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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
Rheumatoid arthritis (RA) is a common autoimmune systemic inflammatory disease affecting approximately 1% of the worldwide population. The interaction of genetic and environmental factors results in a cascade of immune reactions, which ultimately lead to the development of synovitis, joint damage, and structural bone damage. These, in turn, lead to pain, disability, and emotional, social, and economic challenges. A number of extraarticular manifestations and comorbidities are present in patients with RA, which result in increased mortality. The American College of Rheumatology and European League Against Rheumatism recently published updated disease classification criteria in an effort to identify RA earlier so that effective treatment can be employed to prevent irreversible changes.

(Am J Manag Care. 2012;18:S295-S302)
Rheumatoid arthritis (RA) is a common, chronic, inflammatory, autoimmune disease of unknown etiology affecting approximately 1% of the world population.1-3 The synovium, or membrane present in the synovial joints that lines the joint capsules and creates synovial fluid for the joints in the hands and feet, is the first structure affected. The subsequent inflammatory changes lead to cartilage and bone destruction.1,4 In addition, the corresponding systemic inflammation may result in disorders of multiple organ systems.1 The health-related quality of life in patients with RA is significantly reduced by the pain, fatigue, loss of bodily function, and heavy economic burden associated with disease progression.5 It is also recognized that mortality in patients with RA is increased compared with the general population.6 This manuscript is the first of 3 in this supplement designed to review the pathophysiology, treatment, and managed care implications of RA. This article will provide an overview of the diagnosis, pathophysiology, epidemiology, symptoms, assessment, and prognosis of RA.

Symptoms and Diagnosis

The diagnosis of RA is made clinically based primarily on physical examination findings.1 The 2 main classification criteria are summarized in Table 1.7,8 The classification criteria published in 1987 by the American College of Rheumatology (ACR), formerly the American Rheumatism Association, have been criticized for their focus on identifying patients with more-established RA disease (ie, those who have already developed chronic erosive disease).8 Consequently, the 1987 criteria failed to identify patients with early disease, who could gain the most benefit from available therapies.7 Recently, the ACR and European League Against Rheumatism (EULAR) created a joint working group with the primary goal of developing classification criteria to identify patients earlier in the disease process.8 As with the 1987 effort, the 2010 classification criteria are a means to identify patients for clinical trials, to differentiate patients with synovitis, and to determine the group at highest risk for developing persistent or erosive RA. However, the 2010 ACR/EULAR classification criteria also created a schematic for identifying definite RA.8

There are some important differences between the 1987 and 2010 classification criteria for RA, as shown in Table 1.7,8 The 1987 criteria required a score of at least 4 from a tally of 7 domains, including: morning stiffness, the overall number of joints involved, hand involvement, presence of symmetry, rheumatoid nodules, positive rheumatoid factor (RF) test, and radiographic changes.7 In the 2010 criteria, patient assessment was recommended for those with clinical synovitis in at least 1 joint not explained by another disease. Assessment involves a scoring system from 0 to 5, based on the number and type of joint(s) involved. An involved joint was defined as joint swelling or tenderness on examination indicative of active synovitis. Large joints include the shoulders, elbows, hips, knees, and ankles. Small joints refer to the metacarpophalangeal (MCP), proximal interphalangeal (PIP), second through fifth metatarsophalangeal (MTP), thumb interphalangeal joints, and wrists. The distal interphalangeal, first carpometacarpal joints, and the first metatarsophalangeal joints are excluded from assessment due to their involvement in osteoarthritis. There was no specific requirement for hand arthritis, rheumatoid nodules, or symmetric arthritis in the 2010 criteria. The authors noted that symmetric involvement was not an independent feature of RA, although the likelihood of bilateral presentation was increased with greater joint involvement and more progressive disease.

Similar to the 1987 criteria, the 2010 criteria utilize the presence or absence of RF (a high-affinity autoantibody directed against the Fc portion of immunoglobulin) as one of the domains. In addition, the 2010 criteria utilize the presence or absence of a marker that was identified more recently, the anti-citrullinated protein antibody (ACPA).8 Values for RF and ACPA, markers of autoimmune dysfunction, are scored according to ranges of values, where normal is defined as less than the upper limit of normal (ULN) for the laboratory or assay, low-positive is between the ULN and less than 3 times the ULN, and high-positive is greater than 3 times the ULN. Markers of inflammation, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, are scored based on whether they are normal or abnormal according to reference laboratory standards. Unlike the 1987 criteria, the 2010 criteria considered duration of therapy, but not the presence or absence of radiographic changes, to factor into the final score. In the 2010 RA classification criteria, a score of at least 6 out of 10 was considered to be indicative of RA, and hence a patient would be considered for treatment.8 The authors recommend that the 2010 ACR/EULAR criteria be used for assessment of existing and future patients to facilitate earlier use of treatments capable of altering disease progression.


From the existing data, some general conclusions may be drawn regarding the epidemiology of RA. The overall world prevalence of RA is approximately 0.5% to 1%, but may be declining in the United States.8-10 Using data from 1995 and 2005, the prevalence of RA in adult Americans was estimated at 1.29 million (0.6%), down from the previous estimate of 2.1 million. In 1995, the prevalence of RA in American women (1.06%) was nearly double that in men (0.61%). Interestingly, because most data were derived from patients in Minnesota, they may not be generalizable beyond Caucasians.9 There is regional variation in the prevalence of RA. The incidence appears to be highest in Pima Indians (5.3%) and Chippewa Indians (6.8%), and lowest in people from China and Japan (0.2%-0.3%), suggesting the possibility that genetic factors contribute to RA.10 These differences in regional RA prevalence also may suggest a role for environmental factors.

The exact cause of RA is unknown. The leading hypothesis for this (and most other autoimmune disorders) is that RA is the result of an environmental exposure or “trigger” in a genetically susceptible individual.11 Some environmental factors related to gender have emerged. Women who actively take oral contraceptives have a lower incidence of RA (~0.3/1000 women years) compared with women who never took oral contraceptives (~0.65/1000 women years) or those who previously took oral contraceptives (~0.55/1000 women years).10 Both female subfertility and the immediate postpartum period after a first pregnancy (especially when breastfeeding) appear to increase the risk of RA.10 Other potential environmental triggers include viral infections, such as those of Epstein-Barr virus, parvovirus, and bacterial infections with organisms such as Proteus and Mycoplasma. Heat-shock proteins and other stressors (eg, hypothalamic-pituitaryadrenal changes during adverse or traumatic life events) affect immune regulation and cytokine production.1 Heatshock proteins create immune complexes that may trigger the production of RF.1 The gastrointestinal microbiome has also been implicated in triggering autoantibody production, depending on the bacteria present.1 Several environmental factors are capable of creating posttranslational modifications of barrier tissues through peptidyl arginine deiminase, type IV (PADI4), an enzyme responsible for post-translational citrullination of peptide antigens on arginine residues. PADI4 has the ability to alter citrullination of mucosal proteins, and it is associated with Porphyromonas gingivalis, present in periodontal disease and in patients who smoke cigarettes.1,12 Cigarette smoking appears to be associated with an increased risk of RA, and the development of a positive RF.12

Twin studies show concordance rates of 15% to 30% between monozygotic twins and 5% among dizygotic twins, suggesting that 50% to 60% of RA cases are due to genetic factors.1,10 Among the genetic factors linked to RA susceptibility are differences in human leukocyte antigen (HLA)-DRB1 alleles, especially in patients positive for RF and ACPA.1 HLA-DRB1 genotypes appear to affect both disease susceptibility and disease severity.10 Gene-environment interactions have been observed; there is an increased incidence of RA in HLA-DRB1 individuals who smoke cigarettes. Chromosome 6, which contains the genes for HLA-DRB1, influences a number of immune processes, including production of tumor necrosis factor (TNF).10


The hallmark swelling, bony erosions, and synovial thickening reflect the underlying inflammatory and autoimmune processes. The interaction of environmental factors and genetic susceptibility leads to altered post-transcriptional regulation and self-protein citrullination early in the disease process.1 Citrullination is a normal physiologic process in dying cells, and under normal circumstances, the cells do not come in contact with the immune system. When clearance is inadequate, however, peptidylarginine deiminase (PAD) enzymes and citrullinated proteins leak out of the dying cells and contact the immune system. The PAD enzymes citrullinate extracellular proteins containing arginine, creating citrullinated antigens. Patients with certain HLA-DRB1 genotypes, termed shared epitopes, generate peptides no longer recognized as “self” and consequently develop ACPA. Downstream consequences include immune complex development and loss of tolerance to self.1,13 RF is also indicative of autoantibody production.1 Van de Sande and colleagues demonstrated, using contrast-enhanced magnetic resonance imaging (MRI) and joint synovial biopsy of healthy individuals and patients with RF and/or ACPA, that systemic autoantibody production and inflammation precedes inflammation and adhesion molecule formation in the synovium, indicating that perhaps a “second hit” is required to involve the synovium in RA.14 The initial development of RF and ACPA can precede the development of clinical RA involving the synovium by up to 15 years.15

The relationship between loss of self tolerance and synovial involvement is unclear at this time, but synovitis occurs when leukocytes infiltrate the synovium.1 Leukocyte accumulation reflects cell migration, which is enabled by endothelial activation and expression of adhesion molecules such as E-selectin, intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule.1,14 Local hypoxia, cytokine release, insufficient lymphangiogenesis (which limits cellular egress), fibroblast activation, and synovial reorganization increase inflamed tissue and may contribute to the joint symptoms of RA.1

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