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Supplements Improving Clinical and Managed Care Outcomes in Rheumatoid arthritis: a Focus on Comparative Effecti

Comparative Effectiveness of Current Treatments for Rheumatoid Arthritis

Allan Gibofsky, MD, JD, FACP, FCLM
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

 
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