AVISE Anti-CarP

A Blood Test to Risk-Stratify Rheumatoid Arthritis

AVISE Anti-CarP is a specialized lab test to help identify rheumatoid arthritis (RA) patients with an increased risk for erosive joint damage. Classifying RA early may give the best chance of gaining and maintaining control over the permanent and debilitating effects from RA.

For patients with rheumatoid arthritis (RA), treating the disease early and appropriately is essential for the best chance of remission or comfortable management¹. Not all cases of RA are identical, however. Clinical features and prognosis of each patient’s case help inform the best course of treatment for the individual. There are a few biological markers, measured by a blood test, which indicate a poor prognosis and the necessity for more robust treatment, such as biological therapy^1,2.

The main biomarkers for RA are autoantibodies, which are indicative of an immune system imbalance. Which autoantibodies test positive can allow a doctor to diagnose and generate a prognosis for RA^3,4. Here are the current commonly-used biomarkers and what they can mean for RA prognosis and treatment.

What are autoantibodies?

RA is an autoimmune disorder, meaning that the immune system reacts to parts of its own body. The proteins that cells produce sometimes become modified slightly, either due to inflammation or by other means. In RA and other autoimmune diseases, white blood cells incorrectly identify these modified proteins as foreign antigens, which typically come from pathogens like viruses or bacteria. In response, the immune system starts attacking self-cells as it would invading microbes^3,4.

Antibodies produced by immune cells normally recognize and bind to pathogen proteins. However, some are made that will specifically recognize modified self-proteins. These are known as autoantibodies. The presence of autoantibodies in a person’s blood are indicators that they have an autoimmune disorder, often long before the onset of any symptoms. A few autoantibodies have been identified in RA patients and are used to diagnose the disease. Which types are present, and their relative abundance, can also serve as prognostic factors^3,4.

Rheumatoid factor (RF)

Rheumatoid factor (RF) is an autoantibody that reacts to and attacks healthy tissue in the body. Though RF is present in small amounts in some healthy individuals and people with conditions other than RA, it is found in 53-80% of RA patients. RF can be detected in the bloodstream up to ten years prior to the onset of symptoms in RA patients; however, not everybody who tests positive for RF ends up developing RA in the future^4,5.

RF as a prognostic factor RF was the first autoantibody identified as an RA marker, and RF assays have an accuracy that has been eclipsed by more recent biomarkers. The presence of RF is associated with markers of inflammation in the joints. Similarly, patients who are positive for RF have a greater chance of developing joint erosion damage, and an even higher risk if present in conjunction with other RA biomarkers^5,6.

Anti-citrullinated protein antibodies (ACPA)

During inflammation, some amino acids in proteins get converted into citrulline molecules. Sometimes white blood cells will produce antibodies that recognize and bind to proteins that have been citrullinated. These are called anti-citrullinated protein antibodies (ACPA). Like RF, ACPA are present in about 50-78% of RA patients and can be detected as early as ten years before symptoms develop. However, not all people who test positive for ACPA end up with RA later in their lives^7,8.

ACPA as a prognostic factor

ACPA assays are currently the most sensitive and accurate tests for diagnosing RA, both before and after symptoms develop. Like RF, ACPA positivity is associated with higher inflammation, as well as higher disease activity, and very high levels have been shown to correlate with more severe disease. The presence of ACPA along with RF are included in the American College of Rheumatology 2010 diagnostic criteria for RA⁶.

Anti-CarP antibodies

Distinct from citrullinated proteins, some proteins undergo carbamylation. When this process is out of balance the body can develop antibodies which recognize and bind to carbamylated proteins. These are called anti-CarP antibodies, and have recently been identified as useful biomarkers for the diagnosis and prognosis of RA. While not as specific for RA as ACPA, 33% of RA patients have anti-CarP antibodies in their blood. They can also be detected years before the onset of symptoms and have been found in RA patients who do not test positive for either RF or ACPA. Therefore, Anti-CarP has recently become recognized as a useful marker for determining the status of RA in patients where the traditional biomarkers otherwise could not^9-11.

Anti-CarP antibodies as prognostic factor

References

1. Fautrel B, Alten R, Kirkham B, et al. Call for action: how to improve use of patient-reported outcomes to guide clinical decision making in rheumatoid arthritis. Rheumatology international. 2018;38(6):935-947.

2. Acosta-Merida A, Naranjo A, Rodriguez-Lozano C. Prognostic Factors for Sustained Remission in a "Real Life" Cohort of Rheumatoid Arthritis Patients. Reumatologia clinica. 2018.

3. Malmstrom V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nature reviews Immunology. 2017;17(1):60-75.

4. Bugatti S, Manzo A, Montecucco C, Caporali R. The Clinical Value of Autoantibodies in Rheumatoid Arthritis. Frontiers in medicine. 2018;5:339.

5. Tiwari V, Bergman MJ. Rheumatoid Factor. In: StatPearls. Treasure Island (FL): StatPearls Publishing LLC.; 2018.

6. Harrison MJ, Paget SA, Niewold TB. Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis. QJM: An International Journal of Medicine. 2007;100(4):193-201. 7. Alivernini S, Galeazzi M, Peleg H, et al. Is ACPA positivity the main driver for rheumatoid arthritis treatment? Pros and cons. Autoimmunity reviews. 2017;16(11):1096-1102.

8. Sakkas LI, Daoussis D, Liossis SN, Bogdanos DP. The Infectious Basis of ACPA-Positive Rheumatoid Arthritis. Frontiers in microbiology. 2017;8:1853.

9. Verheul MK, Böhringer S, van Delft MAM, et al. Triple Positivity for Anti–Citrullinated Protein Autoantibodies, Rheumatoid Factor, and Anti–Carbamylated Protein Antibodies Conferring High Specificity for Rheumatoid Arthritis. Arthritis & Rheumatology. 2018;70(11):1721-1731.

10. Li L, Deng C, Chen S, et al. Meta-Analysis: Diagnostic Accuracy of Anti-Carbamylated Protein Antibody for Rheumatoid Arthritis. PloS one. 2016;11(7):e0159000.

11. Regueiro C, Nuño L, Ortiz AM, et al. Value of Measuring Anti-Carbamylated Protein Antibodies for Classification on Early Arthritis Patients. Scientific Reports. 2017;7(1):12023.

12. Shi J, Knevel R, Suwannalai P, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(42):17372-17377.

13. Truchetet ME, Dublanc S, Barnetche T, et al. Association of the Presence of Anti-Carbamylated Protein Antibodies in Early Arthritis With a Poorer Clinical and Radiologic Outcome: Data From the French ESPOIR Cohort. Arthritis & rheumatology (Hoboken, NJ). 2017;69(12):2292-2302.

14. Humphreys JH, Verheul MK, Barton A, et al. Anticarbamylated protein antibodies are associated with long-term disability and increased disease activity in patients with early inflammatory arthritis: results from the Norfolk Arthritis Register. Annals of the Rheumatic Diseases. 2016;75(6):1139.

15. Markusse IM, de Vries-Bouwstra JK, Han KH, et al. Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis. Arthritis research & therapy. 2014;16(5):430.