Diagnostic Testing and Imaging Studies

Introduction

Rheumatoid arthritis (RA) is a clinical diagnosis that relies heavily on the history of articular and extraarticular manifestations and joint examination; these are supplemented by results of diagnostic tests and imaging.

Laboratory Tests

Rheumatoid Factor (RF)

Serum RF is closely associated with RA and may help confirm a suspected diagnosis; it may also help define the severity and ultimately or prognosis of the disease. RF is an autoantibody, classically IgM, that binds to the Fc part of IgG; it is present in 75% to 85% of patients with established RA. Some patients may be seronegative for RF, but may become positive with persistence of synovitis. The RF test is not specific to RA; by definition, 5% of the general population have positive tests for RF, and this increases to 15% or more of elderly persons who will test positive for IgM-RF. In addition, the RF test is also positive in a number of conditions other than RA, including psoriatic arthritis (PsA; ~10-15% RF positive), Sjogren’s syndrome (>50% RF positive), cryoglobulinemia (vast majority are RF positive), various infections (e.g., bacterial endocarditis, mycobacterial disease, hepatitis, etc.) chronic interstitial lung disease and lymphoproliferative malignancies, among others.

Given that the prevalence of RA in the general population is ~0.8%, but that 5% or more will be RF positive, random screening of the population using the RF test would be expected to generate a large number of false-positive results. The discriminatory value of this test increases when it is judiciously applied to those considered to have a reasonable risk of having the disease, based on history and physical examination. High levels of RF somewhat increase the specificity of the test for RA, but RF levels do not reliably correlate with fluctuations of disease activity in an individual patient. Therefore, serial measurement of RF levels is rarely indicated.

A few exceptions include the first year of disease, when conversion from seronegativity to seropositivity may occur, or with the use of second-line drugs, when conversion to seronegativity may indicate a good therapeutic response. However, some of the more effective agents (e.g., cyclosporine, TNF inhibitors) may not alter serum RF levels, despite clinical improvement and some therapeutic agents (e.g., rituximab) that impact antibodies and autoantibodies may affect RF titers apart from impact on clinical disease. Some of the very highest RF titers are seen not in patients with RA but in those with other disorders, such as Sjogren’s syndrome, macroglobulinemias and leishmaniasis. In patients with RA, high serum titers of RF (>1:640 using dilutional assays or >300 IU/mL using quantitative nephelometric assays) have been associated with more aggressive and more severe disease, radiographic erosions, extra-articular manifestations (e.g., rheumatoid nodules, vasculitis, etc.) and functional disability. In addition to IgM, other isotypes of RF can be seen (e.g., IgG-RF and IgA-RF).

Anti-Cyclic Citrullinated Peptide (CCP) Antibodies

Antibodies against cyclic citrullinated peptide (CCPs) have been advocated as an additional useful diagnostic tool in RA patients. Currently, the second generation of anti-CCP (CCP2) antibody testing is in the most widespread use. While somewhat less sensitive than serum RF (70% CCP+ in RA of <2 years’ duration), CCP antibodies are more specific for RA than RF. Citrulline, a non-natural amino acid, is generated by a post-translational modification of arginine residues by the enzyme PADI-4 that may arise in the course of local inflammation or cellular apoptosis.

The presence of CCP antibodies has been correlated with early RA, aggressive RA, radiographic damage and shared epitope homozygosity, particularly among cigarette smokers. When present with positive serologic tests for RF, this imparts a poor prognostic outlook. Groups of RA patients found to be RF- and CCP-negative may have better overall outcomes (e.g., radiographic damage or disease progression over time).

Synovial Fluid Analysis

The synovial fluid in RA is usually yellowish, turbulent, or cloudy and, due to its inflammatory nature, has a low viscosity. Cell counts are typically inflammatory, with leukocyte counts more than 2,000 and as high as 75,000 cells/mm³ or more (mean values are often >20,000 cells/mm³). Differential counts on rheumatoid synovial fluid show a predominance of neutrophils (usually >70%). As rheumatoid patients are at greater risk for infectious arthritis, patients presenting with an acute monoarticular flare or chronic recalcitrant monoarthritis should undergo synovial fluid aspiration and analysis to exclude acute bacterial infections or chronic fungal or mycobacterial infections.

Acute-Phase Reactants

Elevations in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels provide surrogate measures of active systemic inflammation. These tests may help assess the activity of RA and, along with clinical outcomes, gauge the response to therapy. Sustained elevations of acute-phase reactants (eg, ESR, CRP) in RA have been shown to correlate with poor functional and radiographic outcomes. Unfortunately, not all patients with chronic inflammatory synovitis will have an elevated ESR or CRP, as these may be influenced by disease duration, concurrent therapies, or comorbidities.

Other Laboratory Abnormalities

Other laboratory abnormalities seen with uncontrolled rheumatoid inflammation include a normochromic, normocytic anemia (anemia of chronic disease), thrombocytosis, peripheral eosinophilia, mild hypoalbuminemia and polyclonal hypergammaglobulinemia.

Genetic Testing

RA has a genetic component, although the penetrance is incomplete. The risk of RA in the general population is approximately 0.8%; for persons with a first degree relative with RA, that increases to 5%. However, even with an identical twin with RA, the prevalence only increases to approximately 20%. Human leukocyte antigen (HLA) genotyping has shown associations between certain class II Major Histocompatibility Complex (MHC) alleles (e.g., HLA-DR4) and the development and severity of RA. The presence of HLA-DR4 and associated alleles seems to define a more aggressive variant of RA, with a greater incidence of articular erosions, rheumatoid nodules, secondary Sjogren’s syndrome and other extra-articular features of RA. These findings may be more common when a “double dose” of these associated alleles is seen.

Molecular techniques have been used to identify subtypes of the serologically identified HLA-DR4 molecule. These include the HLA-DR4 alleles designated DRB1*0401 and DRB1*0404 as well as the closely related alleles of HLA-DR1 designated DRB1*0101. However, heterogeneity of these associations limits the utility of such testing in racially diverse populations. Even in relatively homogenous populations, the strength of the associations is such that they have limited predictive value for individual patients.

Imaging Studies

Plain Radiography

In the early stages of RA, plain radiographs may show only soft tissue swelling or joint effusion. However, uncontrolled synovial inflammation, over time, can result in radiographic abnormalities. Plain radiographs are useful in helping to establish prognosis, assessing joint damage longitudinally and determining when surgery is appropriate. Radiographic erosions (found at any time) appear to connote a higher risk for future erosions, articular damage and a more aggressive clinical course.

Characteristic radiographic findings in RA include soft tissue swelling, juxta-articular osteopenia (due to chronic adjacent inflammation), concentric or symmetric loss of articular cartilage with diminution of the joint spaces and periarticular, bony erosions (e.g., in the metacarpophalangeal (MCP), proximal interphalangeal (PIP), metatarsophalangeal (MTP) and intercarpal or carpometacarpal joints). In patients with early RA, erosive disease may develop after only a few months of active synovitis. While erosions are seen in 8% to 40% of patients with <6 months of disease, 70% of RA patients will develop bony erosions within the first 2 years of disease.

Magnetic Resonance Imaging (MRI)

MRI may demonstrate erosions much earlier than conventional radiographs and provides superior detail in the depiction of articular and periarticular structures. MRI can detect synovial inflammation, cartilage loss, periarticular erosions and also bone marrow edema (indicating inflammation). However, it is more costly and is not routinely employed in the clinic as a general screening or assessment tool. While MRI will identify erosions earlier than plain X-rays, not all erosions identified on MRI will necessarily progress to X-ray erosions.

Ultrasonography

High-resolution ultrasonography (US) has become a more widely used modality for the assessment of patients with RA. US can detect bony erosions in RA patients with greater sensitivity than plain X-rays and comparable to that of MRI. In addition, synovial fluid and thickened synovial tissue can be readily detected, particularly in the joints of the hands. With the use of power color Doppler technology, which assesses blood flow, US can quantify disease activity within the synovium. Limitations to US include relative inaccessibility of certain articulations and operator dependency.