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Anti-CCP Testing for Rheumatoid Arthritis

Policy Number: MP-353

Latest Review Date: September 2019

Category: Medicine

Policy Grade: Active Policy but no longer scheduled for regular literature reviews and updates.

POLICY:

Measurement of anti-CCP may be considered medically necessary when used as part of the diagnostic workup for rheumatoid arthritis.

Measurement of anti-CCP is considered not medically necessary when used to monitor disease activity and/or treatment response and is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Autoantibodies directed against cyclic citrullinated proteins (anti-CCP) are found in many patients with rheumatoid arthritis (RA). Citrullination refers to the post-translational modification of the amino acid arginine to citrulline by the enzyme peptidylarginine deiminase (PAD). The physiologic role of citrullination is unclear; however, it has been shown to occur during apoptosis, and is thought to play a role in the degradation of intracellular proteins by unfolding protein molecules and thereby exposing them to degradation enzymes. PAD enzymes can be found in monocytes and macrophages associated with inflammation, including in the synovial fluid of patients with active RA. In patients with RA and active joint inflammation, levels of anti-CCP are higher in the synovial fluid than in the peripheral circulation. Anti-CCP found in the serum is thought to be a result of diffusion of these antibodies from the synovial fluid into the general circulation.

Autoantibodies against CCP have been recognized and measured for several decades, by means of the anti-perinuclear factor (APF) and the anti-keratin antibody (AKA). However, these older tests were performed by a cumbersome immunofluorescence assay and were not commonly used in routine clinical practice. Following the recognition that APF and AKA activity were entirely dependent upon citrullination, attention turned toward measuring anti-CCP antibodies. Serum Anti-CCP levels are currently measured using an ELISA assay. The first generation of anti-CCP testing (CCP1) used citrullinated proteins derived from human filaggrin. This method of testing was expensive and difficult to standardize, since it required purification of sufficient quantities of the human antigen. The second generation of anti-CCP testing (CCP2) uses a synthetic peptide antigen, thus making the test cheaper and easy to standardize. CCP2 is currently the only commercially available method for testing for anti-CCP antibodies.

KEY POINTS:

A literature review was most recently performed on September 21, 2019.

Summary of Evidence

Anti-CCP positivity has prognostic potential, but the absolute level of anti-CCP has not been demonstrated to be a useful measure of future severity of disease. Treatment with DMARDs may reduce anti-CCP to a small degree, but there is no convincing evidence that the reduction in anti-CCP levels correlates with disease activity and/or treatment response. Therefore, the use of anti-CCP for monitoring disease activity is investigational.

Some publications continued to assess the sensitivity and specificity of anti-CCP testing for the diagnosis of RA. A number of related studies assessed the utility of anti-CCP in predicting future erosive arthritis. Several studies evaluated the incremental utility of incorporating anti-CCP into existing and/or new algorithms for diagnosing RA. Finally, a small number of articles evaluated anti-CCP as a marker of disease activity. Studies that evaluated the sensitivity and specificity of anti-CCP testing in the diagnosis of RA generally agreed with research noted above in demonstrating a modest sensitivity and a high specificity.

Studies that assessed the predictive ability of anti-CCP for erosive arthritis confirmed that anti-CCP is a strong independent predictor of future erosive arthritis. In a cohort of 238 patients with the diagnosis of RA followed for a ten year period, Syversen et al evaluated the predictive ability of anti-CCP, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and other clinical variables. They reported that anti-CCP was the strongest independent predictor of erosive arthritis. Patients with low or moderate anti-CCP levels were 2.6 times (95% CI: 0.9–7.2) more likely to exhibit radiographic progression of joint damage and patients with high levels of anti-CCP were 9.9 times (95% CI: 2.7–36.7) more likely to have radiographic progression. Bukhari et al reported data from the Norfolk Arthritis registry, which followed an inception cohort of 427 patients with inflammatory polyarthritis for five years. This study also reported that anti-CCP was a strong independent predictor of erosive arthritis (OR 10.2, 95% CI: 6.2–16.9). The authors also concluded that anti-CCP testing was most useful in patients who are rheumatoid factor negative, since 63% of patients who were rheumatoid factor negative and anti-CCP positive developed erosive arthritis. In this population, anti-CCP testing may result in an earlier diagnosis of RA, earlier administration of DMARD therapy, and an improvement in long-term functional status.

Other relevant publications attempted to determine the utility of incorporating anti-CCP into existing or new diagnostic algorithms for RA. These studies offer insights into the incremental diagnostic information provided by anti-CCP testing. Liao et al performed a retrospective analysis of 292 patients seen in their arthritis center, who had both rheumatoid factor and anti-CCP drawn. Using the final diagnosis assigned by the treating rheumatologist, these authors tested the diagnostic accuracy of the original ACR criteria for RA, and compared three alternate methods for incorporating anti-CCP. These were 1) adding anti-CCP to ACR criteria, 2) substituting anti-CCP for rheumatoid nodules (CCP 7 criteria), and 3) substituting anti-CCP for both rheumatoid nodules and radiographic joint changes (CCP 6 criteria).

For all patients, the ACR criteria had a low sensitivity of 51% and a high specificity of 91%, as expected. The addition of anti-CCP improved the sensitivity slightly to 55% with no change in specificity. For the CCP six and CCP seven criteria, the sensitivity was increased further to 74% and 77% respectively, with a corresponding decrease in specificity of 81% and 79%. Anti-CCP appeared to have greater utility in the subgroup of patients with symptoms for less than six months. For these patients, the addition of anti-CCP resulted in a larger improvement in sensitivity from 25–44% with no decrease in specificity.

In a prospective study, Yamane et al assessed the diagnostic utility of anti-CCP in 435 patients seen with arthritic symptoms over a three year period, 209 of which were diagnosed with RA. These authors compared numerous permutations of anti-CCP, rheumatoid factor, C-reactive protein, and the presence of swollen joints as means of diagnosing RA, using clinician diagnosis as the gold standard. They also examined the variability in diagnostic performance by length of symptoms, with particular emphasis on patients with symptom duration of less than three months. The specificity of anti-CCP testing alone was highest in patients with symptoms for less than three months (95.4%, 95% CI: 91.4–99.3), with a correspondingly high positive predictive value of 87.8%. Therefore, the authors concluded that for this patient population, a positive anti-CCP by itself is sufficient to confirm a diagnosis of RA. The combination of anti-CCP with other clinical and lab markers resulted in a diagnostic algorithm that had a high specificity, ranging from 90.7–98.7 and a low sensitivity, ranging from 19.4–65.6. None of the tested combinations were clearly superior to the others, nor were they demonstrably superior to the ACR criteria.

A few studies evaluated the utility of anti-CCP as a marker of disease activity and/or treatment response. These studies were consistent with previous research reporting that anti-CCP was not useful for monitoring disease activity or response to treatment.

Serum 14-3-3ηis a novel RA mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA. The MBDA score did not reflect clinical disease activity in patients enrolled in AMPLE and should not be used to guide decision-making in the management of RA, particularly for patients who receive abatacept or adalimumab as the first biologic agent.

Physician Guidelines and Position Statements

In response to requests, input was received from one Physician Specialty Society (American College of Rheumatology) and two Academic Medical Centers while this policy was under review. While the various Physician Specialty Societies and Academic Medical Centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the Physician Specialty Societies or Academic Medical Centers, unless otherwise noted. Evidence corroborates prior studies in concluding that anti-CCP has a modest sensitivity, a high sensitivity, and is a strong predictor of future erosive arthritis. Some evidence exists suggesting that anti-CCP offers unique diagnostic information that may aid in the diagnosis of RA, especially for patients with short duration of symptoms. Thus, it may be considered medically necessary in the diagnosis of rheumatoid arthritis. The evidence suggests that anti-CCP is not useful as a measure of disease activity and/or response to treatment.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS: 

CCP, antibody testing, Cyclic citrullinated peptide antibody testing, Diastat, anti-CCP.

APPROVED BY GOVERNING BODIES:

Siemens Healthcare Diagnostics obtained FDA clearance in 2013 to offer U.S. laboratories an anti-cyclic citrullinated peptide (anti-CCP) IgG assay to aid diagnosis of rheumatoid arthritis (RA), a chronic, progressive autoimmune disease affecting approximately 1.3 million Americans. Available on the company’s IMMULITE® 2000/2000 XPi immunoassay systems, the anti-CCP IgG assay affords laboratories the ability to integrate RA testing onto an automated, random-access analyzer.

With a clinical specificity of 97 percent, the IMMULITE anti-CCP IgG assay offers laboratories and clinicians a highly accurate diagnostic tool for fast and early RA diagnosis. The assay also helps rule out other inflammatory and arthritic conditions, enabling physicians to determine an appropriate treatment path.

The INOVA Diagnostics QUANTA Lite™ CCP IgG ELISA and the Axis-Shield Diagnostics Diastat™ anti-CCP ELISA test received 510(k) marketing clearance from the U.S. Food and Drug Administration (FDA) in 2002 for use as an aid in the diagnosis of rheumatoid arthritis.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT Codes:

86200             

Cyclic citrullinated peptide (CCP), antibody

REFERENCES:

  1. Aletaha D, Neogi T, Silman AJ et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010; 69(9):1580-8.
  2. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum 2002; 46(2):328-46.
  3. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31(3):315-24.
  4. Arthritis Foundation. Disease Center. Rheumatoid Arthritis. Available at: http://www.arthritis.org/conditions-treatments/disease-center/rheumatoid-arthritis/. Accessed 2/21/13.
  5. Avouac J, Gossec L and Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: A systematic literature review. Ann Rheum Dis 2006; 65(7):845-51.
  6. Bongi SM, Manetti R, Melchiorre D, et al. Anti-cyclic citrullinated peptide antibodies are highly associated with severe bone lesions in rheumatoid arthritis anti-CCP and bone damage in RA. Autoimmunity 2004; 37(6-7):495-501.
  7. Bukhari M, Thomson W, Naseem H, et al. The performance of anti-cyclic citrullinated peptide antibodies in predicting the severity of radiologic damage in inflammatory polyarthritis: Results from the Norfolk Arthritis Register. Arthritis Rheum 2007; 56(9):2929-35.
  8. Dejaco C, Duftner C, Klotz W et al. Third generation anti-cyclic citrullinated peptide antibodies do not predict anti-TNF-alpha treatment response in rheumatoid arthritis. Rheumatol Int 2010; 30(4):451-4.
  9. Fleischmann R, Connolly SE, Maldonado MA, Schiff M. Brief Report: Estimating Disease Activity Using Multi-Biomarker Disease Activity Scores in Rheumatoid Arthritis Patients Treated With Abatacept or Adalimumab. Arthritis Rheumatol. 2016;68(9):2083.
  10. Huizinga TW, Machold KP, Breedveld FC, et al. Criteria for early rheumatoid arthritis: from Bayes’ law revisited to new thoughts on pathogenesis. Arthritis Rheum 2002; 46(5):1155-9.
  11. Hwang SM, Kim JO, Yoo YM et al. Performance analysis of the ARCHITECT anti-cyclic citrullinated peptide antibody in the diagnosis of rheumatoid arthritis. Clin Chem Lab Med 2010; 48(2):225-30.
  12. Kaarela K, Kauppi MJ and Lehtinen KE. The value of the ACR 1987 criteria in very early rheumatoid arthritis. Scand J Rheumatol 1995; 24(5):279-81.
  13. Landmann T, Kehl G, Bergner R. The continuous measurement of anti-CCP-antibodies does not help to evaluate the disease activity in anti-CCP-antibody-positive patients with rheumatoid arthritis. Clin Rheumatol 2010; 29(12):1449-53.
  14. Liao KP, Batra KL, Chibnik L, et al. Anti-CCP revised criteria for the classification of rheumatoid arthritis. Ann Rheum Dis 2008 Jan 30 [epub ahead of print].
  15. Maksymowych WP, Naides SJ, Bykerk V, Siminovitch KA, van Schaardenburg D, Boers M, LandewéR, van der Heijde D, Tak PP, Genovese MC, Weinblatt ME, Keystone EC, Zhukov OS, Abolhosn RW, Popov JM, Britsemmer K, van Kuijk AW, Marotta A. Serum 14-3-3ηis a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis. J Rheumatol. 2014;41(11):2104.
  16. Papadopoulos NG, Tsiaousis GZ, Pavlitou-Tsiontsi A et al. Does the presence of anti-CCP autoantibodies and their serum levels influence the severity and activity in rheumatoid arthritis patients? Clin Rev Allergy Immunol 2008; 34(1):11-5.
  17. Qin X, Deng Y, Xu J et al. Meta-analysis: diagnostic value of serum anti-mutated citrullinated vimentin antibodies in patients with rheumatoid arthritis. Rheumatol Int 2011; 31(6):785-94.
  18. Raza K, Breese M, Nightingale P, et al. Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol 2005; 32(2):231-8.
  19. Ronnelid J, Wick MC, Lampa J, et al. Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann Rheum Dis 2005; 64(12):1744-9.
  20. Ryu HJ, Takeuchi F, Kuwata S et al. The diagnostic utilities of anti-agalactosyl IgG antibodies, anti-cyclic citrullinated peptide antibodies, and rheumatoid factors in rheumatoid arthritis. Rheumatol Int 2011; 31(3):315-9.
  21. Saraux A, Bertholet JM, Chales G, et al. Ability of the American College of Rheumatology 1987 criteria to predict rheumatoid arthritis in patients with early arthritis and classification of these patients two years later. Arthritis Rheum 2001; 44(11):2485-91.
  22. Sghiri R, Bouagina E, Zaglaoui H, et al. Diagnostic performances of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis. Rheumatol Int 2007; 27(12):1125-30.
  23. Shidara K, Inoue E, Tanaka E et al. Comparison of the second and third generation anti-cyclic citrullinated peptide antibody assays in the diagnosis of Japanese patients with rheumatoid arthritis. Rheumatol Int 2011; 31(5):617-22.
  24. Silveira IG, Burlingame RW, von Mahlen CA, et al. Anti-CCP antibodies have more diagnostic impact than rheumatoid factor (RF) in a population tested for RF. Clin Rheumatol 2007; 26(11):1883-9.
  25. Syversen SW, Gaarder PI, Goll GL, et al. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann Rheum Dis 2008; 67(2):212-7.
  26. Vis M, Bos WH, Wolbink G, et al. IgM-rheumatoid factor, anti-cyclic citrullinated peptide, and anti-citrullinated human fibrinogen antibodies decrease during treatment with the tumor necrosis factor blocker infliximab in patients with rheumatoid arthritis. J Rheumatol 2008; 35(3):425-8.
  27. Visser H, le Cessie S and Vos K. How to diagnose rheumatoid arthritis early: a prediction model for persistent erosive arthritis. Arthritis Rheum 2002; 46(2):357-65.
  28. Wagner E, Skoumal M, Bayer PM et al. Antibody against mutated citrullinated vimentin: a new sensitive marker in the diagnosis of rheumatoid arthritis. Rheumatol Int 2009; 29(11):1315-21.
  29. Whiting PF, Smidt N, Sterne JA et al. Systematic review: accuracy of anti-citrullinated Peptide antibodies for diagnosing rheumatoid arthritis. Ann Intern Med 2010; 152(7):456-64; W155-66.
  30. Yamane T, Hashiramoto A, Tanaka Y, et al. Easy and accurate diagnosis of rheumatoid arthritis using anti-cyclic citrullinated peptide 2 antibody, swollen joint count, and C-reactive protein/rheumatoid factor. J Rheumatol 2008; 35(3):414-20.
  31. Zendman AJ, van Venrooij WJ and Pruijn GJ. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology, 2006; 45(1):20-5.

POLICY HISTORY:

Medical Policy Group, April 2009 (3)

Medical Policy Administration Committee, May 2009

Available for comment May 12-June 25, 2009

Medical Policy Group, April 2011; Updated Key Points

Medical Policy Group, August 2011; (3) Updated Key Points & References

Medical Policy Group, August 2012 (3): Active Policy but no longer scheduled for regular literature reviews and updates.

Medical Policy Group, September 2019 (9): Updates Description, Key Points, and References. Added key word: anti-CCP. No change to policy statement.


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