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Immunologic Research

, Volume 65, Issue 1, pp 17–24 | Cite as

Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome

  • Entela Nuri
  • Mara Taraborelli
  • Laura Andreoli
  • Marta Tonello
  • Maria Gerosa
  • Antonia Calligaro
  • Lorenza Maria Argolini
  • Rajesh Kumar
  • Vittorio Pengo
  • Pier Luigi Meroni
  • Amelia Ruffatti
  • Angela Tincani
Environment and Autoimmunity

Abstract

Hydroxychloroquine (HCQ) was suggested to play a role in lowering antiphospholipid antibody titers and preventing thrombotic recurrences in patients with systemic lupus erythematosus, but few data are available in patients with primary antiphospholipid syndrome (PAPS). In this retrospective, propensity score-matched cohort study, we evaluated the impact of HCQ on aPL titers and the incidence of thrombotic events in 57 exposed patients compared to 57 not exposed patients. These were matched for sex/type of disease onset/follow-up duration, age at the beginning of the follow-up ±10 years and initial date of the follow-up ±5 years. At baseline, no significant differences in demographical, clinical and serological features were observed between the two groups except for positive anti-extractable nuclear antigen antibodies (21 % in HCQ exposed vs 0 % in HCQ not exposed, P = 0.001). Both the levels of IgG anti-cardiolipin and IgG/IgM anti-β2-glycoprotein I (anti-β2GPI) were significantly reduced at end of follow-up compared to the baseline in HCQ-exposed patients, while there were no differences in the other group. Moreover, anti-β2GPI IgG titers were significantly decreased when the end of follow-up was compared between the two groups (P < 0.002). Among patients with a history of thrombosis, the annual incidence of recurrence was 1.16 % in HCQ exposed and 1.71 % in not exposed patients, with a significant reduction in the incidence of arterial events (0 vs 1.14 %). This study shows a strong reduction in aPL titers together with an apparent decrease in the incidence of arterial thrombosis recurrence in PAPS patients treated with HCQ.

Keywords

Primary antiphospholipid syndrome Antiphospholipid antibodies Hydroxychloroquine Thrombosis 

References

  1. 1.
    Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.CrossRefPubMedGoogle Scholar
  2. 2.
    Hughes GRV. The anticardiolipin syndrome. Clin Exp Rheumatol. 1985;3:285.PubMedGoogle Scholar
  3. 3.
    McChesney EW, Banks WF Jr, Sullivan DJ. Metabolism of chloroquine and hydroxychloroquine in albino and pigmented rats. Toxicol Appl Pharmacol. 1965;7:627–36.CrossRefPubMedGoogle Scholar
  4. 4.
    Rynes RI. Hydroxychloroquine treatment of rheumatoid arthritis. Am J Med. 1998;85:18–22.CrossRefGoogle Scholar
  5. 5.
    Clark P, Casas E, Tugwell P, Medina C, Gheno C, Tenorio G, et al. Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial. Intern Med. 1993;119:1067–71.Google Scholar
  6. 6.
    Nayak V, Esdaile JM. The efficacy of antimalarials in systemic lupus erythematosus. Lupus. 1996;5(Suppl 1):S23–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Molad Y, Gorshtein A, Wysenbeek AJ, Guedj D, Majalda R, Weinberger A, et al. Protective effect of hydroxychloroquine in systemic lupus erythematosus. Prospective long-term study of an Israeli cohort. Lupus. 2002;11:356–61.CrossRefPubMedGoogle Scholar
  8. 8.
    Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA. Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med. 1990;89:322–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Petri M, Lakatta C, Magder L, Goldman D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med. 1994;96:254–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Borba EF, Bonfá E. Long term beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy. J Rheumatol. 2001;28:780–5.PubMedGoogle Scholar
  11. 11.
    Petri M. Hydroxychloroquine use in the Baltimore lupus cohort: effects on lipids, glucose and thrombosis. Lupus. 1996;5(Suppl. 1):S16–22.CrossRefPubMedGoogle Scholar
  12. 12.
    No authors listed, A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian hydroxychloroquine study group. N Engl J Med. 1991; 324:150–4.Google Scholar
  13. 13.
    Wallace DJ, Linker-Israeli M, Metzger AL, Stecher VJ. The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus. 1993;2(Suppl. 1):S13–5.PubMedGoogle Scholar
  14. 14.
    Kyburz D, Brentano F, Gay S. Mode of action of hydroxychloroquine in RA evidence of an inhibitory effect on toll-like receptor signaling. Nat Clin Pract Rheumatol. 2006;2:458–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Goldman FD, Gilman AL, Hollenback C, Kato RM, Premack BA, Rawlings DJ. Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties. Blood. 2000;95:3460–6.PubMedGoogle Scholar
  16. 16.
    Wallace DJ. Does hydroxychloroquine sulfate prevent clot formation in systemic lupus erythematosus? Arthritis Rheum. 1987;30:1435–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Ruiz-Irastorza G, Egurbide MV, Pijoan JI, Garmendia M, Villar I, Martinez-Berriotxoa A, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus. 2006;15:577–83.CrossRefPubMedGoogle Scholar
  18. 18.
    Kaiser R, Cleveland CM, Criswell LA. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum Dis. 2009;68(2):238–41.CrossRefPubMedGoogle Scholar
  19. 19.
    Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz M, et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum. 2010;62:863–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Broder A, Putterman C. Hydroxychloroquine use is associated with lower odds of persisently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus. J Rheumatol. 2013;40:30–3.CrossRefPubMedGoogle Scholar
  21. 21.
    Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost. 2009;7:1737–40.CrossRefPubMedGoogle Scholar
  22. 22.
    Tincani A, Allegri F, Balestrieri G, Reber G, Sanmarco M, Meroni P, et al. Minimal requirements for antiphospholipid antibodies ELISAs proposed by the European Forum on antiphospholipid antibodies. Thromb Res. 2004;114:553–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Balestrieri G, Tincani A, Spatola L, Allegri F, Prati E, Cattaneo R, et al. Anti-b 2-glycoprotein I antibodies: a marker of antiphospholipid syndrome? Lupus. 1995;4:122–30.CrossRefPubMedGoogle Scholar
  24. 24.
    Ho KT, Ahn CW, Alarco GS, Baethge BA, Tan FK, Roseman J, et al. Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events. Rheumatology (Oxford). 2005;44:1303–7.CrossRefGoogle Scholar
  25. 25.
    Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep. 2011;13:77–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Blood. 2008;112:1687–95.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Andreoli L, Pregnolato F, Burlingame RW, Allegri F, Rizzini S, Fanelli V, Radice A, Corace C, Sinico RA, Meroni PL, Tincani A. ANuc in PAPS: a hint at systemic autoimmunity? J Autoimmun. 2008;30:51–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Shoenfeld Y. APS—more systemic disease than SLE. Clin Rev Allergy Immunol. 2007;32:129–30.CrossRefPubMedGoogle Scholar
  29. 29.
    Erkan D, et al. Antiphospholipid syndrome clinical research task force report. Lupus. 2011;20:219–24.CrossRefPubMedGoogle Scholar
  30. 30.
    Lombard-Platlet S, Bertolino P, Deng H, Gerlier D, Rabourdine-Combe C. Inhibition by chloroquine of the class II histocompatibility complexrestricted presentation of endogenous antigens varies according to the cellular origin of the antigen- presenting cells, the nature of the T-cell epitope, and the responding cell. Immunology. 1993;80:566.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Lafyatis R, York M, Marshak-Rothstein A. Antimalarial agents: closing the gate on Toll-like receptors? Arthritis Rheum. 2006;54:3068–70.CrossRefPubMedGoogle Scholar
  32. 32.
    Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, De Ramón E. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2013;74(6):1011–8.CrossRefGoogle Scholar
  33. 33.
    Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R et al., Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th international congress on antiphospholipid antibodies. Lupus. 2011; 20: 206–18.Google Scholar
  34. 34.
    Pengo V, Ruffatti A, Legnani C, Gresele P, Barcellona D, Erba N, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010;8:237–42.CrossRefPubMedGoogle Scholar
  35. 35.
    Jancinova V, Nosal R, Petrikova M. On the inhibitory effect of chloroquine on blood platelet aggregation. Thromb Res. 1994;74:495–504.CrossRefPubMedGoogle Scholar
  36. 36.
    Genton E, Gent M, Hirsh J, Harker LA. Platelet-inhibiting drugs in the prevention of clinical thrombotic disease (third of three parts). N Engl J Med. 1975;293:1296–300.CrossRefPubMedGoogle Scholar
  37. 37.
    Schmidt-Tanguy A, Voswinkel J, Henrion D, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Entela Nuri
    • 1
  • Mara Taraborelli
    • 1
  • Laura Andreoli
    • 1
  • Marta Tonello
    • 2
  • Maria Gerosa
    • 3
    • 4
  • Antonia Calligaro
    • 2
  • Lorenza Maria Argolini
    • 3
    • 4
  • Rajesh Kumar
    • 1
  • Vittorio Pengo
    • 5
  • Pier Luigi Meroni
    • 3
    • 4
    • 6
  • Amelia Ruffatti
    • 2
  • Angela Tincani
    • 1
  1. 1.Rheumatology and Clinical Immunology Unit, ASST Spedali CiviliUniversity of BresciaBresciaItaly
  2. 2.Rheumatology Unit, Department of Medicine - DIMEDUniversity of PaduaPaduaItaly
  3. 3.Division of RheumatologyASST Gaetano PiniMilanItaly
  4. 4.Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly
  5. 5.Department of Cardiac, Thoracic and Vascular SciencesUniversity of PaduaPaduaItaly
  6. 6.IRCSS Istituto Auxologico ItalianoMilanItaly

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