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Introduction
The diagnosis of rheumatic disease is often challenging due to the heterogeneity of clinical presentation and lack of specific clinical findings, including diagnostic tests; there is rarely a gold standard on which to rely. The "background noise" of rheumatic symptoms also confounds the issue: it is estimated that each year, 15% of the American population will see a physician for musculoskeletal complaints. As with any diagnostic test, the clinician's estimate of pre-test likelihood of rheumatic disease as determined by clinical evaluation, in large part determines the usefulness (or predictive value) of the available diagnostic tests.
In general, no definitive diagnosis can be made through blood tests or other non-invasive evaluation; serologic markers of autoimmunity and inflammation are no match for a thorough clinical evaluation including history, physical examination and routine (that is, non-exotic, non-rheumatic) diagnostic evaluation. Even invasive testing such as tissue biopsy is often non-diagnostic in patients with suspected rheumatic disease. Finally, it is not rare for patients with suspected or even documented rheumatic disease to develop non-rheumatic problems (eg, the patient with lupus who develops subacute bacterial endocarditis); it is important to keep an open mind and to consider diagnostic evaluation for infection, malignancy or other non-rheumatic disorders that could account for the presentation.
Criteria for classification of many rheumatic disease have been established primarily to insure comparability of studies of specific disorders. In clinical practice, this often translates into their use as diagnostic criteria, which may be reasonable as long as excessively strict adherence to the criteria is avoided. It is important to understand how the criteria were derived and what their limitations may be when applied to actual clinical practice. Most criteria were determined by a committee of recognized experts, each of whom is assumed to be able to readily diagnose the disorder.
Erythrocyte Sedimentation Rate (ESR)
The ESR is a highly sensitive but nonspecific measure of "bodywide" inflammation. It is determined largely by fibrinogen and is among a large group of acute phase reactants that include C-reactive protein (CRP), ferritin, and haptoglobin. Among the rheumatic diseases, the sensitivity of this test is highest (90 to 99%) in polymyalgia rheumatica and temporal arteritis, perhaps in part because the ESR is one of the findings used to clinically define these diseases. Recent studies have suggested lower sensitivity (about 80%) in PMR than that usually quoted.
Rheumatoid Factor (RF)
The rheumatoid factor is an IgM antibody directed against the Fc portion of IgG; while it may be directly involved in tissue inflammation and injury, its role in the pathogenesis and perpetuation of RA or other rheumatic diseases is unknown. It is said to be present in the serum of 70 to 90% of patients with RA, but, as discussed above, its true sensitivity may be lower, especially if milder disease is considered. It has variable specificity: among patients with a variety of infectious or inflammatory disorders, including viral infection, subacute bacterial endocarditis and hepatitis, false-positive results are common. Normal aged patients are also said to be low-titer RF-positive more often than younger control patients who have less than 5% incidence.
Antinuclear Antibody (ANA)
The ANA is associated with a variety of rheumatic and non-rheumatic diseases. However, the utility of detecting an ANA in an individual patient, and the link between its presence and disease pathogenesis are largely unknown. The ANA is almost always present in SLE (Table 2), but its specificity may be low in settings in which SLE is rare. Some sub-types of ANAs (also called the "precipitin panel" including such autoantibodies as anti-ds-DNA, anti-ss-DNA, anti-Ro (SSA), anti-La (SSB), anti-RNP, and anti-Sm) are more specific but lack sensitivity.
Miscellaneous autoantibodies
A variety of other autoantibodies have been described in well-defined clinical contexts.
Anti-centromere antibody (directed against the kinetochore region of the nucleus) is detected in approximately 50% of patients with CREST syndrome (or the limited form of scleroderma); such patients often have a positive ANA in moderate to high titer, most commonly in a speckled pattern. Anti-Scl-20 (or anti-DNA-topoisomerase I) is observed in 20-50% of patients with scleroderma (also called diffuse scleroderma, or progressive systemic sclerosis). These autoantibodies are considered highly specific for these disease states, although anti-centromere antibody has also been found in 30% of patients with primary biliary cirrhosis.
Anti-Jo-1 antibody, which targets histidyl t-RNA synthetase, is found in 20% of patients with idiopathic inflammatory myositis, including polymyositis and dermatomyositis; it is associated with interstitial lung disease. Other "myositis specific antibodies" include those directed against other syntetases, Mi-2, and signal recognition protein (SRP). Recent studies have found associations between each of these antibody systems and specific clinical subtypes of myositis.
Antiphospholipid antibodies include the lupus anticoagulant, anti-cardiolipin antibodies (including IgG and IgM), and the false-positive RPR. They are associated with venous and arterial thrombosis as well as recurrent miscarriage among other manifestations currently termed the "Antiphospholipid antibody syndrome" (Table 3). These antibodies may be associated with rheumatic disease or may be detected in an otherwise healthy patient. The best means of detection, interpretation and management remain controversial. For stroke patients with a positive anti-cardiolipin antibody (in moderate titer or higher) or positive lupus anticoagulant, moderate to high intensity anticoagulation is recommended, but for other manifestations of disease (including recurrent miscarriage).optimal management is not well-defined. Anti-platelet agents, including aspirin and various doses and means of anticoagulation are under study. Available evidence to date suggests that corticosteroid therapy is not effective for such patients.
Anti-ribosomal P protein is a recently described autoantibody detectable in the serum of patients with lupus-induced psychosis (Bonfa). The sensitivity and specificity of this test appear to warrant its measurement in patients with lupus and neuropsychiatric symptoms of uncertain origin; however, its high sensitivity and specificity have been challenged.
Antineutrophilic cytoplasmic antibodies (ANCA) are also recently reported family of possibly pathogenic proteins that were first described in Wegener's Granulomatosis, but have since been detected in a variety of rheumatic and non-rheumatic disorders. Two patterns of ANCA have been commonly reported: cytoplasmic staining (c-ANCA), generally due to antibody specific for PR-3 antigen, that is 70 to 90 % sensitive for active, diffuse WG or a crescentic or necrotizing glomerulonephritis (GN).
Complement
Among some patients with SLE, complement is consumed faster than it is synthesized and serum levels drop, as measured by a low CH50 (a functional measure of complement activity), C3 or C4. Such patients generally have active, multisystem disease, especially nephritis. For these patients, serial measurement of serum complement levels or function may be a useful additional piece of information to argue for or against active disease. One study found such testing of particular usefulness in differentiating pregnancy with active lupus from pre-eclampsia with inactive lupus (Buyon). For many or perhaps most patients with SLE, however, complement measurement results are not a predictor of impending or current flare as it simply does not correlate well enough to be useful.
HLA-B27
The association of the HLA-B27 allele with the spondyloarthropathies, especially ankylosing spondylitis, has led to testing for this genetic marker in the evaluation of patients with rheumatic symptoms. The diagnostic sensitivity of this test (that is, its prevalence in patients with known disease) is approximately 95% in ankylosing spondylitis, 80% in Reiter's disease, 70% in patients with spondylitis and psoriasis, and 50% spondylitis associated with inflammatory bowel disease. Moreover, patients without rheumatic symptoms but who are HLA-B27 positive have an increased
Uric Acid
Given the extensive understanding of uric acid metabolism and key role this by-product plays in the pathogenesis of gout, it may be counter-intuitive to suggest that measuring serum levels of uric acid is only occasionally helpful. In fact, in acute gout (proven by synovial fluid analysis) the level of uric acid may be slightly lower than usual for that patient. The reason for this is not entirely clear. Moreover, the absolute level of uric acid in known gout is not critical to management unless urate-lowering therapy is planned; however, for most patients with acute gout, such therapy is
Radiographs
Radiographic evaluation in patients with rheumatic symptoms is useful when particular problems are suspected or need to be excluded. For example, fracture, osteomyelitis, avascular necrosis, tumor (especially neoplasms metastatic to bone), and joint space pathology (including erosions, osteophytes, calcification or narrowing) may be assessed by plain radiographs. However, in the acute setting, xrays are often disappointing in that they reveal only non-specific information that is already apparent: an effusion and soft tissue swelling is present (or absent), without other
Miscellaneous Diagnostic Tests
In select situations, more aggressive diagnostic testing is indicated in patients with suspected rheumatic disease. Electromyography (EMG) and/or nerve conduction studies (NCS) are particularly useful confirming or detecting a compressive neuropathies (such as carpal tunnel syndrome), myopathy (as seen in dermatomyositis) or mononeuritis multiplex (observed in vasculitic disorders, most commonly presenting as a foot drop).