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Extended report
Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus
  1. J G Hanly1,2,
  2. M B Urowitz3,
  3. L Su4,
  4. S-C Bae5,
  5. C Gordon6,
  6. A Clarke9,
  7. S Bernatsky10,
  8. A Vasudevan11,
  9. D Isenberg12,
  10. A Rahman12,
  11. D J Wallace8,
  12. P R Fortin3,
  13. D Gladman3,
  14. J Romero-Dirz7,
  15. J Sanchez-Guerrero7,
  16. M A Dooley13,
  17. I Bruce14,
  18. K Steinsson15,
  19. M Khamashta16,
  20. S Manzi17,
  21. R Ramsey-Goldman18,
  22. G Sturfelt19,
  23. O Nived19,
  24. R van Vollenhoven20,
  25. M Ramos-Casals21,
  26. C Aranow22,
  27. M Mackay22,
  28. K Kalunian23,
  29. G S Alarcón24,
  30. B J Fessler24,
  31. G Ruiz-Irastorza25,
  32. M Petri26,
  33. S Lim27,
  34. D Kamen28,
  35. C Peschken29,
  36. V Farewell4,
  37. K Thompson1,
  38. C Theriault1,
  39. J T Merrill30
  1. 1Department of Medicine, Division of Rheumatology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
  2. 2Department of Pathology, Division of Rheumatology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
  3. 3Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital and University of Toronto, Toronto, Ontario, Canada
  4. 4MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge, UK
  5. 5Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
  6. 6Rheumatology Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
  7. 7Instituto Nacional de Ciencias Medicas y Nutrición, Mexico City, Mexico
  8. 8Cedars-Sinai/David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  9. 9Divisions of Clinical Immunology/Allergy and Clinical Epidemiology, Montreal General Hospital, McGill University Health Centre, Montreal, Quebec, Canada
  10. 10Divisions of Rheumatology and Clinical Epidemiology, Montreal General Hospital, McGill University Health Centre, Montreal, Quebec, Canada
  11. 11Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, USA
  12. 12Centre for Rheumatology Research, University College, London, UK
  13. 13University of North Carolina, Chapel Hill, North Carolina, USA
  14. 14Arthritis Research UK Epidemiology Unit, School of Translational Medicine, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
  15. 15Center for Rheumatology Research, Landspitali University hospital, Reykjavik, Iceland
  16. 16Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, King's College London School of Medicine, London, UK
  17. 17Division of Rheumatology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  18. 18Northwestern University and Feinberg School of Medicine, Chicago, Illinois, USA
  19. 19Department of Rheumatology, University Hospital Lund, Lund, Sweden
  20. 20Department of Rheumatology, Karolinska Institute, Stockholm, Sweden
  21. 21Servicio Enfermedades Autoinmunes Hospital Clínico y Provincial, Barcelona, Spain
  22. 22Columbia University Medical Center, New York, New York, USA
  23. 23UCSD School of Medicine, La Jolla, California, USA
  24. 24Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
  25. 25Autoimmune Disease Unit, Department of Internal Medicine, Hospital de Cruces, University of the Basque Country, Barakaldo, Spain
  26. 26Department of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
  27. 27Emory University, Atlanta, Georgia, USA
  28. 28Medical University of South Carolina, Charleston, South Carolina, USA
  29. 29University of Manitoba, Winnipeg, Manitoba, Canada
  30. 30Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  1. Correspondence to Dr J G Hanly, Division of Rheumatology, Nova Scotia Rehabilitation Centre (2nd Floor), 1341 Summer Street, Halifax, NS B3H 4K4, Canada; john.hanly{at}


Objective Neuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events.

Methods Patients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression.

Results Disease duration at enrolment was 5.4±4.2 months, follow-up was 3.6±2.6 years. Patients were 89.1% female with mean (±SD) age 35.2±13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-β2 glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events.

Conclusion In a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.

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  • Funding JGH was supported by Canadian Institutes of Health Research grant MOP-57752, Capital Health Research Fund. MBU's work was supported by the Canadian Institutes of Health Research (grant MOP-49529), the Lupus Foundation of Ontario, the Ontario Lupus Association, Lupus UK, the Lupus Foundation of America, the Lupus Alliance of Western New York, the Conn Smythe Foundation, the Lupus Flare Foundation and the Tolfo Family of Toronto, Ontario, Canada. LS was supported by MRC (UK) grant U.1052.00.009 and VF was supported by MRC (UK) grant U.1052.00.009. S-CB's work was supported by the Korea Healthcare technology R&D project, Ministry for Health and Welfare, Republic of Korea (A080588). The Montreal General Hospital Lupus Clinic is partially supported by the Singer Family Fund for Lupus Research. AC is a national scholar of the Fonds de la Recherché en Santé de Quebec. PRF is a distinguished senior investigator of the Arthritis Society, with additional support from the Arthritis Centre of Excellence, University of Toronto. RR-G's work was supported by the NIH (grants UL-1RR-025741, K24-AR-02318 and P60-AR-48098). GR-I is supported by the Department of Education, Universities and Research of the Basque Government.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Capital Health Research Ethics Board, Halifax, Nova Scotia, Canada, and by each of the participating centre's own institutional research ethics review boards.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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