Home Evaluation of the clinical performance of anti-mutated citrullinated vimentin antibody and 14-3-3 eta testing in rheumatoid arthritis
Article
Licensed
Unlicensed Requires Authentication

Evaluation of the clinical performance of anti-mutated citrullinated vimentin antibody and 14-3-3 eta testing in rheumatoid arthritis

  • Heather A. Nelson ORCID logo , Thomas B. Martins , Abdulrahman Saadalla and Vijayalakshmi Nandakumar EMAIL logo
Published/Copyright: November 7, 2024
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 63 Issue 4

Abstract

Objectives

Early rheumatoid arthritis (RA) detection is crucial for improving patient prognosis. Anticyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factors (RF) support RA diagnosis but are undetectable in ∼20 % of cases. Recently, antibodies against mutated citrullinated vimentin (anti-MCV) and detection of 14-3-3 eta have emerged with implications for preclinical RA diagnosis and monitoring treatment. The objective of this study was to assess the clinical performance of anti-MCV antibodies and 14-3-3 eta in RA and to compare it to current RA criteria anti-CCP and RF markers, individually and in combination.

Methods

A retrospective chart review of 326 subjects submitted for RA serology testing identified 134 RA positive and 192 RA negative disease control individuals. Fifty healthy controls specimens were also included. Performance of anti-MCV and 14-3-3 eta, alone and combined with CCP3.1 and RF, was assessed.

Results

Anti-MCV had a sensitivity of 71 % and a specificity of 92 %. 14-3-3 eta had a sensitivity of 43 % and a specificity of 90 %. In comparison, CCP3.1 and RF displayed a sensitivity of 79 % and 84 % and a specificity of 92 % and 61 %, respectively. ROC curve analysis demonstrated CCP3.1 and anti-MCV had superior diagnostic performance compared to RF and 14-3-3 eta. In our cohort, anti-MCV and 14-3-3 eta failed to identify seronegative RA patients. Different combinations of double antibody positivity increased specificity at the cost of lost sensitivity.

Conclusions

Individually, 14-3-3 eta, anti-MCV and CCP3.1 assays had ≥90 % specificity in diagnosed RA patients, with better sensitivities for anti-MCV and CCP3.1 than 14-3-3 eta. Overall diagnostic performance of anti-MCV was similar to CCP3.1 and RF, all of which outperformed 14-3-3 eta in our cohort.

Keywords: anti-MCV; anticyclic citrullinated peptide antibodies (CCP); diagnosis; rheumatoid factor; 14-3-3 eta
Corresponding author: Vijayalakshmi Nandakumar, PhD, ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA; and Exsera BioLabs, Division of Rheumatology, University of Colorado Anschutz Medical Campus, 1775, Aurora Ct, Room M21-3105, Aurora, CO 80045, USA, E-mail:
Heather A. Nelson and Thomas B. Martins contributed equally to this work and share first authorship.

Funding source: ARUP Institute for Clinical and Experimental Pathology

Acknowledgments

The authors thank ORGENTEC Diagnostika and Augurex Life Sciences Corp for supplying the assay kits used in this study. These companies played no role in the design of study, choice of enrolled patients, review and interpretation of data or preparation of the manuscript.

  1. Research ethics: The collection of these specimens and review of medical records were approved by the University of Utah Institutional Review Board (IRB# 00148778) on 1/27/2022.

  2. Informed consent: Not applicable.

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: Financial support for this work was provided by the ARUP Institute for Clinical and Experimental Pathology at ARUP Laboratories.

  7. Data availability: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

  8. Role of sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, preparation of manuscript, or final approval of manuscript.

References

1. Aletaha, D, Smolen, JS. Diagnosis and management of rheumatoid arthritis. JAMA 2018;320:1360. https://doi.org/10.1001/jama.2018.13103.Search in Google Scholar PubMed

2. Korpela, M, Laasonen, L, Hannonen, P, Kautiainen, H, Leirisalo-Repo, M, Hakala, M, et al.. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study. Arthritis Rheum 2004;50:2072–81. https://doi.org/10.1002/art.20351.Search in Google Scholar PubMed

3. Aletaha, D, Neogi, T, Silman, AJ, Funovits, J, Felson, DT, Bingham, CO3rd, et al.. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69:1580–8. https://doi.org/10.1136/ard.2010.138461.Search in Google Scholar PubMed

4. Dörner, T, Egerer, K, Feist, E, Burmester, GR. Rheumatoid factor revisited. Curr Opin Rheumatol 2004;16:246–53. https://doi.org/10.1097/00002281-200405000-00013.Search in Google Scholar PubMed

5. Nishimura, K, Sugiyama, D, Kogata, Y, Tsuji, G, Nakazawa, T, Kawano, S, et al.. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 2007;146:797–808. https://doi.org/10.7326/0003-4819-146-11-200706050-00008.Search in Google Scholar PubMed

6. Whiting, PF, Smidt, N, Sterne, JA, Harbord, R, Burton, A, Burke, M, et al.. Systematic review: accuracy of anti-citrullinated Peptide antibodies for diagnosing rheumatoid arthritis. Ann Intern Med 2010;152:456–64, w155–66. https://doi.org/10.7326/0003-4819-152-7-201004060-00010.Search in Google Scholar PubMed

7. Klareskog, L, Rönnelid, J, Lundberg, K, Padyukov, L, Alfredsson, L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol 2008;26:651–75. https://doi.org/10.1146/annurev.immunol.26.021607.090244.Search in Google Scholar PubMed

8. Lee, AN, Beck, CE, Hall, M. Rheumatoid factor and anti-CCP autoantibodies in rheumatoid arthritis: a review. Clin Lab Sci 2008;21:15–8.Search in Google Scholar

9. Taylor, P, Gartemann, J, Hsieh, J, Creeden, J. A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis. Autoimmune Dis 2011;2011:815038. https://doi.org/10.4061/2011/815038.Search in Google Scholar PubMed PubMed Central

10. Shidara, K, Inoue, E, Tanaka, E, Hoshi, D, Seto, Y, Nakajima, A, 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;31:617–22. https://doi.org/10.1007/s00296-009-1336-2.Search in Google Scholar PubMed

11. Gaalen, FAV, Visser, H, Huizinga, TWJ. A comparison of the diagnostic accuracy and prognostic value of the first and second anti-cyclic citrullinated peptides (CCP1 and CCP2) autoantibody tests for rheumatoid arthritis. Ann Rheum Dis 2005;64:1510. https://doi.org/10.1136/ard.2004.035089.Search in Google Scholar PubMed PubMed Central

12. Van Steendam, K, Tilleman, K, De Ceuleneer, M, De Keyser, F, Elewaut, D, Deforce, D. Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins. Arthritis Res Ther 2010;12:R132. https://doi.org/10.1186/ar3070.Search in Google Scholar

13. Hueber, W, Hassfeld, W, Smolen, JS, Steiner, G. Sensitivity and specificity of anti-Sa autoantibodies for rheumatoid arthritis. Rheumatology (Oxford) 1999;38:155–9. https://doi.org/10.1093/rheumatology/38.2.155.Search in Google Scholar

14. Bang, H, Egerer, K, Gauliard, A, Lüthke, K, Rudolph, PE, Fredenhagen, G, et al.. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum 2007;56:2503–11. https://doi.org/10.1002/art.22817.Search in Google Scholar

15. Lee, YH, Bae, SC, Song, GG. Diagnostic accuracy of anti-MCV and anti-CCP antibodies in rheumatoid arthritis: a meta-analysis. Zeitschrift fur Rheumatologie. 2015;74:911–8. https://doi.org/10.1007/s00393-015-1598-x.Search in Google Scholar

16. Luime, JJ, Colin, EM, Hazes, JM, Lubberts, E. Does anti-mutated citrullinated vimentin have additional value as a serological marker in the diagnostic and prognostic investigation of patients with rheumatoid arthritis? A systematic review. Ann Rheum Dis 2010;69:337–44. https://doi.org/10.1136/ard.2008.103283.Search in Google Scholar

17. Kilani, RT, Maksymowych, WP, Aitken, A, Boire, G, St-Pierre, Y, Li, Y, et al.. Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation. J Rheumatol 2007;34:1650–7.Search in Google Scholar

18. Wang, D, Cui, Y, Lei, H, Cao, D, Tang, G, Huang, H, et al.. Diagnostic accuracy of 14-3-3 η protein in rheumatoid arthritis: a meta-analysis. Int J Rheum Dis 2020;23:1443–51. https://doi.org/10.1111/1756-185x.13921.Search in Google Scholar

19. Wu, Y, Dai, Z, Wang, H, Wang, H, Wu, L, Ling, H, et al.. Serum 14-3-3η is a marker that complements current biomarkers for the diagnosis of RA: evidence from a meta-analysis. Immunol Invest 2022;51:182–98. https://doi.org/10.1080/08820139.2020.1817069.Search in Google Scholar

20. Tango, T. Equivalence test and confidence interval for the difference in proportions for the paired-sample design. Stat Med 1998;17:891–908. https://doi.org/10.1002/(sici)1097-0258(19980430)17:8<891::aid-sim780>3.3.co;2-2.10.1002/(SICI)1097-0258(19980430)17:8<891::AID-SIM780>3.0.CO;2-BSearch in Google Scholar

21. DeLong, ER, DeLong, DM, Clarke-Pearson, DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837–45. https://doi.org/10.2307/2531595.Search in Google Scholar

22. Bizzaro, N, Tonutti, E, Tozzoli, R, Villalta, D. Analytical and diagnostic characteristics of 11 2nd- and 3rd-generation immunoenzymatic methods for the detection of antibodies to citrullinated proteins. Clin Chem 2007;53:1527–33. https://doi.org/10.1373/clinchem.2007.087569.Search in Google Scholar

23. Bartoloni, E, Alunno, A, Bistoni, O, Bizzaro, N, Migliorini, P, Morozzi, G, et al.. Diagnostic value of anti-mutated citrullinated vimentin in comparison to anti-cyclic citrullinated peptide and anti-viral citrullinated peptide 2 antibodies in rheumatoid arthritis: an Italian multicentric study and review of the literature. Autoimmun Rev 2012;11:815–20. https://doi.org/10.1016/j.autrev.2012.02.015.Search in Google Scholar PubMed

24. Zhu, J-N, Nie, L-Y, Lu, X-Y, Wu, H-X. Meta-analysis: compared with anti-CCP and rheumatoid factor, could anti-MCV be the next biomarker in the rheumatoid arthritis classification criteria? Clin Chem Lab Med 2019;57:1668–79. https://doi.org/10.1515/cclm-2019-0167.Search in Google Scholar PubMed

25. Abdelhafiz, D, Kilborn, S, Bukhari, M. The role of 14-3-3 η as a biomarker in rheumatoid arthritis. Rheumatol Immunol Res 2021;2:87–90. https://doi.org/10.2478/rir-2021-0012.Search in Google Scholar PubMed PubMed Central

26. Carrier, N, Marotta, A, de Brum-Fernandes, AJ, Liang, P, Masetto, A, Ménard, HA, et al.. Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis. Arthritis Res Ther 2016;18:37. https://doi.org/10.1186/s13075-016-0935-z.Search in Google Scholar PubMed PubMed Central

27. Hirata, S, Marotta, A, Gui, Y, Hanami, K, Tanaka, Y. Serum 14-3-3η level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab. Arthritis Res Ther 2015;17:280. https://doi.org/10.1186/s13075-015-0799-7.Search in Google Scholar PubMed PubMed Central

28. Shovman, O, Gilburd, B, Watad, A, Amital, H, Langevitz, P, Bragazzi, NL, et al.. Decrease in 14-3-3η protein levels is correlated with improvement in disease activity in patients with rheumatoid arthritis treated with Tofacitinib. Pharmacol Res 2019;141:623–6. https://doi.org/10.1016/j.phrs.2018.11.009.Search in Google Scholar PubMed

29. van Beers-Tas, MH, Marotta, A, Boers, M, Maksymowych, WP, van Schaardenburg, D. A prospective cohort study of 14-3-3η in ACPA and/or RF-positive patients with arthralgia. Arthritis Res Ther 2016;18:76. https://doi.org/10.1186/s13075-016-0975-4.Search in Google Scholar PubMed PubMed Central

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2024-1112).

Received: 2024-09-24
Accepted: 2024-10-13
Published Online: 2024-11-07
Published in Print: 2025-03-26

© 2024 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Beyond test results: the strategic importance of metadata for the integration of AI in laboratory medicine
  4. Reviews
  5. Reference, calibration and referral laboratories – a look at current European provisions and beyond
  6. How has the external quality assessment/proficiency testing of semen analysis been developed in the past 34 years: a review
  7. Opinion Papers
  8. Data flow in clinical laboratories: could metadata and peridata bridge the gap to new AI-based applications?
  9. A comprehensive survey of artificial intelligence adoption in European laboratory medicine: current utilization and prospects
  10. Guidelines and Recommendations
  11. Guidelines for the correct use of the nomenclature of biochemical indices of bone status: a position statement of the Joint IOF Working Group and IFCC Committee on Bone Metabolism
  12. Candidate Reference Measurement Procedures and Materials
  13. Absolute quantitation of human serum cystatin C: candidate reference method by 15N-labeled recombinant protein isotope dilution UPLC-MS/MS
  14. General Clinical Chemistry and Laboratory Medicine
  15. Performance evaluation of the introduction of full sample traceability system within the specimen collection process
  16. Pre-analytical stability of haematinics, lactate dehydrogenase and phosphate in whole blood at room temperature up to 24 h, and refrigerated serum stability of lactate dehydrogenase, folate and vitamin B12 up to 72 h using the CRESS checklist
  17. Comparison of capillary finger stick and venous blood sampling for 34 routine chemistry analytes: potential for in hospital and remote blood sampling
  18. Performance evaluation of enzymatic total bile acid (TBA) routine assays: systematic comparison of five fifth-generation TBA cycling methods and their individual bile acid recovery from HPLC-MS/MS reference
  19. Clinical performance of a new lateral flow immunoassay for xylazine detection
  20. Evaluation of revised UK-NEQAS CSF-xanthochromia method for subarachnoid hemorrhage: outcome data provide evidence for clinical value
  21. Strategies to verify equimolar peptide release in mass spectrometry-based protein quantification exemplified for apolipoprotein(a)
  22. Evaluation of the clinical performance of anti-mutated citrullinated vimentin antibody and 14-3-3 eta testing in rheumatoid arthritis
  23. Diagnostic performance of specific biomarkers for interstitial lung disease: a single center study
  24. Reference Values and Biological Variations
  25. Neonatal reference intervals for serum steroid hormone concentrations measured by LC-MS/MS
  26. Paediatric reference intervals for haematology parameters analysed on Sysmex XN-9000: a comparison of methods in the framework of indirect sampling
  27. Cardiovascular Diseases
  28. Analytical characteristics and performance of a new hs-cTnI method: a multicenter-study
  29. Diabetes
  30. Use of labile HbA1c as a screening tool to minimize clinical misinterpration of HbA1c
  31. Letters to the Editor
  32. Current trends and future projections in the clinical laboratory test market: implications for resource management and strategic planning
  33. Particulate matter in water: an overlooked source of preanalytical error producing erroneous chemistry test results
  34. “Activation” of macro-AST by pyridoxal-5-phosphate in the assay for aspartate aminotransferase
  35. The correlation of albumin with total protein concentrations in cerebrospinal fluid across three automated analysers – relevance to the diagnosis of subarachnoid haemorrhage in clinical chemistry practice
  36. Adult reference intervals for serum thyroid‐stimulating hormone using Abbott Alinity i measuring system
  37. Cell population data in venous thrombo-embolism and erysipelas: a potential diagnostic tool?
  38. Diagnostic performances and cut-off verification of blood pTau 217 on the Lumipulse platform for amyloid deposition in Alzheimer’s disease
  39. The first case of Teclistamab interference with serum electrophoresis and immunofixation
  40. Congress Abstracts
  41. Annual meeting of the Royal Belgian Society of Laboratory Medicine (RBSLM): “A Neurological Journey: Brain Teasers for Laboratory Medicine”
https://doi.org/10.1515/cclm-2024-1112
Keywords for this article
anti-MCV; anticyclic citrullinated peptide antibodies (CCP); diagnosis; rheumatoid factor; 14-3-3 eta

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Beyond test results: the strategic importance of metadata for the integration of AI in laboratory medicine
  4. Reviews
  5. Reference, calibration and referral laboratories – a look at current European provisions and beyond
  6. How has the external quality assessment/proficiency testing of semen analysis been developed in the past 34 years: a review
  7. Opinion Papers
  8. Data flow in clinical laboratories: could metadata and peridata bridge the gap to new AI-based applications?
  9. A comprehensive survey of artificial intelligence adoption in European laboratory medicine: current utilization and prospects
  10. Guidelines and Recommendations
  11. Guidelines for the correct use of the nomenclature of biochemical indices of bone status: a position statement of the Joint IOF Working Group and IFCC Committee on Bone Metabolism
  12. Candidate Reference Measurement Procedures and Materials
  13. Absolute quantitation of human serum cystatin C: candidate reference method by 15N-labeled recombinant protein isotope dilution UPLC-MS/MS
  14. General Clinical Chemistry and Laboratory Medicine
  15. Performance evaluation of the introduction of full sample traceability system within the specimen collection process
  16. Pre-analytical stability of haematinics, lactate dehydrogenase and phosphate in whole blood at room temperature up to 24 h, and refrigerated serum stability of lactate dehydrogenase, folate and vitamin B12 up to 72 h using the CRESS checklist
  17. Comparison of capillary finger stick and venous blood sampling for 34 routine chemistry analytes: potential for in hospital and remote blood sampling
  18. Performance evaluation of enzymatic total bile acid (TBA) routine assays: systematic comparison of five fifth-generation TBA cycling methods and their individual bile acid recovery from HPLC-MS/MS reference
  19. Clinical performance of a new lateral flow immunoassay for xylazine detection
  20. Evaluation of revised UK-NEQAS CSF-xanthochromia method for subarachnoid hemorrhage: outcome data provide evidence for clinical value
  21. Strategies to verify equimolar peptide release in mass spectrometry-based protein quantification exemplified for apolipoprotein(a)
  22. Evaluation of the clinical performance of anti-mutated citrullinated vimentin antibody and 14-3-3 eta testing in rheumatoid arthritis
  23. Diagnostic performance of specific biomarkers for interstitial lung disease: a single center study
  24. Reference Values and Biological Variations
  25. Neonatal reference intervals for serum steroid hormone concentrations measured by LC-MS/MS
  26. Paediatric reference intervals for haematology parameters analysed on Sysmex XN-9000: a comparison of methods in the framework of indirect sampling
  27. Cardiovascular Diseases
  28. Analytical characteristics and performance of a new hs-cTnI method: a multicenter-study
  29. Diabetes
  30. Use of labile HbA1c as a screening tool to minimize clinical misinterpration of HbA1c
  31. Letters to the Editor
  32. Current trends and future projections in the clinical laboratory test market: implications for resource management and strategic planning
  33. Particulate matter in water: an overlooked source of preanalytical error producing erroneous chemistry test results
  34. “Activation” of macro-AST by pyridoxal-5-phosphate in the assay for aspartate aminotransferase
  35. The correlation of albumin with total protein concentrations in cerebrospinal fluid across three automated analysers – relevance to the diagnosis of subarachnoid haemorrhage in clinical chemistry practice
  36. Adult reference intervals for serum thyroid‐stimulating hormone using Abbott Alinity i measuring system
  37. Cell population data in venous thrombo-embolism and erysipelas: a potential diagnostic tool?
  38. Diagnostic performances and cut-off verification of blood pTau 217 on the Lumipulse platform for amyloid deposition in Alzheimer’s disease
  39. The first case of Teclistamab interference with serum electrophoresis and immunofixation
  40. Congress Abstracts
  41. Annual meeting of the Royal Belgian Society of Laboratory Medicine (RBSLM): “A Neurological Journey: Brain Teasers for Laboratory Medicine”
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 3.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2024-1112/html?lang=en&srsltid=AfmBOooCH_LZbMmcP7PRE9VFKw_NJK87RV1i7F-maDA7nbX0hdrvIU3a
Scroll to top button