Advertisement

Abatacept induced long-term non-progressive reduction in gamma-globulins and autoantibodies: dissociation from disease activity control

  • 83 Accesses

Abstract

Objectives

To evaluate long-term effects on gamma-globulins and autoantibodies of abatacept (ABA) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients.

Method

Eighteen RA patients undergoing abatacept (ABA-RA) and 18 age/sex-matched patients treated with TNFi (TNFi-RA) were compared regarding clinical data, total gamma-globulins (TGG), specific subtypes (IgG, IgM, IgA), free light chains (FLC), IgM/IgG rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP3), and anti-mutated citrullinated vimentin (anti-MCV), assessed before and every 6 months, up to 24 months. Exclusion criteria: previous abatacept/rituximab or low TGG (< 0.7 g/dL).

Results

At baseline, female sex (78 vs. 78%), age (55 vs. 53 years), DAS28 (5.73 vs. 5.67), TGG (1.4 vs. 1.35 g/dL), IgG (1168 vs. 1079 mg/dL), IgM (107 vs. 113 mg/dL), IgA (333 vs. 322 mg/dL), kappa (342 vs. 249 mg/dL), lambda (170 vs. 150 mg/dL), IgM-RF (76 vs. 53 UI), IgG-RF (63 vs. 25 UI), anti-CCP3 (216 vs. 189 UI), and anti-MCV (202 vs. 102 UI) were comparable in ABA-RA and TNFi-RA (p > 0.05). Similar disease activity improvement was observed in both groups. In ABA-RA, significant decreases (p < 0.05) were observed in TGG (1.4 vs. 1.05 g/dL), IgG (1168 vs. 997), IgA (333 vs. 278 mg/dL), kappa (342 vs. 257 mg/dL), lambda (170 vs. 144 mg/dL), IgM-RF (76 vs. 37 UI), IgG-RF (65 vs. 24 UI), anti-CCP3 (216 vs. 183 UI), and anti-MCV (202 vs. 60 UI) at 6 months, without further decreases. In contrast, TNFi-RA showed no decrease in any of such parameters. ABA-RA also had more often transient IgG levels under the lower limit of normality (66.7% vs. 33.3%, p = 0.046). No severe infection occurred. DAS28, ESR, and CRP correlated significantly to gamma-globulins and FLC at baseline (p < 0.05), but these correlations were longitudinally lost in ABA-RA, but not in TNFi-RA.

Conclusion

ABA, but not TNFi, induces a safe, persistent, long-term, and non-progressive reduction in gamma-globulins and autoantibodies, including anti-MCV. This pattern is dissociated from disease activity control.

Key Points
ABA induces a long-term and non-progressive reduction in gamma-globulins and FLC, which occurs regardless of disease activity control.
ABA-induced reduction in gamma-globulins and FLC promotes a dissociation of such parameters and disease activity.
The same pattern of reduction is observed in autoantibodies: IgM-RF, IgG-RF, anti-CCP3, and anti-MCV.
Low transient IgG can be observed in RA patients treated with ABA, but does not correlate to infection.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

References

  1. 1.

    Scarsi M, Paolini L, Ricotta D, Pedrini A, Piantoni S, Caimi L et al (2014) Immunoglobulins in patients with rheumatoid arthritis abatacept reduces levels of switched memory B cells, autoantibodies, and immunoglobulins in patients with rheumatoid arthritis. J Rheumatol 41:666–672. https://doi.org/10.3899/jrheum.130905

  2. 2.

    Derksen VF, Ajeganova S, Trouw LA, van der Helm-Van Mil AH, Hafström I, Huizinga TW et al (2016) Rheumatoid arthritis phenotype at presentation differs depending on the number of autoantibodies present. Ann Rheum Dis 76:716–720. https://doi.org/10.1136/annrheumdis-2016-209794

  3. 3.

    Hokkonen H, Mullazehi M, Berglin E, Hallmans G, Wadell G, Rönnelid J et al (2011) Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. Arthritis Res Ther 13:R13. https://doi.org/10.1186/ar3237

  4. 4.

    Conigliaro P, Chimenti MS, Triggianese P, Sunzini F, Novelli L, Perricone C, , Perricone R (2016) Autoantibodies in inflammatory arthritis. Autoimmun Rev 15:673–683. https://doi.org/10.1016/j.autrev.2016.03.003

  5. 5.

    Mathsson L, Mullazehi M, Wick MC, Sjöberg O, Van Vollenhoven R, Klareskog L 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. https://doi.org/10.1002/art.23188

  6. 6.

    Lee YH, Bae SC, Song GG (2015) Diagnostic accuracy of anti-MCV and anti-CCP antibodies in rheumatoid arthritis: a meta-analysis. Z Rheumatol 74:911–918. https://doi.org/10.1007/s00393-015-1598-x

  7. 7.

    Syversen SW, Goll GL, Van Der Heijde D, Landewé R, Lie BA, Odegård S 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. https://doi.org/10.1136/ard.2009.113092

  8. 8.

    Bang H, Egerer K, Gauliard A, Luthke K, Rudolph PE, Fredenhagen G et al (2007) Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum 56:2503–2511. https://doi.org/10.1002/art.22817

  9. 9.

    Ursum J, Nielen MM, van Schaardenburg D, van der Horst AR, van de Stadt RJ, Dijkmans BA, Hamann D (2008) Antibodies to mutated citrullinated vimentin and disease activity score in early arthritis: a cohort study. Arthritis Res Ther 10:R12. https://doi.org/10.1186/ar2362

  10. 10.

    Van Kooten C, Banchereau J (2000) CD40-CD40 ligand. J Leuk Biol 67:2–17. https://doi.org/10.1002/jlb.67.1.2

  11. 11.

    Cutolo M, Nadler SG (2013) Advances in CTLA-4-Ig-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis. Autoimmun Rev 12:758–767. https://doi.org/10.1016/j.autrev.2013.01.001

  12. 12.

    Alten R, Mariette X, Lorenz HM, Nüßlein H, Galeazzi M, Navarro F, Chartier M, Heitzmann J, Poncet C, Rauch C, le Bars M (2019) Predictors of abatacept retention over 2 years in patients with rheumatoid arthritis: results from the real-world ACTION study. Clin Rheumatol 38:1413–1424. https://doi.org/10.1007/s10067-019-04449-w

  13. 13.

    Alten R, Mariette X, Hm L, Galeazzi M, Cantagrel A, Nüßlein HG et al (2017) Real-world predictors of 12-month intravenous abatacept retention in patients with rheumatoid arthritis in the ACTION observational study. RMD Open 3:e000538. https://doi.org/10.1136/rmdopen-2017-000538

  14. 14.

    Alten R, Nüßlein HG, Mariette X, Galeazzi M, Lorenz HM, Cantagrel A, Chartier M, Poncet C, Rauch C, le Bars M (2017) Baseline autoantibodies preferentially impact abatacept efficacy in patients with rheumatoid arthritis who are biologic naïve: 6-month results from a real-world, international, prospective study. RMD Open 3:e000345. https://doi.org/10.1136/rmdopen-2016-000345

  15. 15.

    Nüßlein HG, Alten R, Galeazzi M, Lorenz HM, Nurmohamed MT, Bensen WG, Burmester GR, Peter HH, Peichl P, Pavelka K, Chartier M, Poncet C, Rauch C, le Bars M (2016) Efficacy and prognostic factors of treatment retention with intravenous abatacept for rheumatoid arthritis: 24-month results from an international, prospective, real-world study. Clin Exp Rheumatol 34:489–499

  16. 16.

    Harrold LR, Litman HJ, Connolly SE, Kelly S, Hua W, Alemao E, Rosenblatt L, Rebello S, Kremer JM (2018) Effect of anticitrullinated protein antibody status on response to abatacept or antitumor necrosis factor-α therapy in patients with rheumatoid arthritis: a US national observational study. J Rheumatol 45:32–39. https://doi.org/10.3899/jrheum.170007

  17. 17.

    Gottenberg JE, Ravaud P, Cantagrel A, Combe B, Flipo RM, Schaeverbeke T, Houvenagel E, Gaudin P, Loeuille D, Rist S, Dougados M, Sibilia J, le Loët X, Marcelli C, Bardin T, Pane I, Baron G, Mariette X (2012) Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry. Ann Rheum Dis 71:1815–1819. https://doi.org/10.1136/annrheumdis-2011-201109

  18. 18.

    Gottenberg JE, Courvoisier DS, Hernandez MV, Iannone F, Lie E, Canhão H et al (2016) Brief report: association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: results from the Pan-European registry analysis. Arthritis Rheumatol 68:1346–1352. https://doi.org/. https://doi.org/10.1002/art.39595

  19. 19.

    Endo Y, Koga T, Kawashiri SY, Morimoto S, Nishino A, Okamoto M et al (2019) Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan. Scand J Rheumatol 12:1–5. https://doi.org/10.1080/03009742.2019.1627411

  20. 20.

    Sokolove J, Schiff M, Fleischmann R, Weinblatt ME, Connolly SE, Johnsen A, Zhu J, Maldonado MA, Patel S, Robinson WH (2016) Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial. Ann Rheum Dis 75:709–714. https://doi.org/10.1136/annrheumdis-2015-207942

  21. 21.

    Ribeiro AC, Laurindo IM, Guedes LK, Saad CG, Moraes JC, Silva CA, Bonfa E (2013) Abatacept and reduced immune response to pandemic 2009 influenza A/H1N1 vaccination in patients with rheumatoid arthritis. Arthritis Care Res 65:476–480. https://doi.org/10.1002/acr.21838

  22. 22.

    Adler S, Krivine A, Weix J, Rozenberg F, Launay O, Huesler J, Guillevin L, Villiger PM (2012) Protective effect of A/H1N1 vaccination in immune-mediated disease-a prospectively controlled vaccination study. Rheumatology (Oxford) 51:695–700. https://doi.org/10.1093/rheumatology/ker389

  23. 23.

    Migita K, Akeda Y, Akazawa M, Tohma S, Hirano F, Ideguchi H, Kozuru H, Jiuchi Y, Matsumura R, Suematsu E, Miyamura T, Mori S, Fukui T, Izumi Y, Iwanaga N, Tsutani H, Saisyo K, Yamanaka T, Ohshima S, Mori N, Matsumori A, Takahi K, Yoshizawa S, Kawabe Y, Suenaga Y, Ozawa T, Hamada N, Komiya Y, Matsui T, Furukawa H, Oishi K (2015) Effect of abatacept on the immunogenicity of 23-valent pneumococcal polysaccharide vaccination (PPSV23) in rheumatoid arthritis patients. Arthritis Res Ther 17:357–367. https://doi.org/10.1186/s13075-015-0863-3

  24. 24.

    Conigliaro P, Triggianese P, Giampà E, Sole Chimenti M, Kroegler B, Perricone R (2017) Effects of abatacept on T-lymphocyte sub-populations and immunoglobulins in patients affected by rheumatoid arthritis. Isr Med Assoc J 19:406–410

  25. 25.

    Wunderlich C, Oliviera I, Figueiredo CP, Rech J, Schett G (2017) Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients-a longitudinal analysis. Semin Arthritis Rheum 46:709–714. https://doi.org/10.1016/j.semarthrit.2016.09.011

  26. 26.

    Tsuboi H, Matsumoto I, Hagiwara S, Hirota T, Takahashi H, Ebe H, Yokosawa M, Yagishita M, Takahashi H, Kurata I, Ohyama A, Honda F, Asashima H, Miki H, Umeda N, Kondo Y, Hirata S, Saito K, Tanaka Y, Horai Y, Nakamura H, Kawakami A, Sumida T (2016) Effectiveness of abatacept for patients with Sjögren’s syndrome associated with rheumatoid arthritis. An open label, multicenter, one-year, prospective study: ROSE (Rheumatoid Arthritis with Orencia Trial toward Sjögren's syndrome Endocrinopathy) trial. Mod Rheumatol 26:891–899. https://doi.org/10.3109/14397595.2016.1158773

  27. 27.

    Meiners PM, Vissink A, Kroese FG, Spijkervet FK, Smitt-Kamminga NS, Abdulahad WH, Bulthuis-Kuiper J, Brouwer E, Arends S, Bootsma H (2014) Abatacept treatment reduces disease activity in early primary Sjögren’s syndrome (open-label proof of concept ASAP study). Ann Rheum Dis 73:1393–1936. https://doi.org/10.1136/annrheumdis-2013-204653

  28. 28.

    Van Vollenhoven RF, Fleischmann RM, Furst DE, Lacey S, Lehane PB (2015) Longterm safety of rituximab: final report of the rheumatoid arthritis global clinical trial program over 11 years rheumatoid arthritis global. J Rheumatol 42:1761–1766. https://doi.org/10.3899/jrheum.150051

  29. 29.

    Gottenberg JE, Ravaud P, Bardin T, Cacoub P, Cantagrel A, Combe B et al (2010) Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the AutoImmunity and Rituximab Registry. Arthritis & Rheumatism 62:2625–2632. https://doi.org/10.1002/art.27555

  30. 30.

    Jansen DTSL, Emery P, Smolen JS, Westhovens R, Le Bars M, Connolly SE et al (2018) Conversion to seronegative status after abatacept treatment in patients with early and poor prognostic rheumatoid arthritis is associated with better radiographic outcomes and sustained remission: post hoc analysis of the AGREE study. RMD Open 4:e000564. https://doi.org/10.1136/rmdopen-2017-000564

  31. 31.

    Lv Q, Yin Y, Li X, Shan G, Wu X, Liang D, Li Y, Zhang X (2014) The status of rheumatoid factor and anti-citrullinated peptide antibody are not associated with the effect of anti-TNFα agent treatment in patients with rheumatoid arthritis: a meta-analysis. PLoS One 9:e89442. https://doi.org/10.1371/journal.pone.0089442

Download references

Author information

Correspondence to Ana C. Medeiros-Ribeiro.

Ethics declarations

Disclosures

None.

Ethical standards

The procedures were in accordance with the 1964 Declaration of Helsinki and its later amendments and were approved by the local ethical committee on human experimentation (Comissão de Ética para Análise de Projetos de Pesquisa do HCFMUSP – CAPPesq, project no. 2009/51897-5). An informed consent was obtained from all participants prior to their inclusion in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dinis, V.G., Viana, V.T., Leon, E.P. et al. Abatacept induced long-term non-progressive reduction in gamma-globulins and autoantibodies: dissociation from disease activity control. Clin Rheumatol (2020). https://doi.org/10.1007/s10067-020-04932-9

Download citation

Keywords

  • Anti-mutated citrullinated vimentin and anti-cyclic citrullinated peptide
  • Biological therapies
  • Infections and arthritis
  • Rheumatoid arthritis
  • Rheumatoid factor