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Serum levels of anti-CCP antibodies, anti-MCV antibodies and RF IgA in the follow-up of patients with rheumatoid arthritis treated with rituximab

Abstract

Rheumatoid arthritis (RA) is characterized by the presence of circulating rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA), which are positive in about 70–80% of patients. APCA have a higher specificity and therefore a higher diagnostic power than RF, but are less informative than RF in monitoring the course of the disease in patients under treatment. Recently, it has been reported that the anticitrullinated vimentin (a-MCV) antibody test can identify a particular subgroup of APCA that may be negative for anticyclic citrullinated peptide (a-CCP) antibodies. Concerning RF, the RF IgA isotype has been described as a more specific marker of erosive joint damage than total RF. The aim of our study was to monitor the levels of a-CCP, a-MCV, total RF and RF IgA in the follow-up of patients with RA treated with B-lymphocytedepletive rituximab (RTX), to detect any differences or peculiarities in patterns of these autoantibodies, especially in relation to their potential use as predictive markers of therapeutic response. We studied 30 patients with RA treated with RTX. All patients were previously unresponsive to at least 6 months of therapy with disease-modifying antirheumatic drugs (DMARDs; methotrexate, leflunomide, cyclosporine, chloroquine) and/or at least 6 months of therapy with anti-TNF biologics. The evaluation of response to RTX was made at month +6 using the EULAR criteria (DAS28). a-CCP, a-MCV, total RF and RF IgA were determined at baseline (before the first infusion of RTX) and after 1, 3 and 6 months. In serum samples obtained before treatment two cytokines essential for Blymphocyte proliferation, interleukin 6 (IL-6) and B-lymphocyte stimulator (BLyS) were also determined. In all patients a significant and consistent reduction in all the tested antibodies was found during follow-up, with no differences in respect of the degree of response to RTX. Of note, at baseline, generally a higher titre of all autoantibodies was seen in patients who then showed a better response to RTX. Finally, there were no differences in serum concentrations of IL-6 and BLyS in patients in relation to the presence or absence of the autoantibodies investigated, nor was there any significant correlation between the serum concentrations of the cytokines and the titres of the autoantibodies. Thus, neither a-MCV compared to a- CCP, nor RF IgA compared to routine total RF, provided any additional predictive information in the follow-up of patients with RA treated with RTX.

References

  1. 1.

    De Vita S, Zaja F, Sacco S et al (2002) Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum 46:2029–2033

    PubMed  Article  Google Scholar 

  2. 2.

    Edwards JC, Leandro MJ, Cambridge G (2002) B-lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders. Biochem Soc Trans 30:824–828

    PubMed  Article  Google Scholar 

  3. 3.

    Leandro MJ, Edwards JC, Cambridge G et al (2002) An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 46:2673–2677

    PubMed  Article  Google Scholar 

  4. 4.

    Meijer JM, Pijpe J, Vissink A et al (2009) Treatment of primary Sjogren syndrome with rituximab: extended follow-up, safety and efficacy of retreatment. Ann Rheum Dis 68:284–285

    PubMed  Article  Google Scholar 

  5. 5.

    De Vita S, Quartuccio L, Fabris M (2007) Rituximab in mixed cryoglobulinemia: increased experience and perspectives. Dig Liver Dis 39(Suppl 1):S122–S128

    PubMed  Article  Google Scholar 

  6. 6.

    Taylor RP, Lindorfer MA (2008) Immunotherapeutic mechanisms of anti-CD20 monoclonal antibodies. Curr Opin Immunol 20:444–449

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Maloney DG, B. Smith AR (2002) Rituximab: mechanism of action and resistance. Semin Oncol 29(Suppl 2):2–9

    PubMed  Article  Google Scholar 

  8. 8.

    Uchida J, Hamaguchi Y, Oliver JA et al (2004) The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 199:1659–1669

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Szodoray P, Alex P, Dandapani V et al (2004) Apoptotic effect of rituximab on peripheral blood B cells in rheumatoid arthritis. Scand J Immunol 60:209–218

    PubMed  Article  Google Scholar 

  10. 10.

    Rehnberg M, Amu S, Tarkowski A et al (2009) Short- and long-term effects of anti-CD20 treatment on B cell ontogeny in bone marrow of patients with rheumatoid arthritis. Arthritis Res Ther 11:R123

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Ziswiler HR, Aeberli D, Villiger PM, Möller B (2009) High-resolution ultrasound confirms reduced synovial hyperplasia following rituximab treatment in rheumatoid arthritis. Rheumatology (Oxford) 48:939–943

    Article  Google Scholar 

  12. 12.

    Wilk E, Witte T, Marquardt N et al (2009) Depletion of functionally active CD20+ T cells by rituximab treatment. Arthritis Rheum 60:3563–3571

    PubMed  Article  Google Scholar 

  13. 13.

    Nishimura K, Sugiyama D, Kogata Y et al (2007) Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 146:797–808

    PubMed  Article  Google Scholar 

  14. 14.

    Visser H, le Cessie S, Vos K et al (2002) How to diagnose rheumatoid arthritis early. A prediction model for persistent (erosive) arthritis. Arthritis Rheum 46:357–365

    PubMed  Article  Google Scholar 

  15. 15.

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

    PubMed  Article  Google Scholar 

  16. 16.

    Kastbom A, Strandberg G, Lindroos A et al (2004) Anti-CCP antibody test predicts the disease course during three years in early rheumatoid arthritis (the TIRA project). Ann Rheum Dis 63:1085–1089

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Chan MT, Owen P, Dunphy J et al (2005) Anti-cyclic citrullinated peptide antibodies are associated with erosive arthritis in SLE. Arthritis Rheum 52:S611

    Google Scholar 

  18. 18.

    Szodoray P, Szabó Z, Kapitány A et al (2010) Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis. Autoimmun Rev 9:140–143

    PubMed  Article  Google Scholar 

  19. 19.

    Vallbracht I, Rieber J, Oppermann M et al (2004) Diagnostic and clinical value of anti-citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis 63:1079–1084

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Bobbio-Pallavicini F, Alpini C, Caporali R et al (2004) Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment. Arthritis Res Ther 6:R264–R272

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Alessandri C, Bombardieri M, Papa N et al (2004) Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following ant-TNFalpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis 63:1218–1221

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Bang H, Egerer K, Gauliard A et al (2007) Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum 56:2503–2511

    PubMed  Article  Google Scholar 

  23. 23.

    Snir O, Widhe M, Hermansson M et al (2010) Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients. Arthritis Rheum 62:44–52

    PubMed  Article  Google Scholar 

  24. 24.

    Mutlu N, Bicakcigil M, Tasan DA et al (2009) Comparative performance analysis of 4 different anti-citrullinated protein assays in the diagnosis of rheumatoid arthritis. J Rheumatol 36:491–500

    PubMed  Article  Google Scholar 

  25. 25.

    Vossenaar R, Despres N, Lapointe E et al (2004) Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin, Arthritis Res Ther 6:R142–R150

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Nicaise Roland P, Grootenboer Mignot S, Bruns A et al (2008) Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in anti-CCP-negative patients and for monitoring infliximab therapy. Arthritis Res Ther 10:R142

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    van der Linden MP, van der Woude D, Ioan-Facsinay A et al (2009) Value of anti-modified citrullinated vimentin and thirdgeneration anti-cyclic citrullinated peptide compared with second-generation anti-cyclic citrullinated peptide and rheumatoid factor in predicting disease outcome in undifferentiated arthritis and rheumatoid arthritis. Arthritis Rheum 60:2232–2241

    PubMed  Article  Google Scholar 

  28. 28.

    Qin X, Deng Y, Xu J et al (2010) Meta-analysis: diagnostic value of serum anti-mutated citrullinated vimentin antibodies in patients with rheumatoid arthritis. Rheumatol Int. DOI: 10.1007/s00296-009-1343-3

  29. 29.

    Luime JJ, Colin EM, Hazes JM, Lubberts E (2010) Does antimutated 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 69:337–344

    PubMed  Article  Google Scholar 

  30. 30.

    Mathsson L, Mullazehi M, Wick MC et al (2008) Antibodies against citrullinated vimentin in rheumatoid arthritis: higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides. Arthritis Rheum 58:36–42

    PubMed  Article  Google Scholar 

  31. 31.

    Syversen SW, Goll GL, van der Heijde D et al (2010) Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a 10-year prospective study. Ann Rheum Dis 69:345–351

    PubMed  Article  Google Scholar 

  32. 32.

    Robecchi A, Daneo V (1959) Research on the behaviour, nature and meaning of the rheumatoid factor. Acta Rheumatol Scand 5:245–262

    PubMed  Google Scholar 

  33. 33.

    Berling E, Johansonn T, Sundin U et al (2006) Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis 65:453–458

    Article  Google Scholar 

  34. 34.

    Bobbio-Pallavicini F, Caporali R, Alpini C et al (2007) High IgA rheumatoid factor levels are associated with poor clinical response to tumour necrosis factor alpha inhibitors in rheumatoid arthritis. Ann Rheum Dis 66:302–307

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Sfikakis PP (2010) The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Curr Dir Autoimmun 11:180–210

    PubMed  Article  Google Scholar 

  36. 36.

    Perosa F, Prete M, Racanelli V, Dammacco F (2010) CD20- depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med 267:260–277

    PubMed  Article  Google Scholar 

  37. 37.

    Buch MH (2010) Sequential use of biologic therapy in rheumatoid arthritis. Curr Opin Rheumatol 22:321–329

    PubMed  Article  Google Scholar 

  38. 38.

    Benucci M, Li Gobbi F, Sabadini L et al (2009) The economic burden of biological therapy in rheumatoid arthritis in clinical practice: cost-effectiveness analysis of sub-cutaneous anti-TNFalpha treatment in Italian patients. Int J Immunopathol Pharmacol 22:1147–1152

    PubMed  Google Scholar 

  39. 39.

    Dörner T, Kinnman N, Tak PP (2010) Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol Ther 125:464–475

    PubMed  Article  Google Scholar 

  40. 40.

    Tas SW (2009) Personalised treatment of arthritis in the next eRA. Neth J Med 67:362–363

    PubMed  Google Scholar 

  41. 41.

    Kishimoto T (2006) Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther 8(Suppl 2):S2

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Mackay F, Mackay CR (2002) The role of BAFF in B-cell maturation, T-cell activation and autoimmunity. Trends Immunol 23:113–115

    PubMed  Article  Google Scholar 

  43. 43.

    Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    PubMed  Article  Google Scholar 

  44. 44.

    van Gaalen FA, Visser H, Huizinga TW (2005) A comparison of the diagnostic accuracy and prognostic value of the first and second anti-cyclic citrullinated peptides autoantibody (CCP1 and CCP2) tests for rheumatoid arthritis. Ann Rheum Dis 64:1510–1512

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Bizzaro N, Tonutti E, Tozzoli R et al (2007) Analytical and diagnostic characteristics of 11 second- and third-generation immunoenzymatic methods for the detection of antibodies to citrullinated proteins. Clin Chem 53:1527–1533

    PubMed  Article  Google Scholar 

  46. 46.

    Mathsson L, Mullazhei M, Wick MC et al (2008) Antibodies against citrullinated vimentin in rheumatoid arthritis: higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides. Arthritis Rheum 58:36–45

    PubMed  Article  Google Scholar 

  47. 47.

    Damjanovska L, Thabet MM, Leverht EW et al (2010) The diagnostic value of anti-MCV antibodies in differentiating early inflammatory arthritis. Ann Rheum Dis 69:730–732

    PubMed  Article  Google Scholar 

  48. 48.

    De Rycke L, Verhelst X, Kruithof E et al (2005) Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis 64:299–302

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Thurlings RM, Vos K, Wijbrandts CA et al (2008) Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response. Ann Rheum Dis 67:917–925

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Quartuccio L, Fabris M, Salvin S et al (2009) Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis. Rheumatology (Oxford) 48:1557–1559

    Article  Google Scholar 

  51. 51.

    Pyrpasopoulou A, Douma S, Triantafyllou A et al (2010) Response to rituximab and timeframe to relapse in rheumatoid arthritis patients: association with B-cell markers. Mol Diagn Ther 14:43–48

    PubMed  Article  Google Scholar 

  52. 52.

    van Vollenhoven RF, Chatzidionysiou K, Gabay C et al (2009) Rheumatoid factor predicts response to rituximab in a European registry-based cohort: 6-month results from the collaborative European registries for rituximab in rheumatoid arthritis (CERERRA). Ann Rheum Dis 68(Suppl3):579

    Google Scholar 

  53. 53.

    Bruns A, Nicaise-Roland P, Hayem G et al (2009) Prospective cohort study of effects of infliximab on rheumatoid factor, anticyclic citrullinated peptide antibodies and antinuclear antibodies in patients with long-standing rheumatoid arthritis. Joint Bone Spine 76:248–253

    PubMed  Article  Google Scholar 

  54. 54.

    Mariette X, Roux S, Zhang J et al (2003) The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome. Ann Rheum Dis 62:168–171

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Becker-Merok A, Nikolaisen C, Nossent HC (2006) B-lymphocyte activating factor in systemic lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease measures and time. Lupus 15:570–576

    PubMed  Article  Google Scholar 

  56. 56.

    Fabris M, Quartuccio L, Sacco S et al (2007) B-Lymphocyte stimulator (BLyS) up-regulation in mixed cryoglobulinaemia syndrome and hepatitis-C virus infection. Rheumatology (Oxford) 46:37–43

    Article  Google Scholar 

  57. 57.

    Tan SM, Xu D, Roschke V et al (2003) Local production of B lymphocyte stimulator protein and APRIL in arthritic joints of patients with inflammatory arthritis. Arthritis Rheum 48:982–992

    PubMed  Article  Google Scholar 

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Correspondence to Martina Fabris.

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Fabris, M., De Vita, S., Blasone, N. et al. Serum levels of anti-CCP antibodies, anti-MCV antibodies and RF IgA in the follow-up of patients with rheumatoid arthritis treated with rituximab. Autoimmun Highlights 1, 87–94 (2010). https://doi.org/10.1007/s13317-010-0013-5

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Keywords

  • Anticitrullinated peptide antibodies
  • Antimodified citrullinated vimentin antibodies
  • Rheumatoid factor
  • Rheumatoid arthritis
  • Rituximab