ImmunologyTier 1Medical Sciences concept

Rheumatoid factor - target antigen and mechanism

Core concept

RF = an autoantibody against the Fc portion of IgG (the CH2-CH3 interface)
- Classically IgM anti-IgG; IgA and IgG isotypes also occur (IgA-RF correlates with extra-articular disease and smoking)
- An antibody against an antibody - so RF-containing complexes are large, fix complement, and lodge in vessels
Anti-CCP (ACPA) targets something entirely different: citrullinated peptides - vimentin, fibrinogen, alpha-enolase, type II collagen
- Peptidylarginine deiminase (PAD) converts arginine -> citrulline; the neo-epitope is presented by HLA-DRB1 shared epitope alleles
- RF: anti-antibody. ACPA: anti-post-translationally-modified self-protein. Same disease, different mechanism.

Seronegative RA ~20-30% - RF and ACPA both negative; diagnosis remains clinical
RF positivity in other conditions - this is what makes it a poor rule-in test

Group	Examples
Rheumatic	Sjogren's (~70-90%, the highest of any disease), SLE ~30%, MCTD, systemic sclerosis
Chronic infection	Subacute bacterial endocarditis, hepatitis C (with type II cryoglobulinaemia - RF activity IS the cryoglobulin), TB, leprosy, HIV, malaria, syphilis
Chronic inflammation	Sarcoidosis, ILD, primary biliary cholangitis, bronchiectasis
Malignancy	Lymphoproliferative disease
Healthy	~5% of young adults, up to 10-25% over 70

ACR/EULAR 2010 classification: score >=6/10; high titre (>3x ULN) of either antibody scores 3, low titre scores 2 - titre matters, not just positivity

Do not order RF as a screening test for joint pain - low pre-test probability makes a positive result more likely false than true
- Order anti-CCP when you need specificity, and RF/anti-CCP together only in genuine inflammatory polyarthritis
Seropositivity predicts: erosive disease, rheumatoid nodules, rheumatoid vasculitis, interstitial lung disease, Felty's syndrome, and worse response to conventional DMARD monotherapy -> earlier escalation
RF-positive with low complement and cryoglobulins -> look for hepatitis C
RF positive with fever and a new murmur -> endocarditis, not RA
Rituximab and abatacept work better in seropositive patients; ACPA status is used to select therapy
Antibody titres do not track disease activity - do not repeat them to monitor; use CRP/ESR and joint counts (DAS28)

Rheumatoid arthritis - diagnosis and management
Risk factors for rheumatoid arthritis development (smoking, periodontitis, shared epitope)
Causes of false-positive serological testing
Cryoglobulinaemia; Sjogren's syndrome
Biologic and targeted therapy mechanisms in RA

3 more sections, plus exam facts

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