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

Overview of Epidemiology, Pathophysiology, and Diagnosis of Rheumatoid Arthritis

Allan Gibofsky, MD, JD, FACP, FCLM
The underlying factors associated with immune activation and disease progression involve the adaptive and innate immune pathways, along with cytokines, growth factors, and intracellular signaling molecules. The genetic variation of immune activation in patients with RA leads to the cascade of immunity and destruction present in RA. The Figure demonstrates that the synovial membrane becomes infiltrated with various inflammatory cell types, which ultimately work together to cause joint destruction.1 Dendritic cells express cytokines (interleukin [IL]-12, 15, 18, and 23), HLA class II molecules, and costimulatory molecules (CD80/86), and are involved in antigen presentation and T-cell activation. T cells require 2 signals for activation, where the first signal is antigen-specific and involves T-cell receptors and IL-2. The second signal, or costimulatory signal, involves interaction of CD80/86 on the antigen-presenting (dendritic cell) and CD28 on the T cell.1,16 Blockade of the costimulatory signal through competitive inhibition of CD80/86 prevents T-cell activation and the downstream events.17 When T-cell activation does occur, T helper (Th) cells (eg, Th0, Th1, Th17) are recruited. Th17 cells produce IL-17A, IL-17F, IL-21, IL-22, and TNF-α. Dendritic cells and recruited macrophages both secrete transforming growth factor β, IL-1β, IL-6, IL-21, and IL-23 to support Th17 differentiation, creating an inflammatory environment. IL-17A works with TNF-α to promote the activation of fibroblasts and chondrocytes. Non-specific T-cell contact-activation is mediated through CD40 and CD40 ligand, CD200 and CD200 ligand, ICAM-1, and leukocyte-function-associated antigen-1. Th17 cells also trigger humoral adaptive immunity mediated by synovial B-cells. B-cells are triggered by factors including a proliferation-inducing ligand, B-lymphocyte stimulator, and CC and CXC chemokines.1 B cells secrete autoantibodies, present antigens to T cells, and stimulate synovial fibroblasts through the secretion of cytokines (eg, lymphotoxin-β [Ltβ] and TNF).15 Derived plasma cells also are involved in autoantibody production, autoantigen presentation, and cytokine production involving IL-6, TNF-α, and Ltβ.1,18

Cells of the innate immune system, including macrophages, mast cells, and natural killer cells, also are important in the pathophysiology of synovial inflammation in RA. Macrophage maturation is mediated by granulocyte colonystimulating factor and granulocyte-macrophage colonystimulating factor. Macrophages are activated by toll-like receptors and nucleotide-binding oligomerization domainlike receptors. Macrophages secrete TNF-α, IL-1, IL-6, IL-12, IL-15, IL-18, IL-23, and are involved in the release of matrix degradation enzymes, phagocytosis, antigen presentation, and reactive oxygen intermediates. Neutrophils, present in the synovial fluid, synthesize inflammatory prostaglandins, proteases, and reactive oxygen intermediates. Mast cells release cytokines, chemokines, proteases, and vasoactive amines.1

Intracellular signal transduction pathways may also be involved in the pathogenesis of RA, since cytokine release reflects the way cells respond to environmental stress.18 Janus kinase pathways, mitogen-activated protein kinases (MAPKs), p38 MAPK, c-Jun N-terminal kinase, nuclear factor-κB (NF-κB), and receptor activator of nuclear factor kappa-B ligand (RANKL) all may contribute to response to inflammation.1,18 Fibroblast-like synoviocytes change characteristics in the setting of RA. In RA, fibroblast-like synoviocytes express altered levels of cytokines, chemokines, adhesion molecules, matrix metalloproteinases, and tissue inhibitors of metalloproteinase. The reason for the resulting synovial hyperplasia is incompletely understood, but the altered fibroblast-like synoviocytes contribute to local cartilage destruction, synovial inflammation, and T-cell and B-cell survival. The altered fibroblast-like synoviocytes are resistant to apoptosis, possibly through mutations of tumorsuppressor gene P53, expression of heat-shock proteins, modulation of the endoplasmic reticulum, and cytokine-induced activation of NF-κB, which favors fibroblast-like synoviocyte survival in the presence of ligation with the TNF-α receptor.1 In addition, RANKL and macrophage colony-stimulating factor promote osteoclast differentiation and articular cartilage invasion.1

TNF-α and IL-6 are thought to play the most central role in the pathogenesis of RA. TNF-α activates cytokines, chemokine expression, and endothelial-cell adhesion molecules, protects fibroblasts, promotes angiogenesis, suppresses regulatory T cells, and promotes pain. IL-6 promotes leukocyte activation and autoantibody production, and contributes to anemia, cognitive dysfunction, and dysregulation of lipid metabolism.1 Both TNF-α and IL-6, as well as RANKL, amplify osteoclast activation and differentiation.1

Disease Burden and Prognosis

The complex pathophysiology of RA leads to synovial hyperplasia, cartilage damage, and bony erosion, usually affecting up to 80% of patients within 1 year of diagnosis. Eroded bone does not appear to demonstrate any evidence of repair in RA, suggesting that the main goal should be to prevent bony erosion, as noted in the 2010 ACR/EULAR classification criteria.1,8 Joint damage leads to pain and disability.19 Up to one-third of patients are work-disabled within 2 years of disease onset, and approximately 50% are work-disabled after 10 years.15,19 The physical, emotional, and social impact of RA contributes to poor health-related quality of life.19 Disease severity is correlated with the degree of pain and physical functioning, although patients score their pain worse than physicians estimate.20,21

The disease burden of RA is not limited to the affected joints and its physical impact. RA is associated with a number of systemic complications related to the underlying disease process. Table 2 summarizes the components of extra-articular RA.1,2,11,22 A number of organs and organ systems are potentially involved in RA, particularly in severe disease.2 It appears that persistence of inflammatory mediators contributes to the extra-articular involvement. Patients with extra-articular manifestations of RA appear to have higher mortality, especially among men relative to women.2 It appears that a majority of the deaths in patients with RA are related to cardiovascular disease.1,6 The decline of mortality in the general population over the last 40 years has not been mirrored in the RA population, and it does not appear to be explained solely by traditional cardiovascular risk factors, such as dyslipidemia, smoking, diabetes, and hypertension.1,6,23 Cardiovascular mortality appears to be at least 1.5-fold higher in the RA population than in the general population, and it probably relates to a combination of differences in traditional cardiovascular risk factors and RA disease–related factors.1,6

Assessment of Disease Activity

The prognosis of RA is affected by the severity of the disease and the effectiveness of treatment.24 Clinical remission, defined as the absence of significant signs and symptoms of inflammation with or without additional treatment, occurs in 20% or less of patients. In contrast, remission or achievement of low disease activity (LDA), usually with continuing treatment, may be achieved in up to 75% of patients.24 Despite achievement of LDA, radiographic evidence of the progression of joint damage and synovitis through monitoring of MRI or ultrasound results have been noted.24 More than one-third of patients with clinical remission exhibit signs of synovitis on ultrasound.25 In addition, rapid radiological progression in the first year after diagnosis is prognostic for functional disability over 8 years compared with persons without rapid progression.26 Although radiographic evidence of disease progression 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.

A number of disease activity indexes have been developed for use in clinical trials and the office setting to standardize definitions and guide treatment. The development of standardized measures of disease activity (which define remission, LDA, and high disease activity [HDA]) allows for a “treat-to-target” strategy using pharmacologic therapy.15 These targets allow physicians and patients to set goals for treatment. A detailed review of the indices/ scales is beyond the scope of this manuscript, but a few will be briefly highlighted. The Disease Activity Score (DAS) 28 is a scoring of 28 tender or swollen joints, a patient global assessment, and a physician global assessment, along with ESR (DAS28-ESR) or CRP (DAS28-CRP).24 Values define HDA, moderate disease activity (MDA), LDA, or remission. Changes in scores define improvement or worsening in disease, depending on the direction of the change. Other commonly used scales include the simplified disease activity index (SDAI), the clinical disease activity index (CDAI), the routine assessment of patient index data 3 (RAPID3), and the ACR criteria for percent improvement in involved joint count (eg, ACR20, ACR50, and ACR70).27,28 Importantly, all of these indices are slightly different in the number and type of data points collected. It should be noted that ACR criteria and CDAI are generally used in randomized clinical trials, whereas RAPID3 (a measure of physical function, pain, and global status) is used mostly by US rheumatologists in clinical practice. A recent study compared HDA, LDA, and the achievement of remission (defined by 8 different indices) in patients treated with anti-TNF agents and found a large variation in resulting classification of LDA, HDA, and remission according to the various indices.29 In keeping with these limitations of disease activity indices and their reliance on joint involvement, there is much interest in developing novel markers for early RA, and investigations are ongoing.30

For use in clinical trials, the ACR/EULAR recently recommended incorporation of 1 of 2 possible approaches to define clinical remission.31 The investigators may select a Boolean criterion, wherein all 4 of the following must be satisfied: tender joint count of 1 or fewer, swollen joint count of 1 or fewer, C-reactive protein level of 1 mg/dL or less, and patient global assessment of 1 or fewer (on a 0-10 scale). Alternatively, the SDAI may be used with a target score of 3.3 or less.31

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