From the Guidelines
For a patient with suspected rheumatoid arthritis (RA) and a negative rheumatoid factor (RF) test, the next step should be testing for anti-citrullinated protein antibodies (ACPA), also known as anti-CCP antibodies, as recommended by the 2016 update of the EULAR recommendations for the management of early arthritis 1. This approach is supported by the fact that ACPA is more specific for RA than RF and can identify seronegative RA cases.
- Comprehensive laboratory testing including complete blood count, inflammatory markers (ESR, CRP), and liver and kidney function tests should be performed to assess the patient's overall condition and potential contraindications for treatment.
- Imaging studies such as X-rays of affected joints to assess for erosions and ultrasonography or MRI to detect early synovitis are important for evaluating the extent of joint involvement.
- A thorough clinical evaluation by a rheumatologist is essential, as RA diagnosis relies heavily on clinical presentation and the pattern of joint involvement. If clinical suspicion remains high despite negative serologies, treatment may still be initiated with disease-modifying antirheumatic drugs (DMARDs), typically starting with methotrexate at 7.5-15 mg weekly, potentially with folic acid supplementation to reduce side effects, as suggested by the EULAR recommendations 1. Early DMARD therapy is crucial as it can prevent joint damage and improve long-term outcomes, and patients at risk of persistent arthritis should be started on DMARDs as early as possible, ideally within 3 months, according to the 2016 EULAR update 1. Some patients may have seronegative RA, where both RF and ACPA are negative, but the disease is still present based on clinical manifestations and other laboratory findings.
From the FDA Drug Label
- For RA Study 1, weighted difference stratified by region (US, rest of the world) and Rheumatoid Factor (RF) status (positive greater than 20 IU/mL, negative < 20 IU/mL) at baseline;
The FDA drug label does not answer the question.
From the Research
Next Steps in Diagnosis and Treatment
If a rheumatoid factor (RF) test is negative, the next steps in diagnosis and treatment for a patient with suspected rheumatoid arthritis (RA) may include:
- Repeating the RF test, as RF can be negative in early stages of RA or in some patients with RA 2, 3
- Ordering additional tests, such as anti-cyclic citrullinated peptide (anti-CCP) antibody, to increase the sensitivity of diagnosis 2, 4, 3
- Evaluating clinical symptoms, disease duration, and other autoantibody tests, such as antinuclear antibody (ANA) and anti-dsDNA, to support the diagnosis of RA 2, 5
- Considering other rheumatic diseases with arthritis, such as psoriatic arthritis, lupus, and osteoarthritis, as differential diagnoses 6
Diagnostic Tests
The following diagnostic tests may be used to support the diagnosis of RA:
- RF test: measures the level of RF in the blood, which can be elevated in patients with RA 2, 3
- Anti-CCP antibody test: measures the level of anti-CCP antibody in the blood, which is highly specific for RA 2, 4, 3
- ANA test: measures the level of ANA in the blood, which can be elevated in patients with RA and other autoimmune diseases 5
- C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) tests: measure the level of inflammation in the blood, which can be elevated in patients with RA 3
Appropriate Use of Diagnostic Tests
The use of diagnostic tests should be guided by clinical suspicion and appropriateness criteria, as overuse of tests can result in unnecessary referrals, patient anxiety, and increased costs 5. The American College of Rheumatology (ACR) and other professional organizations have developed guidelines for the diagnosis and treatment of RA, which include recommendations for the use of diagnostic tests 4, 5.