Laboratory tests - rheumatoid factor (RF)
What it is
- An autoantibody against the Fc portion of IgG
- Routinely measured isotype is IgM (IgA and IgG RF exist but are not standard)
- *A pan-immune-activation marker, not a rheumatoid arthritis test*
Positivity in healthy people
- Positive in 2-5% of healthy young adults
- Prevalence rises with age - up to 10-25% over 70
- Rises further with chronic infection, chronic inflammation and cigarette smoking
- *This age effect is why RF is nearly useless as a screening test in the elderly*
Mechanism
- Produced by B cells in germinal centres during sustained immune complex exposure
- Physiological transient RF occurs during many infections - it helps clear immune complexes
- Persistent high-titre RF reflects a chronic, oligoclonal or clonal B-cell response
- -> the reason very high titres point to cryoglobulinaemia, Sjogren syndrome and lymphoproliferative disease rather than to RA severity alone
- In RA: shared-epitope + smoking drives RF positivity; anti-CCP requires PTPN22 in addition
Performance in RA
Performance in RA
| RF | Anti-CCP | |
|---|---|---|
| Sensitivity | ~70-80% | ~60-80% |
| Specificity | ~80% (false positive 2-25%) | >90-95% |
| Predicts erosive disease | Yes | Yes, better |
| Predates clinical onset | Yes | Yes, by up to 10 years |
- Order RF only in a patient with an inflammatory joint presentation - ordering it as a screen generates false positives at a rate that outnumbers true disease
- The two together: RF+ and anti-CCP+ is the most specific combination; anti-CCP alone is more useful than RF alone
- In the 2010 ACR/EULAR criteria, high-positive (>3x ULN) RF or anti-CCP scores 3 points, low-positive 2
What a positive RF means in RA
- Associated with: more severe joint and radiographic damage, rheumatoid nodules (almost always RF+), vasculitis, ILD, Felty syndrome, better rituximab response
- *NOT useful for monitoring disease activity* - the titre does not track the disease and should not be repeated
RF positivity by rheumatic disease
| Frequency | |
|---|---|
| Sjogren syndrome | 75-95% |
| Rheumatoid arthritis | 26-90% (~70-80% established) |
| Mixed cryoglobulinaemia | 40-100% |
| MCTD | 50-60% |
| SLE | 15-35% |
| Polymyositis/dermatomyositis | 5-10% |
- *A VERY high titre points to cryoglobulinaemia or primary Sjogren syndrome, not to severe RA*
RF positivity in non-rheumatic disease
- Infection
- Bacterial endocarditis 25-50% - the classic trap: fever, arthralgia, purpura, positive RF, low complement
- Hepatitis B/C 20-75% (hepatitis C -> cryoglobulinaemia -> very high RF)
- Parasitic disease 20-90%, leprosy 5-58%, syphilis up to 13%, TB ~8%
- Pulmonary: sarcoidosis, interstitial fibrosis, silicosis, asbestosis
- Hepatic: primary biliary cholangitis 45-70%, chronic hepatitis
- Malignancy: 5-25%, especially B-cell neoplasms
- After multiple immunisations: 10-15%
- Healthy elderly
How to use the result
- Positive RF + inflammatory polyarthritis -> supports RA; add anti-CCP and X-rays
- Positive RF + no synovitis -> does not diagnose anything. Work through the alternatives above
- Very high titre -> check cryoglobulins, C4 (low in cryoglobulinaemia), hepatitis C, and assess for Sjogren and lymphoma
- Positive RF + fever + murmur -> blood cultures and echocardiogram before immunosuppression
- Negative RF does not exclude RA - ~30% of RA is seronegative at presentation; repeat serology and re-image
- Do not repeat RF to follow disease - use joint counts, CRP and a composite index
Related tests
- Anti-CCP (ACPA) - the better test for diagnosis and prognosis; order alongside RF
- Cryoglobulins - if very high RF, purpura, neuropathy or low C4
- Hepatitis B and C serology - before immunosuppression anyway
Associations
- Rheumatoid arthritis - nodules, vasculitis, ILD, Felty syndrome, more erosive disease
- Sjogren syndrome - and, with cryoglobulinaemia and low C4, MALT lymphoma risk
- Mixed cryoglobulinaemia - hepatitis C, purpura, neuropathy, membranoproliferative GN
- Infective endocarditis
- Chronic hepatitis B and C, primary biliary cholangitis
- Chronic lung disease - sarcoidosis, silicosis, asbestosis
- B-cell malignancy
- Ageing, smoking
Natural history
- RF (and anti-CCP) appear years before clinical RA - present in stored sera up to a decade earlier
- In established RA, seropositivity is fixed and predicts a worse long-term course
- Seroconversion to negative on treatment happens but does not change prognosis or management
- In healthy people, an isolated low-titre RF has low positive predictive value and most never develop rheumatic disease
- Persistently high-titre RF with low C4 in Sjogren syndrome is a lymphoma risk marker requiring ongoing surveillance
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