Diagnosis of Rheumatoid Arthritis
The diagnosis of RA, at present, is a clinical one. It is predominantly based on patient history and physical examination as well as certain subjective patient-reported criteria. History and physical examination offer the best indication of disease likelihood, while serology and imaging provide additional diagnostic and prognostic insight. The exclusion and ruling out of other inflammatory conditions is also important. Subjective patient-reported criteria include duration of morning stiffness and painful joint counts. Other criteria from patient examination include soft-tissue swelling of joints ( Soft Tissue Swelling and Juxta-Articular Osteoporosis), the symmetry of the affected joints, and the presence of subcutaneous nodules. Objective laboratory criteria are also important, including rheumatoid factor and evidence of radiological changes suggestive of joint erosions. These criteria were primarily intended to categorize patients, especially for the purpose of conducting clinical research, rather than to assist rheumatologists in reaching a diagnosis. One of the criteria for diagnosing RA is the presence of bone erosions on radiograph. Radiographic Assessment of Rheumatoid ArthritisPrevention of bone erosion is one of the main aims of treatment because it is generally irreversible. To wait until all of the American College of Rheumatology (ACR) criteria for RA ( Diagnosis of Rheumatoid Arthritis, American College of Rheumatology Criteria) are met is therefore likely to result in a worse outcome for the patient. Most patients and rheumatologists would agree that it would be better to treat the patient as early as possible and prevent bone erosion from occurring, even if this means treating patients who do not fulfill the ACR criteria ( Fig.2687). The ACR criteria are, however, very useful for categorizing patients with established RA, for example for epidemiological purposes.
Diagnosis of Rheumatoid Arthritis, American College of Rheumatology Criteria
The American College of Rheumatology (ACR) published in 1958, and then revised in 1987, the currently accepted criteria for the classification of rheumatoid arthritis (RA). These criteria perform with a sensitivity of 89% and a specificity of 74%. Within the United States, the ACR criteria are the most widely recognized clinical guidelines for the diagnosis of RA.6612 The ACR revised criteria for classification of RA are depicted in Fig.2687.
Figure 2687 – 1987 American College of Rheumatology Criteria for the Classification of RA
Table 5, Page 319, Arthritis Rheum. 1988;31(3):315-324, Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
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At least 4 criteria have to be met and persist to establish a diagnosis of RA, although many patients are treated despite not meeting the criteria, because these criteria are relatively insensitive for early disease.
Diagnostic Tests
No single diagnostic test definitively confirms the diagnosis of rheumatoid arthritis (RA). In addition to the rheumatologist’s evaluation of joint counts (including joint location), documentation of the patient’s age and history, the presence of rheumatoid nodules ( Rheumatoid Nodules), the duration of morning stiffness, the presence of extra-articular manifestations of RA ( Extra-Articular Manifestations of Rheumatoid Arthritis), and several additional physician-calculated assessments, are useful. These assessments include the calculation of a patient’s disease activity score and health assessment questionnaire, which can be completed to assess the patient’s therapeutic needs. Several tests can provide objective data that increase diagnostic certainty and allow disease progression to be monitored. Diagnostic tests include imaging (radiographic evaluation Radiographic Assessment of Rheumatoid Arthritis), rheumatoid factor (RF) ( Rheumatoid Factor (Immunoglobulin M)), and anti-cyclic citrulinated peptide (CCP) ( Anti-Cyclic Citrullinated Peptide Test). RF, anti-CCP (especially for early, undifferentiated arthritis), erythrocyte sedimentation rate ( Erythrocyte Sedimentation Rate), radiographic plain film ( X-ray Imaging), ultrasound, or magnetic resonance imaging ( Magnetic Resonance Imaging) are all important diagnostic tests to be performed. Several blood tests are commonly conducted to detect and rule out other causes of arthritis such as systemic lupus erythematosus. Full blood count, renal function tests, liver enzyme tests (alanine transaminase and aspartate transaminase), and antinuclear antibody tests are also utilized to rule in or rule out the diagnosis in the appropriate clinical setting.
Rheumatoid Factor (Immunoglobulin M)
Rheumatoid factor (RF) is an antibody that is detectable in the blood. RF is commonly used as a blood test for the diagnosis of rheumatoid arthritis (RA). RF is present in about 70% to 80% of adults (but a much lower proportion of children) who have RA. RFs are autoantibodies (predominantly of the immunoglobulin M [IgM] type), which are reactive with the Fc (constant) portion of IgG. A negative RF does not rule out RA, rather, the arthritis is called seronegative. During the first year of illness, RF is frequently negative. Approximately 80% of patients eventually convert to seropositive status. Additionally, the presence of RF factor is not specific for RA. RF is present in 5% of healthy individuals and in other pathological conditions, such as systemic lupus erythematosus, Sjögren’s syndrome, chronic liver disease, sarcoidosis, and tuberculosis.7189 RF has been the primary blood test used to diagnose RA and to distinguish RA from other types of arthritis as well as from other inflammatory conditions. Because both the sensitivity and specificity of RF are not ideal, RF can be negative in patients who have clinical signs of RA, and may be positive in patients who do not have the disease. Because of the low specificity of RF for RA, newer serological tests have been recently developed.
While testing for RF is not a useful screening tool due to its poor predictive value, increased titers are present in 70% - 90% of RA patients.7189 Amos, et al., conducted a study of 56 patients who were subsequently diagnosed as having RA, and reported that 33% of patients at 3 months were RF positive, 55% of patients at 6 months were RF positive, and 76% of patients at 12 months were RF positive. The presence of RF may be of prognostic significance because patients with high titers tend to have more severe disease.7189 A positive RF result is a strong predictor of radiographic progression in early RA.4580, 10527
Anti-Cyclic Citrullinated Peptide Test
Antibodies to citrulline-containing proteins (anti-cyclic citrullinated peptide [CCP] antibodies) are found in most patients with RA.. This antibody can appear prior to the development of physical symptoms of RA, as well as during very early courses of the disease.10298, 10602 Similar to rheumatoid factor (RF) positivity ( Rheumatoid Factor (Immunoglobulin M)), in both early and established RA, anti-CCP antibodies may indicate a more aggressive course of RA.4646, 10628, 10656, 10979 Additionally, anti-CCP antibodies may predict the eventual development of RA in patients initially diagnosed with undifferentiated arthritis, or patients with unexplained joint inflammation who are RF negative.4567 Anti-CCP’s greatest utility in predicting disease progression, however, is when it is used in conjunction with RF testing. Numerous studies have illustrated a very high predictive value of disease progression in patients with positive results for both RF and anti-CCP antibodies.10298, 10602, 10896, 10979
The development of RA is clearly associated with the presence anti-CCP antibodies, but the predisposition to develop RA may be triggered by smoking Smoking Hypothesis in Rheumatoid Arthritis in genetically predisposed individuals, according to recent studies. Autoantibodies directed against citrulline-containing proteins have a specificity of nearly 100% in patients with RA. Lundberg, et al., postulated that citrullination, an enzymatic modification of the amino acid arginine, results in citrullinated residues that may break immunologic tolerance and lead to RA.10425 Klareskog, et al., presented results from their Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study that indicate a clear relationship between smoking, anti-CCP antibodies, and human leukocytic antigen DRB1 (HLA-DRB1). Their results suggest that previous smoking induces a dose-dependent increase in anti-CCP that, in the presence of the HLA-DRB1 shared epitope, leads to increased risk of developing RA.4533
The anti-CCP test detects the presence of anti-citrullinated protein antibodies. Anti-CCP antibodies are as sensitive as, and more specific than, immunoglobulin M (IgM) RFs Rheumatoid Factor (Immunoglobulin M) in early and fully established disease and may predict the eventual development of RA when they are found in undifferentiated arthritis. Anti-CCP antibodies are a predictor of erosive disease in RA. Like RF, the anti-CCP test can accurately detect approximately 80% of RA patients, but unlike RF, rarely is it positive in patients without the disease, giving it a specificity of 90% - 95%. One study by Jansen, et al., using a CCP1 assay showed a 97% specificity for RA, when both anti-CCP and IgM RF were positive in the early stage of arthritis.4571 In addition, anti-CCP antibodies can be often detected in early stages of the disease, or even before clinical onset of the disease. For this reason, CCP can be useful in diagnosing early RA. An elevated and positive CCP can be found in a significant number of patients who have a negative RF, and therefore can help to make a more accurate diagnosis. According to the American College of Rheumatology, antibodies to CCP are detected in about 50% - 60% of patients with early RA (as early as 3-6 months after the onset of symptoms). Early detection and diagnosis of RA allows physicians to begin aggressive treatment of the condition if clinically warranted, minimizing the associated complications and reducing damage to healthy tissues associated with poorly controlled disease.
Acute-Phase Reactants
Acute-phase reactants (or acute-phase proteins,
such as C-reactive protein [CRP] C-Reactive Protein) are a class of proteins whose plasma concentrations increase
(positive acute-phase proteins including CRP) or decrease (negative
acute-phase proteins) in response to inflammation. This response (either
an increase or decrease) is called the acute-phase reaction. In response
to injury, proinflammatory cells including neutrophil granulocytes
and macrophages, secrete a number of cytokines ( Cytokine Dysregulation) into the bloodstream, most notable of which are
The liver responds by producing a large number
of acute-phase reactants (positive acute-phase proteins), including
CRP, mannose-binding protein, alpha 1-antitrypsin, alpha 1-antichymotrypsin,
C-Reactive Protein
C-reactive protein (CRP) is produced in the liver
and is classified as an acute-phase protein on the basis of its increase
in plasma concentration in response to inflammation and infection.
CRP plays an important role in stimulating the complement system,
and cytokines ( Cytokine Dysregulation), particularly
Erythrocyte Sedimentation Rate
Erythrocyte sedimentation rate (ESR) is the rate at which red blood cells (RBCs) settle out in a tube of blood under standardized conditions. A high rate of sedimentation usually indicates the presence of inflammation. ESR is another measure of acute-phase reactants. The ESR is a simple test dating back to ancient Greece. A specific amount of diluted, unclotted whole blood is placed in a narrow tube and left undisturbed for 1 hour. Over time the red cells settle by gravity and accumulate at the bottom of the tube, while the plasma rises to the top. The height (in millimeters) of the red cell column within this tube after 1 hour has passed represents the ESR. Certain inflammatory disorders result in the production of abnormal proteins ( Acute-Phase Reactants), which bind to the erythrocytes (RBCs) and make them "sticky." This causes the erythrocytes to clump together (or aggregate) and settle out of the plasma more rapidly. An elevated ESR therefore serves as an indirect marker of inflammatory disease. Although each laboratory report generally lists a normal range (or reference range) for the ESR, there is variability from patient to patient with regard to age and gender. In general, normal ESR values increase with increasing age, and females tend to have higher sedimentation rates than males.10374
ESR is primarily influenced by the fibrinogen concentration in plasma.4574 It can be affected by a number of other factors in blood, including the size and shape of erythrocytes and the concentration of other dissolved plasma proteins (e.g., immunoglobulins). Despite its simplicity, ESR only indirectly measures the acute-phase response and may be altered by underlying medical conditions including tuberculosis, renal disease, systemic lupus erythematous, and rheumatic fever. Normal ESR values are higher in females, compared with males.4574 Like C-reactive protein (CRP), ESR can provide information about nonspecific inflammation. However, ESR is slower to normalize (and conversely to rise) than CRP making it potentially less effective at assessing therapeutic response. In broad terms, ESR correlates with activity of disease in rheumatoid arthritis and may be predictive of joint injury.4706 Patients with consistently elevated ESR are more likely to require total joint arthroplasty.10647
Radiographic Evaluation
Radiographic evaluation of the affected joints very early in the course of rheumatoid arthritis (RA) usually is not helpful in establishing a diagnosis. Imaging in Rheumatoid Arthritis Radiographs upon diagnosis generally reflect physical examination results, namely, evidence of soft tissue swelling ( Soft Tissue Swelling and Juxta-Articular Osteoporosis) and articular effusion ( Fig.2644). The diagnosis, however, may be bolstered by the typical pattern of symmetrical joint involvement. Periarticular osteopenia, followed by cartilage loss and bone erosions, may become evident very early in disease course as well. The greatest value of imaging at diagnosis, particularly with radiographs, may be to discern the patient’s pattern of disease, and subsequently, appropriate course of therapy.7189
Figure 2644 – Roentgen’s X-ray of the Hand of His Wife (Alfred von Kolliker), Taken 23 January 1896
Roentgen’s X-ray of the Hand of His Wife, 1896. Wikimedia website. http://commons.wikimedia.org/wiki/Image:Roentgen-x-ray-von-kollikers-hand.jpg. Accessed March 9, 2007
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References:| 4533. | Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38-46. |
| 4567. | Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet . 2001;358(9285):903-911. |
| 4571. | Jansen AL, van der Horst-Bruinsma I, van Schaardenburg D, van de Stadt RJ, de Koning MH, Dijkmans BA. Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J Rheumatol. 2002;29(10):2074-2076. |
| 4574. | Bain BJ. Some influences on the ESR and the fibrinogen level in healthy subjects. Clin Lab Haematol. 1983;5(1):45-54. |
| 4576. | Roentgen’s X-ray of the Hand of His Wife, 1896. Wikimedia website. http://commons.wikimedia.org/wiki/Image:Roentgen-x-ray-von-kollikers-hand.jpg Accessed March 9, 2007. |
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| 4646. | Combe B, Dougados M, Goupille P, et al. Prognostic factors for radiographic damage in early rheumatoid arthritis: a multi-parameter prospective study. Arthritis Rheum . 2001;44(8):1736-1743. |
| 4706. | Komatsubara Y, Hiramatsu S, Hongo I, Maeda A, Soda T. Multi-variate analysis of serum protein rheumatoid arthritis. Scand J Rheumatol . 1976;5(2):97-102. |
| 4711. | Larsen A. The relation of radiographic changes to serum acute-phase proteins and rheumatoid factor in 200 patients with rheumatoid arthritis. Scand J Rheumatol . 1988;17(2):123-129. |
| 4733. | Nielen MM, van Schaardenburg D, Reesink HW, et al. Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis. Arthritis Rheum . 2004;50(8):2423-2427. |
| 6612. | Blumberg SN, Fox DA. Rheumatoid arthritis: guidelines for emerging therapies. Am J Manag Care. 2001;7(6):617-626. |
| 6907. | Jansen LM, van der Horst-Bruinsma IE, van Schaardenburg D, Bezemer PD, Dijkmans BA. Predictors of radiographic joint damage in patients with early rheumatoid arthritis. Ann Rheum Dis .2001;60(10):924-927. |
| 7189. | Lipsky P. Rheumatoid arthritis. In: Fauci AS, ed. Harrison’s Rheumatology . 16th ed. New York, NY: McGraw-Hill; 2006:85-104. |
| 10134. | Stenger AA, Van Leeuwen MA, Houtman PM, et al. Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression. Br J Rheumatol. 1998;37(11):1157-1163. |
| 10280. | Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315-324. |
| 10298. | Rantapää-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2741-2749. |
| 10374. | McConkey B, Crockson RA, Crockson AP. The assessment of rheumatoid arthritis. A study based on measurements of the serum acute-phase reactants. Q J Med. 1972;41(162):115-125. |
| 10425. | Lundberg K, Nijenhuis S, Vossenaar ER, et al. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res Ther. 2005;7(3):R458-R467. |
| 10527. | Scott DL. Radiological progression in established rheumatoid arthritis. J Rheumatol Suppl. 2004;31(suppl 69):55-65. |
| 10602. | Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380-386. |
| 10628. | van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 2004;50(3):709-715. |
| 10647. | Wolfe F, Zwillich SH. The long-term outcomes of rheumatoid arthritis: a 23-year prospective, longitudinal study of total joint replacement and its predictors in 1,600 patients with rheumatoid arthritis. Arthritis Rheum. 1998;41(6):1072-1082. |
| 10656. | Forslind K, Ahlmén M, Eberhardt K, Hafström I, Svensson B; BARFOT Study Group. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis. 2004;63(9):1090-1095. |
| 10856. | Plant MJ, Jones PW, Saklatvala J, Ollier WE, Dawes PT. Patterns of radiological progression in early rheumatoid arthritis: results of an 8 year prospective study. J Rheumatol . 1998;25(3):417-426. |
| 10896. | Vallbracht I, Rieber J, Oppermann M, Förger F, Siebert U, Helmke K. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis. 2004;63(9):1079-1084. |
| 10979. | Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis. 2004;63(9):1085-1089. |
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