What is rheumatoid factor?

What is Rheumatoid Factor?

Rheumatoid factor (RF) is an antibody directed against the Fc region of immunoglobulin G, serving as a key diagnostic marker for rheumatoid arthritis with moderate sensitivity (60%) but lower specificity (70%) compared to anti-citrullinated protein antibody testing. 1

Definition and Characteristics

• RF is an autoantibody that targets the crystallizable fragment (Fc) portion of denatured immunoglobulin G (IgG) 2
• It exists in multiple isotypes, with IgM being the most commonly measured in clinical practice 3
• RF can be detected through various laboratory methods, with ELISA being a common technique 4

Clinical Significance

Diagnostic Value

• RF testing is essential in the diagnostic workup for rheumatoid arthritis and contributes significantly to the 2010 ACR/EULAR classification criteria 1
• In these criteria, RF positivity (particularly at high levels) contributes 2-3 points toward the required 6-point threshold for RA diagnosis 1
• NICE guidelines recommend testing for RF in all patients with suspected RA who have synovitis 5

Limitations

• Approximately 30% of RA patients may have negative RF tests, emphasizing that a negative result does not rule out RA 1
• RF can be found in patients with other autoimmune and non-autoimmune conditions, as well as in healthy individuals, limiting its specificity 3
• Normal inflammatory markers and negative RF should not delay referral when clinical suspicion of RA is high 1

Clinical Applications

Diagnostic Approach

• For optimal diagnostic accuracy, it is recommended to measure both RF and anti-cyclic citrullinated peptide (anti-CCP) antibodies together 3
• Consider measuring anti-CCP antibodies in people with suspected RA if they are negative for RF, especially when combination therapy is being considered 5
• Urgent specialist referral is recommended for patients with suspected persistent synovitis, even if blood tests show normal acute-phase response or negative RF 5

Prognostic Value

• High serum RF levels are associated with:
  • Higher disease activity
  • More progressive joint destruction
  • Poorer life prognosis due to organ damage
  • Decreased responsiveness to certain treatments, particularly TNF inhibitors with Fc regions 2

Treatment Considerations

• RF status may influence treatment selection, particularly regarding biologic therapies
• Patients with high serum RF levels may respond better to certolizumab pegol (CZP), a TNF inhibitor without the Fc region, as it maintains efficacy in these patients 2
• When serum IgM-RF levels are high, antibody drugs with Fc regions may be more likely to bind to RF and be degraded, potentially reducing their effectiveness 2

Important Caveats

• RF testing should be part of a comprehensive assessment for RA diagnosis, not used in isolation
• A positive RF test alone is insufficient for diagnosing RA due to its presence in other conditions
• RF levels may fluctuate over time and can sometimes revert to negative 5
• The presence of RF before symptom onset may help identify individuals at risk for developing RA 6

Understanding RF's role in diagnosis, prognosis, and treatment selection is crucial for optimal management of patients with suspected or confirmed rheumatoid arthritis.