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Antibody to cyclic citrullinated peptide (anti-CCP)
(CCP Antibodies – ACPAs – Rheumatoid Arthritis–Specific Autoantibodies)
Synonyms
- Anti-CCP
- CCP Antibody
- Anti–cyclic citrullinated peptide antibody
- ACPA (Anti–citrullinated protein antibody)
- CCP IgG
- Anti-citrulline antibody
Units of Measurement
- U/mL (most common)
- kU/L
Note: 1 U/mL = 1 kU/L → Units are numerically identical.
Description
Anti-CCP antibodies are autoantibodies against citrullinated peptides. Citrullination is a post-translational modification of arginine residues catalyzed by PAD (peptidyl arginine deiminase) enzymes.
Anti-CCP antibodies are:
- Highly specific (>95%) for Rheumatoid Arthritis (RA)
- Present years before symptoms
- Predictive of erosive, aggressive RA
They are now preferred over rheumatoid factor (RF) for the diagnosis and prognosis of RA.
Physiological and Pathological Background
Citrullination occurs during:
- Inflammation
- Synovial injury
- Smoking
- Infection (e.g., Porphyromonas gingivalis)
In genetically susceptible individuals (HLA-DRB1 shared epitope), citrullinated proteins trigger autoimmunity → chronic synovitis → RA.
Clinical Significance
Elevated Anti-CCP
1. Rheumatoid Arthritis (Most Important)
- 70–80% positive in RA patients
- More specific than RF (RF specificity ~70%)
- Positive result supports diagnosis even in early arthritis
- Predicts rapid progression and joint erosions
2. Pre-clinical or “At-Risk” RA
Anti-CCP may appear:
- Years before symptoms
- In asymptomatic individuals with family history
- In smokers with arthralgia
3. Other Autoimmune Diseases (low frequency)
- Psoriatic arthritis (rare)
- SLE (low titers)
- Sjögren syndrome
- Autoimmune hepatitis
Levels usually much lower than in RA.
Negative Anti-CCP
Seen in:
- Seronegative RA (up to 20–30%)
- Viral arthritis
- Osteoarthritis
- Reactive arthritis
- Gout
- Fibromyalgia
A negative result does not exclude RA, especially early RA.
Reference Intervals
(Tietz 8E + Mayo Clinic + ARUP + ACR/EULAR 2010 RA Criteria)
General Cutoffs
(Assay dependent; values below are common ranges)
| Anti-CCP Level | Interpretation |
| < 20 U/mL | Negative |
| 20–39 U/mL | Weak positive |
| 40–59 U/mL | Moderate positive |
| ≥ 60 U/mL | Strong positive → Highly predictive of RA |
ACR/EULAR RA Classification Points
- High-positive Anti-CCP contributes 3 points
- Low-positive Anti-CCP contributes 2 points
(≥6 points → RA classification)
Diagnostic Uses
1. Early Diagnosis of Rheumatoid Arthritis
Most valuable when:
- RF negative
- Early or undifferentiated arthritis
- Symmetrical small-joint symptoms
2. Prognosis in RA
High titers predict:
- Faster disease progression
- More erosive arthritis
- Need for aggressive treatment (DMARDs, biologics)
3. Monitoring Treatment (Limited Use)
Not routinely used to monitor therapy; levels may remain positive despite improvement.
4. Predicting Risk in Pre-Symptomatic Individuals
Especially in:
- First-degree relatives of RA patients
- Smokers
- Anti-CCP positive, RF negative arthralgia
Analytical Notes
- Measured via ELISA or chemiluminescent immunoassay.
- Biotin >5 mg/day may cause assay interference.
- Hemolysis/lipemia have minimal effect.
- Autoantibody levels may remain persistently high even after treatment.
Clinical Pearls
- Anti-CCP is the most specific marker for RA.
- Anti-CCP positive RA tends to be more severe than RF-positive alone.
- Combined Anti-CCP + RF positivity → >98% specificity for RA.
- In undifferentiated arthritis, Anti-CCP predicts future development of RA.
- Presence of Anti-CCP in smokers dramatically increases RA risk.
Interesting Fact
Cyclic citrullinated peptide assays were introduced in the late 1990s and revolutionized RA diagnosis by providing a far more specific test than traditional rheumatoid factor.
References
- Tietz Clinical Chemistry & Molecular Diagnostics, 8th Edition - Autoantibodies.
- ACR/EULAR 2010 Rheumatoid Arthritis Classification Criteria.
- Mayo Clinic Laboratories - CCP Antibody Test Catalog.
- ARUP Consult - Autoimmune Arthritis Diagnostic Pathways.
- IFCC Immunoassay Standards for Autoantibody Testing.
- EULAR RA Guidelines - Biomarker Use.
- NIH / MedlinePlus - Anti-CCP Test Overview.