title: Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome.
abstract: Placental ischemic disease and adverse pregnancy outcomes are frequently observed in patients with antiphospholipid syndrome (APS). Despite the administration of conventional antithrombotic treatment a significant number of women continue to experience adverse pregnancy outcomes, with uncertain prevention and management. Efforts to develop effective pharmacological strategies for refractory obstetric APS cases will be of significant clinical benefit for both mothers and fetuses. Although the antimalarial drug, hydroxychloroquine (HCQ) is increasingly used to treat pregnant women with APS, little is known about its efficacy and mechanism of action of HCQ. Because complement activation plays a crucial and causative role in placental ischemia and abnormal fetal brain development in APS we hypothesised that HCQ prevents these pregnancy complications through inhibition of complement activation. Using a mouse model of obstetric APS that closely resembles the clinical condition, we found that HCQ prevented fetal death and the placental metabolic changes -measured by proton magnetic resonance spectroscopy in APS-mice. Using111In labelled antiphospholipid antibodies (aPL) we identified the placenta and the fetal brain as the main organ targets in APS-mice. Using this same method, we found that HCQ does not inhibit aPL binding to tissues as was previously suggested from in vitro studies. While HCQ did not affect aPL binding to fetal brain it prevented fetal brain abnormal cortical development. HCQ prevented complement activation in vivo and in vitro. Complement C5a levels in serum samples from APS patients and APS-mice were lower after treatment with HCQ while the antibodies titres remained unchanged. HCQ prevented not only placental insufficiency but also abnormal fetal brain development in APS. By inhibiting complement activation, HCQ might also be an effective antithrombotic therapy.
authors.affiliation: Division of Women's Health, St Thomas' Hospital, King's College London, London, SE1 7EH, UK.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bertolaccini
authors.affiliation: Division of Women's Health, St Thomas' Hospital, King's College London, London, SE1 7EH, UK.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Contento
authors.affiliation: BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Lennen
authors.affiliation: Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, SE1 7EH, UK.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sanna
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, London, SE1 7EH, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Blower
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, London, SE1 7EH, UK.
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Ma
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, London, SE1 7EH, UK.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Sunassee
authors.affiliation: Division of Women's Health, St Thomas' Hospital, King's College London, London, SE1 7EH, UK; MRC Centre for Inflammation Research, Queen's Medical Research Institute University of Edinburgh, Edinburgh, EH16 4TJ, UK. Electronic address: guillermina.girardi@kcl.ac.uk.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Girardi
mesh_terms: D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000188:drug therapy*; D001921:Brain / Q000002:abnormalities / Q000187:drug effects* / Q000196:embryology; D003167:Complement Activation / Q000187:drug effects*; D015926:Complement C3a / Q000032:analysis; D015936:Complement C5a / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010920:Placenta / Q000098:blood supply / Q000187:drug effects*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000188:drug therapy*; D011256:Pregnancy Outcome; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D006886:Hydroxychloroquine; D015926:Complement C3a; D015936:Complement C5a
keywords: Animal model; Antiphospholipid syndrome; Hydroxychloroquine; Pregnancy; Proton magnetic resonance spectroscopy; SPECT/CT