Approach Considerations
No test results are pathognomonic for rheumatoid arthritis (RA); instead, the diagnosis is made by using a combination of clinical, laboratory, and imaging features. Criteria for diagnosis have been established by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR; now the European Alliance of Associations for Rheumatology), [45] Multiple measures have been developed for assesssing disease activity in RA, using patient report, clinician assessment, and/or laboratory findings. These measures can facilitate a treat-to-target approach. The ACR has published assessments and ratings of these measures; see Guidelines. [2]
Laboratory Studies
Potentially useful laboratory studies in suspected RA fall into 3 categories—markers of inflammation, hematologic parameters, and immunologic parameters—and include the following:
-
Erythrocyte sedimentation rate (ESR)
-
C-reactive protein (CRP) level
-
Complete blood count (CBC)
-
Rheumatoid factor (RF) assay
-
Antinuclear antibody (ANA) assay
The ESR and the CRP level are associated with disease activity. The CRP value over time correlates with radiographic progression.
Although viral infections may trigger RA, or mimic early RA, routine viral screening by serologic testing does not significantly facilitate the diagnosis of RA in patients with early RA, nor is it helpful as a potential identifier of disease progression. [46]
Hematologic parameters
The CBC commonly demonstrates anemia of chronic disease and correlates with disease activity; it improves with successful therapy. Hypochromic anemia suggests blood loss, commonly from the gastrointestinal (GI) tract (associated with the use of nonsteroidal anti-inflammatory drugs [NSAIDs]). Anemia may also be related to disease-modifying antirheumatic drug (DMARD) therapy.
Thrombocytosis is common and is also associated with disease activity. Thrombocytopenia may be a rare adverse event of therapy and may occur in patients with Felty syndrome. Leukocytosis may occur but is usually mild. Leukopenia may be a consequence of therapy or a component of Felty syndrome, which may then respond to DMARD therapy.
Immunologic parameters
Immunologic parameters include autoantibodies (eg, RF, anti-CCP antibodies, and ANA). RF is an immunoglobulin (Ig) M antibody directed against the Fc fragment of IgG that is present in approximately 60-80% of patients with RA over the course of their disease (but in fewer than 40% of patients with early RA). RF values fluctuate somewhat with disease activity, though RF titers generally remain high even in patients with drug-induced remissions.
RF is not specific for RA; it is also present in other connective tissue diseases, infections, and autoimmune disorders, as well as in 1-5% of healthy people. The presence of RF predicts radiographic progression of bone erosions, independent of disease activity. [47]
ANA assays are positive in approximately 40% of patients with RA. However, test results for antibodies to most nuclear antigen subsets are negative.
Assays for anti-citrullinated protein antibody (ACPA; often tested as anti-CCP) are used clinically for diagnosing RA. ACPA-positive and ACPA-negative RA may be 2 distinct disease subsets, with different underlying pathogeneses and risks. [48, 49] ACPA-positive patients may have a more erosive RA disease course than ACPA-negative patients. [50] However, a 2011 study suggests that reassessment of ACPA or IgM RF during the first year after onset of arthritis does not provide significant additional information. [51]
Initial studies of anti–mutated citrullinated vimentin (anti-MCV) assays reported sensitivity comparable to that of ACPA [52] ; however, subsequent studies have found the specificity of anti-MCV to be lower than that of ACPA. [53, 54, 55] Anti-MCV and anti-CCP levels may correlate with disease activity. [52, 56]
Studies of anti-CCP antibodies suggest a sensitivity and specificity as good as or better than those of RF, with an increased frequency of positive results in early RA. The presence of both anti-CCP antibodies and RF is highly specific for RA. Additionally, the presence of anti-CCP antibodies, like that of RF, indicates a worse prognosis.
A trial that tested for 4 novel RA biomarkers improved the diagnosis of early RA in patients who tested negative on conventional tests. [57] In the study comprising 293 RA patients, 97 healthy control subjects, and 87 rheumatic control patients with other arthritides, the panel of 4 biomarkers—UH-RA.1, UH-RA.9, UH-RA.14 and UH-RA.21—had 83% specificity for RA. [57] These markers were found in 37% of patients with early RA and 26% of those who were seronegative for RF and ACPA. The investigators suggested that in addition to an improved diagnosis in early RA, these biomarkers may also have prognostic significance. [57]
Pregnancy
RA often goes into remission during pregnancy. The presence of RF neither helps predict nor correlates with the outcome of arthritis during pregnancy. The ESR cannot be used to assess RA disease activity during pregnancy, because pregnancy alters the normal values. The volume expansion that occurs during pregnancy can result in lower hematocrit values.
Diagnostic Criteria
Historically, the diagnosis of RA was based on the 1987 American College of Rheumatology (ACR) criteria. [58] Those criteria were intended to discriminate established RA from other definite rheumatologic disorders; they lacked the sensitivity to identify early inflammatory arthritis. With the recognition that early therapeutic intervention significantly improves clinical outcomes and reduces irreversible joint damage and disability, this lack of sensitivity was acknowledged to be significant.
Consequently, in 2010 the ACR and the European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism; EULAR) published new classification criteria for RA. [45] According to the ACR/EULAR criteria, patients who should be tested are those with at least 1 joint with definite clinical synovitis that is not better explained by another disease (eg, lupus, psoriatic arthritis, gout). The 2010 ACR/EULAR classification system is a score-based algorithm for RA that incorporates the following 4 factors:
-
Joint involvement
-
Serology test results
-
Acute-phase reactant test results
-
Patient self-reporting of the duration of signs and symptoms
Joint involvement consists of swelling or tenderness upon examination. The presence of synovitis may be confirmed on imaging studies. Points are allocated as follows:
-
1 large joint (ie, shoulders, elbows, hips, knees, ankles) = 0 points
-
2-10 large joints = 1 point
-
1-3 small joints (with or without involvement of large joints), such as MCP, PIP, second to fifth MTP, thumb interphalangeal (IP), and wrist joints = 2 points
-
4-10 small joints (with or without involvement of large joints) = 3 points
-
More than 10 joints (at least 1 small joint, plus any combination of large and additional small joints or joints such as the temporomandibular, acromioclavicular, or sternoclavicular) = 5 points
At least 1 serology test result is needed for RA classification. Points are allocated as follows:
-
Negative rheumatoid factor (RF) and negative anti−citrullinated protein antibody (ACPA; in the ACR/EULAR criteria set, tested as anti−cyclic citrullinated peptide [anti-CCP]) = 0 points
-
Low-positive RF or low-positive ACPA = 2 points
-
High-positive RF or high-positive ACPA = 3 points
Serology test results are defined as follows:
-
Negative – International unit (IU) values that do not exceed the upper limit of normal (ULN) for the reporting laboratory or assay
-
Low-positive – IU values that exceed the ULN but are no more than 3 times the ULN for the reporting laboratory or assay
-
High-positive – U values > 3 times higher than the ULN for the reporting laboratory or assay
-
When RF is available only as a positive or negative finding, a positive result should be scored as low-positive RF.
At least 1 test acute-phase reactant test result is needed for classification. Local laboratory standards determine which results are normal and which are abnormal. Points are allocated as follows:
-
Normal C-reactive protein (CRP) and normal erythrocyte sedimentation rate (ESR) = 0 points
-
Abnormal CRP or abnormal ESR = 1 point
Points for the patient’s self-reporting of the duration of signs or symptoms of synovitis in clinically involved joints are allocated as follows:
-
Shorter than 6 weeks = 0 points
-
6 weeks or longer = 1 point
The highest possible score is 10 points. Patients with a total score of 6 or higher are classified as having definite RA.
A systematic literature review by Radner et al concluded that the ACR/EULAR criteria have a pooled sensitivity for RA of 0.82 (95% confidence index [CI], 0.79-0.84) and a specificity of 0.61 (95% CI, 0.59-0.64). These authors' review of research that directly compared the 2010 ACR/EULAR criteria with 1987 ACR criteria found that the ACR/EULAR criteria had higher overall sensitivity (+0.11 compared with 1987 criteria) at the cost of lower overall specificity (-0.04). [59]
Radiography
Radiography remains the first choice for imaging in RA; it is inexpensive, readily available, and easily reproducible, and it allows easy serial comparison for assessment of disease progression. [60] Views of the hands, wrists, knees, feet, elbows, shoulders, hips, cervical spine, and other joints should be assessed with radiography when indicated (see the images below). Erosions may be present in the feet, even in the absence of pain and in the absence of erosions in the hands.
Juvenile rheumatoid arthritis. Widespread osteopenia, carpal crowding (due to cartilage loss), and several erosions affecting the carpal bones and metacarpal heads in particular in a child with advanced juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis).
Rheumatoid arthritis. Lateral view of the cervical spine in a patient with rheumatoid arthritis shows erosion of the odontoid process.
Rheumatoid arthritis. Anteroposterior radiograph of the knee shows uniform joint-space loss in the medial and lateral knee compartments without osteophytosis. A Baker cyst is seen medially (arrowhead).
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) provides a more accurate assessment and earlier detection of lesions than radiography does [61] ; however, the cost of the examination and the small size of the joints involved militate against its widespread use. MRI is used primarily in patients with abnormalities of the cervical spine (see the images below); early recognition of erosions on the basis of MRI images has been sufficiently validated.
Rheumatoid arthritis. T1-weighted sagittal magnetic resonance image of the cervical spine shows basilar invagination with cranial migration of an eroded odontoid peg. There is minimal pannus. The tip of the peg indents the medulla, and there is narrowing of the foramen magnum due to the presence of the peg. Inflammatory fusion of several cervical vertebral bodies is shown.
Sagittal T2-weighted magnetic resonance image of cervical spine in same patient as in previous image. Compromised foramen magnum is easily appreciated, and there is increased signal intensity within upper cord; this is consistent with compressive myelomalacia. Further narrowing of canal is seen at multiple levels.
Ultrasonography
In recent decades, rheumatologists have increasingly incorporated musculoskeletal ultrasound (US) into the management of RA in clinical practice. [62, 63, 64] US has multiple roles in this setting. In patients with musculoskeletal symptoms but without clinical synovitis, it can help predict progression to RA. In patients with early undifferentiated, US can help predict the development of persistent arthritis and facilitate differential diagnosis of RA versus other types of arthritis, such as psoriatic arthritis. In patients with established RA, US can be used to assess response to therapy and to evaluate new symptoms. In patients with RA in remission, it can detect subclinical inflammation. [63]
Ultrasonography allows recognition of effusions in joints that are not easily accessible (eg, the hip and, in obese patients, the shoulder) and of cysts (Baker cysts). It can be used to to guide articular and periarticular aspiration, injection, or biopsy (see the image below). High-resolution gray-scale (B-mode) US can identify synovial proliferation, and is superior to plain radiographs for detecting bone and cartilage. Doppler US can demonstrate joint vascularity, active inflammation, and neovascularization.
Rheumatoid arthritis. Ultrasonography-guided synovial biopsy of the second metacarpophalangeal joint of the right hand in a patient with rheumatoid arthritis of the hands. The biopsy needle is seen as a straight echogenic line on the left side of the image in an oblique orientation.
Imaging of Specific Structures
Hand
Hand imaging in RA can include radiography, MRI, ultrasonography, and computed tomography (CT), though the last of these plays only a minimal role. Radiography is the mainstay of imaging RA in the hands: It is inexpensive and easily reproducible, and it allows easy serial comparison for assessment of disease progression. Its main disadvantage is the absence of specific radiographic findings in early disease; erosions may only be visualized later.
MRI is sensitive than radiography to early changes in RA, and in the appropriate clinical setting, it is more accurate than plain radiography in the diagnosis of the disease. However, a systematic literature review concluded that widespread use of MRI for the diagnosis of early RA and for helping determine the prognosis of early RA is not currently recommended, though MRI bone edema may be predictive of progression in certain RA populations. [65]
Ultrasonography has been applied to the assessment of RA with the goal of improving on the current standard of conventional radiography. Like MRI, ultrasonography serves as an early diagnostic tool and can help in evaluating the cause of joint swelling in a patient with RA. [66, 67] However, the results of one study suggested that NSAID use may mask the ultrasonographic gray scale and power Doppler signal in the assessment of synovitis in RA, resulting in lower scoring despite continuing disease activity. [68]
See Rheumatoid Arthritis Hand Imaging for complete information on this topic.
Spine
Spinal imaging in RA involves radiography, MRI, and CT. As with hand imaging in RA, the mainstay of imaging remains plain radiography. Only about 50% of patients with radiographic evidence of atlantoaxial subluxation are actually symptomatic.
The role of plain radiography is to establish whether the patient has risk factors for cord compression. The major role for CT and MRI is in preoperative assessment of the 2 main indications for surgical intervention—namely, neurologic deficit and severe pain. [69, 70] Although CT scanning can document bone damage and alignment abnormalities, especially with more detailed multiplanar reconstruction, MRI has become the preferred modality for evaluation of the spinal cord and neural elements. [71]
See Rheumatoid Arthritis Spine Imaging for complete information on this topic.
Joint Aspiration
Consider joint aspiration when making the definitive diagnosis of RA or when ruling out coexistent infection or crystal arthritis in an acutely swollen joint. New-onset monoarticular arthritis or an unusual pattern of a joint flare in a patient with RA should encourage strong consideration of joint aspiration and synovial fluid analysis.
Analysis of synovial fluid includes Gram staining, cell count, culture, and assessment of overall appearance. In patients with RA, analysis typically reveals inflammation (white blood cell [WBC] count > 2000/µL, generally in the range of 5000-50,000/µL). Usually, neutrophil predominance (60-80%) is observed in the synovial fluid (in contrast with mononuclear cell predominance in the synovium). Because of a transport defect, glucose levels of synovial fluids (as well as pleural and pericardial fluids) in patients with RA are often low compared with serum glucose levels.
Histologic Findings
Early in the course of the RA disease process, there is an influx of inflammatory cells into the synovial membrane, with subsequent angiogenesis, proliferation of chronic inflammatory (mononuclear) cells and resident synovial cells, and marked histologic changes—a 2-cell-layer lining membrane changes to a thickened membrane that often has villous projections into the joint space (see the images below).
Rheumatoid arthritis. The hallmark of rheumatoid arthritis is a perivascular mononuclear cell infiltrate in the synovium (pictured here). The early stages are noted to have plasma cells as well, and syphilis needs to be part of the differential diagnosis.
Rheumatoid arthritis. The inflammation involved in rheumatoid arthritis can be intense. It is composed of mononuclear cells and can resemble a pseudosarcoma.
The lymphoplasmacytic infiltration of the synovium with neovascularization seen in RA is similar to that seen in other conditions characterized by inflammatory synovitis. Early rheumatoid nodules are characterized by small-vessel vasculitis and later by granulomatous inflammation.
Measures of Disease Activity
In 2019, the ACR published revised recommendations for the measurement of disease activity in RA, for clinical use at the point of care. The ACR assessed the feasibility of various measures, based on the number of items included in the measure, time to complete, need for provider joint counts, need for laboratory testing, commercial availability, and need for advanced imaging. The guidelines identified the following 5 measures as preferred for regular use in most clinic settings [2] :
-
28-joint Disease Activity Score, using either the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level (DAS28-ESR/CRP)
-
Clinical Disease Activity Index (CDAI)
-
Simplified Disease Activity Index (SDAI)
-
Routine Assessment of Patient Index Data 3 (RAPID3)
-
Patient Activity Scale-II (PAS-II)
In addition, the following measures met a minimum standard for regular use:
-
Disease Activity Score (DAS)
-
Patient-derived DAS28
-
Hospital Universitario La Princesa Index (HUPI)
-
Multi-biomarker Disease Activity Score (MBDA score, VECTRA DA)
-
Rheumatoid Arthritis Disease Activity Index (RADAI)
-
Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5)
-
Routine Assessment of Patient Index Data 5 (RAPID5)
All of the recommended measures result in a continuous index with defined ranges for low, moderate, or high disease activity or clinical remission. [72] See Table 3, below.
Table 3. Rheumatoid Arthritis Disease Activity Cutoffs (Open Table in a new window)
Tool |
Tool Type |
Remission |
Low Disease Activity |
Moderate Disease Activity |
High Disease Activity |
Patient Activity Scale–II (PAS-II) |
Patient-driven |
≤0.25 |
0.25-3.70 |
3.71 to < 8.0 |
≥8.0 |
Routine Assessment of Patient Index Data 3 (RAPID3) |
Patient-driven |
≤3 |
4-6 |
7-12 |
≥13 |
Clinical Disease Activity Index (CDAI) |
Patient and provider composite |
≤2.8 |
>2.8-10 |
>10 to 22 |
>22 |
Simplified Disease Activity Index (SDAI) |
Patient, provider, and laboratory composite |
≤3.3 |
>3.3 to ≤11.0 |
>11.0 to ≤26 |
>26 |
28-joint Disease Activity Score (DAS28-ESR/CRP) |
Patient, provider, and laboratory composite |
< 2.6 |
2.6-3.1 |
3.2-5.1 |
>5.1 |
Remission
A joint ACR/EULAR guideline on remission criteria for RA, first published in 2011 and updated in 2022, includes two definitions, one a Boolean-based definition and the other based on a composite index of RA activity, either the SDAI or the CDAI (the latter omits CRP). The Boolean-based definition requires that the patient satisfy all of the following to be considered in remission [3] :
-
Tender joint count of 1 or less
-
Swollen joint count of 1 or less
-
Patient global assessment of 2.0 or less (on a 0-10 scale)
-
Optional: CRP 1 mg/dL or lower
To be considered in remission using the traditional index definition, the patient must have an SDAI score of less than 3.3, or a CDAI score of 2.8 or lower. [3]
-
Juvenile rheumatoid arthritis. Ankylosis in the cervical spine at several levels due to long-standing juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis).
-
Juvenile rheumatoid arthritis. Widespread osteopenia, carpal crowding (due to cartilage loss), and several erosions affecting the carpal bones and metacarpal heads in particular in a child with advanced juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis).
-
Rheumatoid arthritis. Rheumatoid changes in the hand. Photograph by David Effron MD, FACEP.
-
Rheumatoid arthritis. Rheumatoid nodules at the elbow. Photograph by David Effron MD, FACEP.
-
Rheumatoid arthritis. Soft-tissue swelling and early erosions in the proximal interphalangeal joints in a patient with rheumatoid arthritis of the hands.
-
Rheumatoid arthritis. Subluxation in the metacarpophalangeal joints, with ulnar deviation, in a patient with rheumatoid arthritis of the hands.
-
Rheumatoid arthritis. Coronal, T1-weighted magnetic resonance imaging scan shows characteristic pannus and erosive changes in the wrist in a patient with active rheumatoid arthritis. Courtesy of J. Tehranzadeh, MD, University of California at Irvine.
-
Rheumatoid arthritis. Lateral view of the cervical spine in a patient with rheumatoid arthritis shows erosion of the odontoid process.
-
Boutonniere deformity.
-
Rheumatoid arthritis. Anteroposterior radiograph of the knee shows uniform joint-space loss in the medial and lateral knee compartments without osteophytosis. A Baker cyst is seen medially (arrowhead).
-
Rheumatoid arthritis. Ultrasonography-guided synovial biopsy of the second metacarpophalangeal joint of the right hand in a patient with rheumatoid arthritis of the hands. The biopsy needle is seen as a straight echogenic line on the left side of the image in an oblique orientation.
-
Plain lateral radiograph of the normal cervical spine taken in extension shows measurement of anterior atlantodental interval (yellow line) and posterior atlantodental interval (red line).
-
Rheumatoid arthritis. Lateral flexion view of the cervical spine shows atlantoaxial subluxation.
-
Rheumatoid arthritis. Lateral view of the cervical spine in a patient with rheumatoid arthritis shows erosion of the odontoid process.
-
Rheumatoid arthritis. T1-weighted sagittal magnetic resonance image of the cervical spine shows basilar invagination with cranial migration of an eroded odontoid peg. There is minimal pannus. The tip of the peg indents the medulla, and there is narrowing of the foramen magnum due to the presence of the peg. Inflammatory fusion of several cervical vertebral bodies is shown.
-
Sagittal T2-weighted magnetic resonance image of cervical spine in same patient as in previous image. Compromised foramen magnum is easily appreciated, and there is increased signal intensity within upper cord; this is consistent with compressive myelomalacia. Further narrowing of canal is seen at multiple levels.
-
Rheumatoid arthritis. Lateral radiograph of the same patient as in Images 4-5. Midcervical vertebral-body fusions are shown. The eroded peg is difficult to visualize, but inferior subluxation of the anterior arch of C1 is shown.
-
Lateral radiograph of a normal cervical spine shows the McGregor line. The odontoid tip should not protrude more than 4.5 mm above the line, which is drawn from the posterior edge of the hard palate to the most caudal point of the occiput.
-
Normal lateral magnified radiograph of the cervical spine shows the Ranawat method of detection of cranial settling. This method is used to measure the distance from the center of the pedicles (sclerotic ring) of C2 to a line drawn connecting the midpoints of the anterior and posterior arches of C1. (Normal values are 15 mm or greater for males and 13 mm or greater for females.)
-
Lateral radiograph of the cervical spine shows how the cervical height index (CHI) is calculated. The distance from the center of the sclerotic ring of C2 to the tip of the spinous process of C2 (dotted line) is measured. This is then divided into the distance from the center of the sclerotic ring of C2 to the midpoint of the inferior border of the body of C7. A CHI of less than 2 mm is a sensitive predictor of neurologic deficit.
-
X-ray shows total hip replacement, with prosthesis, in patient with osteoarthritis.
-
Rheumatoid arthritis. This gross photo shows destruction of the cartilage and erosion of the underlying bone with pannus from a patient with rheumatoid arthritis.
-
Rheumatoid arthritis. The hallmark of rheumatoid arthritis is a perivascular mononuclear cell infiltrate in the synovium (pictured here). The early stages are noted to have plasma cells as well, and syphilis needs to be part of the differential diagnosis.
-
Rheumatoid arthritis. The inflammation involved in rheumatoid arthritis can be intense. It is composed of mononuclear cells and can resemble a pseudosarcoma.
-
Rheumatoid arthritis. A 72-year-old man with long-standing rheumatoid arthritis developed blue-grayish discoloration of his skin. He had been on hydroxychloroquine for approximately 15 years. The diagnosis was hydroxychloroquine-related hyperpigmentation. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.
-
Rheumatoid arthritis. A 64-year-old woman with rheumatoid arthritis has developed nodules on the dorsal and volar aspect of her fingers, as well as the posterior aspect of her heels. The diagnosis is rheumatoid nodules with methotrexate-induced accelerated nodulosis. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.
-
Rheumatoid arthritis. A 64-year-old woman with rheumatoid arthritis has developed nodules on the dorsal and volar aspect of her fingers, as well as the posterior aspect of her heels. The diagnosis is rheumatoid nodules with methotrexate-induced accelerated nodulosis. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.
Tables
Tool |
Tool Type |
Remission |
Low Disease Activity |
Moderate Disease Activity |
High Disease Activity |
Patient Activity Scale–II (PAS-II) |
Patient-driven |
≤0.25 |
0.25-3.70 |
3.71 to < 8.0 |
≥8.0 |
Routine Assessment of Patient Index Data 3 (RAPID3) |
Patient-driven |
≤3 |
4-6 |
7-12 |
≥13 |
Clinical Disease Activity Index (CDAI) |
Patient and provider composite |
≤2.8 |
>2.8-10 |
>10 to 22 |
>22 |
Simplified Disease Activity Index (SDAI) |
Patient, provider, and laboratory composite |
≤3.3 |
>3.3 to ≤11.0 |
>11.0 to ≤26 |
>26 |
28-joint Disease Activity Score (DAS28-ESR/CRP) |
Patient, provider, and laboratory composite |
< 2.6 |
2.6-3.1 |
3.2-5.1 |
>5.1 |
