Rheumatoid Arthritis - RA | Choose the Right Test

Medical Experts

Contributor

McMillin

Professor of Pathology (Clinical), University of Utah

Scientific Director, Mass Spectrometry Platform; Medical Director, Clinical Toxicology and Pharmacogenomics, ARUP Laboratories

Contributor

Nandakumar

Vijayalakshmi (Viji) Nandakumar, PhD, MS

Former Medical Director, Immunology, ARUP Laboratories

Rheumatoid arthritis (RA) is an autoimmune disorder with progressive and destructive polyarthritis characterized by joint swelling, joint tenderness, and destruction of synovial joints. RA is the most common adult inflammatory arthritis worldwide. Imaging techniques may be useful to differentiate RA from other arthritic disorders by enabling visualization of structural changes; however, joint damage is rarely apparent in early disease. As such, early diagnosis of RA generally requires the use of several laboratory tests, such as tests for rheumatoid factor (RF), anticitrullinated protein antibodies (anti-CCP or ACPA), anticarbamylated protein antibodies (anti-CarP), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), in combination with clinical evaluation. The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have defined a set of RA classification criteria for use in RA diagnosis. Treatments for RA, such as disease-modifying tumor necrosis factor alpha (TNF-α) inhibitors (eg, adalimumab, infliximab) or thiopurine prodrugs (eg, azathioprine), may require laboratory testing to evaluate dosage requirements or primary/secondary response failures.

Quick Answers for Clinicians

What other conditions should be considered in the differential diagnosis of rheumatoid arthritis?

The symptoms for rheumatoid arthritis (RA) are often nonspecific. Therefore, multiple conditions must be considered in the differential diagnosis of RA. Some of these conditions are septic arthritis, gout, and systemic autoimmune rheumatic diseases such as systemic lupus erythematosus, mixed connective tissue disease, and Sjögren syndrome. Careful evaluation is necessary for proper diagnosis and medical management of these conditions.

What is the significance of autoantibody testing in rheumatoid arthritis?

Autoantibodies such as rheumatoid factor (RF), anticitrullinated protein antibodies (anti-CCP or ACPA), and anticarbamylated protein antibodies (anti-CarP) are a distinctive feature of rheumatoid arthritis (RA). Additionally, their presence tends to precedes the onset of other findings, making them useful tests for RA diagnosis. Autoantibody testing may also be useful in predicting the severity of disease course.^,

When is it appropriate to perform pharmacogenetics testing in patients with rheumatoid arthritis?

Germline pharmacogenetics testing is appropriate before initiation of treatment with thiopurine prodrugs. Thiopurine prodrugs are metabolized and converted into their active state primarily by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) enzymatic activity in the body. Therefore, patients who have reduced or no TPMT and/or NUDT15 function may experience hematopoietic toxicity after thiopurine treatment. Laboratory testing to detect loss-of-function variants in the TPMT and NUDT15 genes, or to directly determine TPMT enzymatic activity, may be helpful in determining safe, effective dosage of these drugs. For more detailed information, including recommended laboratory tests, visit the Pharmacogenetics section or the ARUP Consult Germline Pharmacogenetics topic.

When is it appropriate to test for response to treatment in patients with rheumatoid arthritis?

Therapeutic drug monitoring (TDM) may be appropriate to monitor and optimize dosage or to evaluate whether the prescribed rheumatoid arthritis (RA) treatment regimen has been followed. In some cases, patients being treated for RA with medications (eg, monoclonal antibody therapeutics) either do not demonstrate response at all (primary response failure) or they demonstrate response initially but have later relapses (secondary response failure), despite increased dosage and/or more frequent administration of the drug. TDM may be warranted if primary or secondary response failure is suspected. For more information about TDM for monoclonal antibody drugs, refer to the ARUP Consult Laboratory Testing for Monoclonal Antibody Therapeutics topic.

Indications for Testing

Diagnostic testing for RA is appropriate in patients with signs and symptoms of inflammatory polyarthritis as determined by a physical examination and patient history. Laboratory testing may also be appropriate to monitor disease progression during treatment.

Criteria for Diagnosis

The ACR/EULAR classification criteria for RA are used to definitively diagnose RA. The criteria include both clinical and laboratory factors. For more information, refer to the 2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative.

Laboratory Testing

No single laboratory test can confirm the diagnosis of RA. As described in the ACR/EULAR criteria for diagnosis, several factors should be examined together for definitive diagnosis.

Serology

Anti-CCP is more specific to RA than is RF. Higher titers of anti-CCP have increased specificity for RA. Additionally, anti-CCP is thought to have a higher positive predictive value (PPV) for an erosive course of disease and may be of prognostic significance.

RF is an autoantibody that can belong to any immunoglobulin class (eg, immunoglobulin M [IgM], IgG, or IgA). RF is present in most patients with RA; however, it lacks diagnostic specificity. Higher titers of RF have increased specificity for RA. Additionally, the presence of abnormal concentrations of all three serotypes of RF (IgM, IgG, and IgA) is highly specific for RA.

Anti-CarP may also be present in patients with RA. Because it may be found in individuals who are seronegative for both anti-CCP and RF, anti-CarP may be a useful additional biomarker for the diagnosis of RA. Anti-CarP may also be useful in predicting joint damage, disease activity, and radiologic outcome in patients with RA.^,^,

Compared with anti-CP and RF (either alone or together), the presence of all three markers, anti-CCP, RF, and anti-CarP, has a higher specificity for RA, but a lower sensitivity.

The presence of anti-CCP, RF isotypes, and anti-CarP may predict and predate the development of RA.^,

Acute Phase Reactants

Increased CRP and/or ESR concentrations indicate inflammation; however, increased acute phase reactant concentrations are not specific to RA and may be present in other inflammatory diseases. CRP testing may be useful both for diagnosis and in monitoring disease progression.

Pharmacogenetics

Germline pharmacogenetics testing can be conducted before treatment begins to determine appropriate dosing, or after treatment, such as in the case of unexpected adverse effects or toxicity. RA may be treated using thiopurine prodrugs that are metabolized and converted into their active state primarily by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) enzymatic activity in the body. As such, reduced or no TPMT and/or NUDT15 function may lead to hematopoietic toxicity after thiopurine treatment. Laboratory testing to detect loss-of-function variants in the TPMT and NUDT15 genes, or to directly determine TPMT enzymatic activity, may be helpful in determining safe, effective dosage of these drugs. Note that direct detection of TPMT enzymatic activity must be performed with blood collected before drug administration. For more detailed information, including recommended laboratory tests, visit the ARUP Consult Germline Pharmacogenetics topic.

Therapeutic Drug Monitoring

In contrast to pharmacogenetics testing, which is generally performed before treatment initiation, TDM is performed during treatment to monitor medication efficacy and whether the prescribed treatment regimen has been followed.

TDM may be appropriate for TNF-α inhibitor monoclonal antibody drugs (eg, adalimumab, infliximab) used for the treatment of patients with chronic inflammatory and autoimmune diseases, including RA. Refer to the ARUP Consult Laboratory Testing for Monoclonal Antibody Therapeutics topic for more detailed information.

Laboratory testing may also be appropriate to monitor whether the prescribed treatment regimen (eg, leflunomide or other commonly used medications) has been followed. For more information, visit the ARUP Consult Therapeutic Drug Monitoring topic.