Definition
Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis. Although most readily recognized by its articular manifestations, RA can affect any organ system. The presentation and disease course are distinct for any individual patient, making diagnosis and management a thoughtful, complex, and dynamic process. The diagnostic criteria for RA (Box 1)1 may be used to classify disease in patients in the appropriate clinical setting, but in early disease the criteria may be less helpful in establishing the diagnosis. Whether disease expression is confined to mild articular manifestations or manifests as severe, multisystem disease, our current understanding demands that patients receive early and aggressive therapy. Achieving prompt control of local and systemic inflammatory processes minimizes damage of articular structures, preserves function, and reduces early mortality.
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Prevalence
RA affects about 1% of the world’s population2 when defined by either the presence of serum rheumatoid factor (RF) or erosive changes on radiographs in a patient with a compatible clinical presentation. Its incidence is two to three times greater in women, and this disparity is most pronounced in patients younger than 50 years.3 The incidence of RA continues to increase with age until about the seventh decade of life.4
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Pathophysiology
The cause of RA is unknown. The combination of genetic susceptibility with an as-yet-unidentified inciting event (or events) leads to disease expression. The concordance of RA in identical twins is reported as 15% to 30%, suggesting that nongenetic factors have a predominant impact on disease expression.2,5 However, the association of HLA-DR with RA is well established. There is an increased relative risk of RA of about 4 to 5 in patients with this allele.6 Whether shared alleles contribute to disease severity is controversial. More data are needed to establish the precise role of genetic factors.
Infectious agents have long been suspected as potential triggers of RA. Although investigations have failed to identify any one organism in synovial tissue or fluid, polymerase chain reaction techniques have detected bacterial nucleotide sequences in synovial tissues in RA patients. Viral pathogens are also under study, with the Epstein-Barr virus (EBV) targeted for several reasons. RA patients have been found to have higher levels of virus-infected B cells and higher levels of EBV antibody titers than the general population. In addition, the ability of the virus to activate B cells to produce RF has generated interest in this virus as a potential trigger.7 Other viruses of interest include parvovirus B19 and the retroviruses, but conclusive data definitely identifying any viral pathogen as a causative agent are lacking. In fact, bacterial and viral antigenic particles may be carried to sites of inflammation by gut-associated macrophages.8
Rheumatoid factor, an immunoglobulin (Ig)M antiglobulin against the Fc portion of human IgG, is detected in about 70% of patients with RA. Evidence suggests its participation in disease pathogenesis. The presence of RF in RA is associated with extra-articular manifestations of disease, and its absence is generally associated with milder disease. Its proposed mechanisms include enhanced presentation of immune-complexed antigens, cross-linkage and stabilization of low-avidity IgG antibodies, and cryoprecipitation.4 RF is not specific for RA, despite its name, and it may be found in other conditions including bacterial infection, lymphoproliferative disorders, liver disease, and other autoimmune disorders.
Although inciting factors have yet to be identified, the presence and activity of a number of proinflammatory chemokines and cytokines have established roles in disease pathogenesis. The activation and infiltration of T cells and macrophages in the synovium result in production of interleukin-1, -2, -6, -8, -10, -17; tumor necrosis factor-α (TNF-α); platelet-derived growth factor; insulin-like growth factor; and transforming growth factor β.9 These effector molecules are implicated in synovial tissue inflammation and proliferation, cartilage and bone destruction, and systemic effects. B cells also infiltrate the synovium and differentiate into plasma cells, producing polyclonal immunoglobulin and RF. In addition, synovial fibroblasts are activated, releasing collagenases and activating metalloproteinase gene expression, which leads to destruction of matrix tissues. The net result of these activities is pannus formation with articular cartilage invasion, periarticular erosions and osteoporosis, and joint swelling with destruction of periarticular structures. Cigarette smoking increases the risk of developing RA and negatively influences disease course.10,11
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Box 1: Criteria for the Classification of Rheumatoid Arthritis
For classification purposes, a patient has rheumatoid arthritis if he or she has satisfied at least four of these seven criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not to be made.
Morning stiffness
Morning stiffness in and around the joints
Lasting at least 1 hour before maximal improvement
Arthritis of three or more joint areas
At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician
The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints.
Arthritis of hand joints
At least one area swollen (as defined in 2) in a wrist or in an MCP or PIP joint
Symmetrical arthritis
Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body
Bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry
Rheumatoid nodules
Subcutaneous nodules over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician
Serum rheumatoid factor
Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects
Radiographic changes
Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in, or most marked adjacent to, the involved joints
Osteoarthritis changes alone do not qualify
MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal.
Adapted with permission from Kirkham BW, Lassere MN, Edmonds JP, et al: Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 2006;54:1122-1131.
Clinical Manifestations
Generally, signs and symptoms of RA begin insidiously and are additive over weeks to months. They commonly include fatigue, malaise, generalized stiffness, and generalized arthralgias or myalgias. Synovitis usually develops gradually, often involving the hands, wrists, knees, or feet, often symmetrically. However, in 10% to 15% of patients, the onset of disease is explosive, with polyarthritis, fever, lymphadenopathy, and splenomegaly developing over days to weeks.2,8 It is imperative in patients with the latter manifestation to consider other common causes of acute polyarthritis, such as parvovirus infection.
Evidence of articular disease in RA can appear as swelling, tenderness, warmth, and painful motion. The outward appearance of the joints does not necessarily correlate with the amount of active synovitis or pain expressed by the patient. Patients often complain of morning stiffness, a characteristic of inflammatory arthritis. Stiffness, known as gelling, can also manifest after brief periods of inactivity. The joints most often involved in RA include the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints, wrists, elbows, shoulders, knees, ankles, and subtalar and metatarsophalangeal (MTP) joints. The cervical spine is the only characteristic axial location, and atlantoaxial subluxation is a known complication. Inadequately treated articular inflammation progresses to weakening or destruction of supportive structures, including the associated joint ligaments, tendons, cartilage, and bone. In addition, the pain associated with ongoing synovitis often leads to decreased motion at the affected joints. This, in addition to the ongoing pathologic tissue changes, results in loss of range of motion or, at its most extreme, soft-tissue contractures, fibrosis, and bony ankylosis.