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Supplements Improving Clinical and Managed Care Outcomes in Rheumatoid Arthritis: New Guidelines, Therapies, and

Current Therapeutic Agents and Treatment Paradigms for the Management of Rheumatoid Arthritis

Allan Gibofsky, MD, JD, FACP, FCLM
Effective management of rheumatoid arthritis (RA) is based on early treatment with pharmacological agents that are appropriate for the degree of disease activity and the presence or absence of indicators of poor prognosis. The 2012 American College of Rheumatology (ACR) treatment recommendations provide clear guidance for pharmacologic management of patients with RA. Although the optimal use of biologic and non-biologic disease-modifying drugs has transformed the treatment of RA to the extent that remission is a reasonable expectation, choice of a particular agent for use in a specific clinical situation remains unclear. Recently, Cochrane reviews as well as a Comparative Effectiveness Review by the Agency for Healthcare Research and Quality have examined the safety and efficacy of these drugs, with a particular emphasis on biologics. The conclusions of these reviews will be examined in the context of the ACR treatment recommendations.

(Am J Manag Care. 2014;20:S136-S144)
Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease that usually manifests clinically as symmetric arthritis that affects the small joints of the hands and feet. The characteristic feature of RA is inflammation of the synovium, the membranous lining of the joints, with associated local production of degradative enzymes that eventually destroy joint structures.1 In addition to the pain, disability, and work limitation associated with joint damage, the systemic inflammatory effects of RA also cause and/or contribute to extraarticular comorbidities and psychosocial deficits that further impair health-related quality of life and increase morbidity and mortality in patients with RA compared with the general population.2

During the past 15 years, the treatment of RA has been revolutionized by the development of new disease-modifying antirheumatic drugs (DMARDs), particularly biologic agents. Together with new disease management paradigms, these agents have made remission of disease a realistic goal for the treatment of RA.3 This article will review current therapeutic options for RA, how they are used, and their effectiveness and safety.

Therapeutic Goals of RA Treatment

The advances in the treatment of RA that have been made over the past 15 years are best exemplified by changes in the expectations for therapeutic outcome. Historically, treatment of RA focused on symptom control and pain management. In 2010, an international task force published a series of recommendations for a treat-to-target management approach to RA. This treatment strategy emphasized that the primary target for treatment of RA should be a state of clinical remission. Although low disease activity (LDA) may be an acceptable alternative therapeutic objective, particularly in patients with established, long-standing disease and considerable joint damage, this goal should be secondary to achieving remission. Until the desired outcome is reached, therapy should be adjusted as often as monthly in patients with high/moderate disease activity; adjustments should be made every 3 to 6 months in patients with sustained LDA or remission.3 This strategy was subsequently incorporated into the European League Against Rheumatism (EULAR) recommendations for the management of RA in 2010 and 2013, which also emphasized that treatment with synthetic DMARDs should begin as soon as the diagnosis of RA is made.4,5 Similarly, in the most recent American College of Rheumatology (ACR) guideline for the management of RA, remission or LDA is the goal of treatment in both early (disease duration <6 months) and established RA.6

The issue of what constitutes remission during RA treatment has evolved over time. In the first attempt by the ACR to define remission in RA, a distinction was made between “complete remission,” which implied a total absence of inflammation and immunological activity related to RA that would be difficult to measure, and “clinical remission,” a state that could be defined using conventional clinical measurements.7 The criteria for remission that were initially developed have not been widely used in clinical trials, both because some of the elements of the criteria are no longer assessed and because the criteria were so stringent that very few patients achieved remission.8

With the development of validated indices of disease activity such as the Disease Activity Score in 28 joints (DAS28), an attempt was made to establish a level of disease activity that could define remission. In an analysis of a large cohort of patients with RA who were receiving treatment, DAS28 scores (calculated using the erythrocyte sedimentation rate [ESR] as an index of inflammation) were validated against the 1981 ACR remission criteria. Based on the results of the analysis, clinical remission was defined as DAS28 less than 2.6.9 Subsequent studies have suggested that this degree of disease activity is not sufficiently stringent to define remission.10,11 The value of DAS28 indicative of remission also differs if the DAS28 is calculated using C-reactive protein (CRP) as the index of inflammation rather than ESR. When CRP is used, remission is defined as DAS28 less than 2.3.12 Most recently, a collaborative committee of the ACR and EULAR assessed the use of core set measures including, at a minimum, joint counts and levels of an acute-phase reactant to define remission. Based on these analyses, the committee has suggested 2 possible approaches to defining clinical remission in RA clinical trials. A patient can be considered to be in remission when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all less than 1 or, alternatively, when the score on the Simplified Disease Activity Index (SDAI) is less than or equal to 3.3.8 The SDAI is the numerical sum of 5 parameters that are measured during assessment of RA (tender and swollen joint counts, physician and patients global assessments of disease, and CRP).13

ACR Recommendations for Treatment of RA

A list of the medications currently used for the management of RA in the United States is shown in Tables 1 to 3. The available medications include corticosteroids, 4 conventional DMARDs, 1 targeted DMARD, and 9 biologic DMARDs (5 tumor necrosis factor [TNF] inhibitors and 4 other biologic DMARDs that act at other points in the inflammatory cascade).14,15

Tofacitinib is the most recent addition to the list of available agents for the treatment of RA, having received approval from the US Food and Drug Administration (FDA) in November, 2012. Tofacitinib is an oral inhibitor of janus kinase (JAK), an intracellular enzyme in a pathway that transmits signals from cytokine or growth factor–receptor interactions on the cellular membrane to the nucleus, where they can alter genomic expression.15 Other JAK inhibitors are in development. Other intracellular kinases that are potential targets for RA therapy include p38 mitogen-activated phosphokinase (MAPK) and spleen tyrosine kinase (Syk).16 Development of fostamatinib, the Syk inhibitor that was furthest along in the clinical testing process, was suspended in 2013 based on marginal efficacy results in phase 3 clinical trials.

Corticosteroids are used for management of the symptoms associated with a variety of inflammatory, autoimmune conditions. Corticosteroids are synthetic forms of cortisol that act by binding to steroid-specific receptors in the cytoplasm of cells, inhibiting the movement of inflammatory cells, neutrophil function, and prostaglandin production. In patients with RA, corticosteroids are prescribed based on their ability to reduce signs and symptoms of inflammation, joint pain, and swelling.14

Although there has been some renewed interest in using low-dose corticosteroids as a bridge to DMARD therapy in early RA, use of these drugs is limited by their adverse event profile. In a study that compared adverse 5-7.5, mg, or >7.5 mg daily) with adverse events in control subjects receiving no corticosteroids, investigators found a relationship between dosage and adverse events. Results showed there was a linear, dose-dependent increase in subcutaneous hematomas, leg edema, fungal infection, shortness of breath, and sleep disturbances. In addition, at dosages greater than 7.5 mg/day, increases in depression, glaucoma, and increased blood pressure were recorded.17

The ACR recommendations for the use of DMARDs are divided into 2 sections: treatment of early RA, defined as disease duration of less than 6 months, and treatment of established RA.6 The use of early RA as a separate treatment category is based on evidence indicating that delay in treatment is a strong prognostic factor for poor treatment response and that early, aggressive treatment increases the probability of effective response to treatment. One of the earliest indicators of the importance of treatment timing in determining therapeutic response was a meta-analysis of 14 randomized controlled trials (RCTs) that analyzed factors that affected the response to treatment (defined as achievement of an ACR 20 response) of approximately 1400 patients with RA. Disease duration at the initiation of treatment was one of the strongest predictors of response to therapy, with longer duration predicting a poorer response. The ACR20 response rate, regardless of the specific DMARD used, was 53% in RA patients with disease duration 1 year or less compared with 35% to 43% of those with a disease duration greater than 1 year.18

Early RA

The benefits of treating very early RA (≤4 months disease duration) were tested in a post hoc analysis of data from the Combination or Methotrexate and Etanercept (COMET) study. In this study, the response in patients with RA to treatment in terms of LDA (DAS28 <3.2) and remission (DAS 28 <2.6 or SDAI ≤3.3) was assessed after 52 weeks in patients with very early RA compared with patients with early RA (>4 months but <2 years). Combination therapy with etanercept and methotrexate (MTX) in patients with very early disease resulted in improvements in LDA and remission relative to early therapy (79% vs 62%; P = .014 and 70% vs 48%; P =.004, respectively). In patients receiving MTX alone, this effect was not seen. Patients with early RA and very early RA had similar rates of LDA and remission. No radiographic evidence of progression was found in 80% of the group receiving combination therapy, regardless of duration of RA. However, among patients who received MTX monotherapy, a higher percentage of patients with very early disease had no radiographic progression when compared with patients with early disease (73.9% vs 50%; P <.01). The authors concluded that very early treatment events in patients receiving corticosteroids (ie, <5 mg, with combined MTX and etanercept improves clinical outcomes compared with MTX monotherapy.19 These observations concerning the efficacy of early treatment of RA with DMARDs are particularly pertinent in light of one study’s finding that 41% of patients received a DMARD within 6 months of symptom onset. Time to referral to a rheumatologist represented the largest component of this delay.20

In the ACR algorithm for the treatment of early RA (disease duration <6 months), the choice of initial therapy is based on the level of disease activity (low, moderate, or high) and the presence or absence of features of poor disease prognosis. The level of disease activity is based on cut points of various instruments that are commonly used to measure disease activity. Thus, for example, if the DAS28 is used for assessment of disease activity, low disease activity would be defined as a score of 2.6 to 3.2; moderate disease activity, 3.2 to 5.1; high disease activity, greater than 5.1. Other instruments for which cut points are provided include the Routine Assessment of Patient Index Data (RAPID-3), Clinical Disease Activity Index (CDAI), and the SDAI. Designation of a patient as having features of poor prognosis is based on the presence of 1 or more of the following features: functional limitation, extra-articular disease, RA vasculitis, presence of rheumatoid factor, or anti-cyclic citrullinated peptide antibodies, and bony erosions on x-rays.6

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