Abstract
Objectives
Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context.
Methods
An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available.
Results
The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found in patients with primary Sjögren’s syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies.
Conclusions
IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity.
Funding source: Phadia AB
Award Identifier / Grant number: In-kind provision of RF/ACPA reagents
Funding source: Thermo Fisher Scientific
Award Identifier / Grant number: In-kind provision of RF/ACPA reagents
Funding source: Orgentec
Award Identifier / Grant number: In-kind provision of RF/ACPA reagents
Funding source: Cambridge Life Science
Award Identifier / Grant number: In-kind provision of RF/ACPA reagents
Acknowledgments
We thank all participating diagnostic companies for in-kind provision of the assays, technical training and support and the constructive discussions. Furthermore, we are very thankful to the laboratory technicians of all participating laboratories for their most appreciated assistance in the performance of the RF/ACPA analyses.
-
Research funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. All participating diagnostic companies in-kind provided the RF/ACPA assays, technical training and support free of charge (see competing interests).
-
Author contributions: LVH, XB, BVDC, DS, GS, PV contributed to the study conception and design. Patient samples were selected by LVH, BVDC, DS, DA, PV, CB, EN, RP, SC, CD, IH, LB, FB, CW, RM, DK, CS, AK, RJ, BJ, EK and PJ. Material preparation and data collection was performed by LS, SVDB, LB, LVH, AV, GV, JR; data analysis by LVH and XB. Manuscript was prepared by LVH, XB, DS and GS and commented by all authors. The final manuscript was read and approved by all authors. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Competing interests: XB, LVH, GS and DS have received speaker fees from Thermo Fisher Scientific and have been a consultant for Thermo Fisher Scientific; LB and IH have received speaker fees from Thermo Fisher Scientific. All participating diagnostic companies in-kind supported with RF/ACPA assays and technical training: Thermo Fisher Scientific, Phadia AB, Uppsala, Sweden; Cambridge Life Science, Ely, UK; Orgentec, Mainz, Germany.
-
Informed consent: Informed consent was obtained if applicable for individuals included in this study.
-
Ethical approval: Ethical approval was granted by the Institutional Review Board of University Hospital Leuven and OLV Hospital Aalst with Belgian registration number: B322201939877.
-
Data availability: All data relevant to the study are included in the article or uploaded as supplementary information.
References
1. Smolen, JS, Aletaha, D, Barton, A, Burmester, GR, Emery, P, Firestein, GS, et al.. Rheumatoid arthritis. Nat Rev Dis Prim 2018;8:18001. https://doi.org/10.1038/nrdp.2018.1.Search in Google Scholar PubMed
2. van Nies, JA, Krabben, A, Schoones, JW, Huizinga, TW, Kloppenburg, M, van der Helm-van, Mil AH. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis 2014;73:861–70. https://doi.org/10.1136/annrheumdis-2012-203130.Search in Google Scholar PubMed
3. Burgers, LE, Raza, K, van der Helm-van Mil, AH. Window of opportunity in rheumatoid arthritis - definitions and supporting evidence: from old to new perspectives. RMD Open 2019;3:e000870. https://doi.org/10.1136/rmdopen-2018-000870.Search in Google Scholar PubMed PubMed Central
4. Nielen, MM, van Schaardenburg, D, Reesink, HW, van de Stadt, RJ, van der Horst-Bruinsma, IE, de Koning, MH, et al.. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004;50:380–6. https://doi.org/10.1002/art.20018.Search in Google Scholar PubMed
5. Brink, M, Hansson, M, Mathsson-Alm, L, Wijayatunga, P, Verheul, MK, Trouw, LA, et al.. Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis. Arthritis Res Ther 2016;18:43. https://doi.org/10.1186/s13075-016-0940-2.Search in Google Scholar PubMed PubMed Central
6. Kelmenson, LB, Wagner, BD, McNair, BK, Frazer-Abel, A, Demoruelle, MK, Bergstedt, DT, et al.. Timing of elevations of autoantibody isotypes prior to diagnosis of rheumatoid arthritis. Arthritis Rheumatol 2020;72:251–61. https://doi.org/10.1002/art.41091.Search in Google Scholar PubMed PubMed Central
7. Aletaha, D, Neogi, T, Silman, AJ, Funovits, J, Felson, DT, COr, B, 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
8. Conrad, K, Roggenbuck, D, Reinhold, D, Dörner, T. Profiling of rheumatoid arthritis associated autoantibodies. Autoimmun Rev 2010;9:431–5. https://doi.org/10.1016/j.autrev.2009.11.017.Search in Google Scholar PubMed
9. Aho, K, Heliövaara, M, Maatela, J, Tuomi, T, Palosuo, T. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol 1991;18:1282–4.Search in Google Scholar
10. Nell-Duxneuner, V, Machold, K, Stamm, T, Eberl, G, Heinzl, H, Hoefler, E, et al.. Autoantibody profiling in patients with very early rheumatoid arthritis: a follow-up study. Ann Rheum Dis 2010;69:169–74. https://doi.org/10.1136/ard.2008.100677.Search in Google Scholar PubMed
11. Rantapää-Dahlqvist, S, de Jong, BA, Berglin, E, Hallmans, G, Wadell, G, Stenlund, H, et al.. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003;48:2741–9. https://doi.org/10.1002/art.11223.Search in Google Scholar PubMed
12. Bennett, GA, Cobb, S, Jacox, R, Jessar, RA, Ropes, MW. Proposed diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 1956;7:121–4.Search in Google Scholar
13. Ropes, MW, Bennett, GA, Cobb, S, Jacox, R, Jessar, RA. Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 1958;9:175–6.Search in Google Scholar
14. Arnett, FC, Edworthy, SM, Bloch, DA, McShane, DJ, Fries, JF, Cooper, NS, et al.. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. https://doi.org/10.1002/art.1780310302.Search in Google Scholar
15. Dietz, WH, Porcell, O, Moon, TE, Peters, CJ, Purcell, RH. IgM levels and IgM-mediated immune responses in patients with acute hepatitis A, acute hepatitis B and chronic HB antigenaemia. Clin Exp Immunol 1976;23:69–72.Search in Google Scholar
16. Haberman, AM, William, J, Euler, C, Shlomchik, MJ. Rheumatoid factors in health and disease: structure, function, induction and regulation. Curr Dir Autoimmun 2003;6:169–95.10.1159/000066861Search in Google Scholar
17. Shmerling, RH, Delbanco, TL. The rheumatoid factor: an analysis of clinical utility. Am J Med 1991;91:528–34. https://doi.org/10.1016/0002-9343(91)90190-9.Search in Google Scholar
18. 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
19. Falkenburg WJJ, F, von Richthofen, HJ, Koers, J, Weykamp, C, Schreurs, MWJ, Bakker-Jonges, LE, et al.. Clinically relevant discrepancies between different rheumatoid factor assays. Clin Chem Lab Med 2018;56:1749–58. https://doi.org/10.1515/cclm-2017-0988.Search in Google Scholar PubMed
20. Jónsson, T, Valdimarsson, H. Is measurement of rheumatoid factor isotypes clinically useful? Ann Rheum Dis 1993;52:161–4. https://doi.org/10.1136/ard.52.2.161.Search in Google Scholar PubMed PubMed Central
21. Sieghart, D, Platzer, A, Studenic, P, Alasti, F, Grundhuber, M, Swiniarski, S, et al.. Determination of autoantibody isotypes increases the sensitivity of serodiagnostics in rheumatoid arthritis. Front Immunol 2018;24:876. https://doi.org/10.3389/fimmu.2018.00876.Search in Google Scholar PubMed PubMed Central
22. Martinez-Prat, L, Nissen, MJ, Lamacchia, C, Bentow, C, Cesana, L, Roux-Lombard, P, et al.. Comparison of serological biomarkers in rheumatoid arthritis and their combination to improve diagnostic performance. Front Immunol 2018;9:1113. https://doi.org/10.3389/fimmu.2018.01113.Search in Google Scholar PubMed PubMed Central
23. Vallbracht, I, Rieber, J, Oppermann, M, Förger, F, Siebert, U, Helmke, K. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis 2004;63:1079–84. https://doi.org/10.1136/ard.2003.019877.Search in Google Scholar PubMed PubMed Central
24. Van Hoovels, L, Vander Cruyssen, B, Sieghart, D, Bonroy, C, Nagy, E, Pullerits, R, et al.. Multicenter study to improve clinical interpretation of rheumatoid factor and anti-citrullinated protein/peptide antibodies test results. RMD Open 2022;8:e002099. https://doi.org/10.1136/rmdopen-2021-002099.Search in Google Scholar PubMed PubMed Central
25. Bas, S, Genevay, S, Meyer, O, Gabay, C. Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology 2003;42:677–80. https://doi.org/10.1093/rheumatology/keg184.Search in Google Scholar PubMed
26. Falkenburg, WJ, van Schaardenburg, D, Ooijevaar-de Heer, P, Wolbink, G, Rispens, T. IgG subclass specificity discriminates restricted IgM rheumatoid factor responses from more mature anti-citrullinated protein antibody-associated or isotype-switched IgA responses. Arthritis Rheumatol 2015;67:3124–34. https://doi.org/10.1002/art.39299.Search in Google Scholar PubMed
27. Infantino, M, Manfredi, M, Meacci, F, Sarzi-Puttini, P, Ricci, C, Atzeni, F, et al.. Anti-citrullinated peptide antibodies and rheumatoid factor isotypes in the diagnosis of rheumatoid arthritis: an assessment of combined tests. Clin Chim Acta 2014;436:237–42. https://doi.org/10.1016/j.cca.2014.05.019.Search in Google Scholar PubMed
28. Van Hoovels, L, Jacobs, J, Vander Cruyssen, B, Van den Bremt, S, Verschueren, P, Bossuyt, X. Performance characteristics of rheumatoid factor and anti-cyclic citrullinated peptide antibody assays may impact ACR/EULAR classification of rheumatoid arthritis. Ann Rheum Dis 2018;77:667–77. https://doi.org/10.1136/annrheumdis-2017-212365.Search in Google Scholar PubMed
29. Silvestris, F, Goodwin, JS, Williams, RCJ. IgM, IgA and IgG rheumatoid factors in patients with rheumatoid arthritis and normal donors. Clin Rheumatol 1985;4:392–8. https://doi.org/10.1007/bf02031890.Search in Google Scholar
30. Wang, Y, Shen, N, Vyse, TJ, Anand, V, Gunnarson, I, Sturfelt, G, et al.. Selective IgA deficiency in autoimmune diseases. Mol Med 2011;17:1383–96. https://doi.org/10.2119/molmed.2011.00195.Search in Google Scholar PubMed PubMed Central
31. Jónsson, T, Arinbjarnarson, S, Thorsteinsson, J, Steinsson, K, Geirsson, AJ, Jónsson, H, et al.. Raised IgA rheumatoid factor (RF) but not IgM RF or IgG RF is associated with extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol 1995;24:372–5. https://doi.org/10.3109/03009749509095183.Search in Google Scholar PubMed
32. Ingegnoli, F, Castelli, R, Gualtierotti, R. Rheumatoid factors: clinical applications. Dis Markers 2013;35:727–34. https://doi.org/10.1155/2013/726598.Search in Google Scholar PubMed PubMed Central
33. 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
34. Meek, B, Kelder, JC, Claessen, AME, van Houte, AJ, Ter Borg, EJ. Rheumatoid factor isotype and Ro epitope distribution in primary Sjögren syndrome and rheumatoid arthritis with keratoconjunctivitis sicca. Rheumatol Int 2018;38:1487–93. https://doi.org/10.1007/s00296-018-4090-5.Search in Google Scholar PubMed
35. Maślińska, M, Mańczak, M, Kwiatkowska, B. Usefulness of rheumatoid factor as an immunological and prognostic marker in pSS patients. Clin Rheumatol 2019;38:1301–7. https://doi.org/10.1007/s10067-019-04438-z.Search in Google Scholar PubMed
36. Lee, KA, Kim, KW, Kim, BM, Won, JY, Kim, HA, Moon, HW, et al.. Clinical and diagnostic significance of serum immunoglobulin a rheumatoid factor in primary Sjogren’s syndrome. Clin Oral Investig 2019;23:1415–23. https://doi.org/10.1007/s00784-018-2545-4.Search in Google Scholar PubMed
37. Jónsson, T, Steinsson, K, Jónsson, H, Geirsson, AJ, Thorsteinsson, J, Valdimarsson, H. Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis. Rheumatol Int 1998;18:119–22. https://doi.org/10.1007/s002960050069.Search in Google Scholar PubMed
38. Bossuyt, X, Coenen, D, Fieuws, S, Verschueren, P, Westhovens, R, Blanckaert, N. Likelihood ratios as a function of antibody concentration for anti-cyclic citrullinated peptide antibodies and rheumatoid factor. Ann Rheum Dis 2009;68:287–9. https://doi.org/10.1136/ard.2007.085597.Search in Google Scholar PubMed
39. Bossuyt, X. Anticitrullinated protein antibodies: taking into account antibody levels improves interpretation. Ann Rheum Dis 2017;76:e33. https://doi.org/10.1136/annrheumdis-2016-211039.Search in Google Scholar PubMed
40. Trouw, LA, Toes, RE. Rheumatoid arthritis: autoantibody testing to predict response to therapy in RA. Nat Rev Rheumatol 2016;12:566–8. https://doi.org/10.1038/nrrheum.2016.151.Search in Google Scholar PubMed
41. Derksen, VF, Ajeganova, S, Trouw, LA, van der Helm-van Mil, AH, Hafström, I, Huizinga, TW, et al.. Rheumatoid arthritis phenotype at presentation differs depending on the number of autoantibodies present. Ann Rheum Dis 2017;76:716–20. https://doi.org/10.1136/annrheumdis-2016-209794.Search in Google Scholar PubMed
42. Takeuchi, T. Biomarkers as a treatment guide in rheumatoid arthritis. Clin Immunol 2018;186:59–62. https://doi.org/10.1016/j.clim.2017.07.019.Search in Google Scholar PubMed
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2022-0244).
© 2022 Walter de Gruyter GmbH, Berlin/Boston
