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

Epidemiology, Pathophysiology, and Diagnosis of Rheumatoid Arthritis: A Synopsis

Allan Gibofsky, MD, JD, FACP, FCLM
Intracellular signaling pathways are also involved in the pathogenesis of RA. All of the various cytokines, chemokines, antibodies, and antigens that contribute to inflammation bind to receptors on the cell surface of specific target cells. Receptor binding typically results in a cascade of intracellular signaling events that ultimately converges upon the nucleus of the cell and alters gene expression in ways that can affect cell function. In particular, changes in gene expression in immune cells are frequently associated with production and secretion of inflammatory mediators in response to a particular stimulus. Secretion of these mediators into the extracellular milieu results in further amplification and/or modification of the original signal. Examples of intracellular signaling pathways include the mitogen-activated protein kinase (MAPK) pathway, the Janus kinases (JAK) pathway, the signal transducers and activators of transcription (STAT) pathway, spleen tyrosine kinase (Syk) signaling, and the nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) pathway. Crosscommunication between pathways has been reported.

Intracellular signaling pathways are essential for a normal immune response, and aberrations in these pathways may contribute to autoimmune disease.34 The first generation of small molecules directed against intracellular targets is now being used for the treatment of RA.35 Further understanding of these pathways will likely lead to the identification of additional therapeutic targets. The inflammation of RA is also associated with characteristic changes in mesenchymal tissue. FLSs, which are normally resident in the synovium, proliferate and change their phenotype in the setting of RA.9 In the inflamed synovium, cell contact between FLSs and T cells results in the induction of a variety of inflammatory mediators and adhesion molecules, including IL-6, TNF, interferon-g, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1.36 Altered FLSs invade the cartilage of the joint and produce a variety of proteases that contribute to joint destruction.37

Assessment of Disease Activity

A variety of tools for assessment of disease activity have been developed for use in clinical trials and in the office setting. These are used both to standardize definitions and to guide treatment. In particular, the development of standardized measures of disease activity, which define remission, low disease activity, and high disease activity, is required for use of a “treat-to-target” strategy using pharmacologic therapy. In the “treat-to-target” paradigm, the baseline disease activity of a patient is determined and therapy is initiated with the primary goal of maximizing long-term health-related quality of life. After therapy is initiated, progress toward the goal is reassessed at regular intervals and therapy is adjusted based on the degree of goal attainment.38

The Disease Activity Score using 28 joints (DAS28) is one of the most commonly used assessments of disease activity in RA clinical trials. The DAS28 includes an evaluation of 28 joints for swelling and tenderness by the physician, separate physician and patient assessments of global disease activity, and a laboratory assessment of inflammation (either erythrocyte sedimentation rate [ESR] or plasma level of C-reactive protein [CRP]). The resultant numbers are plugged into an empirical formula to generate a DAS28 value. DAS28 scores have been used in clinical trials to define levels of disease activity. The definitions of disease activity, which were calculated using the DAS28(ESR) formula, were low (DAS28 <3.2), moderate (3.2< DAS28 ≤ 5.1), and high (DAS28 >5.1). A DAS less than 2.6 corresponds to a state of remission according to the American Rheumatism Association criteria.39 There is some discrepancy between DAS28 values calculated using CRP and ESR. Given the more common current usage of CRP for calculation of DAS28, disease activity cut points were developed for DAS28(CRP) in 2010. In this schema, disease remission is defined as DAS28 less than 2.3, low disease activity is from 2.3 to 3.8, moderate disease activity is from 3.8 to 4.9, and high disease activity is greater than 4.9.40 DAS assessment is used in both clinical trials and clinical practice.

Other commonly used scales in clinical trials and clinical practice include the simplified disease activity index (SDAI), which is the numerical sum of 5 measured parameters (tender and swollen joint count, physician and patient global assessments of disease, and CRP), and the Routine Assessment of Patient Index Data 3 (RAPID3), which is a measure of physical function, pain, and global status.41,42 Other scales commonly used in clinical trials include the ACR response, which measures percentage improvement from baseline, and the Clinical Disease Activity Index (CDAI), which is calculated as the sum of the swollen and tender joint count and the physician and patient global assessments.43,44 The CDAI is probably the easiest scale to use, as it is simply an arithmetic sum of 4 measured parameters. As a result of its simplicity, it is perhaps the most widely used scale in clinical practice. Based on the limitations of current measurements of disease activity, there is considerable interest in developing novel markers for early RA.

Patient-reported outcomes are also routinely used to assess current patient status and outcome of treatment of RA, particularly functional status and quality of life. Functional status is typically measured with the Health Assessment Questionnaire (HAQ) or one of its numerous variants. The HAQ consists of a series of 41 questions in 8 categories that evaluate patient difficulties with activities of daily living over the past week.44,4 General quality of life in patients with RA has typically been evaluated with the Short Form 36, whereas disease-specific quality of life can be measured with the Rheumatoid Arthritis Quality of Life instrument.45,46

In 2011, a joint committee of the ACR and the European League Against Rheumatism (EULAR) suggested 2 possible approaches to defining clinical remission in clinical trials of RA. 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 or equal to 1, or alternatively, when the score on the SDAI is less than or equal to 3.3.47

An estimate of the rate of real-world remission of RA during treatment was obtained by applying the 2011 ACR/EULAR criteria for remission to 2 large cohorts of patients in clinical practice. The probability of remission at a given clinic visit using the ACR/EULAR criteria was 7.5% in one cohort and 8.9% in the other. For patients who achieved remission, the probability of remaining in remission ranged from 6.0% to 14.1% after 2 years. Based on this 2011 analysis, less than 3% of all RA patients can be expected to experience a remission lasting 2 years or longer.48 Additionally, some patients in clinical remission have been noted to show radiographic evidence of disease progression or synovitis on MRI or ultrasound examination.49

An analysis of clinical and radiological follow-up data for 290 patients with RA showed that patients who experienced rapid radiological progression in the first year after RA diagnosis were more likely to experience functional disability over an 8-year period compared with patients without rapid progression.50 Although radiographic imaging is a useful and specific way to evaluate disease progression and the effectiveness of treatment, it is less useful for routine monitoring in the office setting, and thus is not included in the previously discussed ACR/EULAR criteria for remission. The 2012 update of the ACR RA treatment recommendations reviews other indicators of poor prognosis in patients with RA, including functional limitation on standardized health questionnaires, extra-articular disease, positive RF, positive ACPA, and bony erosions documented by radiograph.51

Disease Burden

In a radiographic study of 42 patients with early RA, 45% of patients experienced bone erosion of the joints within 4 months after diagnosis.52 Aside from causing joint damage that results in pain, disability, and work limitation, RA is a systemic disease that can continue to have manifestations even after the joint damage is controlled. A more complete consideration of the burden of RA must also include the comorbidities, psychosocial deficits, and impairment of health-related quality of life that accompany the extra-articular manifestations of RA (Figure).53

Systemic comorbidities associated with RA include cardiovascular disease, pulmonary disease, gastrointestinal disease, cancers, and psychiatric disease.2 Cardiovascular disease has attracted particular interest, as it appears to be an important source of mortality in RA. The results of a 2008 meta-analysis that included more than 110,000 patients from 24 observational studies showed that patients with RA have a 50% increased risk of cardiovascular disease compared with the general population. Mortality risks for ischemic heart disease and cerebrovascular accident were increased by 59% and 52%, respectively.54

RA is also associated with a heavy burden of psychosocial comorbidities, which have received considerably less attention than the other comorbidities. RA is associated with decreased health-related quality of life, increased fatigue and depression, and impaired cognitive function.54 Considering that the focus in clinical trials of therapies for RA has typically been on jointrelated symptoms, the ability of currently available therapies for RA to address the psychosocial aspects of RA is unclear.

Symptoms and Diagnosis

The most recent classification criteria for RA were developed by a joint committee of the ACR and EULAR and published in 2010.55 These classification criteria can be applied to any patient who has active synovitis in at least 1 joint that is not explained by a non-RA diagnosis. Numerical scores are assessed in 4 domains of RA: joint involvement, serology, acute phase reactants, and duration of symptoms. A patient with a score of 6 or more points out of 10 can be classified as having RA.55 The 2010 ACR/EULAR classification criteria replaced the ACR criteria promulgated in 19878; its primary weakness was a failure to identify patients with early disease who could benefit from early initiation of therapy. Although the 2010 classification criteria were designed to identify patients with RA for clinical trials, the cutoff score of 6 or greater based on these criteria is also the preferred approach for diagnosing RA clinically.55 Testing in other cohorts will be required to provide further evidence regarding validity of the classification criteria for diagnosis.

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