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Rheumatoid Arthritis: Many Management Strategies, No Cure

Maureen McMahon, MD, MS
Rheumatoid arthritis (RA) is a chronic inflammatory syndrome characterized by synovitis, joint swelling, and debilitating pain that result from bone and cartilage erosion. Uncontrolled, severe RA leads to joint deformity, disability, and premature death. The etiology of RA is not completely understood, but it is known to involve interplay between environmental factors, susceptibility genes, epigenetic factors, and posttranslational modifications in genetically predisposed individuals. A positive family history is the strongest risk factor for RA, and genomewide association studies have identified over 100 susceptible loci associated with RA—most within the human leukocyte antigen region. The inflammatory course of RA involves innate and adaptive immune cells activated by exogenous factors and autologous antigens, such as antibodies to citrullinated proteins and rheumatoid factor. Mediators of the immune response, cytokines, such as tumor necrosis factor-alpha, play a key role in the progression of RA, and are the targets for biologic treatment of RA. While traditional treatment approaches have focused on disease-modifying antirheumatic drugs, biologic therapies are providing a more targeted approach to disease management in the long term. This article reviews current treatment guidelines for RA, with a focus on the role and relevance of traditional treatment options in the era of biologic therapeutics.
Am J Manag Care. 2016;22:-S0

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation (synovitis) and the formation of rheumatoid pannus, leading to erosion of adjacent cartilage and bone and resulting in joint deformity, pain, severe disability, and premature death.1-5 Due to its systemic comorbidities, which include rheumatoid nodules, vasculitis, and pulmonary and cardiovascular involvement, RA is often defined as a syndrome.2-4 In 2005, an estimated 1.5 million (0.6%) adults in the United States were affected by RA, with women slightly more susceptible than men.2,6 An epidemiological study in 2005 estimated the lifetime risk of RA to be 4% for women and 2% for men.2,7 

The past decade has seen significant advances in the treatment of RA, along with recent updates to diagnosis and classification of the disease, with a focus on early recognition and treatment.1,4,8 Despite the significant strides, however, full remission in patients with RA, or continued remission after withdrawal of treatment, can be difficult to achieve.9 This article focuses on the application of conventional, new, and emerging treatment options for RA, and provides a review of current RA treatment recommendations and the challenges of current therapeutics.
 
Epidemiology and Etiology of RA
Although the etiology of RA is not yet completely understood, it is believed to result from a combination of environmental factors, susceptibility genes, epigenetic factors, and posttranslational modifications in individuals predisposed with a genetic susceptibility.4,5,10-12 A positive family history, considered the strongest risk factor for RA, increases the risk of RA more than 3 to 5 times.13 Studies have shown patterns of increased prevalence in specific ethnic populations, such as Pima Indians and Chippewa Indians, and in studies of migrant populations.11 The importance of genetic factors has further been demonstrated in studies with twins, where 50% to 60% of the occurrence of RA can be explained by genetic effects.11 The overall heritability of RA is 50% to 60%, with higher rates among those who are anticitrullinated protein antibody (ACPA) seropositive for RA (40%-55%) compared with those testing seronegative (20%).12,13 The clinical course of ACPA-positive RA is also much more aggressive than that of ACPA-negative RA. The presence or absence of ACPA denotes 2 genetically distinct diseases characterized by different antibodies.14,15
 
Genetic Factors
Genomewide association studies using single nucleotide polymorphisms have identified over 100 genetic susceptibility loci associated with RA. The largest and most influential association lies within the human leukocyte antigen (HLA) region, the HLA-DRB1 complex. This gene complex codes for the major histocompatibility complex (MHC) proteins responsible for immune regulation.12 Many of the loci identified implicate immune mechanisms, which may be shared with other chronic inflammatory diseases.4 Multiple risk alleles for RA within the HLA-DRB1 locus encode a 5-amino acid sequence motif known as a shared epitope (SE).16 This sequence motif is carried by the vast majority of patients with RA.16

Although the exact mechanism by which the SE contributes to the pathophysiology of RA is not known, it is hypothesized that the presence of these amino acid sequences alter binding and presentation of antigenic peptides to T-cell lymphocytes, triggering an abnormal immune response.17 The risk of RA in patients with a SE is also linked with seropositivity for ACPA and rheumatoid factor (RF), with a poor association in individuals that test negative for ACPA and RF.4,18 A SE is not only associated with disease susceptibility, but it has also been shown to have a significant impact on radiological severity of the disease, mortality, and treatment response.18

However, some evidence suggests that the relationship between HLA and RA is linked more to the severity of the disease, in addition to its development.19 The functional effect of the loci vary, as some genotypes contribute to small functional effects through altered signaling or activation pathways, while others are associated with more aggressive erosive disease and higher mortality.4 Additionally, data from studies of twins demonstrates that HLA only explains approximately half of the genetic contribution to RA. This has driven a search for non-MHC genes that may be implicated in RA, including linkage to genetic regions associated with autoimmune diseases such as insulin-dependent diabetes.19,20 Many of the loci associated with RA are also implicated in immune mechanisms shared with other chronic inflammatory diseases.4 Other loci, such as PTPN22 polymorphisms, PADI, and peptidyl arginine deiminase, may contribute to RA by interfering in critical processes, such as cytokine signaling, lymphocyte receptor activation threshold, post translational modification of peptides, and innate immune activation.4,21,22
 


 
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