From the Guidelines
Elevated rheumatoid factor (RF) with negative antinuclear antibody (ANA) is most commonly associated with conditions such as chronic infections, inflammatory diseases, and certain malignancies, rather than rheumatoid arthritis itself, as evidenced by the low prevalence of RF positivity in systemic juvenile idiopathic arthritis and adult-onset Still's disease 1.
Causes of Elevated RF with Negative ANA
The causes of elevated RF with negative ANA can be diverse, including:
- Chronic infections like hepatitis C, bacterial endocarditis, and tuberculosis
- Inflammatory conditions such as Sjögren's syndrome, cryoglobulinemia, and sarcoidosis
- Certain malignancies, particularly lymphomas
- Chronic lung diseases
- Aging, as RF positivity increases in elderly populations without autoimmune disease
- Medications that can induce RF elevation
- Genetic factors or subclinical inflammation in healthy individuals
Clinical Approach
When encountering a patient with elevated RF and negative ANA, clinicians should:
- Consider the patient's complete clinical picture, including symptoms and physical examination findings
- Interpret RF levels in the clinical context, recognizing that RF alone is not diagnostic
- Potentially warrant further investigation with additional autoantibody panels or imaging studies to determine the underlying cause According to the most recent and highest quality study, the prevalence of RF positivity in systemic juvenile idiopathic arthritis and adult-onset Still's disease is low, at 4% in both conditions 1, highlighting the need to consider a broad range of potential causes beyond rheumatoid arthritis.
From the Research
Causes of Elevated Rheumatoid Factor with Negative ANA
- Elevated rheumatoid factor (RF) with negative antinuclear antibody (ANA) can be caused by several factors, including rheumatoid arthritis (RA) itself, as RF is a characteristic autoantibody found in RA 2.
- Other conditions such as Sjögren's syndrome (SS) can also lead to elevated RF, even in the absence of ANA 3.
- The presence of anti-Ro/SS-A antibodies, a diagnostic biomarker of SS, can influence disease activity and the effectiveness of disease-modifying antirheumatic drugs (DMARDs) in patients with RA 2.
- Some studies suggest that patients with RF-negative, ANA-positive arthritis are immunogenetically distinct from RF-positive RA and tend to have a better articular prognosis 4.
- The absence of ANA does not rule out the possibility of an autoimmune disorder, as some patients with advanced RA can be positive for ANA, although the titer is often lower compared to other collagen-related diseases 5.
- Genetic factors, including the human leukocyte antigen (HLA) region, can also play a role in the development of autoimmune rheumatic diseases, including RA and SS 6.