Rheumatoid Arthritis - RA

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 antibody (anti-CCP or ACPA), 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 (infliximab and adalimumab) or thiopurine prodrugs (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. As such, 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) and anticitrullinated protein antibodies (anti-CCP or ACPA) are a distinctive feature of rheumatoid arthritis (RA). Additionally, their presence often precedes the onset of disease symptoms. Autoantibody testing may also be useful in predicting the severity of disease course. As such, autoantibody testing leads to more accurate diagnosis and prognosis and often contributes to better disease management.  

When is it appropriate to perform pharmacogenomics 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 compliance in patients receiving treatment for rheumatoid arthritis (RA). In some cases, patients being treated for RA with medications such as infliximab or adalimumab either do not respond at all (primary response failure) or they respond initially but have later relapses (secondary response failure), despite increased dosage and/or more frequent administration of the drug.  If primary or secondary response failure or medication noncompliance is suspected, TDM may be appropriate. For more information about TDM tests, including resources for test result interpretation, visit the Therapeutic Drug Monitoring section or the ARUP Consult Therapeutic Drug Monitoring 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, described below, is used to definitively diagnose RA in a patient and involves several criteria. These include the number and site of involved joints, the presence of serologic abnormalities such as rheumatoid factor (RF) or anticitrullinated protein antibodies (anti-CCP), the presence of an increased acute phase response, as indicated by erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) concentrations, and symptom duration. A score of ≥6 is indicative of RA.  In addition, patients with a history consistent with RA and erosions, such as a cortical break in at least three joints at any of the following sites shown on x-ray: proximal interphalangeal, metacarpophalangeal, wrist, or metatarsophalangeal, should be diagnosed as having RA. 

Criteria for Diagnosis of Rheumatoid Arthritis
Any joint involvement (swelling or tenderness) Score
1 large joint 0
2-10 large joints 1
1-3 small joints 2
4-10 small joints 3
>10 joints (≥1 small joint) 5
Serology (≥1 test result required)
Normal RF and normal anti-CCP 0
Low-positive RF or low-positive anti-CCP 2
High-positive RF or high-positive anti-CCP 3
Acute phase reactants (≥1 test result required)
Normal CRP and ESR 0
Abnormal CRP or ESR 1
Duration of symptoms
<6 wks 0
>6 wks 1
Source: Aletaha, 2010 

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 antibodies are more specific to RA than is RF. Higher titers of anti-CCP have increased specificity for RA. Additionally, anti-CCP antibodies are 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.

The presence of anti-CCP and RF isotypes 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. In addition to diagnosis, CRP testing may be useful 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, therapeutic drug monitoring (TDM) is performed during treatment to monitor medication efficacy and compliance. Infliximab and adalimumab are TNF-α inhibitor drugs used for the treatment of patients with chronic inflammatory and autoimmune diseases, including RA. In some cases, patients either do not respond at all (primary response failure) or they respond initially but have later relapses (secondary response failure), despite increased dosage and/or more frequent administration of the drug.  Immunogenicity of TNF-α antagonist drugs and the development of antidrug antibodies (ADAs) are major causes of secondary treatment failure. Circulating adalimumab concentrations have been shown to vary considerably between patients. These differences are related to route and frequency of administration and patient-related features such as age, sex, weight, drug metabolism, and concomitant medications such as methotrexate and other immunosuppressants. Laboratory testing may be appropriate to monitor drug response for these medications in patients with RA. The table below describes the clinical interpretation of adalimumab/infliximab and antibody testing results.

Adalimumab/Infliximab Activity Neutralizing Antibody Titer Clinical Interpretation
Not detected Not detected Subtherapeutic dose (nonimmune-mediated failure); consider higher dosage of adalimumab or shortening the dosing interval
Not detected Detected Neutralizing antibodies may be responsible for failure (immune-mediated failure); consider alternate anti-TNF-α drug
Detected Not detected Likely caused by a mechanistic failure; consider alternate therapy (non-anti-TNF-α drug)
Detected Detected Future retesting suggested to rule out decreasing activity and/or increasing neutralizing antibodies

Laboratory testing may also be appropriate to monitor medication compliance for leflunomide and other commonly used medications. For more information, visit the ARUP Consult Therapeutic Drug Monitoring topic.

ARUP Laboratory Tests

Serology

Aids in diagnosis of and prognostication in RA

Components: CCP antibody, IgG, and RF

Components: CCP, IgG; RF; and RF, IgA/IgG/IgM

May aid in prognostication in RA

May be useful when combined with anti-CCP testing to predict radiologic damage in RA

RA panel is preferred for the workup of suspected RA or undifferentiated inflammatory arthritides

Aids in diagnosis of RA

Aids in diagnosis of pleural involvement in RA

For information on body fluid reference ranges and/or interpretive guidance, visit http://aruplab.com/bodyfluids/

Highly specific serologic test that aids in the workup of suspected RA or undifferentiated inflammatory arthritides

RA panel is the preferred test

Acute Phase Reactants

Preferred test to assess and monitor inflammation

Use to assess and monitor inflammation

Pharmacogenetics

Genotype test to assess risk, due to genetics, for severe myelosuppression with standard dosing of thiopurine drugs

Use for individuals being considered for thiopurine therapy or who have had an adverse reaction to thiopurine therapy

Preferred test for patients with recent heterologous blood transfusion

Can be performed irrespective of thiopurine therapy

Phenotype test to assess risk for severe myelosuppression with standard dosing of thiopurine drugs

Testing should be performed before initiation of thiopurine therapy

For therapy optimization or toxicity evaluation, order thiopurine metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS)

Therapeutic Drug Monitoring

Use to evaluate response failure to infliximab or biosimilar therapy

Use to determine and adjust dosage or identify the need for change to another anti-TNF-α inhibitor

Use to evaluate response failure to adalimumab therapy

Use to determine and adjust dosage or identify the need for change to another anti-TNF-α inhibitor

Use to monitor methotrexate concentration

Use for TDM and to evaluate full elimination of the drug (eg, in pregnant patients and in cases of possible toxicity)

Phenotype test used to optimize therapy for patients who are taking thiopurine drugs

Thiopurine metabolite concentrations are identified to assess therapeutic and toxic concentrations

If thiopurine therapy has not been initiated, order Thiopurine Methyltransferase, RBC

Medical Experts

Contributor

McMillin

Gwendolyn A. McMillin, PhD
Professor of Clinical Pathology, University of Utah
Scientific Director, Mass Spectrometry Platform; Medical Director, Clinical Toxicology and Pharmacogenomics, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®