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IgA rheumatoid factor is associated with bone mineral density preservation in rheumatoid arthritis

Clinical Rheumatology volume 40, pages 4879–4887 (2021)Cite this article

Abstract

Introduction

Autoantibodies such as IgM rheumatoid factor (RF) and anti-citrullinated proteins/peptides antibodies (ACPA) have previously been incriminated in systemic bone loss in rheumatoid arthritis (RA). There are, however, no data describing association of IgA RF and IgG RF with systemic bone loss.

Objective

This study was aimed to investigate the association of RF isotypes with systemic bone loss among patients with RA.

Methods

RF isotypes and ACPA were measured by enzyme-linked immunosorbent assay among 153 patients with RA. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry.

Results

Ninety-four (61.4%) patients had positive IgA RF, 89 (58.2%) had positive IgG RF, 109 (71.2%) had positive IgM RF, whereas 122 (80.3%) RA patients tested positive for ACPA. Compared to the IgA RF-negative patients, IgA RF-positive patients exhibited higher disease activity and had higher RF titers.

Seven (4.6%) patients had low BMD at femoral neck, 12 (7.8%) at total femur, and 47 (30.7%) at lumbar spine. IgA RF was found to be associated with protection against low BMD at spine (OR = 0.47, 95% CI = 0.23–0.95, p = 0.034). This association was further confirmed in the multivariate regression analysis taking into account several potential confounding factors (OR = 0.21, 95% CI = 0.06–0.65, p = 0.039). No association between low BMD and the presence of IgG RF or IgM RF or ACPA was found.

Conclusion

IgA RF for the first time ever was shown to be associated with BMD preservation at spine in RA.

Key points
• IgA RF was associated with protection against low spinal BMD.
• No association between low BMD and the presence of IgG RF or IgM RF was found.

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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. Arthritis Rheum 62:2569–2581

    Article  Google Scholar 

  2. Tarkowski A, Nilsson LA (1983) Isotype-specific measurement of rheumatoid factor with reference to clinical features of rheumatoid arthritis. J Clin Lab Immunol 12:129–135

    CAS  PubMed  Google Scholar 

  3. Silvestris F, Goodwin JS, Williams RC Jr (1985) IgM, IgA and IgG rheumatoid factors in patients with rheumatoid arthritis and normal donors. Clin Rheumatol 4:392–398

    CAS  Article  Google Scholar 

  4. Allen C, Elson CJ, Scott DG et al (1981) IgG antiglobulins in rheumatoid arthritis and other arthritides: relationship with clinical features and other parameters. Ann Rheum Dis 40:127–131

    CAS  Article  Google Scholar 

  5. Jonsson T, Valdimarsson H (1993) Is measurement of rheumatoid factor iso-types clinically useful? Ann Rheum Dis 52:161–164

    CAS  Article  Google Scholar 

  6. Sieghart D, Platzer A, Studenic P et al (2018) Determination of autoantibody isotypes increases the sensitivity of serodiagnostics in rheumatoid arthritis. Front Immunol. https://doi.org/10.3389/fimmu.2018.00876

    Article  PubMed  PubMed Central  Google Scholar 

  7. Martinez-Prat L, Nissen MJ, Lamacchia C et al (2018) Comparison of serological biomarkers in rheumatoid arthritis and their combination to improve diagnostic performance. Front Immunol. https://doi.org/10.3389/fimmu.2018.01113

    Article  PubMed  PubMed Central  Google Scholar 

  8. Klareskog L, Stolt P, Lundberg K et al (2006) A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54:38–46

    CAS  Article  Google Scholar 

  9. Linn-Rasker SP, van der Helm-van Mil AH, van Gaalen FA et al (2006) Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis 65:366–371

    CAS  Article  Google Scholar 

  10. Chatzidionysiou K, Lie E, Nasonov E et al (2011) Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann Rheum 70:1575–1580

    CAS  Article  Google Scholar 

  11. Gottenberg JE, Courvoisier DS, Hernandez MV et al (2016) Rheumatoid factor and anti-citrullinated protein antibody positivity are associated with a better effectiveness of abatacept: results from the Pan-European registry analysis. Arthritis Rheumatol 68:1346–1352

    CAS  Article  Google Scholar 

  12. Arnason JA, Jónsson T, Brekkan A et al (2004) Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis 63:1090–1095

    Article  Google Scholar 

  13. Árnason JA, Jónsson T, Brekkan Á et al (1987) Relation between bone erosions and rheumatoid factor isotypes. Ann Rheum Dis 46:380–384

    Article  Google Scholar 

  14. Takayanagi H (2009) Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 5:667–676

    CAS  Article  Google Scholar 

  15. Ritchlin CT, Haas-Smith SA, Li P et al (2003) Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 111:821–831

    CAS  Article  Google Scholar 

  16. Geusens P (2012) The role of RANK ligand/osteoprotegerin in rheumatoid arthritis. Ther Adv Musculoskelet Dis 4:225–233

    CAS  Article  Google Scholar 

  17. Kleyer A, Finzel S, Rech J et al (2014) Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis 73:854–860

    Article  Google Scholar 

  18. Harre U, Kittan NA, Schett G (2014) Autoantibody-mediated bone loss. Curr Osteoporos Rep 12:17–21

    Article  Google Scholar 

  19. Harre U, Georgess D, Bang H et al (2012) Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 122:1791–1802

    CAS  Article  Google Scholar 

  20. Orsolini G, Caimmi C, Viapiana O et al (2017) Titer-Dependent effect of anti-citrullinated protein antibodies On systemic bone mass in rheumatoid arthritis patients. Calcif Tissue Int 101:17–23

    CAS  Article  Google Scholar 

  21. Llorente I, Merino L, Ortiz AM et al (2017) Anti-citrullinated protein antibodies are associated with decreased bone mineral density: baseline data from a register of early arthritis patients. Rheumatol Int 37:799–806

    Article  Google Scholar 

  22. Regueiro C, Ortiz AM, Boveda MD et al (2018) PLoS One 13:e0202583

    Article  Google Scholar 

  23. Sharp JT, Wolfe F, Mitchell DM et al (1991) The progression of erosion and joint space narrowing scores in rheumatoid arthritis during the first twenty-five years of disease. Arthritis Rheum 34:660-668S

    CAS  Article  Google Scholar 

  24. Sghiri R, Bouajina E, Bargaoui D et al (2008) Value of anti-mutated citrullinated vimentin antibodies in diagnosing rheumatoid arthritis. Rheumatol Int 29:59–62

    CAS  Article  Google Scholar 

  25. Sghiri R, Bouagina E, Zaglaoui H et al (2007) Diagnostic performances of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis. Rheumatol Int 27:1125–1130

    CAS  Article  Google Scholar 

  26. Kanis JA (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group Osteoporos Int 4:368–381

    CAS  Article  Google Scholar 

  27. Aho K, Heliövaara M, Maatela J et al (1991) Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol 18:1282–1284

    CAS  PubMed  Google Scholar 

  28. Rantapää-Dahlqvist S, de Jong BA, Berglin E et al (2003) Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749

    Article  Google Scholar 

  29. Teitsson I, Withrington RH, Seifert MH et al (1984) Prospective study of early arthritis. I. Prognostic value of IgA rheumatoid factor. Ann Rheum Dis 43:673–678

    CAS  Article  Google Scholar 

  30. Lúthvíksson BR, Jónsson T, Erlendsson K et al (1992) Disease manifestations in patients with isolated elevation of IgA rheumatopid factor. Scand J Rheumatol 21:1–4

    Article  Google Scholar 

  31. Eberhardt KB, Svensson B, Truedsson L et al (1988) The occurrence of rheumatoid factor isotypes in early definite rheumatoid arthritis. J Rheumatol 15:1070–1074

    CAS  PubMed  Google Scholar 

  32. Gioud-Paquet M, Auvinet M, Raffin T et al (1987) IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF detected by ELISA in rheumatoid arthritis. Ann Rheum Dis 46:65–71

    CAS  Article  Google Scholar 

  33. Russell MW, Sibley DA, Nikolova EB et al (1997) IgA antibody as a non-inflammatory regulator of immunity. Biochem Soc Trans 25:466–470

    CAS  Article  Google Scholar 

  34. Schaffer FM, Monteiro RC, Volanakis JE et al (1991) IgA deficiency. Immunodefic Rev 3:15–44

    CAS  PubMed  Google Scholar 

  35. Rossato E, Ben Mkaddem S, Kanamaru Y et al (2015) Reversal of arthritis by human monomeric IgA through the receptor-mediated SH2 domain-containing phosphatase 1 inhibitory pathway. Arthritis Rheumatol 67:1766–1777

    CAS  Article  Google Scholar 

  36. Ben Mkaddem S, Rossato E, Heming N (2013) Anti-inflammatory role of the IgA Fc receptor (CD89): from autoimmunity to therapeutic perspectives. Autoimmun Rev 12:666–669

    CAS  Article  Google Scholar 

  37. MacLellan LM, Montgomery J, Sugiyama F et al (2011) Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice. Arthritis Rheum 63:3897–3907

    CAS  Article  Google Scholar 

  38. Delamere JP, Farr M, Grindulis KA (1983) Sulphasalazine induced selective IgA deficiency in rheumatoid arthritis. Br Med J (Clin Res Ed) 286:1547–1548

    CAS  Article  Google Scholar 

  39. Bugatti S, Bogliolo L, Vitolo B et al (2016) arthritis. Arthritis Res Ther 18:226

    Article  Google Scholar 

  40. Onal M, Xiong J, Chen X et al (2012) Receptor activator of nuclear factor kB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J Biol Chem 287:29851–29860

    CAS  Article  Google Scholar 

  41. Zhu LJ, Dai L, Zheng DH et al (2012) Upregulation of tumor necrosis factor receptor associated factor 6 correlated with synovitis severity in rheumatoid arthritis. Arthritis Res Ther 14:R133

    CAS  Article  Google Scholar 

  42. Hassine HB, Zemni R, Nacef IB et al (2019) A TRAF6 genetic variant is associated with low bone mineral density in rheumatoid arthritis. Clin Rheumatol 38:1067–1074

    Article  Google Scholar 

  43. Amkreutz JAMP, de Moel EC, Theander L et al (2020) The relation between autoantibodies and bone mineral density in patients with rheumatoid arthritis. Arthritis Rheumatol. https://doi.org/10.1002/art.41623

    Article  Google Scholar 

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Acknowledgements

This study was supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia.

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Affiliations

  1. Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Rim Sghiri, Zahid Shakoor & Adel Almogren

  2. Laboratory of Immunology, Research Unit UR 807, Faculty of Medicine of Sousse, Sousse, Tunisia

    Asma Boumiza, Hana Benhassine, Foued Slama & Latifa Guaddah

  3. Department of Rheumatology, Farhat Hached Hospital, Sousse, Tunisia

    Nejla Elamri, Hala Zeglaoui & Elyes Bouajina

  4. Department of Epidemiology, Farhat Hached Hospital, Sousse, Tunisia

    Imed Harrabi & Jihen Sahli

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  1. Rim Sghiri
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  2. Asma Boumiza
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  3. Hana Benhassine
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Correspondence to Rim Sghiri.

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Sghiri, R., Boumiza, A., Benhassine, H. et al. IgA rheumatoid factor is associated with bone mineral density preservation in rheumatoid arthritis. Clin Rheumatol 40, 4879–4887 (2021). https://doi.org/10.1007/s10067-021-05814-4

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  • DOI: https://doi.org/10.1007/s10067-021-05814-4

Keywords

  • Anti-cyclic citrullinated proteins/peptides antibodies
  • Bone mineral density
  • IgA rheumatoid factor
  • IgG rheumatoid factor
  • IgM rheumatoid factor
  • Rheumatoid arthritis