness of tocilizumab in patients refractory to TNF inhibitors or DMARDs.44-48

The role of rituximab in TNF-refractory patients was clarified by recent data.49-51 Rituximab was found to be superior to switching to an alternate TNF inhibitor in non-randomized cohorts.49,50 Another study highlighted the potential consequences of delaying effective therapy in patients who failed to respond to TNF inhibitor therapy. Such patients who were receiving methotrexate were randomized to placebo or rituximab; however, those receiving placebo were given rescue rituximab at about 1 year after initiation. Those patients who initially received rituximab (versus placebo) had improvements in modified Total Sharp Score (a radiographic progression metric) at years 1, 4, and 5, despite rituximab rescue in the placebo group. Most of the progression appeared to occur in the first year in patients given placebo. These results highlighted the potential harms of delaying effective therapy by approximately 1 year.51

This research adds credibility to the practice of either switching patients not responding to a TNF inhibitor to a second TNF inhibitor or switching to an agent with a different mechanism of action. As mentioned previously, RA is considered a heterogeneous disease, and patient response to standard treatments varies. Although disease activity has improved in the last decade with TNF inhibitors, a significant portion of patients still fail to achieve remission or do not show significant improvement with TNF inhibitors. These suboptimal treatment outcomes may be due in part to the limitations of anti-TNF biologics, including lack of efficacy in a significant proportion of patients, loss of efficacy over time, associated risk of infections, and high cost. Data from randomized trials provide evidence to support the benefit of switching from a TNF inhibitor to a biologic DMARD from a different class (eg, abatacept, rituximab) in the difficult-to-treat patient population.

Monitoring Treatment Outcomes and Predicting Response to Treatment

In addition to the traditional measures of treatment efficacy (eg, disease activity monitoring instruments, radiographic assessment), clinicians should monitor the patient for other clinical outcomes and adverse effects of drug therapy.5 Quality-of-life tools, assessment of pain and fatigue, and functional ability are all relevant treatment efficacy outcomes.52 There is also a great deal of interest in developing biomarkers for monitoring treatment response, such as immune target changes (ie, IL-6, TNF-α, autoantibody levels) or disease activity markers, but none are validated or have consistently demonstrated a role in studies.6 When LDA or remission is achieved, it may be possible to reduce the dose or withdraw 1 or more agents. Although this approach has only been modestly successful, disease remission biomarkers could improve the current capability to achieve a meaningful outcome.53-56 With respect to tools that could predict response to treatment, a number of patient, disease, and comorbidity factors have been suggested. As noted previously, patients with RA of longer disease duration do not respond as well to treatment as patients with early disease. Additionally, female sex, prior DMARD use, advanced disease, functional class, and advanced disease activity also affect the likelihood of patient response to DMARD treatment.32 With TNF inhibitor therapy, a better educational background (based on number of years of formal education) was associated with better treatment response, but smoking, the presence of ACPA, glucocorticoid use, and worse baseline disease activity were associated with reduced likelihood of response.27 Tools that can predict the efficacy of an agent could eliminate the expense of administering ineffective therapies, and potentially halt disease progression associated with time to implement an effective therapy, but these tools are currently not well developed. Patients also require monitoring for common and serious adverse effects, such as opportunistic infections.16 There is much interest in developing tools to identify patients at risk for serious infections on a given therapy, but such tools are not completely validated or are limited in current use.57 Until such predictive tools are available on a widespread basis, the ACR provides recommendations for clinical monitoring to prevent serious infections.5


The 2012 ACR treatment recommendations provide a clear framework for pharmacologic treatment approaches to patients with RA. This review provides an assessment of the comparative benefits of agents to assist clinicians and managed care professionals in selecting medications within that framework.5 Early disease with high-risk characteristics warrants aggressive therapy with a combination of methotrexate and biologic therapy to reduce the signs and symptoms of disease, prevent radiographic progression of disease, and most importantly, improve patient-reported outcomes and healthrelated quality of life.Author affiliation: Weill Medical College of Cornell University, Hospital for Special Surgery, New York, NY.

Funding source: This activity is supported by an educational grant from Bristol-Myers Squibb.

Author disclosure: Dr Gibofsky reports consultancy/advisory board membership, honoraria, lectureship, and stock ownership with Abbott, Amgen, Genentech, Pfizer, and UCB. He also reports stock ownership with Johnson & Johnson and GlaxoSmithKline.

Authorship information: Analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: Mail to: Allan Gibofsky, MD, Hospital for Special Surgery, 535 E 70th St, New York, NY 10075. E-mail: gibofskya@

  1. Combe B. Progression in early rheumatoid arthritis. Best Prac Res Clin Rheumatol. 2009;23(1):59-69.
  2. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581.
  3. McInnes IB, Schett G. The pathogensis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-2219.
  4. Felson DT, Smolen JS, Wells G, et al; American College of Rheumatology; European League Against Rheumatism. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;639(3):573-586.
  5. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5):625-639.
  6. Isaacs JD. The changing face of rheumatoid arthritis: sustained remission for all? Nat Rev Immunol. 2010;10(8):605-611.
  7. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010;69(6):964-975.
  8. Macfarlane GJ, Paudyal P, Doherty M, et al; on behalf of the Arthritis Research UK Working Group on Complementary and Alternative Therapies for the Management of the Rheumatic Diseases. A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: rheumatoid arthritis. Rheumatology (Oxford). 2012;51(9):1707-1713.
  9. Kirwan JR, Buttgereit F. Symptom control with low-dose glucocorticoid therapy for rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 4):iv14-iv20.
  10. Bijlsma JW. Disease control with glucocorticoid therapy in rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 4): iv9-iv13.
  11. Hitt E. Prednisone delayed-release tablets approved for RA. Medscape Medical News. Published July 27, 2012. Accessed October 9, 2012.
  12. van Vollenhoven RF. Treatment of rheumatoid arthritis: state of the art in 2009. Nat Rev Rheumatol. 2009;5(10):531-541.
  13. Matsutani T, Murakami M, Lee H-M, et al. Abatacept (CTLA4- IG) suppresses T cell activation and reduces TH17 cells as well as plasma IL-6 in patients with rheumatoid arthritis. Ann Rheum Dis. 2012;71(suppl 3):383.
  14. Donahue KE, Jonas D, Hansen RA, et al. Drug therapy for rheumatoid arthritis in adults: an update: executive summary. Comparative Effectiveness Review Number 55. AHRQ Publication No. 12-EHC025-1. Rockville, MD: Agency for Healthcare Research and Quality; April 2012. Accessed August 14, 2012.
  15. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2009;4:CD007848.
  16. Singh JA, Wells GA, Christensen R, et al. Adverse effect of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;2:CD008794.
  17. Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS ONE. 2012;7(1):e30275.
  18. Yonemoto Y, Okamura K, Takeuchi K, et al. Direct comparison of four biological agents in bio-naïve rheumatoid arthritis. Ann Rheum Dis. 2012;71(suppl 3):185.
  19. Neovius M, Arkema E, Olsson H, Eriksson J, Simard J. Drug discontinuation in 6,657 patients with RA starting their first TFN inhibitor: comparison of adalimumab, etanercept and infliximab. Ann Rheum Dis. 2012;71(suppl 3):368.
  20. Caporali R, Scirè CA, Todoerti M, et al. Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and spondyloarthropathies: results from the Monitornet database. Ann Rheum Dis. 2012;71(suppl 3):370.
  21. Mok CC, Kwan KY, Chan KY, Lee KL, Tam LS. Retention rate of the anti-TNF biologics in the treatment of rheumatic diseases and predictive factors for drug withdrawal: data from the Hong Kong Registry. Ann Rheum Dis. 2012;71(suppl 3):663.
  22. Yazici Y, Regens AL, Swearingen CJ. Comparative effectiveness and time to response among adalimumab, abatacept, etanercept, infliximab and rituximab in a real world routine care registry. Ann Rheum Dis. 2012;71(suppl 3):342.
  23. Canhão H, Rodrigues AM, Mourão AF, et al. Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis [published online]. Rheumatology (Oxford). 2012; doi:10.1093/rheumatology/kes184.
  24. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343(22):1586-1593.
  25. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443-1450.
  26. Emery P, Kvien TK, Combe B, et al. Combination etanercept and methotrexate provides better disease control in very early (<4 months) versus early rheumatoid arthritis (>4 months and < 2 years): post hoc analysis from the COMET study. Ann Rheum Dis. 2012;71(6):989-992.
  27. Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372(9636):375-382.
  28. Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER Study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54(1):26-37.
  29. Bathon J, Robles M, Ximenes AC, et al. Sustained disease remission and inhibition of radiographic progression in methotrexate- naive patients with rheumatoid arthritis and poor prognostic factors treated with abatacept: 2-year outcomes. Ann Rheum Dis. 2011;70(11):1949-1956.
  30. Westhovens R , Robles M, Ximenes AC, et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis. 2009;68(12):1870-1877.
  31. Westhovens R, Wollenhaupt J, Gomez Reino JJ, et al. Efficacy of abatacept in patients with early (≤6 months) RA: results from AGREE post-hoc analysis. Ann Rheum Dis. 2012;71(suppl 3):670.
  32. Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 2000;43(1):22-29.
  33. Boers M, Verhoeven AC, Markusse HM, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997;350(9074):309-318.
  34. Landewé RB, Boers M, Verhoeven AC, et al. COBRA combination therapy in patients with early rheumatoid arthritis: longterm structural benefits of a brief intervention. Arthritis Rheum. 2002;46(2):347-356.
  35. Moreland LW, O’Dell JR, Paulus HE, et al; TEAR Investigators. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis. Arthritis Rheum. 2012;64(9):2824-2835.
  36. Hirano Y, Oishi Y, Yamauchi K, Mieno T. A comparative study of early clinical efficacy among three anti-TNF agents—DRAG RACE study. Ann Rheum Dis. 2012;71(suppl 3):666.
  37. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096-1103.
  38. Schiff M, Fleischmann R, Weinblatt M, et al. Abatacept SC versus adalimumab on background methotrexate in RA: one year results from the AMPLE study. Ann Rheum Dis. 2012;71(suppl 3):60.
  39. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;349(20):1907-1915.
  40. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al; TEMPO Study Investigators. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum. 2006;54(4):1063-1074.
  41. Schoels M, Aletaha D, Smolen JS, Wong JB. Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: systematic review and indirect pairwise meta-analysis. Ann Rheum Dis. 2012;71(8):1303-1308.
  42. Schiff M, Keiserman M, Codding C, et al. Clinical response and tolerability to abatacept in patients with rheumatoid arthritis previously treated with infliximab or abatacept: open-label extension of the ATTEST study. Ann Rheum Dis. 2011;70(11):2003- 2007.
  43. Das S, Horton S, Vital E, Bryer D, Emery P, Buch M. Response to abatacept and tocilizumab in patients who had failed rituximab— initial single center experience. Ann Rheum Dis. 2012;71 (suppl 3):183.
  44. Ogata A. The MUSASHI study: comparison of subcutaneous tocilizumab monotherapy versus intravenous tocilizumab monotherapy: results from a double-blind, parallel-group, comparative phase III non-inferiority study in Japanese patients with rheumatoid arthritis. Ann Rheum Dis. 2012;71(suppl 3):373.
  45. Östör A, Román Ivorra JA, Wollenhaupt J, et al. Comparison of tocilizumab as monotherapy or in combination with nonbiological disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) and an inadequate response to anti-TNF agents. Ann Rheum Dis. 2012;71(suppl 3):372.
  46. Avdeeva AS Alexandrova EN, Panasyuk EY, Lukina GV, Nasonov EL. Comparative effectiveness of tocilizumab (TCZ) and rituximab (RTM) using different disease activity indices (DAS28, SDAI and CDAI) in patients with rheumatoid arthritis. Ann Rheum Dis. 2012;71(suppl 3):667.
  47. Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab (TCZ) monotherapy is superior to adalimumab (ADA) monotherapy in reducing disease activity in patients with rheumatoid arthritis (RA): 24-week data from the phase 4 ADACTA trial. Ann Rheum Dis. 2012;71(suppl 3):152.
  48. Dougados M, Kissel K, Conaghan PG, et al. Clinical, radiographic, and immunogenic effects after 1 year of tocilizumab (TCZ)-based treatment strategy with and without methotrexate (MTX) in RA: the ACT-RAY study. Ann Rheum Dis. 2012;71(suppl 3):185.
  49. Emery P, Gottenberg J-E, Sarzi-Puttini P, et al. Relative effectiveness of rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis and an inadequate response to a single previous TNF inhibitor: results from the SWITCH-RA, a global, comparative effectiveness, observational study. Ann Rheum Dis. 2012;71(suppl 3):381.
  50. Kekow J, Mueller-Ladner U, Schulze-Koops H. Rituximab is more effective than second anti-TNF therapy in rheumatoid arthritis patients and previous TNFα blocker failure. Biologics. 2012;6:191-199.
  51. Keystone E, Cohen SB, Emery P, et al. Sustained inhibition of structural damage in patients with rheumatoid arthritis and an inadequate response to tumour necrosis factor inhibitors prior to rituximab treatment: 5-year data from the REFLEX study. Ann Rheum Dis. 2012;71(suppl 3):374.
  52. Somers TJ, Shelby RA, Keefe FJ, et al. Disease severity and domain-specific arthritis self-efficacy: relationships to pain and functioning in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2010;62(8):848-856.
  53. Funahashi K, Kojima T, Takahashi N, et al. The effectiveness of shortening intervals of infliximab and dose escalation of infliximab with rheumatoid arthritis in multi-center clinical practice. Ann Rheum Dis. 2012;71(suppl 3):367.
  54. Machold KP. Prevention and cure of rheumatoid arthritis: is it possible? Best Prac Res Clin Rheumatol. 2010;249(3):353-361.
  55. Smolen JS, Emery P, Ferraccioli G, et al. Maintenance of remission in rheumatoid arthritis patients with low-moderate disease activity following withdrawal of certolizumab pegol treatment: week 52 results from the CERTAIN study. Ann Rheum Dis. 2012;71(suppl 3):361.
  56. Nieto-González JC, Martínez-Estupiñan L, Hernández D, et al. Modified antiTNF dose patterns in clinical practice: achieving clinical control with minimum effective dosages. Ann Rheum Dis. 2012;71(suppl 3):517.
  57. Stranfeld A, Manger B, Eisterhues C, Krause A, Listing J, Zink A. Validation of the RABBIT risk score for serious infections. Ann Rheum Dis. 2012;71(suppl 3):102.