Elsevier

Autoimmunity Reviews

Volume 13, Issue 6, June 2014, Pages 685-696
Autoimmunity Reviews

Review
14th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends

https://doi.org/10.1016/j.autrev.2014.01.053Get rights and content

Abstract

Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for controlled clinical trials in venous thromboembolism with the new oral direct thrombin or anti-factor Xa inhibitors pending the results of the ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non-warfarin/heparin anticoagulants; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti-B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients.

Introduction

Antiphospholipid Syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL) [1]. Clinical manifestations of aPL represent a broad spectrum: a) asymptomatic aPL positivity (no history of thrombosis or pregnancy morbidity); b) non-criteria manifestations of aPL, e.g., livedo retucularis, thrombocytopenia, hemolytic anemia, cardiac valve disease, aPL-associated nephropathy, skin ulcers, or cognitive dysfunction; c) pregnancy morbidity (recurrent embryonic or fetal loss, preeclampsia, and growth restriction); d) venous, arterial, or small vessel thrombosis; and e) catastrophic APS (multiple organ thromboses commonly associated with microangiopathy).

The current mainstay of treatment for thrombotic APS is heparin followed by long-term anticoagulation with vitamin K antagonists (VKA) such as warfarin. Treatment with VKA in general is problematic because of numerous drug and food interactions, which necessitate frequent monitoring and potential under- or over-anticoagulation. Furthermore, monitoring of anticoagulation may be complicated by variable responsiveness of thromboplastin reagents to aPL, which may may potentially influence the validity of the prothrombin time (PT)/International Normalized Ratio (INR) [2].

The 14th International Congress on aPL was held in Rio de Janeiro, Brazil in September 2013. The APS Treatment Trends Task Force was one of five task forces developed by the meeting organization committee. The goal of the task force was to review potential new treatment strategies for aPL-positive patients rather than traditional anticoagulants or antiplatelet agents. Six subgroups of task force members systematically reviewed in vitro, animal, and completed and ongoing clinical studies in aPL-positive patients; following open discussions before and presentations during the 14th International Congress on aPL, the task force report was finalized.

Section snippets

Oral direct thrombin or anti-factor Xa inhibitors (new generation oral anticoagulants)

The oral direct inhibitors (ODI) of coagulation, also known as new generation oral anticoagulants (NOAC), include the direct thrombin inhibitor (DTI) dabigatran etexilate (Pradaxa®) [3], and the direct anti-factor Xa inhibitors rivaroxaban (Xarelto®) [4], apixaban (Eliquis®) [5], and edoxaban (Lixiana®) [6] (www.emc.medicines.org.uk) (Table 1). These agents, unlike warfarin, are fixed dose with predictable anticoagulant effect, do not interact with dietary constituents or alcohol, and have few

Older non-heparin/warfarin anticoagulants

Older anticoagulants are the indirect anti-factor Xa inhibitors (fondaparinux, idraparinux, idrabiotaparinux, and danaparoid) and the non-oral direct thrombin inhibitors (argatroban, lepirudin, and bivalirudin) [22].

Hydroxychloroquine

Hydroxychloroquine (HCQ) is an important treatment in rheumatic diseases, particularly in SLE, due to its anti-inflammatory, immunomodulatory, and metabolic effects.

Statins

Statins are potent inhibitors of cholesterol synthesis in the mevalonate pathway.

Their observed benefits in primary and secondary prevention of coronary heart disease in the general population are based not only on their lipid lowering effect but also on their pleiotropic immunomodulatory, anti-inflammatory, and anti-thrombotic properties [60]. These additional properties also provide the rationale for their potential application in APS, in which inflammation and the immune-mediated cell

B-cell inhibition

B cells play an important role in APS [80] and are key players in the development, re-activation, and persistence of autoimmune diseases beyond the production of autoantibodies. B-cells orchestrate the immune response by producing antibodies, germinal centers, and cytokines, as well as by their roles in antigen recognition and presentation (independent or dependent of T-cells).

Complement inhibition

Passive transfer of human aPL demonstrates that aPL are pathogenic in vivo in animal models of thrombosis, endothelial cell activation, and pregnancy loss [101], [102]. Endothelial cell activation correlates with a prothrombotic phenotype in vitro and enhances thrombus formation in vivo [102], [103]. Complement activation, specifically C5, is a necessary intermediary event in thrombosis associated with aPL in rodent models [104].

Peptide therapy

β2-Glycoprotein-I consists of five homologous domains (DI to DV) [121]; Domain V binds to negatively charged molecules, most specifically exteriorized phosphatidylserine in phospholipid bilayers in cell membranes of activated or apoptotic cells [122]. Alternatively, it may bind to a specific receptor. Antibodies to different domains exist in patients with APS. Most evidence suggests that anti-DI antibodies are most closely related to pathogenicity, but binding of DV to its receptor is required

Vitamin D

Although the goal of the task force was to review potential new medications for aPL-positive patients, the members also decided to briefly comment on the vitamin D supplementation.

Vitamin D has important immunomodulatory functions; vitamin D deficiency (< 10–20 ng/ml) and insufficiency (< 30 ng/ml) are relatively common in autoimmune diseases [134]. Based on in vitro APS studies, vitamin D may function as an anti-thrombotic immunomodulator by inhibiting β2GPI-mediated TF expression [135].

Antiphospholipid Syndrome Treatment Trends Task Force conclusion

The management of the aPL-positive patients with or without APS is currently sub-optimal due to: a) the fact that anticoagulation is not fully effective; and b) given our limited understanding of the origin, specificities, and biologic activities of aPL, new drug development for aPL-positive patients is challenging.

Barriers to the development of new treatment strategies in APS include the multifactorial nature of thrombosis; controversies about the strength of association between aPL and

Take-home messages

  • Antiphospholipid Syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL).

  • The current treatment for thrombotic APS is heparin followed by long-term anticoagulation with vitamin K antagonists, which is problematic because of numerous drug and food interactions that necessitate frequent monitoring; furthermore, anticoagulation is not effective for all aPL manifestations.

  • Recent studies, based on newly

References (140)

  • A. Schmidt-Tanguy et al.

    Anti-thrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients

    J Thromb Haemost

    (2013)
  • M.F. Marmor et al.

    Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy

    Ophthalmology

    (2011)
  • D.E. Ferrara et al.

    Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells

    J Thromb Haemost

    (2004)
  • G. Medina et al.

    Prevalence of metabolic syndrome in primary antiphospholipid syndrome patients

    Autoimmune Rev

    (2011)
  • M.D. Lockshin et al.

    Statins for the treatment of obstetric complications in antiphospholipid syndrome?

    J Reprod Immunol

    (2010)
  • P.M. Ridker et al.

    Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial

    Lancet

    (2009)
  • P. Youinou et al.

    The antiphospholipid syndrome as a model for B cell-induced autoimmune diseases

    Thromb Res

    (2004)
  • S. Khattri et al.

    B-cell directed therapies in antiphospholipid antibody syndrome—new directions based on murine and human data

    Autoimmun Rev

    (2012)
  • H. Berman 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)
  • A. Tripodi et al.

    Laboratory control of oral anticoagulant treatment by the INR system in patients with the antiphospholipid syndrome and lupus anticoagulant

    Br J Haematol

    (2001)
  • Summary of product characteristics (SPC), EU Pradaxa 150 mg hard capsules: Boehringer Ingelheim International GmBH, Date of first authorization: 08/01/2011. Date of latest renewal of authorization: 01/17/2013. Date of revision of text: 09/2013

  • Summary of product characteristics (SPC), EU. Xarelto 10 mg film-coated tablets. Bayer HealthCare AG. Date of first authorization: 09/30/2008. Date of renewal of authorization: 05/22/2013. Date of revision of text: 06/2013

  • Summary of product characteristics (SPC), EU. Eliquis 5 mg film-coated tablets: Bristol-Myers Squibb-Pfizer. Date of first authorization: 09/18/2011

  • Lixiana® (Edoxaban) 15mg and 30mg tablets: first marketing approval by the Ministry of Health, Labor and Welfare, Japan...
  • G. Agnelli et al.

    Oral apixaban for the treatment of acute venous thromboembolism

    N Engl J Med

    (2013)
  • EINSTEIN Investigators et al.

    Oral rivaroxaban for symptomatic venous thromboembolism (and supplementary appendix)

    N Engl J Med

    (2010)
  • Hokusai-VTE Investigators et al.

    Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism

    N Engl J Med

    (2013)
  • S. Schulman et al.

    Dabigatran versus warfarin for the treatment of acute venous thromboembolism

    N Engl Med

    (2009)
  • EINSTEIN-PE Investigators et al.

    Oral rivaroxaban for the treatment of symptomatic pulmonary embolism

    N Engl J Med

    (2012)
  • T. Baglin et al.

    Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: guidance from British Committee for Standards in Haematology

    Br J Haematol

    (2012)
  • E. Merriman et al.

    Rivaroxaban and false positive lupus anticoagulant testing

    Thromb Haemost

    (2011)
  • D.D. Castellone et al.

    Laboratory monitoring of new anticoagulants

    Am J Haematol

    (2010)
  • M.M. Samama et al.

    Laboratory assessments of new anticoagulants

    Clin Chem Lab Med

    (2011)
  • M.M. Samama et al.

    Assessment of laboratory assays to measure rivaroxaban — an oral, direct factor Xa inhibitor

    Thromb Haemost

    (2010)
  • M.E. Martinuzzo et al.

    Frequent false-positive results of lupus anticoagulant tests in plasmas of patients receiving the new oral anticoagulants and enoxaparin

    Int J Lab Hematol

    (2013)
  • E.S. Eerenberg et al.

    Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects

    Circulation

    (2011)
  • J.W. Eikelboom et al.

    Dabigatran versus warfarin in patients with mechanical heart valves

    N Engl J Med

    (2013)
  • G. Girardi et al.

    Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation

    Nat Med

    (2004)
  • H. Watson et al.

    Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition

    Br J Haematol

    (2012 Dec)
  • T.E. Warkentin et al.

    Heparin-induced thrombocytopenia associated with fondaparinux

    N Engl J Med

    (2007)
  • E. Rota et al.

    Fondaparinux-related thrombocytopenia in a previous low-molecular-weight heparin (LMWH)-induced heparin-induced thrombocytopenia (HIT)

    Thromb Haemost

    (2008)
  • M. Salem et al.

    Fondaparinux thromboprophylaxis-associated heparin-induced thrombocytopenia syndrome complicated by arterial thrombotic stroke

    Thromb Haemost

    (2010)
  • M.H. Edwards et al.

    Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice

    Circulation

    (1997)
  • X.X. Wu et al.

    Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression

    Am J Obstet Gynecol

    (2011)
  • K. Sacre et al.

    Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus

    Arthritis Res Ther

    (2012)
  • R. Johnson et al.

    Hydroxychloroquine in prophylaxis of pulmonary embolism following hip arthroplasty

    Clin Orthop Relat Res

    (1979)
  • G. Ruiz-Irastorza et al.

    Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review

    Ann Rheum Dis

    (2010)
  • D. Wallace

    Does hydroxychloroquine sulfate prevent clot formation in systemic lupus erythematosus? [letter]

    Arthritis Rheum

    (1987)
  • H. Jung et al.

    The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus

    Arthritis Rheum

    (2010)
  • R. Kaiser et al.

    Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort

    Ann Rheum Dis

    (2009)
  • Cited by (270)

    • The evolving concept of multimorbidity and migraine

      2024, Handbook of Clinical Neurology
    • Autoimmune diseases

      2022, Clinical Immunology
    View all citing articles on Scopus
    View full text