Epidemiology, Pathophysiology, and Diagnosis of Rheumatoid Arthritis: A Synopsis
Published Online: May 31, 2014
Allan Gibofsky, MD, JD, FACP, FCLM
Rheumatoid arthritis (RA), one of the more common chronic inflammatory diseases, is characterized by inflammation and swelling of the synovium of the joint, with subsequent destruction of articular structures.1 Patients with active RA also experience systemic inflammation that is associated with a variety of comorbidities, most importantly cardiovascular disease, which contribute to the increased morbidity and mortality noted in this group compared with the general population.2,3
The pain, fatigue, and disability associated with RA result in a significant reduction in health-related quality of life.4 Additionally, RA imposes a substantial economic burden upon patients, due to both increased cost of medical care and loss or reduction of employment, frequently during peak working years.5,6
This article is the first in a 3-article supplement that will review the pathophysiology, treatment, and managed care implications of RA. This article will examine the epidemiology and pathophysiology of RA and provide guidance regarding diagnosis based on current disease classification criteria.
The most recent estimate of the worldwide prevalence of RA was published as part of the Global Burden of Disease 2010 study, which was a comprehensive effort to measure epidemiological levels and trends of 291 diseases in 187 countries. 7 For the purposes of this study, RA was defined using the American College of Rheumatology (ACR) 1987 criteria for the classification of RA.8 In 2010, the global prevalence of RA in patients from 5 to 100 years of age was estimated to be 0.24% (95% confidence interval [CI], 0.23%-0.25%). The prevalence of RA was approximately 2 times higher in females (mean, 0.35%; 95% CI, 0.34%-0.37%) than males (mean, 0.13%; 95% CI, 0.12%-0.13%). The value for global prevalence of RA in 2010 was not perceptibly changed from the prevalence of RA determined in 1990 (mean, 0.25%; 95% CI, 0.24%-0.26%).7
Although the exact cause of RA is unknown, initiation of disease seems to result from an interaction among genetic susceptibility, environmental triggers, and chance.9 In a study of monozygotic and dizygotic twins, the genetic contribution to the variance in liability to RA, which is equivalent to the heritability of RA, was estimated to be 53% based on data from the United Kingdom and 65% based on data from Finland.10 Among the genetic factors linked to RA susceptibility are differences in human leukocyte antigen (HLA)-DRB1 alleles, especially in patients who are positive for rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA).11 The presence of a common amino acid motif (QKRAA) in these alleles seems to be associated with a particular susceptibility to RA and is referred to as the shared epitope.9 There is also evidence of gene-environment interactions; for example, there is an increased incidence of RA in HLA-DRB1 individuals who smoke cigarettes.12 Chromosome 6, which contains the genes for HLA-DRB1, also contains genes that influence a number of immune processes, including modulation of tumor necrosis factor (TNF).13
A variety of environmental factors have been implicated as potential triggers for RA. Hormonal influences on RA in women have been an area of active research, given that RA occurs more often in women. For example, in a case-control study, oral contraceptive use was not associated with a reduced risk of RA; however, breastfeeding for 13 or more months was associated with a reduced risk of RA compared with never breastfeeding (odds ratio, 0.46; 95% CI, 0.24-0.91).14
In an analysis of data from the Nurses’ Health Study, the risk of RA in women with the “shared epitope,” a series of alleles of the third hypervariable region of the HLA-DRB1 molecule that are associated with RA, increased in a cumulative manner with history of smoking.12 Other potential environmental triggers that have been associated with RA include infectious agents (eg, Epstein-Barr virus, cytomegalovirus, Proteus species, Escherichia coli) and their products (eg, heat-shock proteins).9 Although these entities have been frequently associated with RA, whether they are a cause of the disease remains unclear. Proposed mechanisms include molecular mimicry, potential adjuvant effect of pathogens in priming autoreactive immune responses, and bystander activation of autoreactive cells.15
The synovitis, swelling, and joint damage that characterize active RA are the end results of complex autoimmune and inflammatory processes that involve components of both the innate and adaptive immune systems.9 In a susceptible individual, the interaction of environment and genes results in a loss of tolerance of self-proteins that contain a citrulline residue. These proteins are generated via post translational modification of arginine residues to citrulline residues by the enzyme peptidylarginine deiminase.9 Patients with shared epitopes generate citrullinated peptides that are no longer recognized as “self” by the immune system, which consequently develops ACPAs against them.16 Comparison of magnetic resonance imaging (MRI) and synovial biopsy data from healthy individuals with MRI and biopsy data from patients positive for RF and/or ACPA demonstrate that systemic autoantibody production precedes inflammation and adhesion molecule formation in the synovium, indicating that perhaps some secondary event is required to initiate involvement of the synovium in RA.17 In a study of 79 patients with RA, the initial appearance of RF and ACPA preceded the development of clinical RA involving the synovium by a median of 4.5 years.18
Synovitis occurs as a consequence of leukocyte infiltration into the synovium. The accumulation of leukocytes in the synovium does not result from local cellular proliferation but rather from migration of leukocytes from distant sites of formation in response to expression of adhesion molecules and chemokines by activated endothelial cells of synovial microvessels.9 The interior of the inflamed synovium is hypoxic,19 presumably as a result of the proliferation of synovial cells and reduction in synovial capillary flow as a consequence of increased fluid volume in the synovium.20 Hypoxia, in turn, stimulates angiogenesis in the synovium, perhaps by inducing the formation of factors that stimulate vessel formation such as vascular endothelial growth factor.21
Immune activation and RA disease progression is a complex process that involves interactions between components of both the adaptive and innate immune pathways. The nature of these interactions is greatly affected by the local cytokine and chemokine environment of the synovium in which they take place. In established RA, the synovial membrane is populated by a variety of inflammatory cell types that work together to cause joint destruction.9
The importance of the adaptive immune pathway in RA is suggested by the presence of dendritic cells, a major class of antigen-presenting cells that expresses a variety of cytokines, HLA class II molecules, and costimulatory molecules in close proximity to clusters of T cells in the synovium. Dendritic cells present antigens to T cells that are present in the synovium and also serve as one component of the T-cell activation process.22 Activation of T cells requires 2 signals. The first signal is antigen presentation to the T-cell receptor. The second signal, the costimulatory signal, requires interaction of the cell surface protein CD80/86 on the antigen-presenting (dendritic) cell with the CD28 protein on the T cell.23 Blockade of the costimulatory signal through competitive inhibition of CD80/86 interferes with T-cell activation and downstream events.24 The effectiveness of CD80/86 blockade as a treatment for RA validates the concept that T cells play an active role in the pathophysiology of RA.9
When T-cell activation does occur, naïve T helper (Th) cells differentiate into 3 major subpopulations (Th1, Th2, and Th17) with distinct cytokine production profiles and functions.25 Although RA has long been considered to be a disease that is mediated by Th1 cells, recent interest has been focused on the Th17 subpopulation. Dendritic cells and macrophages both secrete transforming growth factor β, interleukin (IL)-1β, IL-6, IL-21, and IL-23, cytokines that support Th17 differentiation and suppress production of regulatory T cells, thus shifting the homeostatic balance in the synovium toward inflammation.9 In turn, Th17 cells produce IL-17A, IL-17F, IL-22, IL-26, interferon-g, the chemokine CCL20, and the transcription factor ROR-g.26 Production of IL-17A stimulates fibroblast-like synoviocytes (FLSs) and macrophage-like synoviocytes to upregulate production of IL-26, which induces production of the inflammatory cytokines IL-1β, IL-6, and TNF-α by monocytes; these cytokines stimulate further differentiation of Th17 cells.27 In addition to antigen-driven inflammatory pathways, inflammation can be mediated through antigen-nonspecific pathways initiated by cell-to-cell contact between activated T cells and macrophages and fibroblasts.28,29
PDF is available on the last page.