Increased IgG Rheumatoid Factor-Positivity in the Asian Rheumatoid Arthritis Patients Irrespective of Ethnicity


Aim of Work: Initial observations implied IgG rheumatoid factor (RF) to be common among Malaysian rheumatoid arthritis (RA) patients. We tested this hypothesis and used a multiethnic RA cohort (Malays, Chinese and Indians) to investigate whether the IgG RF predominance might be genetically or environmentally determined. Patients and Methods: 556 serum samples comprising 171 patients classified as RA according to the 1987 ACR criteria, 60 patients with other rheumatic diseases and 325 non-rheumatic controls were tested for IgG RF, IgM RF and anti-CCP by ELISA. The findings were then tested in a larger RA case-control cohort (n = 1844). Results: IgG RF predominated over IgM RF in all the investigated ethnic groups. The sensitivity, specificity, and diagnostic accuracy of IgG RF (55.6%, 91.2% and 80.2%, respectively) were superior compared to IgM RF, but comparable to anti-CCP. IgG RF was however, also increased in the Malaysian controls, but the IgG RF superiority over IgM RF was still apparent after cutoff adjustment according to the 1987 ACR criteria. Autoantibody levels did not differ between the three ethnic groups. The Receiver Operating Characteristics (ROC) curves showed larger areas under the curves for IgG RF (0.826) and for anti-CCP (0.867) than for IgM RF (0.737). Review of the literature showed consistently higher sensitivity for IgG RF in studies of Asian RA patients as compared to Caucasian and African-American studies. Conclusion: Increased frequency of IgG RF-positive in RA populations with different genetic background living in Malaysia argues for an environmental factor selectively amplifying the IgG RF response.

Share and Cite:

C. Too, J. Rönnelid, Y. Yusoff, J. Dhaliwal, N. Jinah, A. Yahya, H. Hussien, W. Sulaiman, P. Larsson and S. Murad, "Increased IgG Rheumatoid Factor-Positivity in the Asian Rheumatoid Arthritis Patients Irrespective of Ethnicity," Open Journal of Rheumatology and Autoimmune Diseases, Vol. 4 No. 1, 2014, pp. 43-51. doi: 10.4236/ojra.2014.41007.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] J. P. Riedemann, S. Munoz and A. Kavanaugh, “The Use of Second Generation Anti-CCP Antibody (Anti-CCP2) Testing in Rheumatoid Arthritis—A Systematic Review,” Clinical and Experimental Rheumatology, Vol. 23, No. 5, 2005, pp. S69-S76.
[2] S. Nijenhuis, A. J. Zendman, E. R. Vossenaar, G. J. Pruijn and W. J. vanVenrooij, “Autoantibodies to Citrullinated Proteins in Rheumatoid Arthritis: Clinical Performance and Biochemical Aspects of an RA-Specific Marker,” Clinica Chimica Acta, Vol. 350, No. 1, 2004, pp. 17-34.
[3] W. J. van Venrooij, E. R. Vossenaar and A. J. Zendman, “Anti-CCP Antibodies: The New Rheumatoid Factor in the Serology of Rheumatoid Arthritis,” Autoimmunity Reviews, Vol. 3, Suppl. 1, 2004, pp. S17-S19.
[4] G. A. Schellekens, H. Visser, B. A. de Jong, F. H. van den Hoogen, J. M. Hazes, F. C. Breedveld, et al., “The Diagnostic Properties of Rheumatoid Arthritis Antibodies Recognizing a Cyclic Citrullinated Peptide,” Arthritis & Rheumatology, Vol. 43, No. 1, 2000, pp. 155-163.<155::AID-ANR20>3.0.CO;2-3
[5] J. J. Cush, “Early Arthritis Clinics: If You Build It Will They Come?” Journal of Rheumatology, Vol. 32, No. 2, 2005, pp. 203-207.
[6] F. C. Arnett, S. M. Edworthy, D. A. Bloch, D. J. McShane, J. F. Fries, N. S. Cooper, et al., “The American Rheumatism Association 1987 Revised Criteria for the Classification of Rheumatoid Arthritis,” Arthritis & Rheumatology, Vol. 31, No. 3, 1988, pp. 315-324.
[7] U. M. Nowak and M. M. Newkirk, “Rheumatoid Factors: Good or Bad for You?” International Archives of Allergy and Immunology, Vol. 138, No. 2, 2005, pp. 180-188.
[8] T. Jonsson, K. Steinsson, H. Jonsson, A. J. Geirsson, J. Thorsteinsson and H. Valdimarsson, “Combined Elevation of IgM and IgA Rheumatoid Factor Has High Diagnostic Specificity for Rheumatoid Arthritis,” Rheumatology International, Vol. 18, No. 3, 1998, pp. 119-122.
[9] I. Vallbracht, J. Rieber, M. Oppermann, F. Forger, U. Siebert and K. Helmke, “Diagnostic and Clinical Value of Anti-Cyclic Citrullinated Peptide Antibodies Compared with Rheumatoid Factor Isotypes in Rheumatoid Arthritis,” Annals of the Rheumatic Diseases, Vol. 63, No. 9, 2004, pp. 1079-1084.
[10] T. Jonsson, S. Arinbjarnarson, J. Thorsteinsson, K. Steinsson, A. J. Geirsson, H. Jonsson, et al., “Raised IgA Rheumatoid Factor (RF) but Not IgM RF or IgG RF Is Associated with Extra-Articular Manifestations in Rheumatoid Arthritis,” Scandinavian Journal of Rheumatology, Vol. 24, No. 6, 1995, pp. 372-375.
[11] F. C. Hay, L. J. Nineham, R. Perumal and I. M. Roitt, “Intra-Articular and Circulating Immune Complexes and Antiglobulins (IgG and IgM) in Rheumatoid Arthritis; Correlation with Clinical Features,” Annals of the Rheumatic Diseases, Vol. 38, No. 1, 1979, pp. 1-7.
[12] H. G. Kunkel, H. J. Muller-Eberhard, H. H. Fudenberg and T. B. Tomasi, “Gamma Globulin Complexes in Rheumatoid Arthritis and Certain Other Conditions,” Journal of Clinical Investigation, Vol. 40, No. 1, 1961, pp. 117- 129.
[13] D. A. Carson, S. Lawrance, M. A. Catalano, J. H. Vaughan and G. Abraham, “Radioimmunoassay of IgG and IgM Rheumatoid Factors Reacting with Human IgG,” Journal of Immunology, Vol. 119, No. 1, 1977, pp. 295-300.
[14] R. M. Pope, M. Mannik, B. C. Gilliland and D. C. Teller, “The Hyperviscosity Syndrome in Rheumatoid Arthritis Due to Intermediate Complexes Formed by Self-Association of IgG-Rheumatoid Factors,” Arthritis & Rheumatology, Vol. 18, No. 2, 1975, pp. 97-106.
[15] D. Aletaha, T. Neogi, A. J. Silman, J. Funovits, D. T. Felson, C. O. Bingham, et al., “Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology/European League against Rheumatism Collaborative Initiative,” Annals of the Rheumatic Diseases, Vol. 69, No. 9, 2010, pp. 1580-1588.
[16] T. Chun-Lai, L. Padyukov, J. S. Dhaliwal, E. Lundstrom, A. Yahya, N. A. Muhamad, et al., “Shared Epitope Alleles Remain a Risk Factor for Anti-Citrullinated Proteins Antibody (ACPA)—Positive Rheumatoid Arthritis in Three Asian Ethnic Groups,” PLoS One, Vol. 6, No. 6, 2011, Article ID: e21069.
[17] M. M. Ahmed, K. A. Obaid Al-Ruhaimi and S. H. Mohammed, “Evaluation of the Rheumatoid Factors of the IgG, IgM and IgA Isotypes as Prognostic Parameters for Rheumatoid Arthritis among Iraqi Patients,” Indian Journal of Pathology and Microbiology, Vol. 53, No. 3, 2010, pp. 433-438.
[18] N. A. Fathi, A. M. Ezz-Eldin, E. Mosad, R. M. Bakry, H. B. Hamed, S. Ahmed, M. Mahmoud, et al., “Diagnostic Performance and Predictive Value of Rheumatoid Factor, Anti-Cyclic-Citrullinated Peptide Antibodies and HLA-DRB1 Locus Genes in Rheumatoid Arthritis,” International Archives of Medicine, Vol. 1, No. 1, 2008, p. 20.
[19] E. L. Gomez, S. C. Gun, S. D. Somnath, B. D’Souza, A. L. Lim, K. Chinna, et al., “The Prevalence of Rheumatoid Factor Isotypes and Anti-Cyclic Citrullinated Peptides in Malaysian Rheumatoid Arthritis Patients,” International Journal of Rheumatic Diseases, Vol. 14, No. 1, 2011, pp. 12-17.
[20] B. Heidari, A. Firouzjahi, P. Heidari and K. Hajian, “The Prevalence and Diagnostic Performance of Anti-Cyclic Citrullinated Peptide Antibody in Rheumatoid Arthritis: The Predictive and Discriminative Ability of Serum Antibody Level in Recognizing Rheumatoid Arthritis,” Annals of Saudi Medicine, Vol. 29, No. 6, 2009, pp. 467-470.
[21] A. Kapitany, Z. Szabo, G. Lakos, M. Aleksza, A. Vegvari, L. Soos, et al., “Associations between Serum Anti-CCP Antibody, Rheumatoid Factor Levels and HLA-DR4 Expression in Hungarian Patients with Rheumatoid Arthritis,” Israel Medical Association Journal, Vol. 10, No. 1, 2008, pp. 32-36.
[22] H. Kokkonen, M. Mullazehi, E. Berglin, G. Hallmans, G. Wadell, J. Ronnelid, et al., “Antibodies of IgG, IgA and IgM Isotypes against Cyclic Citrullinated Peptide Precede the Development of Rheumatoid Arthritis,” Arthritis Research & Therapy, Vol. 13, No. 1, 2011, p. R13.
[23] S. Bas, T. V. Perneger, E. Kunzle and T. L. Vischer, “Comparative Study of Different Enzyme Immunoassays for Measurement of IgM and IgA Rheumatoid Factors,” Annals of the Rheumatic Diseases, Vol. 61, No. 6, 2002, pp. 505-510.
[24] U. Singh, A. Vishwanath, P. K. Verma, N. K. Singh, R. C. Shukla, S. Singh, et al., “Is Rheumatoid Factor Still a Superior Test for the Diagnosis of Rheumatoid Arthritis?” Rheumatology International, Vol. 30, No. 8, 2010, pp. 1115-1119.
[25] T. R. Mikuls, V. M. Holers, L. Parrish, K. A. Kuhn, D. L. Conn, G. Gilkeson, et al., “Anti-Cyclic Citrullinated Peptide Antibody and Rheumatoid Factor Isotypes in African Americans with Early Rheumatoid Arthritis,” Arthritis & Rheumatology, Vol. 54, No. 9, 2006, pp. 3057-3059.
[26] V. Nell-Duxneuner, K. Machold, T. Stamm, G. Eberl, H. Heinzl, E. Hoefler, et al., “Autoantibody Profiling in Patients with Very Early Rheumatoid Arthritis: A Follow-Up Study,” Annals of the Rheumatic Diseases, Vol. 69, No. 1, 2010, pp. 169-174.
[27] M. Singwe-Ngandeu, A. Finckh, S. Bas, J. M. Tiercy and C. Gabay, “Diagnostic Value of Anti-Cyclic Citrullinated Peptides and Association with HLA-DRB1 Shared Epitope Alleles in African Rheumatoid Arthritis Patients,” Arthritis Research & Therapy, Vol. 12, No. 2, 2010, p. R36.
[28] S. Rantapaa-Dahlqvist, B. A. de Jong, E. Berglin, G. Hallmans, G. Wadell, et al., “Antibodies against Cyclic Citrullinated Peptide and IgA Rheumatoid Factor Predict the Development of Rheumatoid Arthritis,” Arthritis & Rheumatology, Vol. 48, No. 10, 2003, pp. 2741-2749.
[29] L. D. Heinlen, M. T. McClain, J. Merrill, Y. W. Akbarali, C. C. Edgerton, J. B. Harley, et al., “Clinical Criteria for Systemic Lupus Erythematosus Precede Diagnosis, and Associated Autoantibodies Are Present before Clinical Symptoms,” Arthritis & Rheumatology, Vol. 56, No. 7, 2007, pp. 2344-2351.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.