Version May 2024
INTRODUCTION — Rheumatoid arthritis (RA) is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It typically leads to joint destruction through the erosion of cartilage and bone. Untreated, it will lead to loss of physical function, inability to carry out daily tasks of living, and difficulties in maintaining employment. Uncontrolled inflammation may have other health risks including higher rates of cardiovascular disease, osteoporosis, and certain types of cancer (eg, lymphoma).
Early recognition and treatment with disease-modifying antirheumatic drugs (DMARDs) are important to prevent joint damage and disability. However, in patients with early disease, the joint manifestations are often difficult to distinguish from other forms of inflammatory polyarthritis; the more distinctive signs of RA, such as joint erosions, rheumatoid nodules, and other extraarticular manifestations, are seen primarily in patients with longstanding, poorly controlled disease and are frequently absent on initial presentation.
This topic will review the approach to the diagnosis and differential diagnosis of RA. The clinical features of this disorder, its extraarticular manifestations, and laboratory markers that are clinically useful in the diagnosis of RA are discussed in detail separately:
●(See "Clinical manifestations of rheumatoid arthritis".)
●(See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)
●(See "Biologic markers in the assessment of rheumatoid arthritis".)
EVALUATION AND DIAGNOSIS — We suspect rheumatoid arthritis (RA) in any patient presenting with an inflammatory polyarthritis. In such a patient, we perform serologic and radiologic tests to look for evidence confirming the presence of RA.
When to suspect — While the clinical features of RA can be diverse, most patients with chronic RA will have the following features:
●Constitutional symptoms – Many patients with RA may present with symptoms associated with an inflammatory process. These symptoms may include unintentional weight loss, asthenia, fatigue, and myalgias.
●Morning stiffness – Morning stiffness is the hallmark of an inflammatory arthritis. Morning stiffness is generally characterized by difficulty mobilizing the joints after a prolonged period of rest. Morning stiffness lasting for longer than one hour implies the presence of an inflammatory joint disease. However, this is not specific to RA, and this finding can be present in a spectrum of inflammatory diagnoses. (See "Clinical manifestations of rheumatoid arthritis", section on 'Symptoms and physical findings'.)
●Joint manifestations – In general, the patient will notice joint pain and swelling that predominantly affects the small joints of the hands and feet (particularly the metacarpophalangeal [MCP], metatarsophalangeal [MTP], and/or proximal interphalangeal [PIP] joints). However, patients may present with other patterns of joint involvement, including an acute monoarthritis. (See "Clinical manifestations of rheumatoid arthritis", section on 'Upper extremity' and "Clinical manifestations of rheumatoid arthritis", section on 'Lower extremity' and "Clinical manifestations of rheumatoid arthritis", section on 'Palindromic rheumatism'.)
Serologic and radiologic tests are sometimes obtained as part of a broad evaluation of nonspecific complaints and/or of an extraarticular feature. Findings such as joint erosions and RA-associated autoantibodies may become the primary basis for suspecting a diagnosis of RA:
●Elevated acute phase reactants – Elevations of the erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) level are consistent with the presence of an inflammatory state, such as RA. Normal acute phase reactants may occur in untreated patients with RA, but such findings are infrequent and should prompt consideration of alternative diagnoses [1].
The degree of elevation of these acute phase reactants varies with the severity of inflammation and synovitis. As an example, an ESR of 50 to 80 is not uncommon in patients with severely active RA. By comparison, an ESR of 20 to 30 can be observed with only a few mildly to moderately active joints. (See "Acute phase reactants".)
●Autoantibodies – These include rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies. (See 'Confirmatory testing' below.)
●Radiographic abnormalities – Periarticular osteopenia, joint space narrowing, and bone erosions are late manifestations of RA. When present, these manifestations are most often detected on plain radiographs, although they may also be noted on magnetic resonance imaging (MRI) or ultrasonography. (See 'Confirmatory testing' below.)
Patients who have all or most of the features described above have a high probability of RA. Patients who only have one or two of these features have a low probability of RA and merit a closer examination for alternate diagnoses. (See 'Differential diagnosis' below.)
The presence of extraarticular features (eg, rheumatoid nodules, interstitial lung disease, scleritis) may prompt an evaluation for RA, although these patients should also have many of the features described above. The extraarticular features of RA are described in greater depth elsewhere. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)
Establish the presence of inflammatory arthritis — Diagnosing an inflammatory polyarthritis requires a joint examination of the upper and lower extremities to look for evidence of synovitis. Symptomatology alone is not adequate to establish a diagnosis of an inflammatory arthritis. The joint examination and the hallmarks of synovitis are described in detail separately. (See "Evaluation of the adult with polyarticular pain", section on 'Joint examination'.)
RA has a characteristic distribution of joint involvement. In patients with RA, synovitis is typically present in the MCP and PIP joints of the hands. The wrists are also commonly involved, as are the second to fifth MTP joints in the feet. However, any upper- or lower-extremity joint may be affected.
Other patterns of joint involvement may potentially be associated with RA, but for such patients, it is important to exclude other diagnoses for which those patterns may be more characteristic. For example, distal interphalangeal (DIP) involvement strongly suggests a diagnosis of osteoarthritis (OA) or psoriatic arthritis (table 1). (See "Clinical manifestations of rheumatoid arthritis", section on 'Symptoms and physical findings' and 'Osteoarthritis' below and 'Rheumatic' below.)
Potential challenges to identifying synovitis include:
●Early disease – Synovitis and tenosynovitis may be subtle initially and evolve to involve a greater number of joint areas. Patients with symptoms that are suspicious but that lack obvious joint swelling may need to be followed closely before the diagnosis can be made through careful examination. Imaging studies may be used to identify more subtle abnormalities earlier in the course of disease; however, imaging evidence of synovitis and tenosynovitis is not specific to RA [2]. (See 'Radiologic studies' below.)
●Body habitus – In some patients, the presence of subtle synovitis may be difficult to ascertain due to body habitus. In such patients, imaging studies may be useful to confirm the presence of an inflammatory arthritis. (See 'Radiologic studies' below.)
Confirmatory testing — In a patient suspected of having RA who has a pattern of synovitis consistent with this diagnosis, we conduct additional serologic and radiologic tests to confirm the diagnosis.
Serology — We suggest obtaining both RF and anti-citrullinated peptide antibodies in all patients suspected of having RA.
Rheumatoid factor
●Sensitivity and specificity – Estimates of the sensitivity, specificity, and positive predictive value of RF vary depending upon the population examined.
The reported sensitivity of RF in RA (ie, the proportion of patients with RA who are RF positive) ranges from 26 to 90 percent. A meta-analysis reported the overall sensitivity to be 69 percent (95% CI 65-73) [3].
The specificity depends substantially upon the choice of the control group. The overall specificity of RF reported in heterogeneous publications analyzed as part of a meta-analysis was 85 percent [3]. The prevalence of RF in a young healthy population is approximately 4 percent, consistent with a specificity of 96 percent in this group.
High positive RF (ie, above three times the upper limit of normal) is more specific for a diagnosis of RA than low positive RF. However, the specificity of RF drops substantially when examining patients with other rheumatic or inflammatory diagnoses [1]. The prevalence of RF in other conditions is discussed separately. (See "Rheumatoid factor: Biology and utility of measurement", section on 'Clinical disorders associated with rheumatoid factor positivity'.)
●Use in patients with a moderate to high pretest probability of rheumatoid arthritis – We suggest against testing patients with joint pain in the absence of synovitis (eg, nonspecific arthralgias, fibromyalgia, OA) because a positive test result is more likely to represent a false-positive result. (See 'When to suspect' above.)
RF testing in a rheumatology clinic practice with a prevalence of RA of 16 percent demonstrated a specificity of 95 to 97 percent, yielding a positive predictive value of approximately 80 percent [4].
Most studies of patients in early arthritis clinics demonstrate that RF helps predict persistent synovitis and/or RA [5]. In patients with “undifferentiated” inflammatory arthritis, the presence of RF was helpful in predicting a diagnosis of RA, with a positive odds ratio of approximately 30 [6].
RF is generally detectable prior to the clinical onset of RA. A retrospective study of stored blood samples collected as part of routine blood donation demonstrated that nearly 30 percent of those who later develop RA have serum RF present for a median of 4.5 years prior to diagnosis [7,8]
●Use in patients with a low pretest probability of rheumatoid arthritis – We suggest against testing patients with joint pain in the absence of synovitis (eg, nonspecific arthralgias, fibromyalgia, OA) because a positive test result is likely to represent a false-positive result.
RF is a poor screening test for the general population [9]. Population-based studies have shown that a small number of healthy people with a positive RF develop RA over time, especially if more than one isotype is persistently elevated and if there are high levels of RF [9,10]. Although RF may be found in the circulation prior to the development of RA, most asymptomatic persons with a positive RF do not progress to RA. (See "Rheumatoid factor: Biology and utility of measurement".)
As with any diagnostic test, the predictive value of the RF is directly affected by the estimated likelihood of disease prior to ordering the test (ie, the pretest probability) and, with RF, by the proportion of individuals being tested with a nonrheumatic disorder associated with RF production (table 2).
Anti-citrullinated peptide antibodies
●Sensitivity and specificity – Measurement of anti-citrullinated peptide antibodies (ACPA) is useful in the differential diagnosis of early polyarthritis because of the relatively high specificity for RA of these antibodies [11,12]. The sensitivity of current ACPA assays is approximately 70 to 75 percent, while specificity of ACPA for RA is relatively high, usually over 90 percent [3,11,13-19]. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)
High positive ACPA (ie, above three times the upper limit of normal) is more specific for a diagnosis of RA than low positive ACPA [1].
As with RF, ACPA may be present prior to the appearance of symptoms of RA. This phenomenon is discussed separately. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis".)
●Use in patients with a moderate to high pretest probability of rheumatoid arthritis – For patients with an inflammatory, small joint arthritis and with a moderate to high pretest probability of RA, the presence of ACPA testing confirms a diagnosis of RA. (See 'When to suspect' above.)
In a meta-analysis of 37 studies of patients with known or suspected RA, anti-CCP antibody had a sensitivity of 67 percent and a specificity of 95 percent for a diagnosis of RA [3].
●Use in patients with a low pretest probability of rheumatoid arthritis – We suggest against measuring ACPA in patients with a low pretest probability of RA. Although ACPA testing is more specific than RF for RA [3,12], it may be detected in several autoimmune rheumatic diseases, including systemic lupus erythematosus, Sjögren's disease, and psoriatic arthritis, usually in association with a deforming or erosive arthritis. ACPA have also been reported in association with tuberculosis, and, less commonly, chronic obstructive pulmonary disease and alpha-1-antrypsin disease [3,14,18,20-43].
Seronegative rheumatoid arthritis — Both RF and ACPA are negative on presentation in up to 50 percent of patients and remain negative during follow-up in 20 percent of patients with RA. Patients who lack both RF and ACPAs may be diagnosed with RA based upon findings otherwise characteristic of RA if appropriate exclusions have been met. For example, presence of a large number of swollen joints in a symmetric, small joint pattern or the presence of other features of RA may help establish the diagnosis in the absence of positive serologic testing.
Ultimately, seronegative RA is a clinical diagnosis and may be difficult to definitively distinguish from other forms of inflammatory arthritis. The diagnosis of seronegative RA may be secure only after monitoring the patient’s response to therapy over an extended period of time. In patients newly diagnosed with seronegative RA, we suggest a careful review of alternate diagnoses prior to initiating pharmacotherapy. (See 'Inflammatory diagnoses' below.)
Radiologic studies
●Plain film radiography – We suggest obtaining plain film radiographs of the hands and feet in all patients suspected of having RA (see 'When to suspect' above). Even if they do not assist in establishing the initial diagnosis of RA, plain film radiographs of the hands and feet may also be useful to assess the progression of joint damage over time.
•Characteristic findings – Plain radiographs are often normal early in disease. Therefore, radiographic abnormalities are not required to establish a diagnosis of RA.
The early changes evident on plain films may include only soft tissue swelling and periarticular osteopenia (image 1A-C). To be detected by plain radiography, erosions must have eroded through the cortex of the bone around the margins of the joint.
In some patients, erosions occur first in the ulnar styloid (image 2A-B) or MTP joints (image 3A-B). Joint space narrowing may also be present.
In a patient with a moderate to high suspicion of RA, the presence of periarticular osteopenia, joint space narrowing, and bone erosions, or joint subluxation confirms the diagnosis of RA.
Radiologic changes are generally symmetric, except in patients with joint injury or hemiplegia [44,45].
•Frequency of bone erosions – In studies done in the late 1980s and early 1990s, prior to the advent of highly effective biologic therapies, erosions in the MCP (image 4A-B and image 5) and PIP (image 6A-B) joints were identified by plain radiography in 15 to 30 percent of patients in the first year of the disease. By the end of the second year of disease in patients who did not respond to therapy, the cumulative incidence of erosions was 90 percent [46,47]. The frequency of joint erosions in the modern era is likely much lower.
●Ultrasonography – We suggest ultrasonography when the presence of synovitis cannot be determined by physical examination due to body habitus or inaccessibility of the affected joint. In a patient with a moderate to high suspicion of RA, a symmetric polyarthritis, particularly of the MCP, MTP, and/or PIP joints, confirms a diagnosis of RA. (See 'Establish the presence of inflammatory arthritis' above.)
•Synovial hypertrophy – Ultrasonography is a sensitive imaging technique for estimating the degree of inflammation and the volume of inflamed tissue. Direct comparison of color Doppler ultrasonography and contrast-enhanced MRI in one study of 29 patients demonstrated agreement regarding the presence or absence of inflammation between the two techniques in 75 percent of the joints of the hands and wrists [48]. Both imaging modalities found features of inflammation in joints that were neither tender nor swollen on physical examination.
•Bone erosions – Ultrasonography is more sensitive than conventional radiography for the detection of bone erosions; however, it is not routinely used for this purpose, as the clinical significance of erosions that can be detected only on ultrasound is not clear.
In one study, sonography detected 6.5-fold more MCP joint erosions than radiography in early RA and 3.4-fold more erosions in late disease [49]. Moreover, the sonographic erosions corresponded to MRI bone abnormalities.
Ultrasound evaluation for bone erosions and synovitis is described in further detail separately. (See "Musculoskeletal ultrasonography: Clinical applications", section on 'Joints'.)
●Magnetic resonance imaging – We suggest MRI when the presence of synovitis cannot be determined by physical examination and ultrasonography is not available. In a patient with a moderate to high suspicion of RA, a symmetric polyarthritis, particularly of the MCP, MTP, and/or PIP joints, supports a diagnosis of RA. (See 'Establish the presence of inflammatory arthritis' above.)
•Bone marrow edema – Decreased signal from the bone marrow on T1-weighted images and enhancement of the marrow with gadolinium administration is interpreted as bone marrow edema. The presence of marrow edema on MRI is predictive of later development of erosive disease [50].
•Synovial hypertrophy – It is also possible to identify and estimate the quantity of hypertrophic synovial tissue using contrast-enhanced MRI. The presence of MRI-detected synovial proliferation correlates with the later development of bone erosions [51]. Use of this imaging technique outside of research settings may be hastened by the development of MRI scanners that are designed specifically for imaging the extremities [52,53].
•Bone erosions – MRI is also a more sensitive technique than plain radiography for identifying bone erosions; however, it is not routinely used for this purpose, as the clinical significance of erosions detected only detected by MRI is unclear [54].
When radiography and MRI were compared in a group of 55 patients with early arthritis, MRI identified seven times as many erosions in the MCP and PIP joints as plain radiography [55]. MRI also may detect bone erosions earlier in the course of the disease than is possible with plain films [56]. As an example, approximately 45 percent of patients with symptoms for only four months were found to have erosions detected by this method [57].
Diagnosis — Clinicians often use the 2010 American College of Rheumatology/European League Against Rheumatology (ACR/EULAR) classification criteria for RA as a guide to diagnosis. However, many patients with RA will not satisfy these criteria early in the course of disease and may still be appropriate candidates for treatment.
Using these criteria, a classification as “definite RA” is based upon the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the synovitis, and the achievement of a total score of at least 6 (of a possible 10) from the individual scores in four domains [58-60]. The highest score achieved in a given domain is used for this calculation. These domains and their values are:
●Number and site of involved joints:
•2 to 10 large joints (from among shoulders, elbows, hips, knees, and ankles) = 1 point
•1 to 3 small joints (from among the MCP joints, PIP joints, second through fifth MTP joints, thumb IP joints, and wrists) = 2 points
•4 to 10 small joints = 3 points
•Greater than 10 joints (including at least 1 small joint) = 5 points
●Serological abnormality (RF or ACPA)
•Low positive (above the upper limit of normal) = 2 points
•High positive (greater than three times the upper limit of normal) = 3 points
●Elevated acute phase response (ESR or CRP) above the upper limit of normal = 1 point
●Symptom duration at least six weeks = 1 point
Using the ACR/EULAR classification system to diagnose RA comes with important caveats:
●Ultimately, RA is a clinical diagnosis. A patient with polyarticular gout, for example, could potentially be assigned 6 points using the ACR/EULAR classification system for RA. In this case, it would be incumbent upon the clinician to realize that the presence of tophi and episodic pattern of joint involvement was more consistent with a crystalline arthropathy.
●The diagnosis of seronegative RA may be particularly challenging. A diagnosis of seronegative RA may be secure only after monitoring the patient’s response to therapy over an extended period of time. In patients newly diagnosed with seronegative RA, we suggest a careful review of alternate diagnoses prior to initiating pharmacotherapy. A suggested review of systems to evaluate for alternate diagnoses is presented in the table (table 1).
●The 2010 ACR/EULAR criteria were developed primarily to identify patients with early RA. These criteria may fail to identify patients who have very early presentations of RA or inactive disease. In these cases, a presumptive diagnosis of RA may depend primarily on the patient’s history or imaging studies.
These issues are discussed in greater detail elsewhere. (See "Clinical manifestations of rheumatoid arthritis" and 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS — Joint pain involving the hands is a common clinical presentation for a variety of conditions. Rheumatologists are frequently consulted by other clinicians to evaluate patients with this complaint but who lack the characteristic features of rheumatoid arthritis (RA; eg, synovitis affecting the small joints of the hands, rheumatoid factor [RF] or anti-citrullinated peptide antibody [ACPA] positivity). In such patients, a thorough history and physical may uncover alternate diagnoses that should be considered prior to initiating therapy.
Additionally, a failure to respond to typical RA therapies may also prompt consideration of alternate diagnoses.
One approach to the differential diagnosis is to consider patients in terms of inflammatory versus noninflammatory diagnoses. Inflammatory diagnoses are characterized by the presence of synovitis on examination and are often accompanied by constitutional symptoms and acute phase reactant elevation. Noninflammatory diagnoses are characterized by joint dysfunction in the absence of synovitis, constitutional symptoms, and acute phase reactant elevation.
Some alternate diagnoses that should be considered, along with their characteristic features, are described below.
A suggested review of systems to evaluate for alternate diagnoses is presented in the table (table 1). A basic overview of the approach to a patient with polyarticular pain is described separately. (See "Evaluation of the adult with polyarticular pain".)
Inflammatory diagnoses — These diagnoses are typically considered in patients with synovitis on examination who lack autoantibodies specific for RA, such as RF or ACPA (table 1).
Infectious
●Viral polyarthritis – A viral arthritis is typically suspected in a patient who presents with an inflammatory arthritis and concomitant evidence of a viral syndrome.
Viral polyarthritis generally resolves spontaneously. However, several viral infections (eg, hepatitis B virus, Chikungunya) can cause a chronic polyarthritis.
●Lyme arthritis – Lyme arthritis should be suspected in a patient who presents with a mono- or oligoarthritis who lives in an area endemic for Lyme disease. The approach to establishing a diagnosis of Lyme disease is discussed elsewhere. (See "Diagnosis of Lyme disease", section on 'Approach to diagnosis'.)
Lyme arthritis is a late manifestation of Lyme disease; half of patients will not remember having been bitten by a tick. Lyme arthritis is characterized by intermittent or persistent inflammatory arthritis in a few large joints, most typically monoarthritis of the knee. The most commonly involved joints, after the knee, are the shoulder, ankle, elbow, temporomandibular joint, and wrist. Migratory arthralgias without frank arthritis may occur during early localized or early disseminated Lyme disease. (See "Musculoskeletal manifestations of Lyme disease".)
●Other infectious arthritis – Infectious arthritis should be suspected in a patient presenting with a monoarticular arthritis who is at increased risk of infection (eg, diabetes, chronic immunosuppression). The diagnosis is established by culturing the pathogen from the synovial fluid or from the blood.
An infectious arthritis is usually monoarticular, but polyarthritis can occur. Patients with septic arthritis may or may not appear toxic on examination, depending upon the stage of their infection, the presence of medications that can mask infection (eg, glucocorticoids), and other clinical variables. Peripheral blood leukocytosis with a left shift is common but not invariably present.
A low threshold for suspecting infection is required, particularly in compromised hosts. Patients with RA are at increased risk for joint infections because a damaged joint can serve as a nidus of infection. Synovial fluid changes, including marked granulocytosis and low glucose levels, are similar to those seen in RA. (See "Septic arthritis in adults".)
Rheumatic
●Other systemic rheumatic diseases – Early RA may be difficult to distinguish from the arthritis of systemic lupus erythematosus (SLE), Sjögren's disease, inflammatory myopathy (eg, dermatomyositis), and overlap syndromes such as mixed connective tissue disease. In contrast with RA, these disorders are generally characterized by the presence of other systemic features, such as rashes, dry mouth and dry eyes, myositis, or nephritis, and by various autoantibodies not often seen in RA (table 1).
While diagnostic uncertainty in early RA is expected, the diagnosis should become clearer with time.
Morning stiffness, symmetric, erosive arthritis, subcutaneous (“rheumatoid”) nodules, and ulnar deviation of the digits are highly characteristic of RA. However, these features can also be found with other diagnoses:
•Morning stiffness is common in all inflammatory arthritides. Symmetric arthritis can be seen in patients with SLE. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Arthritis and arthralgias'.)
•An erosive arthritis has been described in some overlap syndromes, particularly those associated with anti-tRNA synthetases and anti-U1 RNP antibodies [61]. (See "Mixed connective tissue disease".)
•Infrequently, nodules similar to those seen in RA may occur in patients with SLE, and other nodular lesions (eg, gouty tophi) may mimic rheumatoid nodules. (See "Rheumatoid nodules", section on 'Differential diagnosis'.)
•Ulnar deviation of the digits that can be manually moved back into normal alignment is a Jaccoud’s arthropathy, which is not found with RA. The joint deformities of Jaccoud's arthropathy are caused by loosening and lengthening of periarticular structures and tendons, whereas the joint deformities of RA are caused by cartilage loss and joint destruction. Jaccoud’s arthropathy occurs in up to 5 to 10 percent of patients with Sjögren's disease or SLE and can also occur in sarcoidosis [62]. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus" and "Sarcoid arthropathy" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Joints'.)
●Crystalline arthritis – Crystalline arthritis (gout and acute or chronic calcium pyrophosphate deposition disease [CPPD; pseudogout]) should be suspected in any patient over the age of 50 presenting with an inflammatory mono- or oligoarthritis. The diagnosis is established by the finding of urate or calcium pyrophosphate crystals, respectively, in synovial fluids.
Crystalline arthritis should also be considered in a patient with a polyarticular arthritis who has a long history of recurrent, self-limited flares that initially affected only one or two joints. The hallmark of a crystalline arthritis is its self-limited nature. Unlike RA, even in the absence of therapy, the flare will remit spontaneously in several weeks. However, since crystalline arthritis is not uncommon, its presence does not exclude the diagnosis of RA.
These diagnoses are discussed in detail separately. (See "Clinical manifestations and diagnosis of gout" and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)
●Polymyalgia rheumatica – Polymyalgia rheumatica (PMR) should be suspected in any patient over the age of 50 presenting with an inflammatory arthritis limited to the shoulder and hips. Unlike RA, PMR is usually associated with marked myalgias in the shoulders and hips, and joint involvement tends to be milder [63]. The diagnosis is established by its rapid response to low-dose glucocorticoids.
In patients initially diagnosed with PMR, persistent or recurrent small joint arthritis with tapering of glucocorticoids and the absence of other findings suggestive of PMR may lead to a change in the diagnosis to RA after several months or even years of treatment.
PMR is discussed in detail separately. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)
●Reactive arthritis – Reactive arthritis should be suspected in any patient who presents with a monoarthritis or oligoarthritis following a recent infection (eg, urethritis, enteric) [64]. The following findings are more consistent with reactive arthritis than RA:
•Asymmetric pattern of joint involvement
•Symptoms or signs of enthesopathy (inflammation at the site where a tendon inserts into a bone, eg, the insertion point of the Achilles tendon into the heel)
•Keratoderma blennorrhagica (picture 1) or circinate balanitis (picture 2 and picture 3) (see "Reactive arthritis", section on 'Extraarticular signs and symptoms')
•Radiologic evidence of sacroiliitis and/or spondylitis
•The presence of human leukocyte antigen (HLA) B27
•“Sausage” swelling of the digits, caused by inflammation of the tenosynovium (picture 4)
Reactive arthritis is discussed separately. (See "Reactive arthritis".)
●Inflammatory bowel disease-associated arthritis – Inflammatory bowel disease (IBD)-associated arthritis should be suspected in a patient with an inflammatory arthritis who has a known or suspected diagnosis of IBD. Less commonly, arthritis may be the presenting symptom of IBD.
While IBD-related arthritis is more commonly a large-joint oligoarticular arthritis or spondyloarthritis with sacroiliitis, patients with IBD may infrequently develop a peripheral polyarthritis with prominent involvement of the metacarpophalangeal (MCP) joints that can be mistaken for RA.
As the spectrum of drugs used for IBD-associated arthritis and RA are similar, differentiating between these diagnoses may not be necessary to initiate pharmacotherapy. This diagnosis is discussed separately. (See "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)
●Psoriatic arthritis – Psoriatic arthritis is typically diagnosed in a patient who presents with an oligoarthritis who has psoriasis and is seronegative for RF and ACPA.
However, it can be difficult to distinguish psoriatic arthritis from RA, since the arthritis may precede the rash by several years, and a small number of patients with psoriatic arthritis are RF positive. In such cases, the diagnosis may not be clear until the patient develops features that are highly characteristic of a specific diagnosis (eg, pattern of joint erosions in RA).
Because many therapies for these diagnoses overlap, distinguishing these diagnoses is not necessary prior to initiating pharmacotherapy. Psoriatic arthritis is discussed separately. (See "Clinical manifestations and diagnosis of psoriatic arthritis".)
●Palindromic rheumatism – Palindromic rheumatism is a form of inflammatory arthritis that sequentially affecting one to several joint areas for hours to days, with symptom-free periods that may last from days to months. A minority of patients with this presentation will eventually evolve into RA [65,66]. The diagnosis is made clinically, based on a characteristic history of joint involvement.
However, unlike RA, palindromic rheumatism is associated with inflammation of the periarticular rather than intraarticular structures. Furthermore, the intense, episodic nature of palindromic rheumatism is similar to what is observed in autoinflammatory diseases, rather than RA. (See "Clinical manifestations of rheumatoid arthritis", section on 'Palindromic rheumatism'.)
●Sarcoid arthropathy – Sarcoid arthropathy should be considered in a patient who presents with an inflammatory arthritis and has a prior diagnosis of pulmonary sarcoidosis. The approach to establishing a diagnosis of sarcoid arthropathy is discussed separately. (See "Sarcoid arthropathy", section on 'Diagnostic approach'.)
Chronic arthritis in sarcoidosis may be oligo- or polyarticular and can appear similar to RA in some patients. It most frequently affects the ankles, knees, hands, wrist, and MCP and proximal interphalangeal (PIP) joints.
This disorder is distinguished from RA by the following findings:
•Elevated serum concentrations of angiotensin-converting enzyme (ACE) are found in up to 50 percent of patients
•A chest radiograph may reveal characteristic findings of sarcoidosis
•The pattern of acute arthritis with Lofgren’s syndrome in patients with sarcoidosis is not observed in those with RA
This diagnosis is discussed in detail elsewhere. (See "Sarcoid arthropathy".)
●Multicentric reticulohistiocytosis – Multicentric reticulohistiocytosis should be suspected in a patient who presents with a highly destructive form of arthritis that is unresponsive to immunosuppressive therapies [67-72]. This diagnosis may be accompanied by smooth, shiny, erythematous nodules located in the periungual region. The diagnosis is established radiographically, or through biopsy of a skin lesion.
The rapid joint destruction of multicentric reticulohistiocytosis resembles the arthritis mutilans occasionally observed in psoriatic arthritis. Binucleated or multinucleated foreign body type giant cells are present on skin or synovial biopsies in multicentric reticulohistiocytosis [73,74]. In a minority of patients, an underlying malignancy may be present. (See "Cutaneous manifestations of internal malignancy", section on 'Multicentric reticulohistiocytosis'.)
Paraneoplastic and cancer treatment-related disease — Joint pain or frank polyarthritis can occur in association with cancer. The following are some examples:
●Hypertrophic osteoarthropathy – Patients with hypertrophic osteoarthropathy, sometimes termed hypertrophic pulmonary osteoarthropathy, typically demonstrate clubbing of the digits, joint pain, and periosteal new bone formation. Additionally, they give a characteristic history suggestive of bone pain and often describe the pain as deep and achy; nocturnal pain is common. Joint effusions may occur.
Hypertrophic osteoarthropathy is discussed in detail separately. (See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)
●Myelodysplasia – Patients with myelodysplastic syndrome sometimes develop an inflammatory polyarthritis that mimics RA [75]. The majority of patients are seronegative for RF and few are positive for ACPA or exhibit erosive changes on joint radiography. The arthritis may precede the diagnosis of myelodysplasia in at least half of the patients. In a cohort study of 87 patients with myelodysplastic syndrome, five (6 percent) had inflammatory arthritis that resembled RA [76]. Persistence of anemia, other cytopenias, or elevated acute phase reactants despite control of the arthritis should heighten suspicion of myelodysplasia [75].
This diagnosis is discussed in detail elsewhere. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
●Immune checkpoint inhibitor therapy – Cancer therapy that involves use of immune checkpoint inhibitor (ICI) immunotherapy may result in a number of rheumatologic and other adverse effects, including inflammatory arthritis that resembles RA. The joint symptoms may range from mild to severe and can develop at almost any time during ICI therapy. RF and ACPAs are often absent. This diagnosis is discussed in detail elsewhere. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy", section on 'Inflammatory arthritis'.)
Noninflammatory diagnoses — These diagnoses are typically associated with joint pain or dysfunction in the absence of true synovitis.
Osteoarthritis — Osteoarthritis (OA) can be confused with RA in the middle-aged or older patient when the small joints of the hands are involved. However, different patterns of clinical involvement usually permit the correct diagnosis (table 3). The following are examples:
●Distribution of joint findings – OA of the fingers typically affects the distal interphalangeal (DIP) joints and is frequently associated with Heberden's nodes in this area. By contrast, RA typically affects the MCP and PIP joints and is not associated with Heberden's nodes.
The carpometacarpal joint of the thumb is typically involved in OA.
●Joint examination characteristics – Swelling of the joints is hard and bony in OA. By contrast, soft, warm, boggy, and tender joints are typical of RA.
●Presence of stiffness – Stiffness of the joint is a very common feature of RA but is relatively uncommon in OA. Furthermore, the stiffness of RA is characteristically worse after resting the joint (eg, morning stiffness), while the stiffness of OA, if present, is typically worse after any effort and is often described as evening stiffness. Morning stiffness in OA, when present, is usually transient or lasts no more than a few minutes, unlike the more sustained stiffness typical of RA.
●Radiographs – Radiographs also help distinguish RA from OA. OA is characterized by narrowing of the joint space due to cartilage loss and osteophytes due to bone remodeling, but not erosions or cysts.
Erosive or inflammatory OA can cause severe and rapidly progressive arthritis in the small joints of the hands, often at middle age. Swelling in the PIPs with central joint erosion may be present. Central erosions (found in the center of the joint space) should be distinguished from the marginal erosions of RA, which are found at the margin of the joint space. Distinction from RA can be made by characteristic findings on radiographs as well as a lack of systemic inflammation and serologic markers.
●Rheumatoid factor – OA is classically associated with the absence of RFs and normal levels of acute phase reactants. However, RFs may be present, usually in low titer, consistent with the patient's (older) age.
OA is discussed separately. (See "Clinical manifestations and diagnosis of osteoarthritis".)
Stenosing tenosynovitis — Stenosing tenosynovitis should be suspected in any patient presenting with hand pain associated with triggering or locking of the digits. Stenosing tenosynovitis may be distinguished from RA by eliciting pain over the flexor tendons at the base of the digit and by the absence of synovitis in the joints of the hand.
Narrowing of the flexor tendon sheaths leading to stenosing tenosynovitis is common among patients with diabetes, thyroid disease, or occupational risk factors. Hand pain may be present even in the absence of overt triggering. (See "Trigger finger (stenosing flexor tenosynovitis)".)
Diabetic cheiroarthropathy is a related condition that results in difficulty in the extension of the digits of the hand. This diagnosis is discussed separately. (See "Limited joint mobility in diabetes mellitus".)
Carpal tunnel syndrome — Carpal tunnel syndrome should be suspected in any patient complaining of hand swelling, burning, or numbness, typically at night or in the morning. Carpal tunnel syndrome should also be considered in patients who demonstrate a positive Tinel or Phalen sign, have thenar wasting, and/or demonstrate poor hand dexterity or weakness in the "pinch test." The diagnosis can be confirmed with nerve conduction studies documenting median nerve dysfunction.
Synovitis in the wrist from RA may also cause median nerve entrapment leading to carpal tunnel syndrome. Thus, the presence of carpal tunnel syndrome does not exclude concurrent RA. However, carpal tunnel syndrome is common and observed at higher rates in patients with some comorbid conditions (eg, diabetes).
This diagnosis is discussed separately. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis".)
Hypermobility syndrome — Although the hypermobility syndromes can bear superficial resemblances to RA due to the presence of polyarthralgia, there are important distinguishing features:
●The hypermobility syndromes are associated with hyperextensible joints, and patients lack signs of synovitis.
●The hypermobility syndrome is not associated with significant titers of RF or ACPAs or with elevated levels of acute phase reactants.
This diagnosis is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)
Fibromyalgia — Fibromyalgia may be distinguished from RA by using the following features:
●Fibromyalgia is associated with tender points at nonarticular sites and chronic widespread pain. However, there is no evidence of synovitis, such as swelling, warmth, or diminished joint range of motion, although patients may exhibit joint-line tenderness on examination. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)
●Fibromyalgia is not associated with significant titers of RF or ACPAs or with elevated levels of acute phase reactants.
Although RA is usually not difficult to distinguish from fibromyalgia, diagnostic confusion can arise when assessment of serologies or acute phase reactants is performed and modestly elevated results are observed that are of unclear significance. In addition, a significant minority of patients with RA also develop fibromyalgia. The source of complaints in such patients needs to be carefully assessed to distinguish heightened pain sensitivity from pain related to inflammatory joint disease.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Rheumatoid arthritis (The Basics)")
●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●When to suspect – A patient with rheumatoid arthritis (RA) will typically have constitutional symptoms, morning stiffness, elevated acute phase reactants, and a small-joint arthritis affecting the hands and feet. Joint erosions appear late in the disease process. (See 'When to suspect' above.).
●Evaluation – A diagnosis of RA requires an examination of the extremities to detect the presence of synovitis, which will typically present as a symmetric polyarthritis affecting the metacarpophalangeal (MCP), metatarsophalangeal (MTP), and proximal interphalangeal (PIP) joints.
In a patient suspected of having RA, both MRI and ultrasound can be used to determine the presence of synovitis when the physical examination is not clear. (See 'Establish the presence of inflammatory arthritis' above.)
●Diagnosis
•Use of serologies – In a patient who presents with a symmetric polyarthritis, the presence of rheumatoid factor (RF) or anti-citrullinated peptide antibodies(ACPA) confirms the diagnosis of RA. However, these tests have limited value as a screening tool or to evaluate patients with a syndrome atypical for RA, since both may appear in patients with other rheumatic or inflammatory diagnoses. (See 'Serology' above.)
•Use or radiologic studies – Plain radiographs demonstrating the presence of joint erosions confirms the diagnosis of RA. However, erosions are a late finding of RA, and their absence does not rule out RA. (See 'Radiologic studies' above.)
•Classification criteria – The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria were not designed to establish a diagnosis of RA, although they are often used for this purpose. It is important to remember that these criteria may not identify RA in all patients, particularly after the initiation of immunosuppressive therapies. (See 'Diagnosis' above.)
●Differential diagnosis – Some infections, malignancies, and rheumatic diseases may present with synovitis that can mimic RA. Noninflammatory diagnoses, such as osteoarthritis (OA), carpal tunnel syndrome, and hypermobility syndromes, may present with joint pain or dysfunction in the absence of synovitis. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS and PJW Venables, MA, MB BChir, MD, FRCP, who contributed to earlier versions of this topic review.
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