Rheumatoid Arthritis - RA | Choose the Right Test

Medical Experts

Contributor

Nandakumar

Vijayalakshmi (Viji) Nandakumar, PhD, MS

Former Medical Director, Immunology, ARUP Laboratories

Contributor

Saadalla

Abdulrahman Saadalla, MB, BCh

Assistant Professor (Clinical), University of Utah School of Medicine

Medical Director: Immunology Core Lab and Coagulation

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of the synovium that is characterized by chronic progressive polyarthritis and can lead to joint destruction and disability. RA is the most common adult inflammatory arthritis; prevalence varies between 0.5 and 1% worldwide. Early diagnosis and treatment are important in RA and can lead to significantly better long-term outcomes. The diagnosis of RA is based on clinical evidence of joint involvement in the presence of systemic inflammation and disease-specific serologic biomarkers. Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA, or anticyclic citrullinated protein antibodies [anti-CCP]) are the classic serologic markers included in the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) RA classification criteria. Research continues to focus on the identification and diagnostic performance of additional disease biomarkers (eg, anticarbamylated protein antibodies [anti-CarP], 14-3-3 eta protein, etc.) that can be used for early diagnosis, monitoring, prediction of disease severity, and diagnosis of seronegative disease (ie, in individuals negative for RF and anti-CCP).

Quick Answers for Clinicians

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

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

What is the significance of autoantibody testing in rheumatoid arthritis?

The formation of autoantibodies such as rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA, or anticyclic citrullinated protein antibodies [anti-CCP]), and anticarbamylated protein antibodies (anti-CarP) is a feature of rheumatoid arthritis pathogenesis. Additionally, the presence of these autoantibodies tends to precede the onset of other signs and symptoms; thus, testing for autoantibodies is useful for early RA diagnosis. Autoantibody testing may also be useful in predicting the severity of disease course.^,

What is the role of serum 14-3-3 eta testing in the diagnosis of rheumatoid arthritis?

At present, more data are needed to evaluate the performance of and formally recommend serum 14-3-3 eta testing for the diagnosis of rheumatoid arthritis (RA). However, research suggests that this marker may help distinguish between RA and other immune-mediated conditions and support the diagnosis of RA when used in conjunction with other disease markers. Moreover, studies demonstrate that the inclusion of 14-3-3 eta testing improves diagnostic sensitivity for early RA, as well as the detection of seronegative RA, compared with testing for rheumatoid factor (RF) and/or anticitrullinated protein antibodies (ACPA, or anticyclic citrullinated protein antibodies [anti-CCP]) alone.

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

Germline pharmacogenetic 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. 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 (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 for 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, RA diagnosis is based on several clinical and laboratory features.

Serology

RF is an autoantibody to the fragment crystallizable (Fc) region of immunoglobulin G (IgG) antibodies. Although RF is prevalent in patients with RA, it has limited specificity for RA diagnosis, as it can be present in other inflammatory diseases. Anti-CCP antibodies, on the other hand, 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.

Anti-CarP antibodies and 14-3-3 eta protein may be informative adjunct markers in the workup for RA.^,^, In particular, these biomarkers may be useful in identifying seronegative or early RA.^,^, Anti-CarP has been found to be useful in predicting joint damage, disease activity, and radiologic outcome in patients with RA.^,^, Compared with anti-CCP 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.^,

Acute Phase Reactants

Increased erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) concentrations indicate inflammation; however, increased acute phase reactant levels 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 pharmacogenetic testing can be performed before treatment begins to determine appropriate dosing, or after treatment, such as in the case of unexpected adverse effects or toxicity. RA can 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. 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 tests for 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 pharmacogenetic 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 tumor necrosis factor alpha (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.