Laboratory tests - anticyclic citrullinated peptide antibody (anti-CCP)

What it is

An anti-citrullinated protein antibody (ACPA) - the CCP assay is a synthetic, standardised way of detecting the family
Target: citrullinated self-proteins - fibrinogen, fibronectin, vimentin, histones, type II collagen, alpha-enolase
- Citrullination = peptidylarginine deiminase (PAD) converts arginine -> citrulline; a normal post-translational modification that becomes antigenic in RA
*More SPECIFIC than rheumatoid factor for RA* - the single most useful serological test in inflammatory arthritis

Specificity ~90-95%; sensitivity ~60-80% in established RA (~50-60% in early disease)
Positive in only ~1-2% of healthy controls - unlike RF, which rises with age to 10-25% over 70
Detectable up to 10-15 years before symptom onset
~20-30% of RA is ACPA-negative (with RF-negative "seronegative RA" ~20-30%)
Prevalence in RA is higher in smokers and in those carrying the shared epitope

Gene-environment interaction, the classic worked example
- HLA-DRB1 "shared epitope" (DRB104:01, 04:04, 01:01) presents citrullinated peptides
- PTPN22 R620W - the second major risk allele (required in addition to the shared epitope for ACPA, whereas RF needs only the shared epitope)
- SMOKING - inc PAD activity in the lung -> citrullinated proteins
  - *Smoking + shared epitope -> ~20-40x risk of ACPA-positive RA* - the strongest interaction known in rheumatology
- *Periodontitis (Porphyromonas gingivalis has its own PAD enzyme)*; lung disease, silica
Break of tolerance occurs at MUCOSAL surfaces (lung, gum, gut) years before the joints are involved
ACPA are directly pathogenic: immune complexes -> osteoclast activation -> erosion; and bind to osteoclast precursors causing bone loss before synovitis

	Anti-CCP	RF
Sensitivity	~60-80%	~70-80%
Specificity	*~90-95%*	~80% (false positive 2-25%)
False positives	Few: TB, hepatitis C, psoriatic arthritis, some ILD, occasionally SLE/Sjogren	Common - age, infection, PBC, endocarditis, Sjogren, cryoglobulinaemia
Predicts erosive disease	Yes, better	Yes
Predates onset	Yes, up to 10-15 yr	Yes
Tracks disease activity	No	No

*Order in a patient with inflammatory joint symptoms, not as a screen* - a positive test in an unselected population is more likely false than true

	Points
Negative RF and negative ACPA	0
Low positive (<= 3x ULN) RF or ACPA	2
High positive (>3x ULN) RF or ACPA	3

Total >=6 of 10 classifies as RA (joints, serology, acute phase reactants, duration >=6 weeks)
RF+ AND anti-CCP+ is the most specific combination; anti-CCP alone beats RF alone

Positive + inflammatory polyarthritis -> RA; expect erosive disease; treat early and hard
Positive + arthralgia WITHOUT synovitis -> *"clinically suspect arthralgia" / at-risk - ~30-50% develop RA within 3 years*
- Monitor with ultrasound/MRI for subclinical synovitis; prophylactic treatment remains investigational (PROBE, TREAT EARLIER, APIPPRA)
Negative -> *does not exclude RA*; repeat at 6-12 months, image for erosions, and re-examine the differential (psoriatic arthritis, polymyalgia rheumatica, viral, crystal, connective tissue disease)
*Do NOT repeat the test to monitor disease* - use joint counts, CRP and a composite index (DAS28, SDAI)

Diagnostic confidence -> earlier commitment to a DMARD
Prognosis -> more erosive, more extra-articular disease, worse function -> justifies treat-to-target from the outset
- Methotrexate first-line, escalate at 3 months if the target is not met
Drug choice -> ACPA-positive patients respond better to rituximab and abatacept (abatacept blocks the T-cell costimulation driving ACPA)
Extra-articular risk -> screen for ILD (ACPA titre correlates with RA-ILD), cardiovascular risk, nodules, vasculitis
Modifiable risk -> *smoking cessation and dental care - the only interventions that address the antibody's cause*

Not a monitoring test - do not repeat
Seroconversion to negative on treatment does not alter prognosis or permit de-escalation
Does not distinguish active from inactive disease

RF, CRP/ESR, FBE, UEC, LFT
X-rays of hands and feet; ultrasound or MRI for subclinical synovitis and erosion
Hepatitis B/C, TB screening (QuantiFERON), CXR - before immunosuppression anyway
ANA/ENA if the phenotype suggests a connective tissue disease

Rheumatoid arthritis - erosive disease, nodules, ILD, vasculitis, worse function
*Smoking, periodontitis (P. gingivalis), silica and dust exposure*
HLA-DRB1 shared epitope, PTPN22
Psoriatic arthritis - low-titre positivity in ~5-10%, usually with a polyarticular RA-like phenotype
Interstitial lung disease - ACPA can be positive in ILD before any arthritis
False positives: active tuberculosis, hepatitis C, autoimmune hepatitis, some SLE and Sjogren
Juvenile idiopathic arthritis - polyarticular RF-positive subtype

Present years before symptoms - the pre-clinical phase runs: genetic risk -> mucosal citrullination -> ACPA -> epitope spreading and rising titre -> arthralgia -> synovitis
Seropositive RA has a worse trajectory: faster radiographic progression, more joint damage, more extra-articular disease, higher cardiovascular and lymphoma risk
Titre is fixed for practical purposes - it falls modestly on treatment but does not track activity
Sustained drug-free remission is markedly less likely in ACPA-positive disease - ACPA-negative patients are the ones in whom withdrawal can be attempted
In at-risk individuals (ACPA+ arthralgia), high titre, RF co-positivity and subclinical synovitis on imaging predict progression to RA

10 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.