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Rheumatoid Arthritis: Many Management Strategies, No Cure
Maureen McMahon, MD, MS
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Rheumatoid Arthritis: Many Management Strategies, No Cure

Maureen McMahon, MD, MS
Environmental Factors
In addition to alterations in the genetic code itself, modification of gene expression through environmental effects is also thought to play a significant role in the pathogenesis of RA.4 This includes recurrent exposure to exogenous, endogenous, and/or antimicrobial agents, and pollutants such as smoke and silica.4,21 Smoking is, by far, the most important and well-established environmental factor identified to increase the risk for developing RA,12,19 as studies have found that smoking dramatically increases the risk in the presence or absence of specific HLA genes.10 However, in the presence of HLA genes, the association between smoking and RA brings to light the importance of epigenetics in RA—specifically, changes caused by modification of gene expression due environmental factors rather than by an alteration in the genetic code itself.10

Smoking is associated with an increased risk for ACPAs in SE-positive RA.23 It has been suggested that specific peptides, upon citrullination, are more prone to binding with the MHC complex, thereby predisposing individuals with a SE to have a preferential immune response to citrullinated proteins. Because anticitrulline autoimmunity is linked with seropositivity of RF in RA, the relationship between SEs and ACPAs is also thought to give rise to the relationship between SEs and RF.10 In patients who are RF-positive, the relative risk of developing RA more than doubles in smokers with one SE compared with patients who are SE-negative. This risk increases more than 6-fold in smokers who have double SEs compared with nonsmokers with double SEs and smokers with a single SE.10

There is also accumulating evidence to suggest an association between chronic periodontitis and RA.24 This association may be a result of infection with Porphyromonas gingivalis, triggering or driving an autoimmune response in some subsets of patients with RA.24 Diabetes and a high body mass index have also been associated with an increased risk of developing RA, while higher social class and breast-feeding are associated with a decreased risk.25
 
Pathophysiology of RA
The pathophysiology of RA follows the course of induction, inflammation, and destruction. The course is complicated by the heterogeneous nature of RA, with varying epidemiology, environmental factors, genetics, clinical presentations, and biomarkers acting in tandem over a period of time to produce symptomatic disease.4,21 In genetically predisposed individuals, the combination of susceptibility genes, environmental factors, and epigenetic and posttranslational modifications during a preclinical phase (pre-arthritis) results in symptomatic disease characterized by swelling, pain, stiffness, and joint damage.4
 
Induction

A breach of tolerance occurs during the preclinical phase of RA that results in activities within the immune system generating a response toward target organs that ultimately result in cellular infiltrate and clinical disease.4,26 The process begins with activation of the innate immune response and is perpetuated in tandem with the adaptive immune response. Innate immune cells include monocytes, mast cells, innate lymphoid cells (eg, natural killer cells), and phagocytic cells (eg, macrophages and dendritic cells). Adaptive immune cells include T cells, B cells, plasmablasts, and plasma cells.

The activation is initiated by exogenous factors and antibodies to autologous antigens such as ACPAs and RF. ACPAs, which are produced by B cells, form complexes with citrulline-containing antigens and can subsequently bind to RF.4,26 These complexes are then presented to T cells through activated B cells and phagocytic cells (macrophages and dendritic cells).4,26,27 Although the exact nature of T-cell activities within the joint is unknown, T cells are known to stimulate the production of proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, and are responsible for endothelial activation, resulting in recruitment of inflammatory cells. Through concurrent and subsequent processes, the synovial membrane becomes infiltrated with inflammatory mediators and other contributors that lead to the destruction of cartilage and bone. The entire process is perpetuated through a feedback loop that propels the inflammatory cascade forward.4,26,27
 


 
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