ABSTRACT: New rheumatoid arthritis (RA) classification criteria were published in 2010. Although classification criteria are intended primarily for clinical trials, they may be used as diagnostic aids in clinical practice and may affect treatment strategies. Early achievement and maintenance of remission results in improved functional and radiographic outcomes. Treatment strategies that focus on “treatment to target” have been shown to optimize outcomes in RA. Corticosteroids are used frequently in early arthritis in conjunction with disease-modifying therapies. Currently approved tumor necrosis factor α inhibitors have been used successfully in conjunction with other disease-modifying antirheumatic drugs and more often are used as combination therapy. Newer agents in development have been shown to be effective.
Rheumatoid arthritis (RA), estimated to affect 1.3 million adults in the United States, is the most common of the inflammatory arthritides.1 The pathogenesis is characterized by acute and chronic inflammatory changes to the synovium that over the long term result in joint damage, most of which has been recognized to occur early in the disease course.2,3
New RA classification criteria published in 2010 were developed by a joint working group from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Given the observed limitations of the 1987 criteria for detecting disease at the earliest stages and a shift in focus of disease management to these stages, the new approach sought to identify patients who have undifferentiated inflammatory arthritis factors associated with persistent or erosive disease or both.4-6 Compared with the 1987 criteria, the 2010 criteria have been shown to classify more patients with RA and at an earlier stage of disease, with a sensitivity and specificity of 0.71 and 0.65, respectively, using persistent arthritis as the outcome.6
Although classification criteria are intended for use in the identification of persons with RA primarily for enrollment in clinical trials, they may be used as diagnostic aids in clinical practice6 and may affect treatment strategies. With recognition that clinical outcomes are improved with earlier treatment, identifying patients for whom the risk of structural damage is high has become quite important in guiding management with disease-modifying therapies.4 Here we provide an overview of the latest RA diagnosis and treatment practices.
HOW PATIENTS ARE CLASSIFIED
The new criteria classify patients as having definite RA using a score-based algorithm applied to eligible patients—those for whom there is (1) evidence of clinical synovitis in at least 1 joint and (2) no alternative explanation for synovitis.4 With the emphasis on identification of patients before the development of radiographic erosions, the new classification criteria do not include the presence of these erosions.
Anti–cyclic citrullinated peptide (anti-CCP) antibodies are included in the classification criteria. This has both diagnostic and prognostic advantages because of the high specificity of the anti-CCP antibodies and the association with radiological progression of erosive changes and a more aggressive disease course.7-9
The identification of clinical synovitis as a prerequisite for application of the classification criteria underscores the importance of the physical examination. In cases in which examination findings are negative, imaging studies may play a role in identifying patients. The new criteria provide for classifying patients who have erosive disease typical of RA with a compatible history as having definite RA.4
Conventional radiographs remain a useful aid in diagnosis and in management of patients. Compared with advanced imaging modalities, they have the advantages of ready availability and lower cost, but they are insensitive for detection of the earliest changes of bone erosions. MRI and ultrasonography allow for detection of early inflammatory changes that involve the soft tissue and early stages of bone erosion, allowing for direct visualization of early inflammatory and destructive changes.10
In the clinic, conventional radiographs remain the initial imaging modality of choice, but when the results are negative, advanced imaging may be considered for evaluation of subclinical synovitis and detection of clinical improvement and regression of synovitis.11 The use of advanced imaging for assessment of disease activity probably will evolve over time, with the current emphasis on initiating treatment before development of joint damage and erosive changes and with development of better methods for detecting subclinical disease activity, which may still progress to joint damage.
Early achievement and maintenance of remission results in improved functional and radiographic outcomes.12-15 Treatment strategies that focus on “treatment to target”—measuring disease activity and adjusting therapy with the goal of remission or low disease activity—have been shown to optimize outcomes in RA when compared with a routine approach.16-18
Composite indices, which use changes of a group of variables rather than individual signs and symptoms, have been shown to mirror disease activity more closely than individual variables.19 Composite disease activity scores now in use—including the Disease Activity Score (DAS), the 28-joint Disease Activity Score (DAS 28), the Simplified Disease Activity Index (SDAI), the Clinical Disease Activity Index (CDAI), and the Routine Assessment of Patient Index Data 3 (RAPID3)—have been shown to be predictive of future disease activity.20 They have been used in clinical trials for measures of disease outcome21 and are used in routine clinical practice to guide treatment decisions.
DAS 28 erythrocyte sedimentation rate score–driven therapy in patients with recent-onset RA was shown to result in more patients achieving remission without disability and radiographic progression than routine care.18 SDAI and CDAI definitions of clinical remission have been shown to be more restrictive than that of the DAS 28.22 Using Doppler ultrasonography as the gold standard for detection of synovitis, the SDAI was shown to be superior to the DAS 28 in the definition of clinical remission23; in one study, the SDAI was shown to be a predictor for a change in treatment when compared with the DAS 28 and DAS.24
The RAPID3 uses patient-reported measures only (physical function, pain, and patient global estimate) for assessment and monitoring. This index has been shown to correlate with the DAS 28 and CDAI in clinical trials and in clinical care.25,26 The RAPID3 has the advantage of the lack of requirement of a formal joint count, which allows for the assessment to be completed in a shorter period and may make it a more pragmatic option for use in the clinical setting.26
These agents are used frequently in early arthritis in conjunction with the introduction of disease-modifying therapies because of their more immediate effects on reducing inflammatory symptoms. Low-dose prednisolone (7.5 mg/d) given in conjunction with disease-modifying therapy has been shown to result in higher rates of remission and better radiographic outcomes when used in patients with early RA.27-29
In the Behandel Strategien study, use of prednisone at an initial dosage of 60 mg/d was associated with improvement in functional outcome and less radiographic progression at 1 year of follow-up.14 Because of concerns about the adverse effects of corticosteroids, including fracture, risk of infection, and cardiovascular disease, they should be used for only a limited period and at the lowest effective dose.
Intermittent use of corticosteroids for management of disease flares at dosages of 15 mg/d or less for active synovitis has been associated with improved disease activity compared with placebo in patients with long-standing RA (disease duration longer than 2 years).30 Intra-articular corticosteroids also offer an effective strategy for management of disease flares in cases of monarticular or oligoarticular joint involvement.31
Conventional disease-modifying drugs
Disease-modifying antirheumatic drugs (DMARDs)—methotrexate (MTX), hydroxychloroquine (HCQ), leflunomide, and sulfasalazine (SSZ)—are used widely in the early stages of the RA disease process.32 MTX remains the most frequently used DMARD.
Compared with single-drug therapy, the use of 2 or 3 DMARDs in combination results in better rates of remission induction, improved functional outcomes, and similar adverse event rates.13 However, a recently published Cochrane database systematic review that compared MTX monotherapy with MTX combined with nonbiologic DMARDs did not show a significant advantage of MTX combination therapy in DMARD-naive patients.33
A widely used therapeutic strategy is the initial use of MTX monotherapy for early RA with the addition after 6 months, if required, of SSZ or HCQ or a tumor necrosis factor α (TNF-α) inhibitor. In support of this approach, a recent 2-year double-blind trial of patients with early RA found no differences in mean DAS 28 scores during weeks 48 to 102 among patients randomized to etanercept or triple DMARD therapy (MTX, SSZ, and HCQ) regardless of whether immediate combination treatment was used or MTX monotherapy was initiated and step-up treatment was given.34
At 6 months, immediate combination therapy (MTX and etanercept vs triple combination therapy) was more effective than MTX monotherapy, but there was no significant difference between the groups at 2-year follow-up. Although there was no demonstrated difference in clinical outcomes between the groups, preliminary analysis of the radiographic outcomes suggests that treatment with etanercept and MTX resulted in statistically significant radiographic benefit compared with triple therapy. The final results are not yet published.
Leflunomide monotherapy has been shown to have efficacy similar to that of MTX (the dose of MTX did not exceed 15 mg in trials, although doses in excess of this are used frequently in practice).35 Leflunomide monotherapy also has been used in combination with MTX in patients who have active disease while receiving stable doses.
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