Rheumatoid Factor

Rheumatoid factors (RF) are autoantibodies directed against the Fc portion of IgG. IgM-RF is measured most often, by latex agglutination, nephelometry, turbidimetry or ELISA, and the result is reported in IU/mL. IgA-RF and IgG-RF can also be measured. RF is part of the classification criteria for rheumatoid arthritis, and a high titre predicts erosive disease, extra-articular features and poor prognosis.

It is not specific: RF occurs in other autoimmune diseases, chronic infections, cancers and in healthy older adults. Anti-citrullinated peptide antibody (anti-CCP) is more specific and is requested with it.

Rheumatoid arthritis affects 0.5 to 1% of adults, with a female to male ratio of 3 to 1, and onset most often at 40 to 60 years. RF is positive in 70 to 80% of established rheumatoid arthritis (less in early disease, about 50 to 60%), and in 5 to 10% of healthy people, rising to 10 to 25% in people over 70 years. Sensitivity for rheumatoid arthritis is about 69% and specificity 85%, which is much lower than anti-CCP at 67% and 95%.

Indications. Persistent symmetrical polyarthritis, early morning stiffness over 30 to 60 minutes, small joint swelling of hands and feet, suspected rheumatoid arthritis. Suspected Sjögren syndrome, cryoglobulinaemia and vasculitis. Prognosis in established disease. Not for screening of people without joint symptoms, and not for monitoring disease activity.

Specimen. Serum 1 mL, no fasting. Stable for several days at 2 to 8 °C. Lipaemic or haemolysed samples interfere with turbidimetry.

Reference values (method dependent).

• Negative: under 14 IU/mL (some laboratories under 20 IU/mL).
• Low positive: 14 to 60 IU/mL (up to 3 times the upper limit).
• High positive: over 60 IU/mL (over 3 times the upper limit), and over 100 IU/mL strongly suggests rheumatoid arthritis in the right context.
• Latex agglutination titre: positive at 1 in 80 or more.

Interpretation.

• Positive RF with anti-CCP and compatible joint disease: rheumatoid arthritis is very likely, and both antibodies contribute points to the classification score (high positive gives more points).
• Positive RF with negative anti-CCP: lower specificity, other causes considered.
• Negative RF (seronegative arthritis): does not exclude rheumatoid arthritis (20 to 30% of patients), and seronegative arthritis, psoriatic arthritis, spondyloarthritis, polymyalgia rheumatica, crystal arthritis and osteoarthritis are considered.
• High RF titres predict erosive disease, rheumatoid nodules, vasculitis, interstitial lung disease, Felty syndrome and worse outcome, and predict less response to rituximab and some biologics in seronegative patients.
• RF may precede clinical rheumatoid arthritis by years.

Other conditions with positive RF.

• Autoimmune disease: Sjögren syndrome (75 to 95%), systemic lupus erythematosus (15 to 35%), systemic sclerosis, mixed connective tissue disease, dermatomyositis and juvenile arthritis (polyarticular type 5 to 10%).
• Infections: hepatitis B and C (especially with cryoglobulinaemia), Epstein-Barr virus, endocarditis, tuberculosis, syphilis, leprosy, parasitic infections and chronic osteomyelitis.
• Chronic liver and lung disease (cirrhosis, sarcoidosis, interstitial lung disease) and malignancy (lymphoma, myeloma).
• Mixed cryoglobulinaemia: very high RF activity with low C4.
• Healthy older adults and relatives of patients.

Critical values and findings needing immediate action.

• Positive RF with a hot swollen joint, fever and an inability to bear weight: septic arthritis must be excluded by aspiration and culture.
• High titre RF with palpable purpura, mononeuritis or ulcers: systemic vasculitis, urgent assessment.
• High RF with low C4, proteinuria and purpura: cryoglobulinaemic vasculitis, with hepatitis C testing.
• RF positive with cervical myelopathy symptoms, scleritis or pericarditis: urgent specialist review.

Interferences and pitfalls.

• RF is not diagnostic of rheumatoid arthritis, and a positive result in a patient without joint symptoms has low predictive value (positive predictive value under 10% in primary care).
• Different assays give different values, and results are not interchangeable. The same method is used for serial testing, although repeated measurement is of little value.
• RF titre does not track disease activity, and C-reactive protein, ESR, joint counts and composite scores are used.
• A negative RF does not exclude rheumatoid arthritis, especially early in disease.
• False positives occur from heterophile antibodies, paraproteins, cryoglobulins, hyperglobulinaemia and some drugs (hydralazine, penicillamine, interferon).
• IgA-RF has higher specificity but is not widely available.
• Anti-CCP, imaging (ultrasound or MRI showing synovitis and erosions) and the pattern of joint involvement matter more than RF alone.
• RF can disappear or fall after successful treatment, though not reliably.

Special groups.

• Children: RF is positive in only 5 to 10% of juvenile idiopathic arthritis (polyarticular seropositive type), and carries a poor prognosis.
• Pregnancy: RF may cross the placenta and is not harmful, and most women with rheumatoid arthritis improve.
• Older adults: positivity increases with age without disease.
• Smokers: higher frequency of RF and anti-CCP.
• Regions: chronic infections (tuberculosis, leprosy, schistosomiasis, malaria) cause positive RF.

Follow up tests. Anti-CCP antibody, ESR and C-reactive protein, full blood count, ANA and extractable nuclear antigens, hand and foot radiographs or ultrasound, joint fluid analysis, hepatitis B and C serology, cryoglobulins, complement (C3, C4), creatinine and urinalysis, and HLA-B27 if spondyloarthritis is suspected.