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Published in: Current Rheumatology Reports 4/2016

01-04-2016 | Antiphospholipid Syndrome (S Zuily, Section Editor)

Emerging Therapies in Antiphospholipid Syndrome

Authors: Danieli Andrade, Maria Tektonidou

Published in: Current Rheumatology Reports | Issue 4/2016

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Abstract

Antiphospholipid syndrome (APS) is a hypercoagulable state characterized by arterial and venous thromboses and pregnancy morbidity in the presence of antiphospholipid antibodies. Although warfarin remains the main therapeutic choice in APS, there is still concern about its efficacy, safety, and patient compliance. Patients with refractory APS to conventional therapy as well as patients with non-classical manifestations of APS may have alternative treatment approaches. APS pathogenesis has been further elucidated over the past years identifying new molecules as potential new treatment targets. This review summarizes available data from in vitro and animal models and clinical studies on the role of new potential treatment approaches including new oral anticoagulants and immunoregulatory agents: direct thrombin or factor Xa inhibitors, hydroxychloroquine, statins, B cell inhibition, complement inhibition, peptide therapy, nuclear factor κB and p38 mitogen-activated kinase inhibitors, defibrotide, abciximab, mTOR inhibitor, and other potential targets. Large multicenter prospective studies of well-characterized APS patients are needed to assess the efficacy and safety profile of these potential treatment alternatives.
Literature
1.
2.••
go back to reference Erkan D, Aguiar CL, Andrade D, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13:685–9. This is a systematic review of potential future treatment strategies for antiphospholipid positive patients that includes recommendations for clinicians based on literature review and experts opinion.CrossRefPubMed Erkan D, Aguiar CL, Andrade D, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13:685–9. This is a systematic review of potential future treatment strategies for antiphospholipid positive patients that includes recommendations for clinicians based on literature review and experts opinion.CrossRefPubMed
3.
go back to reference Chighizola CB, Raschi E, Borghi MO, et al. Update on the pathogenesis and treatment of the antiphospholipid syndrome. Curr Opin Rheumatol. 2015;27:476–82.CrossRefPubMed Chighizola CB, Raschi E, Borghi MO, et al. Update on the pathogenesis and treatment of the antiphospholipid syndrome. Curr Opin Rheumatol. 2015;27:476–82.CrossRefPubMed
4.
go back to reference Hoffman R, Brenner B. The promise of novel direct oral anticoagulants. Best Pract Res Clin Haematol. 2012;25:351–60.CrossRefPubMed Hoffman R, Brenner B. The promise of novel direct oral anticoagulants. Best Pract Res Clin Haematol. 2012;25:351–60.CrossRefPubMed
5.
go back to reference Arachchillage DJ, Cohen H. Use of new oral anticoagulants in antiphospholipid syndrome. Curr Rheumatol Rep. 2013;15:331.CrossRefPubMed Arachchillage DJ, Cohen H. Use of new oral anticoagulants in antiphospholipid syndrome. Curr Rheumatol Rep. 2013;15:331.CrossRefPubMed
6.
go back to reference Schaefer JK, McBane RD, Black DF, et al. Failure of dabigatran and rivaroxaban to prevent thromboembolism in antiphospholipid syndrome: a case series of three patients. Thromb Haemost. 2014;112:947–50.CrossRefPubMed Schaefer JK, McBane RD, Black DF, et al. Failure of dabigatran and rivaroxaban to prevent thromboembolism in antiphospholipid syndrome: a case series of three patients. Thromb Haemost. 2014;112:947–50.CrossRefPubMed
7.•
go back to reference Noel N, Dutasta F, Costedoat-Chalumeau N, et al. Safety and efficacy of oral direct inhibitors of thrombin and factor Xa in antiphospholipid syndrome. Autoimmun Rev. 2015;14:680–5. This is the first retrospective observational cases series which examined the safety and efficacy of new oral anticoagulants in APS.CrossRefPubMed Noel N, Dutasta F, Costedoat-Chalumeau N, et al. Safety and efficacy of oral direct inhibitors of thrombin and factor Xa in antiphospholipid syndrome. Autoimmun Rev. 2015;14:680–5. This is the first retrospective observational cases series which examined the safety and efficacy of new oral anticoagulants in APS.CrossRefPubMed
8.
go back to reference Win K, Rodgers GM. New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. Am J Hematol. 2014;89:1017.CrossRefPubMed Win K, Rodgers GM. New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. Am J Hematol. 2014;89:1017.CrossRefPubMed
9.
go back to reference Signorelli F, Nogueira F, Domingues V, Mariz HA, Levy RA. Thrombotic events in patients with antiphospholipid syndrome treated with rivaroxaban: a series of eight cases. Clin Rheumatol. 2015 Jul 30. Signorelli F, Nogueira F, Domingues V, Mariz HA, Levy RA. Thrombotic events in patients with antiphospholipid syndrome treated with rivaroxaban: a series of eight cases. Clin Rheumatol. 2015 Jul 30.
10.•
go back to reference Cohen H, Doré CJ, Clawson S, RAPS Trial Protocol Collaborators, et al. Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE. Lupus. 2015;24:1087–94. This is the first randomized trial comparing rivaroxaban with warfarin in patients with thrombotic APS. The final results of the trial are pending.CrossRefPubMedPubMedCentral Cohen H, Doré CJ, Clawson S, RAPS Trial Protocol Collaborators, et al. Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE. Lupus. 2015;24:1087–94. This is the first randomized trial comparing rivaroxaban with warfarin in patients with thrombotic APS. The final results of the trial are pending.CrossRefPubMedPubMedCentral
11.
go back to reference Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev. 2015;14:358–62.CrossRefPubMed Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev. 2015;14:358–62.CrossRefPubMed
12.
go back to reference Edwards MH, Pierangeli S, Liu X, et al. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation. 1997;96:4380–4.CrossRefPubMed Edwards MH, Pierangeli S, Liu X, et al. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation. 1997;96:4380–4.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
14.
go back to reference Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood. 2010;115:2292–9.CrossRefPubMedPubMedCentral Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood. 2010;115:2292–9.CrossRefPubMedPubMedCentral
15.
go back to reference Kuznik A, Bencina M, Svajger U, et al. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol. 2011;186:4794–804.CrossRefPubMed Kuznik A, Bencina M, Svajger U, et al. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol. 2011;186:4794–804.CrossRefPubMed
16.
go back to reference Wu XX, Guller S, Rand JH. Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol. 2011;205:576–14.PubMedPubMedCentral Wu XX, Guller S, Rand JH. Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol. 2011;205:576–14.PubMedPubMedCentral
17.
go back to reference Marchetti T, Ruffatti A, Wuillemin C, et al. Hydroxychloroquine restores trophoblast fusion affected by antiphospholipid antibodies. J Thromb Haemost. 2014;12:910–20.CrossRefPubMed Marchetti T, Ruffatti A, Wuillemin C, et al. Hydroxychloroquine restores trophoblast fusion affected by antiphospholipid antibodies. J Thromb Haemost. 2014;12:910–20.CrossRefPubMed
18.
go back to reference Johnson R, Charnley J. Hydroxychloroquine in prophylaxis of pulmonary embolism following hip arthroplasty. Clin Orthop Relat Res. 1979;144:174–7.PubMed Johnson R, Charnley J. Hydroxychloroquine in prophylaxis of pulmonary embolism following hip arthroplasty. Clin Orthop Relat Res. 1979;144:174–7.PubMed
19.
go back to reference 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;68:238–41.CrossRefPubMedPubMedCentral 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;68:238–41.CrossRefPubMedPubMedCentral
20.
go back to reference Tektonidou MG, Laskari K, Panagiotakos DB, et al. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum. 2009;61:29–36.CrossRefPubMed Tektonidou MG, Laskari K, Panagiotakos DB, et al. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum. 2009;61:29–36.CrossRefPubMed
21.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
22.
go back to reference Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford). 2002;41:924–9.CrossRef Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford). 2002;41:924–9.CrossRef
23.
go back to reference Erkan D, Lockshin MD, APS ACTION members. APS ACTION—AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking. Lupus. 2012;21:695–8.CrossRefPubMed Erkan D, Lockshin MD, APS ACTION members. APS ACTION—AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking. Lupus. 2012;21:695–8.CrossRefPubMed
24.•
go back to reference Schmidt-Tanguy A, Voswinkel J, Henrion D, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11:1927–9. The first retrospective observational study showing the antithrombotic role of hydroxychloroquine as additional treatment to anticoagulants in patients with primary APS.PubMed Schmidt-Tanguy A, Voswinkel J, Henrion D, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11:1927–9. The first retrospective observational study showing the antithrombotic role of hydroxychloroquine as additional treatment to anticoagulants in patients with primary APS.PubMed
26.
go back to reference Mekinian A, Lazzaroni MG, Kuzenko A, SNFMI and the European Forum on Antiphospholipid Antibodies, 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.CrossRefPubMed Mekinian A, Lazzaroni MG, Kuzenko A, SNFMI and the European Forum on Antiphospholipid Antibodies, 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.CrossRefPubMed
27.
go back to reference Sciascia S, Branch DW, Levy RA et al. The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment. Thromb Haemost. 2015;115. Sciascia S, Branch DW, Levy RA et al. The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment. Thromb Haemost. 2015;115.
28.
go back to reference Ferrara DE, Liu X, Espinola RG, et al. Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum. 2003;48:3272–9.CrossRefPubMed Ferrara DE, Liu X, Espinola RG, et al. Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum. 2003;48:3272–9.CrossRefPubMed
29.
go back to reference Meroni PL, Raschi E, Testoni C, et al. Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum. 2001;44:2870–8.CrossRefPubMed Meroni PL, Raschi E, Testoni C, et al. Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum. 2001;44:2870–8.CrossRefPubMed
30.
go back to reference Cortellaro M, Cofrancesco E, Arbustini E, et al. Systemic cause of unstable atherosclerotic plaques. Atorvastatin and Thrombogenicity of Carotid Atherosclerotic Plaque (ATROCAP) study group. Lancet. 2000;355:1362–3.CrossRefPubMed Cortellaro M, Cofrancesco E, Arbustini E, et al. Systemic cause of unstable atherosclerotic plaques. Atorvastatin and Thrombogenicity of Carotid Atherosclerotic Plaque (ATROCAP) study group. Lancet. 2000;355:1362–3.CrossRefPubMed
31.
go back to reference Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851–61.CrossRefPubMedPubMedCentral Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851–61.CrossRefPubMedPubMedCentral
32.
go back to reference Ferrara DE, Swerlick R, Casper K, et al. Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost. 2004;2:1558–63.CrossRefPubMed Ferrara DE, Swerlick R, Casper K, et al. Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost. 2004;2:1558–63.CrossRefPubMed
33.
go back to reference Girardi G. Pravastatin prevents miscarriages in antiphospholipid antibody-treated mice. J Reprod Immunol. 2009;82:126–31.CrossRefPubMed Girardi G. Pravastatin prevents miscarriages in antiphospholipid antibody-treated mice. J Reprod Immunol. 2009;82:126–31.CrossRefPubMed
34.
go back to reference López-Pedrera C, Ruiz-Limón P, Aguirre MA, et al. Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis. 2010;70:675–82.CrossRefPubMed López-Pedrera C, Ruiz-Limón P, Aguirre MA, et al. Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis. 2010;70:675–82.CrossRefPubMed
35.
go back to reference Erkan D, Willis R, Murthy VL, et al. A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. Ann Rheum Dis. 2014;73:1176–80.CrossRefPubMedPubMedCentral Erkan D, Willis R, Murthy VL, et al. A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. Ann Rheum Dis. 2014;73:1176–80.CrossRefPubMedPubMedCentral
36.
go back to reference Pons I, Espinosa G, Cervera R. Efficacy and safety of rituximab in the treatment of primary antiphospholipid syndrome: analysis of 24 cases from the bibliography review. Med Clin. 2015;144:97–104.CrossRef Pons I, Espinosa G, Cervera R. Efficacy and safety of rituximab in the treatment of primary antiphospholipid syndrome: analysis of 24 cases from the bibliography review. Med Clin. 2015;144:97–104.CrossRef
37.
go back to reference Ramos-Casals M, Brito-Zerón P, Muñoz S, BIOGEAS study group, et al. A systematic review of the off-label use of biological therapies in systemic autoimmune diseases. Medicine. 2008;87:345–64.CrossRefPubMed Ramos-Casals M, Brito-Zerón P, Muñoz S, BIOGEAS study group, et al. A systematic review of the off-label use of biological therapies in systemic autoimmune diseases. Medicine. 2008;87:345–64.CrossRefPubMed
38.
go back to reference Ioannou Y, Lambrianides A, Cambridge G, et al. B cell depletion therapy for patients with systemic lupus erythematosus results in a significant drop in anticardiolipin antibody titres. Ann Rheum Dis. 2008;67:425–6.CrossRefPubMed Ioannou Y, Lambrianides A, Cambridge G, et al. B cell depletion therapy for patients with systemic lupus erythematosus results in a significant drop in anticardiolipin antibody titres. Ann Rheum Dis. 2008;67:425–6.CrossRefPubMed
39.
go back to reference Erre GL, Pardini S, Faedda R, et al. Effect of rituximab on clinical and laboratory features of antiphospholipid syndrome: a case report and a review of literature. Lupus. 2008;17:50–5.CrossRefPubMed Erre GL, Pardini S, Faedda R, et al. Effect of rituximab on clinical and laboratory features of antiphospholipid syndrome: a case report and a review of literature. Lupus. 2008;17:50–5.CrossRefPubMed
40.•
go back to reference Erkan D, Vega J, Ramón G, et al. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013;65:464–71. A prospective pilot study showing a beneficial effect of rituximab in microthrombotic/microangiopathic non-criteria manifestations of APS.CrossRefPubMed Erkan D, Vega J, Ramón G, et al. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013;65:464–71. A prospective pilot study showing a beneficial effect of rituximab in microthrombotic/microangiopathic non-criteria manifestations of APS.CrossRefPubMed
41.
go back to reference Berman H, Rodríguez-Pintó I, Cervera R, Catastrophic Antiphospholipid Syndrome (CAPS) Registry Project Group (European Forum on Antiphospholipid Antibodies), et al. Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev. 2013;12:1085–90.CrossRefPubMed Berman H, Rodríguez-Pintó I, Cervera R, Catastrophic Antiphospholipid Syndrome (CAPS) Registry Project Group (European Forum on Antiphospholipid Antibodies), et al. Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev. 2013;12:1085–90.CrossRefPubMed
42.
go back to reference Rodríguez-Pintó I, Cervera R, Espinosa G. Rituximab and its therapeutic potential in catastrophic antiphospolipid syndrome. Ther Adv Musculoskelet Dis. 2015;7:26–30.CrossRefPubMedPubMedCentral Rodríguez-Pintó I, Cervera R, Espinosa G. Rituximab and its therapeutic potential in catastrophic antiphospolipid syndrome. Ther Adv Musculoskelet Dis. 2015;7:26–30.CrossRefPubMedPubMedCentral
43.
go back to reference Salmon JE, Girardi G, Lockshin MD. The antiphospholipid syndrome as a disorder initiated by inflammation: implications for the therapy of pregnant patients. Nat Clin Pract Rheumatol. 2007;3:140–7.CrossRefPubMed Salmon JE, Girardi G, Lockshin MD. The antiphospholipid syndrome as a disorder initiated by inflammation: implications for the therapy of pregnant patients. Nat Clin Pract Rheumatol. 2007;3:140–7.CrossRefPubMed
44.
go back to reference Ikeda K, Nagasawa K, Horiuchi T, et al. C5a induces tissue factor activity on endothelial cells. Thromb Haemost. 1997;77:394–8.PubMed Ikeda K, Nagasawa K, Horiuchi T, et al. C5a induces tissue factor activity on endothelial cells. Thromb Haemost. 1997;77:394–8.PubMed
45.
go back to reference Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112:1644–54.CrossRefPubMedPubMedCentral Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112:1644–54.CrossRefPubMedPubMedCentral
46.
go back to reference Girardi G, Yarilin D, Thurman JM, et al. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med. 2006;203(9):2165–75.CrossRefPubMedPubMedCentral Girardi G, Yarilin D, Thurman JM, et al. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med. 2006;203(9):2165–75.CrossRefPubMedPubMedCentral
47.
go back to reference Holers VM, Salmon JE, Pickering MC, de Jorge EG, Martinez-Barricarte R, et al. Spontaneous hemolytic uremic syndrome triggered by complement surface recognition domains. J Exp Med. 2007;204:1249–56.CrossRef Holers VM, Salmon JE, Pickering MC, de Jorge EG, Martinez-Barricarte R, et al. Spontaneous hemolytic uremic syndrome triggered by complement surface recognition domains. J Exp Med. 2007;204:1249–56.CrossRef
48.
go back to reference Salmon JE, Heuser C, Triebwasser M et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. Plos Med. 2011;doi: 10.1371. Salmon JE, Heuser C, Triebwasser M et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. Plos Med. 2011;doi: 10.1371.
49.
go back to reference Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233–43.CrossRefPubMed Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233–43.CrossRefPubMed
50.
go back to reference Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370:632–9.CrossRefPubMed Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370:632–9.CrossRefPubMed
51.
go back to reference Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81.CrossRefPubMed Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81.CrossRefPubMed
52.
go back to reference Tektonidou MG, Sotsiou F, Moutsopoulos HM. Antiphospholipid syndrome (APS) nephropathy in catastrophic, primary, and systemic lupus erythematosus-related APS. J Rheumatol. 2008;35(10):1983–8.PubMed Tektonidou MG, Sotsiou F, Moutsopoulos HM. Antiphospholipid syndrome (APS) nephropathy in catastrophic, primary, and systemic lupus erythematosus-related APS. J Rheumatol. 2008;35(10):1983–8.PubMed
53.
go back to reference Canaud G, Kamar N, Anglicheau D, et al. Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes. Am J Transplant. 2013;13:2179–85.CrossRefPubMed Canaud G, Kamar N, Anglicheau D, et al. Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes. Am J Transplant. 2013;13:2179–85.CrossRefPubMed
54.••
go back to reference 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. The first report of the efficacy of eculizumab, an inhibitor of complement activation, in the treatment of CAPS demonstrating the importance of terminal complement components in the pathogenesis of CAPS and the therapeutic benefit of complement inactivation.CrossRefPubMed 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. The first report of the efficacy of eculizumab, an inhibitor of complement activation, in the treatment of CAPS demonstrating the importance of terminal complement components in the pathogenesis of CAPS and the therapeutic benefit of complement inactivation.CrossRefPubMed
55.
go back to reference Ostertag MV, Liu X, Henderson SS, Pierangeli SS. A peptide that mimics the Vth region of beta-2-glycoprotein I reverses antiphospholipid-mediated thrombosis in mice. Lupus. 2006;15:358–65.CrossRefPubMed Ostertag MV, Liu X, Henderson SS, Pierangeli SS. A peptide that mimics the Vth region of beta-2-glycoprotein I reverses antiphospholipid-mediated thrombosis in mice. Lupus. 2006;15:358–65.CrossRefPubMed
56.
go back to reference Pedrera-Lopez CH, Aguirre MA, Limon-Ruiz P, et al. Immunotherapy in antiphospholipid syndrome. Int Immunopharmacol. 2015;27:200–8.CrossRef Pedrera-Lopez CH, Aguirre MA, Limon-Ruiz P, et al. Immunotherapy in antiphospholipid syndrome. Int Immunopharmacol. 2015;27:200–8.CrossRef
57.
go back to reference Ioannou Y, Romay-Penabad Z, Pericleus C, et al. In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of beta2-glycoprotein I; proof of concept. J ThrombHaemost. 2009;7:833–42.CrossRef Ioannou Y, Romay-Penabad Z, Pericleus C, et al. In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of beta2-glycoprotein I; proof of concept. J ThrombHaemost. 2009;7:833–42.CrossRef
58.
go back to reference de la Torre YM, Pregnolato F, D’Amelio F, et al. Antiphospholipid-induced murine fetal loss: novel protective effects of a peptide targeting the beta-2 glycoprotein I phospholipid binding site. Implication for human fetal loss. J Autoimmun. 2012;38:209–15.CrossRef de la Torre YM, Pregnolato F, D’Amelio F, et al. Antiphospholipid-induced murine fetal loss: novel protective effects of a peptide targeting the beta-2 glycoprotein I phospholipid binding site. Implication for human fetal loss. J Autoimmun. 2012;38:209–15.CrossRef
59.
go back to reference Di Simone N, D’Ippolito S, Marana R, et al. Antiphospholipid antibodies affect human endometrial angiogenesis protective effect of synthetic peptide (TIFI) mimicking the antiphospholipid binding site of β(2) glycoprotein I. Am J Reprod immunol. 2013;70:299–08.CrossRefPubMed Di Simone N, D’Ippolito S, Marana R, et al. Antiphospholipid antibodies affect human endometrial angiogenesis protective effect of synthetic peptide (TIFI) mimicking the antiphospholipid binding site of β(2) glycoprotein I. Am J Reprod immunol. 2013;70:299–08.CrossRefPubMed
60.•
go back to reference Agostinis C, Durigutto P, Sblattero D, Borghi M, et al. A non-complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome. Blood. 2014;123:3478–87. This study showed that the CH2-deleted antibody may represent an innovative approach to treat patients with APS refractory to standard therapy.CrossRefPubMed Agostinis C, Durigutto P, Sblattero D, Borghi M, et al. A non-complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome. Blood. 2014;123:3478–87. This study showed that the CH2-deleted antibody may represent an innovative approach to treat patients with APS refractory to standard therapy.CrossRefPubMed
61.
go back to reference Benhamou Y, Bellien J, Armengol G, Brakenhielm E, et al. Role of toll-like receptors 2 and 4 in mediating endothelial dysfunction and arterial remodeling in primary arterial antiphospholipid syndrome. Arthritis Rheumatol. 2014;66:3210–20.CrossRefPubMed Benhamou Y, Bellien J, Armengol G, Brakenhielm E, et al. Role of toll-like receptors 2 and 4 in mediating endothelial dysfunction and arterial remodeling in primary arterial antiphospholipid syndrome. Arthritis Rheumatol. 2014;66:3210–20.CrossRefPubMed
62.
go back to reference Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev. 2013;12:752–7.CrossRefPubMed Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev. 2013;12:752–7.CrossRefPubMed
63.
go back to reference Kubota T, Fukuya Y, Hashimoto R, et al. Possible involvement of chemokine induced platelet activation in thrombophilic diathesis of antiphospholipid syndrome. Ann N Y Acad Sci. 2009;1173:137–45.CrossRefPubMed Kubota T, Fukuya Y, Hashimoto R, et al. Possible involvement of chemokine induced platelet activation in thrombophilic diathesis of antiphospholipid syndrome. Ann N Y Acad Sci. 2009;1173:137–45.CrossRefPubMed
64.
go back to reference Nishimura M, Nii T, Trimova G, et al. The NF-κβ specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome. J Nephropathology. 2013;2:114–21.CrossRefPubMedPubMedCentral Nishimura M, Nii T, Trimova G, et al. The NF-κβ specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome. J Nephropathology. 2013;2:114–21.CrossRefPubMedPubMedCentral
65.
go back to reference Damjanov N, Kauffman RS, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized double-blind, placebo-controlled clinical studies. Arthritis Rheum. 2009;60:1231–41.CrossRef Damjanov N, Kauffman RS, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized double-blind, placebo-controlled clinical studies. Arthritis Rheum. 2009;60:1231–41.CrossRef
66.
go back to reference Marti V, Seixo F, Santaló M, Serra A. Antiphospholipid syndrome and acute myocardial infarction: treatment with thrombectomy and abciximab. Rev Port Cardiol. 2014;33:7–8. Marti V, Seixo F, Santaló M, Serra A. Antiphospholipid syndrome and acute myocardial infarction: treatment with thrombectomy and abciximab. Rev Port Cardiol. 2014;33:7–8.
67.
go back to reference Chambers Jr JD, Haire HD, Deligonul U. Multiple early percutaneous transluminal coronary angioplasty failures related to lupus anticoagulant. Am Heart J. 1996;132:189–90.CrossRefPubMed Chambers Jr JD, Haire HD, Deligonul U. Multiple early percutaneous transluminal coronary angioplasty failures related to lupus anticoagulant. Am Heart J. 1996;132:189–90.CrossRefPubMed
68.
go back to reference Pierangeli SS, Vega-Ostertag M, Harris NE. Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: a pathway to targeted therapies. Thromb Res. 2004;114:467–76.CrossRefPubMed Pierangeli SS, Vega-Ostertag M, Harris NE. Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: a pathway to targeted therapies. Thromb Res. 2004;114:467–76.CrossRefPubMed
69.
go back to reference Falanga A, Vignoli A, Marchetti M, Barbui T. Defibrotide reduces procoagulant activity and increase fibrinolytic properties of endothelial cells. Leukemia. 2003;17:1636–42.CrossRefPubMed Falanga A, Vignoli A, Marchetti M, Barbui T. Defibrotide reduces procoagulant activity and increase fibrinolytic properties of endothelial cells. Leukemia. 2003;17:1636–42.CrossRefPubMed
70.
go back to reference Ferrari PA, Cornelli U, Dian F, et al. Defibrotide in the prevention of deep venous thrombosis in general surgery. Preliminary results of a multicenter study. Minerva Med. 1988;79:557–61. Ferrari PA, Cornelli U, Dian F, et al. Defibrotide in the prevention of deep venous thrombosis in general surgery. Preliminary results of a multicenter study. Minerva Med. 1988;79:557–61.
71.
go back to reference Burcoglu-O’Ral A, Erkan D, Asherson R. Treatment of catastrophic antiphospholipid syndrome with defibrotide, a proposed vascular endothelial cell modulator. J Rheumatol. 2002;29:2006–11.PubMed Burcoglu-O’Ral A, Erkan D, Asherson R. Treatment of catastrophic antiphospholipid syndrome with defibrotide, a proposed vascular endothelial cell modulator. J Rheumatol. 2002;29:2006–11.PubMed
72.
go back to reference Martin KA, Rzucidlo EM, Merenick BL, Fingar DC, Brown DJ, Wagner RJ, et al. The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am J Physiol Cell Physiol. 2004;286:C507–17.CrossRefPubMed Martin KA, Rzucidlo EM, Merenick BL, Fingar DC, Brown DJ, Wagner RJ, et al. The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am J Physiol Cell Physiol. 2004;286:C507–17.CrossRefPubMed
73.
go back to reference Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation. 1999;99:2164–70.CrossRefPubMed Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation. 1999;99:2164–70.CrossRefPubMed
74.
go back to reference Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one year angiographic and intravascular ultrasound follow-up. Circulation. 2001;104:2007–11.CrossRefPubMed Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one year angiographic and intravascular ultrasound follow-up. Circulation. 2001;104:2007–11.CrossRefPubMed
75.
go back to reference Hughson MD, McCarty GA, Brumback RA. Spectrum of vascular pathology affecting patients with the antiphospholipid syndrome. J Am Soc Nephrol. 2002;13:42–52. Hughson MD, McCarty GA, Brumback RA. Spectrum of vascular pathology affecting patients with the antiphospholipid syndrome. J Am Soc Nephrol. 2002;13:42–52.
76.
go back to reference Nochy D, Daugas E, Droz D, et al. The intrarenal vascular lesions associated with primary antiphospholipid syndrome. J Am Soc Nephrol. 1999;10:507–18.PubMed Nochy D, Daugas E, Droz D, et al. The intrarenal vascular lesions associated with primary antiphospholipid syndrome. J Am Soc Nephrol. 1999;10:507–18.PubMed
77.••
go back to reference Canaud G, Bienaimé F, Tabarin F, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;371:303–12. This is a recent study that suggests the role of the mTORC pathway in renal APS vascular lesion pathogenesis and the importance of its inhibition.CrossRefPubMed Canaud G, Bienaimé F, Tabarin F, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;371:303–12. This is a recent study that suggests the role of the mTORC pathway in renal APS vascular lesion pathogenesis and the importance of its inhibition.CrossRefPubMed
78.
go back to reference Zuily S, Regnault V, Wahl D. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;16(371):1553–4. Zuily S, Regnault V, Wahl D. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;16(371):1553–4.
Metadata
Title
Emerging Therapies in Antiphospholipid Syndrome
Authors
Danieli Andrade
Maria Tektonidou
Publication date
01-04-2016
Publisher
Springer US
Published in
Current Rheumatology Reports / Issue 4/2016
Print ISSN: 1523-3774
Electronic ISSN: 1534-6307
DOI
https://doi.org/10.1007/s11926-016-0566-z

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