Yes, you can have CCP antibodies in your blood without having rheumatoid arthritis; however, it remains the most common cause of a positive CCP antibody test.

Having CCP antibodies may predict the development of rheumatoid arthritis in the future, sometimes by two or more years.[7] A study took a group of 83 patients with rheumatoid arthritis who had donated blood before presenting joint symptoms and found that 33% already had CCP antibodies.[14]

Some of the other conditions associated with a positive CCP antibody test may include:

Autoimmune conditions:[10-11],[15]

• Systemic lupus erythematosus.
• Sjögren's syndrome.
• Type 1 autoimmune hepatitis.
• Polymyositis.
• Scleroderma.
• Psoriatic arthritis.
• Inflammatory bowel disease.

Non-autoimmune conditions:[10]

• Osteoarthritis.
• Pulmonary diseases (such as interstitial lung disease, cryptogenic organizing pneumonia, asthma, among others).
• Certain types of cancer (such as colon, breast, lung papillary thyroid cancer, lymphoma, VIPoma).
• Gout.
• Fibromyalgia.
• Rheumatic heart disease.
• Viral infections.
• Neuropathy.

Currently, the significance of CCP antibodies in these conditions has not been studied yet, and it is unknown if this test can be used to diagnose a condition aside from rheumatoid arthritis. A study has shown that higher levels of CCP antibodies are related to rheumatoid arthritis, while lower levels can be attributed to other conditions;[10] however, this is not enough for making assumptions about the other possible clinical uses for this test.

The main goal of the CCP antibody test is to support the diagnosis of rheumatoid arthritis; the suspicion of any other condition has to be considered with caution and will usually require other tests for confirmation.[15]
 

[1] Oxford University Hospitals NHS Foundation Trust. CCP ANTIBODIES. Accessed 25 September 2022. Available from: https://www.ouh.nhs.uk/immunology/diagnostic-tests/tests-catalogue/ccp-antibodies.aspx

[2] National Guideline Centre (UK). Rheumatoid arthritis in adults: diagnosis and management. London: National Institute for Health and Care Excellence (UK); July 2018. Available from: https://pubmed.ncbi.nlm.nih.gov/30102507/

[3] Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998;101(1):273-281. doi:10.1172/JCI1316

[4] Harnden K, Pease C, Jackson A. Rheumatoid arthritis. BMJ. 2016;352:i387. Published 2016 Mar 23. doi:10.1136/bmj.i387. Available from: https://doi.org/10.1136/bmj.i387

[5] LabTestsOnline UK. CCP. Accessed 25 September 2022. Available from: https://labtestsonline.org.uk/tests/ccp

[6] ClinicalTrials.gov. The CCP Study: Coordinated Programme to Prevent Arthritis - Can We Identify Arthritis at a Pre-clinical Stage ? (CCP) [ClinicalTrials.gov Identifier: NCT02012764]. Accessed 25 September 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT02012764

[7] Mekic M, Hadzigrahic E. Anti-Cyclic Citrullinated Peptide Antibody as a Predictor of Rheumathoid Arthritis Complications. Med Arch. 2020;74(3):183-186. doi:10.5455/medarh.2020.74.183-186

[8] Kamiya H, Panlaqui OM. Systematic review and meta-analysis of the risk of rheumatoid arthritis-associated interstitial lung disease related to anti-cyclic citrullinated peptide (CCP) antibody. BMJ Open. 2021;11(3):e040465. Published 2021 Mar 31. doi:10.1136/bmjopen-2020-040465

[9] Harrold LR, Bryson J, Lehman T, et al. Association Between Baseline Anti-cyclic Citrullinated Peptide Antibodies and 6-Month Clinical Response Following or TNF Inhibitor Treatment: A Real-World Analysis of Biologic-Experienced Patients with RA. Rheumatol Ther. 2021;8(2):937-953. doi:10.1007/s40744-021-00310-2

[10] Son JJ, Ishimori M, Mirocha J, Weisman MH, Forbess LJ. Low levels of anti-cyclic citrullinated peptide (CCP) 3.1 associated with diseases other than rheumatoid arthritis. Medicine (Baltimore). 2021;100(16):e25558. doi:10.1097/MD.0000000000025558

[11] Shapiro SC. Biomarkers in Rheumatoid Arthritis. Cureus. 2021;13(5):e15063. Published 2021 May 16. doi:10.7759/cureus.15063. Available from: https://doi.org/10.7759/cureus.15063

[12] Yang X, Cai Y, Xue B, Zhang B. Diagnostic value of anti-cyclic citrullinated peptide antibody combined with rheumatoid factor in rheumatoid arthritis in Asia: a meta-analysis. J Int Med Res. 2021;49(9):3000605211047714. doi:10.1177/03000605211047714

[13] Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146(11):797-808. doi:10.7326/0003-4819-146-11-200706050-00008

[14] Rantapää-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2741-2749. doi:10.1002/art.11223

[15] Vannini A, Cheung K, Fusconi M, et al. Anti-cyclic citrullinated peptide positivity in non-rheumatoid arthritis disease samples: citrulline-dependent or not?. Annals of the Rheumatic Diseases. 2007;66:511-516.
 

The presence of CCP antibodies is highly specific for rheumatoid arthritis[11-12] and even more when compared with the rheumatoid factor (another commonly tested antibody).[11] It is estimated that 20-30% of patients with rheumatoid arthritis and negative results for a rheumatoid factor will be positive for CCP antibodies.[11]

Specificity and sensitivity are useful statistical tools that help us to diagnose or discard specific diagnoses. A test with high specificity is practical for finding true negative cases or discarding a condition when the test result is negative. On the other hand, the sensitivity of a test is relevant for finding true positive cases or confirming a condition when the test result is positive.

In the case of the CCP antibody test, its specificity for rheumatoid arthritis is around 95-96%;[12-13] therefore, if you do not have CCP antibodies in your blood (a negative result), it is highly unlikely (but not impossible) for you to have rheumatoid arthritis.

The sensitivity of the CCP antibody test is around 46-67%,[12-13] which means that having CCP antibodies in your blood (a positive result) is associated with a relatively high chance of having rheumatoid arthritis.

However, these numbers will need some context before your doctor can arrive at a diagnosis. Positive and negative results have to be interpreted alongside other clinical data, such as symptoms, physical examination, medical history, and other tests.
 

CCPs are citrullinated proteins that can be produced when arginine, a regular amino acid, is mistakenly converted into citrulline, an amino acid that is not found in normal human proteins.[3] 

Eventually, CCPs are detected by the immune system, which does not recognise them as a normal part of the body but as something foreign; this triggers a cascade of immune reactions and the production of a special type of antibodies called "autoantibodies".[3] Autoantibodies are characterised by attacking the body's own tissues instead of dealing with external threats, leading to the development of autoimmune conditions. 

Currently, it is believed that these autoantibodies (CCP antibodies) deposit in the lining of joints, contributing to the inflammatory response in rheumatoid arthritis,[3] an autoimmune condition characterised by the inflammation and stiffness of the joints.

The most common and significant cause of high CCP antibody levels is rheumatoid arthritis, a chronic autoimmune condition characterised by inflammation and stiffness of the small joints.[11] As a result, the primary objective of this test is to diagnose the mentioned condition.[5]

Research suggests that people with rheumatoid arthritis have proteins that contain citrulline, an unusual amino acid. When the immune system detects these citrullinated proteins, it produces antibodies that target these proteins in the lining of the joints and promote the inflammatory response that characterises rheumatoid arthritis.[3],[5]

It is important to note that some people without symptoms or patients with very mild symptoms may present a high concentration of CCP antibodies; this can happen in early cases of rheumatoid arthritis.[5]

Positive levels of CCP antibodies may be associated, less frequently, with other inflammatory conditions and certain types of malignancies.[10-11] However, the exact cause is not rigorously understood in those cases.

A positive CCP antibody test means that your body is producing citrullinated proteins (CCPs) and, therefore, your immune system is releasing CCP antibodies into your blood.[1],[3]

A positive result may not be definitive by itself: it has to be interpreted alongside your clinical signs and medical history. A high concentration of CCP antibodies in your blood is strongly correlated with rheumatoid arthritis,[2] especially when coupled with the rheumatoid factor[5] and the acute phase response (detected through the C-reactive protein or the erythrocyte sedimentation rate).[11]

The CCP antibody test is usually requested after —or alongside— a rheumatoid factor test; in these cases, the following outcomes can be interpreted:

• If both are positive, rheumatoid arthritis is highly likely.[5]
• If only the CCP antibody test is positive, it may indicate an early stage rheumatoid arthritis.[5] In these patients, rheumatoid factor may become positive after a few months or years.[11]
• If the CCP antibody test is negative and the rheumatoid factor is positive, which is very uncommon, it may still indicate that the patient has rheumatoid arthritis. However, other chronic inflammatory conditions have to be considered; for example:[11]
  • Systemic lupus erythematosus.
  • Sjögren's syndrome.
  • Hepatitis C infection.
  • Malignancies.
  • Smoking.

Studies suggest that the likelihood of having rheumatoid arthritis increases with higher levels of CCP antibodies.[10] Low positive levels may be related to rheumatoid arthritis, but they may also reflect the presence of osteoarthritis, autoimmune conditions, and malignancy, among other conditions.[10]

The presence of CCP antibodies in patients with rheumatoid arthritis is considered a bad prognosis[7] because it is usually associated with a higher chance of developing complications, such as erosive damage to the joints[11] and interstitial lung disease.[8] 

Studies have also shown that patients with higher levels of CCP antibodies may have a better clinical response to certain drugs. Therefore, a positive CCP antibody test may guide you and your doctor when deciding which therapeutic agent is the most suitable for your particular case.
 

The cyclic citrullinated peptide antibody test (CCP antibody test) is a blood test that measures the presence of anti-citrulline antibodies.[1]

The test is also known as the anti-citrullinated protein antibody (ACPA) test. A CCP antibody test is commonly employed during the diagnosis of rheumatoid arthritis,[1-2] but it can also be used for prognosis.[1-2]

In general, the concentration of CCP antibodies in your blood is measured in units (U) per millilitre (mL), and the normal ranges are as follows:[1]

• Negative: <7 U/mL
• Equivocal (uncertain): 7-10 U/mL
• Positive: >10 U/mL

The normal range for the CCP antibodies (anti-CCP) is the same for men and women and across all ages; however, for technical reasons, the exact range may vary between laboratories and across different regions or countries.

For clinical purposes, positive results can also be interpreted as "low positive" and "high positive", considering "high positive" as a result greater or equal to 2 times the upper limit of the normal range:[10] 

•   A high positive value is a strong indicator of rheumatoid arthritis. 
•   A low positive result may be associated with rheumatoid arthritis, but it can also be related to other conditions.

If you have an "equivocal" value, your doctor may ask you to take the test once again in the future, or they may look for other possible diagnoses.

Do not forget that a physical examination and other tests may be required before providing a reliable diagnosis.
 

Doctors indicate the CCP antibody test in specific situations, and the test should not be taken without indication. The most common reasons someone should take a CCP antibody test will usually fall into one of the three following categories:

1. During the diagnosis of rheumatoid arthritis:

A doctor may indicate a CCP antibody test if you are presenting clinical signs and symptoms of rheumatoid arthritis, such as:[4]

• Inflammation (painful swelling) of the joints, mainly affecting the small joints of hands and feet.[4]
• Stiffness, especially early in the morning.[4]
• Constitutional symptoms (fatigue, malaise, weight loss).[4]
• Extra-articular manifestations (Sjögren's syndrome, interstitial lung disease).[4]

Currently, the 2018 NICE guidelines recommend doctors to indicate a CCP antibody test if the rheumatoid factor is negative in a patient with suspected rheumatoid arthritis.[2]
    
In some clinical settings, such as early arthritis clinics, the CCP antibody test may be indicated earlier to promote the early detection of rheumatoid arthritis.[5] The University of Leeds is currently performing a clinical trial to study the utility of the CCP antibody test for predicting the development of rheumatoid arthritis within one year.[6]

2. After the diagnosis of rheumatoid arthritis:

CCP antibody levels, unless previously requested for diagnostic purposes, may be measured in patients with rheumatoid arthritis for prognostic purposes.[2] 
    
Evidence suggests that higher levels of CCP antibodies may be correlated with a poorer prognosis;[7-9] therefore, measuring CCP antibodies is essential for the early identification of complications and their treatments.
    
A CCP antibody test may also be requested in patients with rheumatoid arthritis for the comparison of baseline levels (for example, before a treatment) with CCP antibody values at some point in the future (a few months after receiving treatment).[9] A few research studies take this approach for determining the efficacy of certain treatments; however, this testing modality is not routinely applied in clinical practice, and its use may vary depending on your doctor or your particular case.

3. During the diagnosis of other conditions:

The test may be used to discard rheumatoid arthritis in patients with inflamed joints or other inflammatory conditions that do not meet the clinical criteria for rheumatoid arthritis.[5]
    
Less frequently, a CCP antibody test may be positive in other autoimmune diseases, certain types of malignancies, viral infections, and other conditions;[10] nonetheless, the test is not routinely requested for these purposes in clinical practice. Currently, it is unknown if it can be used to diagnose any condition other than rheumatoid arthritis.