Rheumatoid Arthritis

■ Rheumatoid arthritis (RA) has an annual incidence of approximately 0.4 per 1000 in females and 0.2 per 1000 in males; recent evidence indicates that the incidence may be rising. ■ A prevalence of 0.4% to 1% is reported in diverse populations worldwide with evidence for geographic variation. ■ Cigarette smoking remains the strongest environmental risk factor for RA; other lifestyle factors and exposures such as alcohol use in moderation may be inversely associated with RA. ■ Childhood and current low socioeconomic status are associated with increased risk of RA. ■ Hormonal and reproductive factors contribute to the female predominance in RA; parity, breastfeeding, and exogenous hormones are modifiers of RA risk in women.

Criteria

2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis

Target population (those who should be tested): Patients 1. who have at least 1 joint with definite clinical synovitis (swelling)* 2. whose synovitis is not better explained by another disease† Classification criteria for RA (score-based algorithm: add score of categories A–D; a score of ≥6/10 is needed to classify a patient as having definite RA)‡
A. Joint involvement	Score
1 large joint¶	0
2–10 large joints	1
1–3 small joints (with or without involvement of large joints)	2
4–10 small joints (with or without involvement of large joints)	3
>10 joints (at least 1 small joint)**	5
B. Serologic results (at least 1 test result is needed for classification	Score
Negative RF and negative ACPA	0
Low-positive RF or low-positive ACPA	2
High-positive RF or high-positive ACPA	3
C. Acute-phase reactants (≥1 test result is needed for classification)	Score
Normal CRP and normal ESR	0
Abnormal CRP or abnormal ESR	1
D. Duration of symptoms	Score
<6/wk	0
≥6/wk	1
*The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA. Patients with long-standing disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA. †Differential diagnoses vary among patients with different presentations but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted. ‡Although patients with a score of <6 of 10 are not classifiable as having RA, their status can be reassessed, and the criteria might be fulfilled cumulatively over time. §Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classified according to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint involvement. ¶“Large joints” refers to shoulders, elbows, hips, knees, and ankles. ∥“Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists. **In this category, at least one of the involved joints must be a small joint; the other joints can include any combination of large and additional small joints, as well as other joints not specifically listed elsewhere (e.g., temporomandibular, acromioclavicular, sternoclavicular). ††“Negative” refers to international unit (IU) values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; “low-positive” refers to IU values that are higher than the ULN but three times or less the ULN for the laboratory and assay. Where rheumatoid factor (RF) information is available only as positive or negative, a positive result should be scored as low positive for RF. ‡‡Normal and abnormal is determined by local laboratory standards. §§“Duration of symptoms” refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, swelling, tenderness) of joints that are clinically involved at the time of assessment regardless of treatment status. ACPA, Anti–citrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate. From Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.

Pathology ■ Synovial tissue in joints with rheumatoid arthritis (RA) is markedly expanded by the recruitment and retention of inflammatory cells along with the formation of villous projections and the generation of pannus tissue that invades and destroys cartilage and bone. ■ The pathogenic events in RA occur in stages, and mechanisms leading to initiation of the disease appear to be distinct from those involved in the perpetuation of inflammation and eventual destruction of joint tissue. ■ Chronic synovitis is maintained by the interactions of cell types native to the joint and inflammatory cells recruited to the joint, with the subsequent establishment of cytokine “networks.” ■ Angiogenesis is a feature of RA that is promoted by soluble and cell surface–bound mediators including growth factors, proinflammatory cytokines, chemokines, matrix components, cell adhesion molecules, proteases, and others. ■ Cartilage destruction results from the production of enzymes that destroy components of the cartilage extracellular matrix by cells within synovial tissue and by chondrocytes; osteoclasts contribute to the destruction of articular bone.

Clinical Features Pre-clinical Features ■ The current understanding of rheumatoid arthritis (RA) development includes a preclinical phase that can be defined by the presence of RA-related autoimmunity in absence of clinically apparent inflammatory arthritis. ■ Growing evidence suggests that RA-related autoimmunity may initially be triggered outside of the joints and at a mucosal site. ■ RA-related autoantibodies, including rheumatoid factor and antibodies to citrullinated protein/peptide antigens, can be used to identify with high accuracy (e.g., positive predictive values of >80%) patients who currently do not have definable synovitis but will develop RA in the future. ■ Clinical trials are under way testing the hypothesis that preclinical RA can be interrupted through pharmacologic interventions to prevent the onset of future clinically apparent RA.

■ Morning stiffness and swelling in the wrists and proximal interphalangeal and metacarpophalangeal joints are the typical features of rheumatoid arthritis (RA). ■ Early diagnosis of RA is critical, but many cases of “early arthritis” are not RA. ■ The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA provide a framework for accurate diagnosis of early RA. ■ Anticitrullinated peptide antibodies occur earlier than rheumatoid factor and are more specific for RA. ■ Aggressive early administration of disease-modifying antirheumatic drugs is critical to a good outcome.

Extra-articular features Rheumatoid arthritis (RA) may be associated with inflammation in extraarticular organs. ■ Features of systemic involvement in RA include constitutional symptoms, distinct organ manifestations, and severe multiorgan disease. ■ Systemic features may be associated with a poor prognosis, especially vasculitis and rheumatoid lung disease.

Imaging ■ Symmetric bilateral rheumatoid arthritis (RA) is commonly seen in the hands and feet, but asymmetric disease is frequently found in large joints. ■ Hands and feet show the earliest radiographic changes in RA, which include soft tissue swelling, erosions, and diffuse joint space narrowing. ■ Radiographic damage to large joints is seen most frequently in the elbow, shoulder, and knee. ■ Sacroiliac joint disease in a patient with RA is relatively insignificant and uncommon. ■ Long-term complications such as atlantoaxial subluxation and basilar invagination can be present and serious but are seen less frequently today in the modern therapeutic era. The lateral cervical spine in flexion is the best way to evaluate patients for atlantoaxial subluxation. Basilar invagination is best appreciated on magnetic resonance imaging (MRI) and computed tomography. ■ Ultrasonography and MRI are becoming popular imaging modalities in clinical rheumatology to detect subclinical disease and potentially provide an additional outcome target for remission.

Antibodies ■ Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by the presence of autoantibodies in peripheral blood and synovial fluid. Most autoantibodies are not directed to joint-specific antigens. ■ Autoantibodies are already present in the earliest stages of the disease and may precede onset by several years. ■ Rheumatoid factors (RFs), or autoantibodies to the Fc portion of IgG, are the longest-known marker antibodies in RA. High-titer IgM-RF and also IgA-RF are of high diagnostic and prognostic value because they are associated with erosive and more severe disease. ■ Anti-citrullinated citrullinated protein antibodies (ACPAs) are directed to antigens containing the unusual amino acid citrulline. They are the most specific marker antibodies for RA and, similar to high-titer RF, are linked to erosive RA. Autoantibodies to carbamylated antigens containing the unusual amino acid homocitrulline may have prognostic value next to ACPAs. ■ Autoantibodies may contribute to the pathophysiology of RA by inducing, maintaining, or modulating the disease process. Although there is increasing evidence for a direct pathogenetic role of ACPAs and RF, the primary (disease-inducing) autoimmune targets remain to be identified.

Assessment ■ Assessment of patients with rheumatoid arthritis (RA) is aimed at evaluating or prognosticating the disease process or disease outcome. ■ The 2010 classification criteria for RA were developed jointly by the American College of Rheumatology and the European League Against Rheumatism to allow assessment and timely institution of treatment in patients with very early and established disease. ■ Core sets of individual measures of the disease process have been defined and include joint swelling and tenderness, the acute-phase response, pain, patient global assessment, and evaluator global assessment. ■ These individual measures can be effectively integrated into composite indices that allow determination of actual disease activity, as well as disease activity states. ■ For therapeutic targeting of low disease activity or remission, clinical disease activity assessment by composite measures has proven to be of at least similar validity as assessment by sonography and thus remains to be the gold standard, targeting sonographic outcomes being afflicted with costly overtreatment without any clinical benefit. ■ In clinical practice, disease activity (the disease process) is the immediate target of therapeutic interventions, but the ultimate goal of treatment is optimal disease outcome, including health-related quality of life. ■ In clinical trials, disease activity states and responses, as well as their time of onset and sustainment, should be reported. ■ The typical proxy for disease outcome is radiographic damage, which is a surrogate for the accrued joint destruction and can be assessed by quantitative scoring. ■ Impairment of physical function (disability) is another important outcome and can be assessed with questionnaires, typically the Health Assessment Questionnaire, or direct functional performance tests, such as grip strength. ■ Physical function is influenced by both disease activity and joint damage; functional disability related to joint damage is currently considered to be irreversible.

Management ■ Early diagnosis and treatment are important for optimal outcomes in rheumatoid arthritis (RA). ■ Disease-modifying antirheumatic drugs (DMARDs) with or without glucocorticoids should be commenced at the earliest opportunity. ■ Disease activity should be monitored regularly and treatment increased until a target (ideally remission) is reached. ■ Biologic DMARD-free and drug-free remission is achievable in a proportion of patients with early RA

■ Disease-modifying antirheumatic drugs (DMARDs) are effective in slowing or halting rheumatoid arthritis (RA) progression and are the mainstays of treatment. ■ Treating RA to the target of complete disease remission is the ultimate goal of RA therapy. ■ The management of RA must encompass the patient as a whole and consider comorbid conditions, desire for pregnancy, patient preference, and cost in management decisions. ■ The effective treatment of RA has been shown to help mitigate the risk of developing complications from RA such as cardiovascular disease and cancers. ■ Eventual withdrawal of DMARD therapy may be possible in select patients, but it does carry a high risk of disease relapse.