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Update on Antiphospholipid Syndrome: Ten Topics in 2017

  • Ilaria Cavazzana
  • Laura Andreoli
  • Maarteen Limper
  • Franco Franceschini
  • Angela Tincani
Systemic Lupus Erythematosus (G Tsokos, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Systemic Lupus Erythematosus

Abstract

Purpose of Review

This review focuses on new clinical aspects of antiphospholipid syndrome (APS) in the last 5 years.

Recent Findings

The pathogenesis of APS is related to endothelial activation by mechanisms other than autoantibody-mediated massive coagulation. These include Toll-like receptors, the m-TORC pathway, and neutrophil activation, inducing an uncontrolled inflammatory cascade. Given these new pathogenetic hypotheses, the treatment of APS could be directed towards a fine balance between anticoagulation and immunomodulation. A hot topic is how to consider asymptomatic antiphospholipid (aPL) carriers, with or without systemic lupus erythematosus (SLE), during pregnancy, or during their life in general: to treat or not to treat? New findings on long-standing APS, regarding survival, comorbidities, and evolution in other autoimmune conditions, have become available, including new insights into aPL as potential risk factors for damage accrual in SLE and potential implications on neuropsychological involvement of children exposed to maternal aPL in utero.

Summary

This review summarizes recent findings on the management, treatment, and prevention of patients affected by APS or with aPL.

Keywords

Anti-phospholipid antibodies Thrombosis’ pathogenesis Asymptomatic carrier APS treatment Obstetric APS Neuropsychological development 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Allen KL, Fonseca FV, Betapudi V, Willard B, Zhang J, McCrae KR. A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies. Blood. 2012;119:884–93.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Wu M, Barnard J, Kundu S, McCrae KR. A novel pathway of cellular activation mediated by antiphospholipid antibody-induced extracellular vesicles. J Thromb Haemost. 2015;13:1928–40.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Borghi MO, Raschi E, Grossi C, Chighizola CB, Meroni PL. Toll-like receptor 4 and β2 glycoprotein I interaction on endothelial cells. Lupus. 2014 Oct;23(12):1302–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Canaud G, Legendre C, Terzi F. AKT/mTORC pathway in antiphospholipid-related vasculopathy: a new player in the game. Lupus. 2015;24:227–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Pierangeli SS, Colden-Stanfield M, Liu X, Barker JH, Anderson GL, Harris EN. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation. 1999;99:1997–2002.PubMedCrossRefGoogle Scholar
  6. 6.
    Dunoyer-Geindre S, de Moerloose P, Galve-de Rochemonteix B, Reber G, Kruithof EKO. NFκ B is an essential intermediate in the activation of endothelial cells by anti-β2-glycoprotein 1 antibodies. Thromb Haemost. 2002;88:851–7.PubMedCrossRefGoogle Scholar
  7. 7.
    • van den Hoogen LL, Fritsch-Stork RD, Versnel MA, Derksen RH, van Roon JA, Radstake TR. Monocyte type I interferon signature in antiphospholipid syndrome is related to proinflammatory monocyte subsets, hydroxychloroquine and statin use. Ann Rheum Dis. 2016;75:e81. The paper analyzes type I interferon signatures in patients with APS, associated with a deficit of reparative endothelial cell progenitors and endothelial damage. PubMedCrossRefGoogle Scholar
  8. 8.
    Urbanus RT, Derksen RH, de Groot PG. Platelets and the antiphospholipid syndrome. Lupus. 2008;17:888–94.PubMedCrossRefGoogle Scholar
  9. 9.
    • Meng H, Yalavarthi S, Kanthi Y, Mazza LF, Elfine MA, Luke CE, et al. Role of neutrophil extracellular traps in antiphospholipid antibody-mediated venous thrombosis. 2017;Arthritis Rheumatol, 69:655–67. This paper describes the role of activated neutrophils in APs in endothelial dysfunction and pathogenesis of thrombosis, by releasing neutrophil extracellular traps. Google Scholar
  10. 10.
    Yalavarthi S, Gould TJ, Rao AN, Mazza LF, Morris LE, Nunez-Alvarez C, et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 2015;67:2990–3003.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Knight JS, Meng H, Coit P, Yalavarthi S, Sule G, Gandhi AA, et al. Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target. JCI Insight. 2017;21:2(18).Google Scholar
  12. 12.
    Mulla MJ, Brosens JJ, Chamley LW, Giles I, Pericleous C, Rahman A, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol. 2009;62:96–111.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Ulrich V, Gelber SE, Vukelic M, Sacharidou A, Herz J, Urbanus RT, et al. ApoE receptor 2 mediation of trophoblast dysfunction and pregnancy complications induced by antiphospholipid antibodies in mice. Arthritis Rheum. 2016;68:730–9.CrossRefGoogle Scholar
  14. 14.
    Marchetti T, Ruffatti A, Wuillemin C, de Moerloose P, Cohen M. Hydroxychloroquine restores trophoblast fusion affected by antiphospholipid antibodies. J Thromb Haemost. 2014;12:910–20.PubMedCrossRefGoogle Scholar
  15. 15.
    Marder W, Knight JS, Kaplan MJ, Somers EC, Zhang X, O'Dell AA, et al. Placental histology and neutrophil extracellular traps in lupus and pre-eclampsia pregnancies. Lupus Sci Med. 2016;3:e000134.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Girardi G, Berman J, Redecha P, Spruce L, Thurman JM, Kraus D, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112:1644–54.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Abrahams VM, Chamley LW, Salmon JE. Emerging treatment models in rheumatology: antiphospholipid syndrome and pregnancy: pathogenesis to translation. Arthritis Rheum. 2017;69:1710–21.CrossRefGoogle Scholar
  18. 18.
    Bertolaccini ML, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R, et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014;13:917–30.PubMedCrossRefGoogle Scholar
  19. 19.
    Chighizola CB, Gerosa M, Meroni PL. New tests to detect antiphospholipid antibodies: anti-domain I beta-2-glycoprotein-I antibodies. Curr Rheumatol Rep. 2014;16:402.PubMedCrossRefGoogle Scholar
  20. 20.
    Pengo V, Ruffatti A, Tonello M, Cuffaro S, Banzato A, Bison E, et al. Antiphospholipid syndrome: antibodies to domain 1 of beta2-glycoprotein 1 correctly classify patients at risk. J Thromb Haemost. 2015;13:782–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Meneghel L, Ruffatti A, Gavasso S, Tonello M, Mattia E, Spiezia L, et al. Detection of IgG anti-domain I beta2 glycoprotein I antibodies by chemiluminescence immunoassay in primary antiphospholipid syndrome. Clin Chim Acta. 2015;446:201–5.PubMedCrossRefGoogle Scholar
  22. 22.
    De Craemer AS, Musial J, Devreese KM. Role of anti-domain 1-beta2 glycoprotein I antibodies in the diagnosis and risk stratification of antiphospholipid syndrome. J Thromb Haemost. 2016;14:1779–87.PubMedCrossRefGoogle Scholar
  23. 23.
    Andreoli L, Chighizola CB, Nalli C, Gerosa M, Borghi MO, Pregnolato F, et al. Clinical characterization of antiphospholipid syndrome by detection of IgG antibodies against beta-glycoprotein I domain 1 and domain 4/5: ratio of anti-domain 1 to anti-domain 4/5 as a useful new biomarker for antiphospholipid syndrome. Arthritis Rheum. 2015;67:2196–204.CrossRefGoogle Scholar
  24. 24.
    Mondejar R, Gonzalez-Rodriguez C, Toyos-Saenz de Miera FJ, Melguizo-Madrid E, Zohoury N, Mahler M, et al. Role of antiphospholipid score and anti-beta2-glycoprotein I domain I autoantibodies in the diagnosis of antiphospholipid syndrome. Clin Chim Acta. 2014;431:174–8.PubMedCrossRefGoogle Scholar
  25. 25.
    •• Radin M, Cecchi I, Roccatello D, Meroni PL, Sciascia S. Prevalence and thrombotic risk assessment of anti-beta2 glycoprotein I domain I antibodies: a systematic review. Seminars in thrombosis and hemostasis. 2017;  https://doi.org/10.1055/s-0037-1603936. This review estimates the prevalence of anti-beta-2-GPI-domain I in patients with APS (analyzing 11 studies and 1585 patients), in order to determine whether anti--beta-2-GPI-domain I-positive individuals are at greater risk of thrombosis.
  26. 26.
    Mahler M, Albesa R, Zohoury N, Bertolaccini ML, Ateka-Barrutia O, Rodriguez-Garcia JL, et al. Autoantibodies to domain 1 of beta 2 glycoprotein I determined using a novel chemiluminescence immunoassay demonstrate association with thrombosis in patients with antiphospholipid syndrome. Lupus. 2016;25:911–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Iwaniec T, Kaczor MP, Celinska-Lowenhoff M, Polanski S, Musial J. Clinical significance of anti-domain 1 beta2-glycoprotein I antibodies in antiphospholipid syndrome. Thromb Res. 2017;153:90–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Meneghel L, Ruffatti A, Gavasso S, Tonello M, Mattia E, Spiezia L, et al. The clinical performance of a chemiluminescent immunoassay in detecting anti-cardiolipin and anti-beta2 glycoprotein I antibodies. A comparison with a homemade ELISA method. Clin Chem Lab Med. 2015;53:1083–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Mattia E, Ruffatti A, Meneghel L, Tonello M, Faggian D, Hoxha A, et al. A contribution to detection of anticardiolipin and anti-beta2glycoprotein I antibodies: comparison between a home-made ELISA and a fluorescence enzyme immunoassay. Clinica Chimica Acta; Int J Clin Chem. 2015;446:93–6.CrossRefGoogle Scholar
  30. 30.
    Devreese KM, Poncet A, Lindhoff-Last E, Musial J, de Moerloose P, Fontana P. A multicenter study to assess the reproducibility of antiphospholipid antibody results produced by an automated system. J Thromb Haemost. 2017;15:91–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Janek D, Slavik L, Ulehlova J, Krcova V, Hlusi A, Prochazkova J. Validation of a new panel of automated chemiluminescence assays for anticardiolipin antibodies in the screening for antiphospholipid syndrome. Clin Lab. 2016;62:1309–15.PubMedCrossRefGoogle Scholar
  32. 32.
    Lakos G, Favaloro EJ, Harris EN, Meroni PL, Tincani A, Wong RC, et al. International consensus guidelines on anticardiolipin and anti-beta2-glycoprotein I testing: report from the 13th International Congress on antiphospholipid antibodies. Arthritis Rheum. 2012;64:1–10.PubMedCrossRefGoogle Scholar
  33. 33.
    Iverson GM, Reddel S, Victoria EJ, Cockerill KA, Wang YX, Marti-Renom MA, et al. Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies. J Immunol. 2002;169:7097–103.PubMedCrossRefGoogle Scholar
  34. 34.
    Shoenfeld Y, Krause I, Kvapil F, Sulkes J, Lev S, von Landenberg P, et al. Prevalence and clinical correlations of antibodies against six beta2-glycoprotein-I-related peptides in the antiphospholipid syndrome. J Clin Immunol. 2003;23:377–83.PubMedCrossRefGoogle Scholar
  35. 35.
    de Laat B, Derksen RH, Urbanus RT, de Groot PG. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta 2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. Blood. 2005;105:1540–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Ioannou Y, Pericleous C, Giles I, Latchman DS, Isenberg DA, Rahman A. Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human beta(2)-glycoprotein I: mutation studies including residues R39 to R43. Arthritis Rheum. 2007;56:280–90.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Pozzi N, Banzato A, Bettin S, Bison E, Pengo V, De Filippis V. Chemical synthesis and characterization of wild-type and biotinylated N-terminal domain 1-64 of beta2-glycoprotein I. Protein Sci: a Publication Protein Soc. 2010;19:1065–78.CrossRefGoogle Scholar
  38. 38.
    Banzato A, Pozzi N, Frasson R, De Filippis V, Ruffatti A, Bison E, et al. Antibodies to domain I of beta(2)glycoprotein I are in close relation to patients risk categories in antiphospholipid syndrome (APS). Thromb Res. 2011;128:583–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Mahler M, Norman GL, Meroni PL, Khamashta M. Autoantibodies to domain 1 of beta 2 glycoprotein 1: a promising candidate biomarker for risk management in antiphospholipid syndrome. Autoimmun Rev. 2012;12:313–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Roggenbuck D, Borghi MO, Somma V, Büttner T, Schierack P, Hanack K, et al. Antiphospholipid antibodies detected by line immunoassay differentiate among patients with antiphospholipid syndrome, with infections and asymptomatic carriers. Arthritis Res Ther. 2016;18:111.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Roggenbuck D, Somma V, Schierack P, Borghi MO, Meroni PL. Autoantibody profiling in APS. Lupus. 2014;23:1262–4.PubMedCrossRefGoogle Scholar
  42. 42.
    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.PubMedCrossRefGoogle Scholar
  43. 43.
    Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum. 2007;57:1487–95.PubMedCrossRefGoogle Scholar
  44. 44.
    Erkan D, Patel S, Nuzzo M, Gerosa M, Meroni PL, Tincani A, et al. Management of the controversial aspects of the antiphospholipid syndrome pregnancies: a guide for clinicians and researchers. Rheumatology (Oxford). 2008;47(Suppl 3):iii23–7.Google Scholar
  45. 45.
    Tincani A, Branch W, Levy RA, Piette JC, Carp H, Rai RS, et al. Treatment of pregnant patients with antiphospholipid syndrome. Lupus. 2003;12:524–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Østensen M, Khamashta M, Lockshin M, Parke A, Brucato A, Carp H, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther. 2006;8:209.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ceccarelli F, Chighizola C, Finazzi G, Meroni PL, Valesini G. Thromboprophylaxis in carriers of antiphospholipid antibodies (APL) without previous thrombosis: “pros” and “cons”. Autoimmun Rev. 2012;11:568–71.PubMedCrossRefGoogle Scholar
  48. 48.
    Reggia R, Andreoli L, Tincani A, Shoenfeld Y. Current treatment strategies for management of antiphospholipid syndrome. Expert Opin Orphan Drugs. 2014;2:1–11.Google Scholar
  49. 49.
    Erkan D, Harrison MJ, Levy R, Peterson M, Petri M, Sammaritano L, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum. 2007;56:2382–91.PubMedCrossRefGoogle Scholar
  50. 50.
    • Erkan D, Unlu O, Sciascia S, Belmont HM, Branch DW, Cuadrado MJ, et al. Hydroxychloroquine in the primary thrombosis prophylaxis of antiphospholipid antibody positive patients without systemic autoimmune disease. Lupus. 2017, 1:961203317724219.  https://doi.org/10.1177/0961203317724219. This is a randomized clinical trial focused on the efficacy of hydroxychloroquine in the primary thrombosis prevention of antiphospholipid antibody (aPL)-positive patients with no other systemic autoimmune diseases.
  51. 51.
    • Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65:17–24. This study shows a strong reduction in aPL titers and a decrease in the incidence of arterial thrombosis recurrence in PAPS patients treated with HCQ. PubMedCrossRefGoogle Scholar
  52. 52.
    Kahlenberg JM, Kaplan MJ. The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus. Arthritis Res Ther. 2011;13:203.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69:20–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Wahl DG, Bounameaux H, de Moerloose P, Sarasin FP. Prophylactic antithrombotic therapy for patients with or without antiphospholipid antibodies: do the benefit outweigh the risk? A decision analysis. Arch Intern Med. 2000;160:2042–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Reduction in C-reactive proteinand LDL cholesterol and cardiovascularevent rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Jajoria P, Murthy V, Papalardo E, Romay-Penabad Z, Gleason C, Pierangeli SS. Statins for the treatment of antiphospholipid syndrome? Ann N Y Acad Sci. 2009;1173:736–45.PubMedCrossRefGoogle Scholar
  57. 57.
    Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, et al. Vitamin D: an instrumental factor in the antiphospholipid syndrome by inhibition of tissue factor expression. Ann Rheum Dis. 2011;70:145–50.PubMedCrossRefGoogle Scholar
  58. 58.
    Piantoni S, Andreoli L, Allegri F, Meroni PL, Tincani A. Low levels of vitamin D are common in primary antiphospholipid syndrome with thrombotic disease. Reumatismo. 2012;64:307–13.PubMedCrossRefGoogle Scholar
  59. 59.
    Soh MC, Pasupathy D, Gray G, Nelson-Piercy C. Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes. Rheumatology. 2013;52:1642–7.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette J-C, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: re-port of an international workshop. Arthritis Rheum. 1999;42:1309–11.PubMedCrossRefGoogle Scholar
  61. 61.
    Fishman P, Falach-Vaknine E, Zigelman R, Bakimer R, Sredni B, Djaldetti M, et al. Prevention of fetal loss in experimental antiphospholipid syndrome by in vivo administration of recombinant interleukin-3. J Clin Invest. 1993;91:1834–7.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Atallah A, Lecarpentier E, Goffinet F, Doret-Dion M, Gaucherand P, Tsatsaris V. Aspirin for prevention of preeclampsia. Drugs. 2017 Oct 16;  https://doi.org/10.1007/s40265-017-0823-0.
  63. 63.
    • Pengo V, Banzato A, Bison E, Zoppellaro G, Padayattil Jose S, Denas G. Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial. Lupus. 2016;25:301–6. This is a multicenter, randomized, open-label trial evaluating rivaroxaban versus warfarin for the prevention of thromboembolic events, major bleeding and death in triple-positive patients with antiphospholipid syndrome. PubMedCrossRefGoogle Scholar
  64. 64.
    Broder A, Putterman C. Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus. J Rheumatol. 2013;40:30–3.PubMedCrossRefGoogle Scholar
  65. 65.
    Krause I, Blank M, Kopolovic J, Afek A, Goldberg I, Tomer Y, et al. Abrogation of experimental systemic lupus erythematosus and primary antiphospholipid syndrome with intravenous gamma globulin. J Rheumatol. 1995;22:1068–74.PubMedGoogle Scholar
  66. 66.
    Tenti S, Guidelli GM, Bellisai F, Galeazzi M, Fioravanti A. Long-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy. Clin Exp Rheumatol. 2013;31:877–82.PubMedGoogle Scholar
  67. 67.
    Emmi G, Urban ML, Scalera A, Becatti M, Fiorillo C, Silvestri E, et al. Repeated low-dose courses of rituximab in SLE-associated antiphospholipid syndrome: data from a tertiary dedicated centre. Semin Arthritis Rheum. 2017;46:e21–3.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang CR, Liu MF. Rituximab usage in systemic lupus erythematosus-associated antiphospholipid syndrome: a single-center experience. Semin Arthritis Rheum. 2016;46:102–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Erkan D, Vega J, Ramón G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013;65:464–71.PubMedCrossRefGoogle Scholar
  70. 70.
    • Leone A, Radin M, Almarzooqi AM, Al-Saleh J, Roccatello D, Sciascia S, et al. Autologous hematopoietic stem cell transplantation in Systemic Lupus Erythematosus and antiphospholipid syndrome: A systematic review. Autoimmun Rev. 2017;16:469–77. This review considered 25 studies (including 279 SLE patients and 54 cases with APS) analyzing the efficacy of HSCT: aPL negativization was reported in 9% in the APS patients and 73% of APS were able to discontinue anticoagulation after HSC. PubMedCrossRefGoogle Scholar
  71. 71.
    Hadaya K, Ferrari-Lacraz S, Fumeaux D, Boehlen F, Toso C, Moll S, et al. Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation. Am J Transplant. 2011;11:2523–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Kronbichler A, Frank R, Kirschfink M, Szilágyi Á, Csuka D, Prohászka Z, et al. Efficacy of eculizumab in a patient with immunoadsorption-dependent catastrophic antiphospholipid syndrome: a case report. Medicine (Baltimore). 2014;93:e143.CrossRefGoogle Scholar
  73. 73.
    de Holanda MI, Pôrto LC, Wagner T, Christiani LF, Palma LMP. Use of eculizumab in a systemic lupus erythemathosus patient presenting thrombotic microangiopathy and heterozygous deletion in CFHR1-CFHR3. A case report and systematic review. Clin Rheumatol. 2017;  https://doi.org/10.1007/s10067-017-3823-2.
  74. 74.
    Zhou H, Sheng L, Wang H, Xie H, Mu Y, Wang T, et al. Anti-β2GPI/β2GPI stimulates activation of THP-1 cells through TLR4/MD-2/MyD88 and NF-κB signaling pathways. Thromb Res. 2013;132:742–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Hamid C, Norgate K, D'Cruz DP, Khamashta MA, Arno M, Pearson JD, et al. Anti-beta2GPI-antibody-induced endothelial cell gene expression profiling reveals induction of novel pro-inflammatory genes potentially involved in primary antiphospholipid syndrome. Ann Rheum Dis. 2007;66:1000–7.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Xia L, Zhou H, Hu L, Xie H, Wang T, Xu Y, et al. Both NF-κB and c-Jun/AP-1 involved in anti-β2GPI/β2GPI-induced tissue factor expression in monocytes. Thromb Haemost. 2013;109:643–51.PubMedCrossRefGoogle Scholar
  77. 77.
    Zhou H, Chen D, Xie H, Xia L, Wang T, Yuan W, et al. Activation of MAPKs in the anti-β2GPI/β2GPI-induced tissue factor expression through TLR4/IRAKs pathway in THP-1 cells. Thromb Res. 2012;130:e229–35.PubMedCrossRefGoogle Scholar
  78. 78.
    Xia L, Zhou H, Wang T, Xie Y, Wang T, Wang X, et al. Activation of mTOR is involved in anti-β2GPI/β2GPI-induced expression of tissue factor and IL-8 in monocytes. Thromb Res. 2017;157:103–10.PubMedCrossRefGoogle Scholar
  79. 79.
    Mak A, Cheung MW, Cheak AA, Ho RC. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford, England). 2010;49:281–8.CrossRefGoogle Scholar
  80. 80.
    Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010;115:1256–62.PubMedCrossRefGoogle Scholar
  81. 81.
    de Jesus GR, Agmon-Levin N, Andrade CA, Andreoli L, Chighizola CB, Porter TF, et al. 14th International Congress on Antiphospholipid Antibodies Task Force report on obstetric antiphospholipid syndrome. Autoimmun Rev. 2014;13:795–813.PubMedCrossRefGoogle Scholar
  82. 82.
    •• Andreoli L, Bertsias GK, Agmon-Levin N, Brown S, Cervera R, Costedoat-Chalumeau N, et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis. 2017;76:476–85. Recent European recommendations as guidelines for rheumatologists and gynecologists. PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Bramham K, Thomas M, Nelson-Piercy C, Khamashta M, Hunt J. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117:6948–51.PubMedCrossRefGoogle Scholar
  84. 84.
    Ruffatti A, Salvan E, Del Ross T, Gerosa M, Andreoli L, Maina A, et al. Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity. A European multicentre retrospective study. Thromb Haemost. 2014;112:727–35.PubMedCrossRefGoogle Scholar
  85. 85.
    Ruffatti A, Hoxha A, Favaro M, Tonello M, Colpo A, Cucchini U, et al. Additional treatments for high-risk obstetric antiphospholipid syndrome: a comprehensive review. Clin Rev Allergy Immunol. 2017;5:28–39.CrossRefGoogle Scholar
  86. 86.
    Albert CR, Schlesinger WJ, Viall CA, Mulla MJ, Brosens JJ, Chamley LW, et al. Effect of hydroxychloroquine on antiphospholipid antibody-induced changes in first trimester trophoblast function. Am J Reprod Immunol (New York, NY : 1989). 2014;71:154–64.CrossRefGoogle Scholar
  87. 87.
    Bertolaccini ML, Contento G, Lennen R, Sanna G, Blower PJ, Ma MT, et al. Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome. J Autoimmun. 2016;75:30–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Meroni PL. Prevention & treatment of obstetrical complications in APS: is hydroxychloroquine the holy grail we are looking for? J Autoimmun. 2016;75:1–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Mekinian A, Lazzaroni MG, Kuzenko A, Alijotas-Reig J, Ruffatti A, Levy P, et al. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: data from a European multicenter retrospective study. Autoimmun Rev. 2015;14:498–502.PubMedCrossRefGoogle Scholar
  90. 90.
    Sciascia S, Branch DW, Levy RA, Middeldorp S, Pavord S, Roccatello D, et al. The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment. Thromb Haemost. 2016;115:285–90.PubMedCrossRefGoogle Scholar
  91. 91.
    Mekinian A, Alijotas-Reig J, Carrat F, Costedoat-Chalumeau N, Ruffatti A, Lazzaroni MG, et al. Refractory obstetrical antiphospholipid syndrome: features, treatment and outcome in a European multicenter retrospective study. Autoimmun Rev. 2017;16:730–4.PubMedCrossRefGoogle Scholar
  92. 92.
    Schreiber K, Breen K, Cohen H, Jacobsen S, Middeldorp S, Pavord S, et al. HYdroxychloroquine to Improve Pregnancy Outcome in Women with AnTIphospholipid Antibodies (HYPATIA) protocol: a multinational randomized controlled trial of hydroxychloroquine versus placebo in addition to standard treatment in pregnant women with antiphospholipid syndrome or antibodies. Semin Thromb Hemost. 2017;43:562–71.PubMedCrossRefGoogle Scholar
  93. 93.
    Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75:795–810.PubMedCrossRefGoogle Scholar
  94. 94.
    Lefkou E, Mamopoulos A, Dagklis T, Vosnakis C, Rousso D, Girardi G. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J Clin Invest. 2016;126:2933–40.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Gelber SE, Brent E, Redecha P, Perino G, Tomlinson S, Davisson RL, et al. Prevention of defective placentation and pregnancy loss by blocking innate immune pathways in a syngeneic model of placental insufficiency. J Immunol (Baltimore, Md : 1950). 2015;195:1129–38.CrossRefGoogle Scholar
  96. 96.
    Gustavsen A, Skattum L, Bergseth G, Lorentzen B, Floisand Y, Bosnes V, et al. Effect on mother and child of eculizumab given before caesarean section in a patient with severe antiphospholipid syndrome: a case report. Medicine. 2017;96:e6338.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kelly RJ, Hochsmann B, Szer J, Kulasekararaj A, de Guibert S, Roth A, et al. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015;373:1032–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Di Simone N, D'Ippolito S, Marana R, Di Nicuolo F, Castellani R, Pierangeli SS, et al. Antiphospholipid antibodies affect human endometrial angiogenesis: protective effect of a synthetic peptide (TIFI) mimicking the phospholipid binding site of beta(2) glycoprotein I. Am J Reprod Immunol (New York, NY : 1989). 2013;70:299–308.CrossRefGoogle Scholar
  99. 99.
    Agostinis C, Durigutto P, Sblattero D, Borghi MO, Grossi C, Guida F, et al. A non-complement-fixing antibody to beta2 glycoprotein I as a novel therapy for antiphospholipid syndrome. Blood. 2014;123:3478–87.PubMedCrossRefGoogle Scholar
  100. 100.
    Mineo C, Lanier L, Jung E, Sengupta S, Ulrich V, Sacharidou A, et al. Identification of a monoclonal antibody that attenuates antiphospholipid syndrome-related pregnancy complications and thrombosis. PLoS One. 2016;11:e0158757.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Zandman-Goddard G, Pierangeli SS, Gertel S, Blank M. Tolerogenic dendritic cells specific for beta2-glycoprotein-I domain-I, attenuate experimental antiphospholipid syndrome. J Autoimmun. 2014;54:72–80.PubMedCrossRefGoogle Scholar
  102. 102.
    Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G, Mercier E, Marchetti T, Balducchi JP, et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood. 2014;123:404–13.PubMedCrossRefGoogle Scholar
  103. 103.
    Jeremic K, Stefanovic A, Dotlic J, Stojnic J, Kadija S, Vilendecic Z, et al. Neonatal outcome in pregnant patients with antiphospholipid syndrome. J Perinat Med. 2015;43:761–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Giron-Gonzalez JA, Garcia del Rio E, Rodriguez C, Rodriguez-Martorell J, Serrano A. Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404 individuals. J Rheumatol 2004;31:1560–1567.Google Scholar
  105. 105.
    Bramham K, Hunt BJ, Germain S, Calatayud I, Khamashta M, Bewley S, et al. Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus. 2010;19:58–64.PubMedCrossRefGoogle Scholar
  106. 106.
    Ruffatti A, Tonello M, Visentin MS, Bontadi A, Hoxha A, De Carolis S, et al. Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study. Rheumatology (Oxford, England). 2011;50:1684–9.CrossRefGoogle Scholar
  107. 107.
    Fischer-Betz R, Specker C, Brinks R, Schneider M. Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischaemic events: an observational study. Lupus. 2012;21:1183–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Danowski A, de Azevedo MN, de Souza Papi JA, Petri M. Determinants of risk for venous and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid syndrome with systemic lupus erythematosus. J Rheumatol. 2009;36:1195–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Lockshin MD, Kim M, Laskin CA, Guerra M, Branch DW, Merrill J, et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum. 2012;64:2311–8.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Yelnik CM, Laskin CA, Porter TF, Branch DW, Buyon JP, Guerra MM, et al. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results. Lupus Sci Med. 2016;3:e000131.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Saccone G, Berghella V, Maruotti GM, Ghi T, Rizzo G, Simonazzi G, et al. Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the PREGNANTS study. Am J Obstet Gynecol. 2017;216:525.e1-.e12.Google Scholar
  112. 112.
    Simchen MJ, Dulitzki M, Rofe G, Shani H, Langevitz P, Schiff E, et al. High positive antibody titers and adverse pregnancy outcome in women with antiphospholipid syndrome. Acta Obstet Gynecol Scand. 2011;90:1428–33.PubMedCrossRefGoogle Scholar
  113. 113.
    Matsuki Y, Atsumi T, Yamaguchi K, Hisano M, Arata N, Oku K, et al. Clinical features and pregnancy outcome in antiphospholipid syndrome patients with history of severe pregnancy complications. Mod Rheumatol / Jpn Rheum Assoc. 2015;25:215–8.CrossRefGoogle Scholar
  114. 114.
    • Rodríguez-Pintó I, Moitinho M, Santacreu I, Shoenfeld Y, Erkan D, Espinosa G, et al. Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of 500 patients from the International CAPS Registry. Autoimmun Rev. 2016;15:1120–4. Multicenter registry on 500 APS patients encountering 522 CAPS episodes: triggers, clinical presentation and mortality rate. PubMedCrossRefGoogle Scholar
  115. 115.
    Asherson RA, Cervera R, Piette JC, Shoenfeld Y, Espinosa G, Petri MA, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore). 2001;80:355–77.CrossRefGoogle Scholar
  116. 116.
    Bucciarelli S, Espinosa G, Cervera R, Erkan D, Gómez-Puerta JA, Ramos-Casals M, et al. European Forum on Antiphospholipid Antibodies. Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum. 2006;54:2568–76.PubMedCrossRefGoogle Scholar
  117. 117.
    Cervera R. 8th international congress on autoimmunity: new perspectives for refractory catastrophic antiphospholipid syndrome. Expert Rev Clin Immunol. 2012;8:617–9.PubMedCrossRefGoogle Scholar
  118. 118.
    Bayraktar UD, Erkan D, Bucciarelli S, Espinosa G, Asherson R. Catastrophic Antiphospholipid Syndrome Project Group. The clinical spectrum of catastrophic antiphospholipid syndrome in the absence and presence of lupus. J Rheumatol. 2007;34:346–52.PubMedGoogle Scholar
  119. 119.
    Berman H, Rodríguez-Pintó I, Cervera R, Morel N, Costedoat-Chalumeau N, Erkan D, et al. Catastrophic Antiphospholipid Syndrome (CAPS) Registry Project Group (European Forum on Antiphospholipid Antibodies). Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev. 2013;12:1085–90.PubMedCrossRefGoogle Scholar
  120. 120.
    Rodríguez-Pintó I, Cervera R, Espinosa G. Rituximab and its therapeutic potential in catastrophic antiphospolipid syndrome. Ther Adv Musculoskelet Dis. 2015;7:26–30.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Sukara G, Baresic M, Sentic M, Brcic L, Anic B. Catastrophic antiphospholipid syndrome associated with systemic lupus erythematosus treated with rituximab: case report and a review of the literature. Acta Reumatol Port. 2015;40:169–75.PubMedGoogle Scholar
  122. 122.
    Rand JH, Wu XX, Wolgast LR, Lei V, Conway EM. A novel 2-stage approach that detects complement activation in patients with antiphospholipid antibody syndrome. Thromb Res. 2017;156:119–25.PubMedCrossRefGoogle Scholar
  123. 123.
    Oku K, Amengual O, Hisada R, Ohmura K, Nakagawa I, Watanabe T, et al. Autoantibodies against a complement component 1 q subcomponent contribute to complement activation and recurrent thrombosis/pregnancy morbidity in anti-phospholipid syndrome. Rheumatology (Oxford). 2016;55:1403–11.CrossRefGoogle Scholar
  124. 124.
    Grosso G, Vikerfors A, Woodhams B, Adam M, Bremme K, Holmström M, et al. Thrombin activatable fibrinolysis inhibitor (TAFI)—a possible link between coagulation and complement activation in the antiphospholipid syndrome (APS). Thromb Res 2017 24. pii: S0049–3848(17)30392–4.Google Scholar
  125. 125.
    Shapira I, Andrade D, Allen SL, Salmon JE. Brief report: induction of sustained remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum. 2012;64:2719–23.PubMedCrossRefGoogle Scholar
  126. 126.
    Owaidah TM, Maghrabi K, Elkarouri MA, Al Mohareeb F, Al Harthi A, Al ZH. Successful treatment of a case of catastrophic antiphospholipid syndrome with autologous BMT: case report and review of literature. Bone Marrow Transplant. 2011;46:597–600.PubMedCrossRefGoogle Scholar
  127. 127.
    Oka S, Ono K, Nohgawa M. Successful treatment of catastrophic antiphospholipid antibody syndrome associated with MALT lymphoma by autologous hematopoietic stem cell transplantation. Intern Med. 2017;56:1207–12.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Eyraud A, Scouppe L, Barnetche T, Forcade E, Lazaro E, Duffau P, et al. Efficacy and safety of autologous haematopoietic stem cell transplantation in systemic sclerosis: a systematic review of literature. Br J Dermatol. 2017;14  https://doi.org/10.1111/bjd.15993.
  129. 129.
    Grika EP, Ziakas PD, Zintzaras E, Moutsopoulos HM, Vlachoyiannopoulos PG. Morbidity, mortality, and organ damage in patients with antiphospholipid syndrome. J Rheumatol. 2012;39:516–23.PubMedCrossRefGoogle Scholar
  130. 130.
    Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74:1011–8.PubMedCrossRefGoogle Scholar
  131. 131.
    • Taraborelli M, Reggia R, Dall'Ara F, Fredi M, Andreoli L, Gerosa M, et al. Longterm outcome of patients with primary antiphospholipid syndrome: a retrospective multicenter study. J Rheumatol. 2017;44:1165–72. Multicenter retrospective study with 115 APS patients with follow-up more than 18 years: clinical features, treatment and evolution. PubMedCrossRefGoogle Scholar
  132. 132.
    Hernandez-Molina G, Espericueta-Arriola G, Cabral AR. The role of lupus anticoagulant and triple marker positivity as risk factors for rethrombosis in patients with primary antiphospholipid syndrome. Clin Exp Rheumatol. 2013;31:382–8.PubMedGoogle Scholar
  133. 133.
    Bazzan M, Vaccarino A, Stella S, Sciascia S, Montaruli B, Bertero MT, et al. Patients with antiphosholipid syndrome and thrombotic recurrences: a real world observation (the Piedmont cohort study). Lupus. 2016;25:479–85.PubMedCrossRefGoogle Scholar
  134. 134.
    Ruiz-Irastorza G, Egurbide MV, Ugalde J, et al. High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus. Arch Intern Med. 2004;164:77–82.PubMedCrossRefGoogle Scholar
  135. 135.
    Petri M, Purvey S, Fang H, Magder LS. Predictors of organ damage in systemic lupus erythematosus: the Hopkins lupus cohort. Arthritis Rheumatism. 2012;64:4021–8.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Ruiz-Irastorza G, Egurbide MV, Martinez-Berriotxoa A, Ugalde J, Aguirre C. Antiphospholipid antibodies predict damage in patients with systemic lupus erythematosus. Lupus. 2004;13:900–5.PubMedCrossRefGoogle Scholar
  137. 137.
    Gladmann DD, Urowitz MB, Rahaman P, Ibanez D, Tam LS. Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol. 2003;30:1955–9.Google Scholar
  138. 138.
    Chambers SA, Allen E, Rahman A, Isenberg D. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford). 2009;48:673–5.CrossRefGoogle Scholar
  139. 139.
    Estevez del Toro M, Chico Capote A, Hechavarria R, Jiménez Paneque R, Kokuina E. Damage in cuban patients with systemic lupus erythematosus. Relation with disease features. Rheumatol Clin. 2010;6:11–5.Google Scholar
  140. 140.
    Becker-Merok A, Nossent HC. Damage accumulation in systemic lupus erythematosus and its relation to disease activity and mortality. J Rheumatol. 2006;33:1570–7.PubMedGoogle Scholar
  141. 141.
    Nossent J, Kiss E, Rozman B, Pokorny G, Vlachoyiannopoulos P, Olesinska M, et al. Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus. Lupus. 2010;19:949–56.PubMedCrossRefGoogle Scholar
  142. 142.
    Alarcon GS, McGwin G Jr, Bastian HM, Roseman J, Lisse J, Fessler BJ, et al. Systemic lupus erythematosus in three ethnic groups. VII. Predictors of early mortality in LUMINA cohort. LUMINA study group. Arthritis Rheum. 2001;45:191–202.PubMedCrossRefGoogle Scholar
  143. 143.
    Yee CS, Hussein H, Skan J, Bowman S, Situnayake D, Gordon C. Association of damage with autoantibody profile, age, race, sex and disease duration in systemic lupus erythematosus. Rheumatology. 2003;42:276–9.PubMedCrossRefGoogle Scholar
  144. 144.
    Mok CC, Ho CT, Wong RW, Lau CS. Damage accrual in southern Chinese patients with systemic lupus erythematosus. J Rheumatol. 2003;30:1513–9.PubMedGoogle Scholar
  145. 145.
    Bruce IN, O'Kneeffe AG, Farewell V, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. Ann Rheum Dis. 2015;74:1706–13.PubMedCrossRefGoogle Scholar
  146. 146.
    • Taraborelli M, Leuenberger L, Lazzaroni MG, Martinazzi N, Zhang W, Franceschini F, et al. The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus. Lupus. 2016;25:1365–8. The paper analyses whether a clinically significant aPL profile is associated with an increased risk of organ damage accrual during a 15-year follow-up in a cohort of 262 SLE. PubMedCrossRefGoogle Scholar
  147. 147.
    Conti F, Ceccarelli F, Perricone C, Leccese I, Massaro L, Pacucci VA, et al. The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: results from a monocentric cohort. Lupus. 2016;25:719–26.PubMedCrossRefGoogle Scholar
  148. 148.
    Taraborelli M, Cavazzana I, Martinazzi N, Lazzaroni MG, Fredi M, Andreoli L, et al. Organ damage accrual and distribution in systemic lupus erythematosus patients followed-up for more than 10 years. Lupus. 2017;26:1197–204.PubMedCrossRefGoogle Scholar
  149. 149.
    Muscal E, Brey RL. Antiphospholipid syndrome and the brain in pediatric and adult patients. Lupus. 2010;19:406–11.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Meroni PL, Raschi E, Testoni C, Borghi MO. Endothelial cell activation by antiphospholipid antibodies. Clin Immunol Orl Fla. 2004;112:169–74.CrossRefGoogle Scholar
  151. 151.
    Branch DW, Dudley DJ, Mitchell MD, Creighton KA, Abbott TM, Hammond EH, et al. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am J Obstet Gynecol. 1990;163:210–6.PubMedCrossRefGoogle Scholar
  152. 152.
    Cederholm A, Svenungsson E, Jensen-Urstad K, Trollmo C, Ulfgren AK, Swedenborg J, et al. Decreased binding of annexin v to endothelial cells: a potential mechanism in atherothrombosis of patients with systemic lupus erythematosus. Arteriosclr Thromb Vasc Biol. 2005;25:198–203.Google Scholar
  153. 153.
    Pierangeli SS, Gharavi AE, Harris EN. Experimental thrombosis and antiphospholipid antibodies: new insights. J Autoimmun. 2000;15:41–7.CrossRefGoogle Scholar
  154. 154.
    Jankowski M, Vreys I, Wittevrongel C, Boon D, Vermylen J, Hoylaerts MF, et al. Thrombogenicity of beta2glycoproteinI-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. Blood. 2003;101:157–62.PubMedCrossRefGoogle Scholar
  155. 155.
    Motta M, Chirico G, Rebaioli CB, Faden D, Lojacono A, Allegri F, et al. Anticardiolipin and anti-beta2 glycoprotein I antibodies in infants born to mothers with antiphospholipid antibody-positive autoimmune disease: a follow-up study. Am J Perinatol. 2006;23:247–51.PubMedCrossRefGoogle Scholar
  156. 156.
    Peixoto MV, de Carvalho JF, Rodrigues CE. Clinical, laboratory, and therapeutic analyses of 21 patients with neonatal thrombosis and antiphospholipid antibodies: a literature review. J Immunol Res. 2014;2014:672603.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Frauenknecht K, Katzav A, Weiss Lavi R, Sabag A, Otten S, Chapman J, et al. Mice with experimental antiphospholipid syndrome display hippocampal dysfunction and a reduction of dendritic complexity in hippocampal CA1 neurones. Neuropathol Appl Neurobiol. 2015;41:657–71.PubMedCrossRefGoogle Scholar
  158. 158.
    Ross G, Sammaritano L, Nass R, Lockshin M. Effects of mothers' autoimmune disease during pregnancy on learning disabilities and hand preference in their children. Arch Pediatri Adolesc Med. 2003;157(4):397–402.CrossRefGoogle Scholar
  159. 159.
    Neri F, Chimini L, Bonomi F, Filippini E, Motta M, Faden D, et al. Neuropsychological development of children born to patients with systemic lupus erythematosus. Lupus. 2004;13:805–11.PubMedCrossRefGoogle Scholar
  160. 160.
    Nacinovich R, Galli J, Bomba M, Filippini E, Parrinello G, Nuzzo M, et al. Neuropsychological development of children born to patients with antiphospholipid syndrome. Arthritis Rheum. 2008;59:345–51.PubMedCrossRefGoogle Scholar
  161. 161.
    Bomba M, Galli J, Nacinovich R, Ceribelli A, Motta M, Lojacono A, et al. Neuropsychiatric aid in children born to patients with rheumatic diseases. Clin Exp Rheumatol. 2010;28:767–73.PubMedGoogle Scholar
  162. 162.
    Marder W, Romero VC, Ganser MA, Hyzy MA, Gordon C, McCune WJ, et al. Increased usage of special educational services by children born to mothers with systemic lupus erythematosus and antiphospholipid antibodies. Lupus Sci Med. 2014;1:e000034.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Yousef Yengej FA, van Royen-Kerkhof A, Derksen R, Fritsch-Stork RDE. The development of offspring from mothers with systemic lupus erythematosus. A systematic review. Autoimmun Rev. 2017;16:701–11.PubMedCrossRefGoogle Scholar
  164. 164.
    Mekinian A, Lachassinne E, Nicaise-Roland P, Carbillon L, Motta M, Vicaut E, et al. European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis. 2013;72:217–22.PubMedCrossRefGoogle Scholar
  165. 165.
    Nalli C, Iodice A, Andreoli L, Galli J, Lojacono A, Motta M, et al. Long-term neurodevelopmental outcome of children born to prospectively followed pregnancies of women with systemic lupus erythematosus and/or antiphospholipid syndrome. Lupus. 2017;26:552–8.PubMedCrossRefGoogle Scholar
  166. 166.
    •• Groot N, de Graeff N, Avcin T, Bader-Meunier B, Dolezalova P, Feldman B, et al. European evidence-based recommendations for diagnosis and treatment of paediatric antiphospholipid syndrome: the SHARE initiative. Ann Rheum Dis. 2017;76:1637–41. The SHARE initiative was launched to develop diagnostic and management regimens for children and young adults with rheumatic diseases. This paper shows the evidence-based recommendations for diagnosis and treatment of paediatric APS. PubMedCrossRefGoogle Scholar
  167. 167.
    Mehrania T, Petri M. Epidemiology of the antiphospholipid syndrome. In: Asherson RA, editor. Handbook of systemic autoimmune diseases, vol. 10. Amsterdam: Elsevier; 2009. p. 13–34.Google Scholar
  168. 168.
    Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, de Jesus GR, Erkan D. The estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis. Arthritis Care Res (Hoboken). 2013;16:1869–73.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ilaria Cavazzana
    • 1
  • Laura Andreoli
    • 1
    • 2
  • Maarteen Limper
    • 3
    • 4
  • Franco Franceschini
    • 1
  • Angela Tincani
    • 1
    • 2
  1. 1.Rheumatology and Clinical Immunology, Spedali CiviliBresciaItaly
  2. 2.Department of Clinical and Experimental SciencesUniversity of BresciaBresciaItaly
  3. 3.Division of Rheumatology and Clinical ImmunologyUtrecht Medical CenterUtrechtThe Netherlands
  4. 4.Division Internal Medicine and Dermatology, Department of Rheumatology and Clinical ImmunologyUniversity Medical Center UtrechtUtrechtthe Netherlands

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