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Machine learning identifies clusters of longitudinal autoantibody profiles predictive of systemic lupus erythematosus disease outcomes
  1. May Yee Choi1,
  2. Irene Chen2,
  3. Ann Elaine Clarke1,
  4. Marvin J Fritzler1,
  5. Katherine A Buhler1,
  6. Murray Urowitz3,
  7. John Hanly4,
  8. Yvan St-Pierre5,
  9. Caroline Gordon6,
  10. Sang-Cheol Bae7,
  11. Juanita Romero-Diaz8,
  12. Jorge Sanchez-Guerrero9,
  13. Sasha Bernatsky10,
  14. Daniel J Wallace11,
  15. David Alan Isenberg12,
  16. Anisur Rahman12,
  17. Joan T Merrill13,
  18. Paul R Fortin14,
  19. Dafna D Gladman3,
  20. Ian N Bruce15,
  21. Michelle Petri16,
  22. Ellen M Ginzler17,
  23. Mary Anne Dooley18,
  24. Rosalind Ramsey-Goldman19,
  25. Susan Manzi20,
  26. Andreas Jönsen21,
  27. Graciela S Alarcón22,
  28. Ronald F van Vollenhoven23,
  29. Cynthia Aranow24,
  30. Meggan Mackay24,
  31. Guillermo Ruiz-Irastorza25,
  32. Sam Lim26,
  33. Murat Inanc27,
  34. Kenneth Kalunian28,
  35. Søren Jacobsen29,
  36. Christine Peschken30,
  37. Diane L Kamen31,
  38. Anca Askanase32,
  39. Jill P Buyon33,
  40. David Sontag2,
  41. Karen H Costenbader34,35
  1. 1Medicine, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
  2. 2Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  3. 3Center for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University of Toronto, Lupus Clinic, Toronto, Ontario, Canada
  4. 4Division of Rheumatology, Department of Medicine and Department of Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
  5. 5Medicine, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
  6. 6Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, Birmingham University Medical School, Birmingham, West Midlands, UK
  7. 7Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Hanyang University Institute for Rheumatology and Hanyang University Institute of Bioscience and Biotechnology, Seoul, The Republic of Korea
  8. 8Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico
  9. 9Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, Ontario, Canada
  10. 10Divisions of Rheumatology and Clinical Epidemiology, McGill University Health Centre, Montreal, Quebec, Canada
  11. 11Division of Rheumatology, Cedars-Sinai/David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  12. 12Centre for Rheumatology, Department of Medicine, University College London, London, UK
  13. 13Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  14. 14Division of Rheumatology, CHU de Québec - Université Laval, Quebec City, Quebec, Canada
  15. 15Epidemiology Unit, University of Manchester, Manchester, UK
  16. 16Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  17. 17Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, USA
  18. 18Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  19. 19Department of Medicine, Division of Rheumatology, Northwestern University and Feinberg School of Medicine, Chicago, Illinois, USA
  20. 20Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
  21. 21Clinical Sciences, Lund University, Lund, Sweden
  22. 22Department of Medicine, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA
  23. 23Rheumatology & Immunology Center, University of Amsterdam, Amsterdam, The Netherlands
  24. 24Division of Autoimmune and Musculoskeletal Disease, Feinstein Institute for Medical Research, Manhasset, New York, USA
  25. 25Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Barakaldo, Spain
  26. 26Division of Rheumatology, Emory University School of Medicine, Atlanta, Georgia, USA
  27. 27Department of Internal Medicine, Division of Rheumatology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey
  28. 28Department of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA
  29. 29Department of Rheumatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  30. 30Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
  31. 31Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
  32. 32Hospital for Joint Diseases, New York University, Seligman Centre for Advanced Therapeutics, New York, New York, USA
  33. 33Division of Rheumatology, New York University School of Medicine, New York, New York, USA
  34. 34Department of Medicine, Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA
  35. 35Medicine, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr May Yee Choi, University of Calgary Cumming School of Medicine, Calgary, AB T2N4N1, Canada; may.choi{at}


Objectives A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes.

Methods Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset.

Results Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2.

Conclusion Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.

  • systemic lupus erythematosus
  • autoantibodies
  • autoimmunity

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Handling editor Josef S Smolen

  • Contributors All authors were involved in the concept and design, data analysis and interpretation and editing for intellectual content. MYC, AEC, MJF and KHC were involved in manuscript drafting. MYC is responsible for the overall content as the guarantor.

  • Funding MYC is supported by the Lupus Foundation of America Gary S. Gilkeson Career Development Award and research gifts in kind from MitogenDx (Calgary, Canada). AEC holds The Arthritis Society Research Chair in Rheumatic Diseases at the University of Calgary. JH’s work was supported by the Canadian Institutes of Health Research (research grant MOP-88526). CG’s work was supported by Lupus UK, Sandwell and West Birmingham Hospitals NHS Trust and the NIHR/Wellcome Trust Clinical Research Facility in Birmingham. S-CB’s work was supported by Basic Science Research Programme through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1A6A1A03038899). The Montreal General Hospital Lupus Clinic is partially supported by the Singer Family Fund for Lupus Research. AR and DAI are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The Hopkins Lupus Cohort is supported by NIH Grants AR043727 and AR069572. PRF presently holds a tier 1 Canada Research Chair on Systemic Autoimmune Rheumatic Diseases at Université Laval, and part of this work was done while he was still holding a Distinguished Senior Investigator of The Arthritis Society. INB is an NIHR Senior Investigator and is funded by Arthritis Research UK, the National Institute for Health Research Manchester Biomedical Research Centre and the NIHR/Wellcome Trust Manchester Clinical Research Facility. MAD’s work was supported by the NIH grant RR00046. RR-G’s work was supported by the NIH (grants 1U54TR001353 formerly 8UL1TR000150 and UL-1RR-025741, K24-AR-02318 and P60AR064464 formerly P60-AR-48098). SM is supported by grants R01 AR046588 and K24 AR002213. GR-I is supported by the Department of Education, Universities and Research of the Basque Government. SJ is supported by the Danish Rheumatism Association (A1028) and the Novo Nordisk Foundation (A05990). KHC is supported by NIH K24 AR066109.

  • Disclaimer The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

  • Competing interests MYC has received consulting fees from Janssen, AstraZeneca, Mallinckrodt Pharmaceuticals and MitogenDx. AEC has received consulting fees, speaking fees and/or honoraria from AstraZeneca, Bristol Myers Squibb and GlaxoSmithKline (<US$10 000 each) and research support from GlaxoSmithKline. MJF is Director of Mitogen Diagnostics (Calgary, Alberta, Canada) and a consultant to Werfen International (San Diego, California, USA; Barcelona, Spain), Aesku Group (Wendelsheim, Germany) and Alexion Canada (<US$10 000). CG has received consulting fees, speaking fees and/or honoraria from Eli Lilly, UCB, GlaxoSmithKline, Merck Serono and BMS (<US$10 000 each) and grants from UCB. Grants from UCB were not to CG but to Sandwell and West Birmingham Hospitals NHS Trust. DDG received consulting fees, speaking fees and/or honoraria from GlaxoSmithKline (<US$10 000). INB has received consulting fees, speaking fees and/or honoraria from Eli Lilly, UCB, Roche, Merck Serono, MedImmune (<US$10 000 each) and grants from UCB, Genzyme Sanofi and GlaxoSmithKline. EMG has paid consultation with investment analysts Guidepoint Global Gerson Lerman Group. KK has received grants from UCB, Human Genome Sciences/GlaxoSmithKline, Takeda, Ablynx, Bristol Myers Squibb, Pfizer and Kyowa Hakko Kirin, and has received consulting fees from Exagen Diagnostics, Genentech, Eli Lilly, Bristol Myers Squibb and Anthera (<US$10 000 each). KHC has consulted for or collaborated on research projects with Janssen, GlaxoSmithKline, Gilead, Exagen Diagnostics, Lilly, Merck, AstraZeneca, Amgen and Neutrolis (<US$10 000 each). The remainder of the authors have no disclosures.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.