Rheumatoid arthritis (RA) 

Rheumatoid arthritis (RA) is an autoimmune, inflammatory disease that causes pain, swelling, stiffness, and loss of function in various joints. The most common joints affected are in the hands, wrists, and knees where there is bilateral /symmetrical progression of the disease. The lining of the joint becomes inflamed, leading to tissue damage, as well as chronic pain, unsteadiness, and deformity. RA can also affect extra-articular sites, including the eyes, mouth, lungs, and heart. 

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Signs and symptoms of RA include pain, tenderness, swelling, and stiffness in more than one joint. Other symptoms include fatigue, fever. and loss of appetite.

Background​

  • The prevalence of RA in the USA is on the increase and during the period from 2004 to 2014 conservative estimate of afflicted adults was 1.28-1.36 million.  RA can begin at any age, but the likelihood increases with age. The onset of RA is highest among adults in their sixties. Women have a two- to- three times greater predisposition for developing RA compared with men. The exact cause of RA is still unknown, but genes, environmental factors, and hormones may be involved in its autoimmune development and progression. Signs and symptoms of RA include pain, tenderness, swelling and stiffness in more than one joint. Other symptoms include fatigue, fever and loss of appetite. 

Diagnostic Testing

  • Rheumatoid factor (RF) and Cyclic Citrullinated Peptide antibodies (ACPA) are serological biomarkers for diagnosis of Rheumatoid Arthritis (RA). The American College of Rheumatology (ACR) includes testing for rheumatoid factors (RFs) among the original and revised (2010) criteria for the classification of rheumatoid arthritis (RA). The 2010 ACR / EULAR RA classification criteria also advise the testing for Cyclic Citrullinated Peptide (CCP) antibody (ACPA).

  • Rheumatoid Factor (RF) is an autoantibody against the Fc portion of immunoglobulin (Ig). Rheumatoid factor IgM, the main isotype identified by RF assays, is found in approximately 70–80% of patients with confirmed RA. RF is positivity RA ranges from 30%-90% in various studies. The presence of all three RF isotypes (IgG, IgA and IgM) at abnormal levels has high specificity for a diagnosis of RA. However, presence of RF isotypes in any combination may be found in other rheumatic conditions (systemic lupus erythematosus, Sjogren’s syndrome), infectious diseases (e.g., hepatitis C virus, subacute bacterial endocarditis, Epstein-Barr virus), malignancy (e.g., B-cell neoplasms), and healthy individuals. The three RF isotypes (IgM, IgA, and IgG) are detected in 52% of RA patients but in fewer than 5% patients with other connective tissue diseases. The presence of RF IgA and RF IgG isotypes in the absence of RF IgM is more prevalent in patients with connective tissue disease than in RA patients. RF positivity has been reported in 5%-25% healthy population. Approximately 30% to 45% of patients with early RA do not have RF, though some may develop RF later in the course of disease.

  • Anti-CCP positivity, particularly at high levels, at any time is associated with higher risk of more severe clinical outcomes, higher disease activity and worse radiographic progression. In early undifferentiated disease, anti-CCP positive patients tend to go on to have more severe, erosive and aggressive disease. Anti-CCP can also be present in other disease states such as some children with juvenile idiopathic arthritis (JIA), psoriatic arthritis, lupus, Sjögrens syndrome, inflammatory myopathies and active tuberculosis. The second generation CCP (CCP2) test has high sensitivity and specificity and is currently recognized as the gold standard of testing for anti-CCP antibodies (ACPA). The accumulated specificity and sensitivity from 164 studies performed from 2002 to 2010 showed a sensitivity in early RA to be 61.6% and 75.2% in established RA and specificity of 94.0% (non-RA controls and 99.0% (healthy controls).

  • Testing for both anti-CCP and RF is beneficial when excluding the diagnosis of RA. The positive predictive value for RA is almost 100% when a patient exhibits positivity for a combination of markers (RF IgM, RF IgA, and a 2nd generation anti-CCP IgG test). However, correlation with clinical findings is indicated for definitive clinical diagnosis of RA.

  • The lack of circulating rheumatoid factor (RF) and anti-citrullinated peptide/protein antibodies (ACPA) suggests against the diagnosis of rheumatoid arthritis (RA). If the clinical symptoms demonstrate symmetrical polyarthritis, classic X-ray features and raised inflammatory markers with joint symptoms including pain, swelling and stiffness, seronegative RF could be considered.  Since there is a significant heterogeneity in the diagnosis of seronegative RA, conditions such as polymyalgia rheumatica, psoriatic arthritis, osteoarthritis, spondylarthritis and other inflammatory arthritis should be ruled out. . 

Rheumatoid arthritis (RA) Tests

Selected References

  1. Aletaha D, et al. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-81.

  2. Sokolova, M. V., Schett, G., & Steffen, U. Autoantibodies in Rheumatoid Arthritis: Historical Background and Novel Findings. Clinical reviews in allergy & immunology. 2021; Sep 8. doi: 10.1007/s12016-021-08890-1. Epub ahead of print. PMID: 34495490.

  3. Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017;39(4):437-446.

  4. Bas S. et al. Comparative study of different enzyme immunoassays for measurement of IgM and IgA rheumatoid factors. Ann Rheum Dis 2002;61:505-510

  5. Van Venrooji WJ, et al. Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol. Nat Rev Rheumatol. 2011;7:391-398

  6. Castro C, et al. Diagnostic testing and interpretation of tests for autoimmunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S238-47.

  7. Hunter, T. M., Boytsov, N. N., Zhang, X., Schroeder, K., Michaud, K., & Araujo, A. B. (2017). Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004–2014. Rheumatology international, 37(9), 1551-1557.

  8. Paalanen K, Rannio K, Rannio T. et al. Does early seronegative arthritis develop   into rheumatoid arthritis? A 10-year observational study. Clin Exp Rheumatol 2019; 37:37–43.