Laboratory Testing in the Rheumatic Diseases

The rheumatic diseases are a diverse group of conditions that affect the musculoskeletal system as well as other organs, where they cause inflammation, damage, and functional impairment. These conditions range from mild joint pain to severe life-threatening manifestations such as systemic vasculitis and rapidly progressive renal failure.

The first steps in the diagnostic process include a detailed history, physical examination (especially focused on the joints), and basic laboratory tests to determine findings suggestive of inflammation as well as the extent of involvement of organ systems (e.g., kidneys). These basic tests can then be followed by evaluation of biomarkers that are indicative of specific diseases. In addition to their value in establishing a diagnosis, laboratory tests can help assess the activity or severity of a rheumatic disease, its prognosis, and the effects of therapy, including drug toxicity.

Markers of Inflammation

For many patients, the initial goal of laboratory testing is to determine the presence of inflammation ( Chapter 36 ). The immediate response to inflammatory stimuli is termed the acute phase response and includes a set of proteins produced primarily in the liver in response to cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1.

Although cytokines and chemokines can be measured in some commercial assays, the most common clinical measures of the acute phase response are the C-reactive protein (CRP) level and the erythrocyte sedimentation rate (ESR). CRP levels provide a nonspecific but useful measure of inflammation of any cause, so they must be interpreted carefully in the evaluation of rheumatic diseases, especially when using high-sensitivity assays that can measure very low concentrations of CRP. Since CRP levels can rise and fall quickly, with a half-life of 5 to 7 hours, the level of this protein can provide a useful measure of disease activity and response to treatment.

The ESR is an indirect measure of acute phase reactants such as fibrinogen, whose production is increased in inflammatory states. The ESR has been traditionally determined using manual approaches such as the Westergren method, which measures the rate of fall of red blood cells (RBCs) in anticoagulated blood in a capillary tube over 60 minutes; in this assay, increased levels of proteins in plasma lead to a faster fall of RBCs. Automated methods to calculate the ESR have good correlation with the Westergren method. The ESR is nonspecific and also depends on the age and sex of the person. In addition, a low CRP but high ESR may indicate a paraproteinemia. Since ESR levels can be slower to change than CRP levels, CRP determinations may be superior to assess the effects of treatment in some settings.

Other molecules, such as serum amyloid protein, fibrinogen, and complement, also are markedly increased during the acute phase response. Patients with inflammation frequently exhibit a leukocytosis or thrombocytosis, most likely reflecting the action of cytokines and other mediators such as glucocorticoids. With chronic inflammation, low albumin levels and anemia of chronic disease can also occur. In systemic lupus erythematosus, lymphopenia, thrombocytopenia, and low CRP values often characterize active disease, with the discordance between laboratory and clinical findings a clue to diagnosis.

Laboratory Evaluation of Arthritis and Related Diseases

One of the most common presentations of rheumatic diseases is pain in and around the joints, collectively called arthralgia or arthritis. The extent of inflammation varies markedly, however, with some forms such as osteoarthritis ( Chapter 241 ) showing only limited evidence of inflammation either locally or systemically.

If inflammatory arthritis is suspected, further testing depends on the type and distribution of joint involvement. If arthritis is present in only one or two joints, joint aspiration to evaluate for infection or crystal-induced disease is typically indicated, especially for acute disease with evidence of severe inflammation such as fever or joint swelling and redness. Measuring the serum uric acid level is usually not helpful in diagnosing acute gout. Blood cultures can provide important information in assessing the presence of joint infection if joint aspiration cannot be performed.

If polyarticular inflammatory arthritis is suspected, laboratory tests often lead to a correct diagnosis. Since rheumatoid arthritis is the most common form of inflammatory polyarthritis in adults, autoantibody tests for it are typically indicated (e.g., rheumatoid factor and antibodies to citrullinated protein antigens).

Rheumatoid Factor

Rheumatoid factor comprises a family of antibody specificities that bind to the immunoglobulin G (IgG) molecule and react with antigenic determinants that are most likely conformational in origin in the Fc portion. IgM rheumatoid factors, which are the most abundant of these antibodies, may be seen in healthy individuals, whereas IgA rheumatoid factors are most specific for an underlying disease process. Rheumatoid factors occur in approximately 60 to 80% of patients with rheumatoid arthritis ( Chapter 243 ) and represent one criterion for the classification or diagnosis of this disease. Furthermore, high levels of rheumatoid factors are often associated with the presence of joint erosion, joint deformity, and a worse prognosis.

Rheumatoid factors also can occur in individuals with a wide range of autoimmune, inflammatory, and infectious diseases (e.g., bacterial endocarditis [ Chapter 61 ] and severe coronavirus disease 2019 [ Chapter 336 ] ), as well as in normal individuals, especially as they age. The frequent occurrence of rheumatoid factors in many conditions likely reflects their functional role in innate immune responses and their ability to promote the binding of IgG to antigen by Fc cross-linking. As a result, the finding of a rheumatoid factor alone may be insufficient to establish the diagnosis of rheumatoid arthritis.

Antibodies to Citrullinated Proteins

Antibodies to citrullinated proteins (ACPAs) are important biomarkers for the classification and diagnosis of rheumatoid arthritis ( Chapter 243 ). Citrulline is a post-translational modification of the amino acid arginine that results from deimidation. This chemical reaction is catalyzed by the enzyme peptidylarginine deiminase and may occur in the setting of inflammation. Citrullination can affect many different proteins, thereby creating antigenic sites on proteins that include vimentin, enolase, and filaggrin.

Although most ACPA assays detect IgG antibodies, some assays also detect IgA. Results can vary among commercially available assays, thereby making it important to know the performance characteristics of the assay being used.

ACPAs are highly associated with rheumatoid arthritis and represent a criterion in the classification of patients with this disease. Depending on the assay, these antibodies occur in 60 to 70% of patients with rheumatoid arthritis and uncommonly in patients with other forms of inflammatory arthritis. If rheumatoid arthritis is being considered, testing for both rheumatoid factor and ACPA increases the sensitivity for diagnosing rheumatoid arthritis while also providing good specificity.

Tests for antibodies to carbamylated proteins also may provide useful serologic information. Similar to citrullination, carbamylation is a post-translational protein modification. Patients with rheumatoid arthritis may have neither rheumatoid factors nor ACPAs, thereby denoting their condition as seronegative rheumatoid arthritis in distinction to seropositive rheumatoid arthritis, in which both are present. Seronegativity often prompts the search for another diagnosis that can produce similar signs and symptoms as rheumatoid arthritis.

ACPAs can be expressed before the onset of other signs and symptoms of rheumatoid arthritis. In patients who have arthralgias without evidence of synovitis by examination, the presence of ACPAs may predict the development of arthritis. In the future, ACPA testing may also help identify at-risk individuals who are likely to develop rheumatoid arthritis. Indeed, several randomized controlled clinical trials have been designed to prevent future rheumatoid arthritis in ACPA-positive individuals, but an effective preventive therapy has not yet been identified.

Laboratory Testing for Other Causes of Inflammatory Arthritis

Although rheumatoid arthritis is a common form of inflammatory arthritis, other conditions, such as Sjögren syndrome ( Chapter 247 ), systemic lupus erythematosus ( Chapter 245 ), and vasculitis ( Chapter 249 ), can produce similar joint findings, and are associated with different autoantibody profiles. Other forms of inflammatory arthritis include the spondyloarthropathies ( Chapter 244 ), such as are seen in psoriatic arthritis, ankylosing spondylitis, and arthritis associated with inflammatory bowel disease. For spondyloarthritis, genetic testing for the human leukocyte antigen (HLA) B27 allele is part of classification criteria and can be part of a diagnostic evaluation, although the frequency of HLA B27 varies markedly depending on the racial and ethnic group. Genetic testing may be helpful in evaluating systemic inflammatory diseases such as familial Mediterranean fever ( Chapter 240 ) that can present with arthritis.

Depending on the clinical findings and initial laboratory testing, other studies may help investigate less common diagnostic possibilities. For example, the serum ferritin level can be markedly elevated in adult-onset Still disease, which can present with arthritis. The laboratory evaluation of inflammatory arthritis may also include serologic tests for infections such as Lyme disease ( Chapter 296 ), human immunodeficiency virus (HIV) infection ( Chapter 355 ), hepatitis ( Chapters 134 and 135 ), or other viral infections such as parvovirus ( Chapter 342 ). Because hepatitis C can cause an inflammatory arthritis in association with an elevated rheumatoid factor, testing for this viral infection is often recommended. Older individuals may report pain, stiffness, and arthralgias as manifestations of polymyalgia rheumatica ( Chapter 250 ), a seronegative inflammatory condition whose most notable laboratory finding is an elevated ESR and/or CRP.

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