Machine learning identifies clusters of longitudinal autoantibody profiles predictive of systemic lupus erythematosus disease outcomes

May Yee Choi; Irene Chen; Ann Elaine Clarke; Marvin J Fritzler; Katherine A Buhler; Murray Urowitz; John Hanly; Yvan St-Pierre; Caroline Gordon; Sang-Cheol Bae; Juanita Romero-Diaz; Jorge Sanchez-Guerrero; Sasha Bernatsky; Daniel J Wallace; David Alan Isenberg; Anisur Rahman; Joan T Merrill; Paul R Fortin; Dafna D Gladman; Ian N Bruce; Michelle Petri; Ellen M Ginzler; Mary Anne Dooley; Rosalind Ramsey-Goldman; Susan Manzi; Andreas Jönsen; Graciela S Alarcón; Ronald F van Vollenhoven; Cynthia Aranow; Meggan Mackay; Guillermo Ruiz-Irastorza; Sam Lim; Murat Inanc; Kenneth Kalunian; Søren Jacobsen; Christine Peschken; Diane L Kamen; Anca Askanase; Jill P Buyon; David Sontag; Karen H Costenbader

doi:10.1136/ard-2022-223808

Machine learning identifies clusters of longitudinal autoantibody profiles predictive of systemic lupus erythematosus disease outcomes

Ann Rheum Dis. 2023 Jul;82(7):927-936. doi: 10.1136/ard-2022-223808. Epub 2023 Apr 21.

Authors

May Yee Choi¹, Irene Chen², Ann Elaine Clarke³, Marvin J Fritzler³, Katherine A Buhler³, Murray Urowitz⁴, John Hanly⁵, Yvan St-Pierre⁶, Caroline Gordon⁷, Sang-Cheol Bae⁸, Juanita Romero-Diaz⁹, Jorge Sanchez-Guerrero¹⁰, Sasha Bernatsky¹¹, Daniel J Wallace¹², David Alan Isenberg¹³, Anisur Rahman¹³, Joan T Merrill¹⁴, Paul R Fortin¹⁵, Dafna D Gladman⁴, Ian N Bruce¹⁶, Michelle Petri¹⁷, Ellen M Ginzler¹⁸, Mary Anne Dooley¹⁹, Rosalind Ramsey-Goldman²⁰, Susan Manzi²¹, Andreas Jönsen²², Graciela S Alarcón²³, Ronald F van Vollenhoven²⁴, Cynthia Aranow²⁵, Meggan Mackay²⁵, Guillermo Ruiz-Irastorza²⁶, Sam Lim²⁷, Murat Inanc²⁸, Kenneth Kalunian²⁹, Søren Jacobsen³⁰, Christine Peschken³¹, Diane L Kamen³², Anca Askanase³³, Jill P Buyon³⁴, David Sontag², Karen H Costenbader^{35

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Affiliations

¹ Medicine, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada may.choi@ucalgary.ca.
² Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
³ Medicine, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada.
⁴ Center for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University of Toronto, Lupus Clinic, Toronto, Ontario, Canada.
⁵ Division of Rheumatology, Department of Medicine and Department of Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
⁶ Medicine, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
⁷ Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, Birmingham University Medical School, Birmingham, West Midlands, UK.
⁸ Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Hanyang University Institute for Rheumatology and Hanyang University Institute of Bioscience and Biotechnology, Seoul, The Republic of Korea.
⁹ Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico.
¹⁰ Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, Ontario, Canada.
¹¹ Divisions of Rheumatology and Clinical Epidemiology, McGill University Health Centre, Montreal, Quebec, Canada.
¹² Division of Rheumatology, Cedars-Sinai/David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
¹³ Centre for Rheumatology, Department of Medicine, University College London, London, UK.
¹⁴ Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
¹⁵ Division of Rheumatology, CHU de Québec - Université Laval, Quebec City, Quebec, Canada.
¹⁶ Epidemiology Unit, University of Manchester, Manchester, UK.
¹⁷ Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁸ Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, USA.
¹⁹ Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
²⁰ Department of Medicine, Division of Rheumatology, Northwestern University and Feinberg School of Medicine, Chicago, Illinois, USA.
²¹ Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
²² Clinical Sciences, Lund University, Lund, Sweden.
²³ Department of Medicine, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA.
²⁴ Rheumatology & Immunology Center, University of Amsterdam, Amsterdam, The Netherlands.
²⁵ Division of Autoimmune and Musculoskeletal Disease, Feinstein Institute for Medical Research, Manhasset, New York, USA.
²⁶ Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Barakaldo, Spain.
²⁷ Division of Rheumatology, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁸ Department of Internal Medicine, Division of Rheumatology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
²⁹ Department of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA.
³⁰ Department of Rheumatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³¹ Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
³² Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
³³ Hospital for Joint Diseases, New York University, Seligman Centre for Advanced Therapeutics, New York, New York, USA.
³⁴ Division of Rheumatology, New York University School of Medicine, New York, New York, USA.
³⁵ Department of Medicine, Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA.
³⁶ Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

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.

Keywords: autoantibodies; autoimmunity; systemic lupus erythematosus.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Antinuclear
Autoantibodies*
DNA
Humans
Immunosuppressive Agents
Lupus Erythematosus, Systemic*
Machine Learning

Substances

Autoantibodies
Antibodies, Antinuclear
DNA
Immunosuppressive Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding