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Systemic lupus erythematosus
European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance
  1. Martin Aringer1,
  2. Ralph Brinks2,
  3. Thomas Dörner3,
  4. David Daikh4,
  5. Marta Mosca5,
  6. Rosalind Ramsey-Goldman6,
  7. Josef S Smolen7,
  8. David Wofsy8,
  9. Dimitrios T Boumpas9,
  10. Diane L Kamen10,
  11. David Jayne11,
  12. R Cervera12,
  13. Nathalie Costedoat-Chalumeau13,
  14. Betty Diamond14,
  15. Dafna D Gladman15,
  16. Bevra Hahn16,
  17. Falk Hiepe3,
  18. Søren Jacobsen17,
  19. Dinesh Khanna18,
  20. Kirsten Lerstrøm19,
  21. Elena Massarotti20,21,
  22. Joseph McCune18,
  23. Guillermo Ruiz-Irastorza22,
  24. Jorge Sanchez-Guerrero23,24,
  25. Matthias Schneider2,
  26. Murray Urowitz25,
  27. George Bertsias26,27,
  28. Bimba F Hoyer3,28,
  29. Nicolai Leuchten1,
  30. Gabriela Schmajuk29,
  31. Chiara Tani5,
  32. Sara K Tedeschi20,21,
  33. Zahi Touma15,30,
  34. Branimir Anic31,
  35. Florence Assan32,
  36. Tak Mao Chan33,
  37. Ann Elaine Clarke34,
  38. Mary K Crow35,
  39. László Czirják36,
  40. Andrea Doria37,
  41. Winfried Graninger38,
  42. Bernadett Halda-Kiss36,
  43. Sarfaraz Hasni39,
  44. Peter M Izmirly40,
  45. Michelle Jung34,
  46. Gábor Kumánovics36,
  47. Xavier Mariette41,42,
  48. Ivan Padjen31,
  49. José M Pego-Reigosa43,
  50. Juanita Romero-Diaz23,
  51. Íñigo Rúa-Figueroa44,
  52. Raphaèle Seror45,
  53. Georg H Stummvoll7,
  54. Yoshiya Tanaka46,
  55. Maria G Tektonidou47,
  56. Carlos Vasconcelos48,
  57. Edward M Vital49,50,
  58. Daniel J Wallace51,
  59. Sule Yavuz52,
  60. Pier Luigi Meroni53,
  61. Marvin J Fritzler54,
  62. Ray Naden55,
  63. Karen Costenbader20,21,
  64. Sindhu R Johnson30,56
  1. 1 University Medical Center and Faculty of Medicine, Department of Medicine III, Division of Rheumatology, TU Dresden, Dresden, Germany
  2. 2 Policlinic and Hiller Research Unit for Rheumatology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  3. 3 Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
  4. 4 Oregon Health and Sciences University and Portland VA Health Care System, Portland, Oregon, USA
  5. 5 Rheumatology Unit, Azienda Ospedaliero Universitaria Pisana, University of Pisa, Pisa, Italy
  6. 6 Medicine/ Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  7. 7 Medical University of Vienna, Wien, Austria
  8. 8 Russell/ Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, California, USA
  9. 9 Medicine, National and Kapodestrian University of Athens, Athens, Greece
  10. 10 Medical University of South Carolina, Charleston, South Carolina, USA
  11. 11 Division of Nephrology, Department of Medicine, University of Cambridge, Cambridge, UK
  12. 12 Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Barcelona, Spain
  13. 13 Internal Medicine, Centre de référence maladies auto-immunes et systémiques rares d'île de France, Cochin Hospital, Université Paris Descartes-Sorbonne Paris Cité, Paris, France
  14. 14 The Feinstein Institute for Medical Research, Manhasset, New York, USA
  15. 15 Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  16. 16 Rheumatology, UCLA School of Medicine, Los Angeles, California, USA
  17. 17 Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
  18. 18 Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
  19. 19 LUPUS EUROPE, Romford, UK
  20. 20 Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  21. 21 Harvard Medical School, Boston, Massachusetts, USA
  22. 22 Autoimmune Diseases Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, UPV/EHU, Bizkaia, The Basque Country, Spain
  23. 23 Immunology and Rheumatology, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico
  24. 24 Department of Medicine, Mount Sinai Hospital/University Health Network, University of Toronto, Toronto, Ontario, Canada
  25. 25 Division of Rheumatology, Department of Medicine, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
  26. 26 Rheumatology, Clinical Immunology and Allergy, University of Crete School of Medicine, Heraklion, Greece
  27. 27 Laboratory of Autoimmunity-Inflammation, Institute of Molecular Biology and Biotechnology, Heraklion, Greece
  28. 28 Department of Rheumatology and Clinical Immunology, University of Schleswig-Holstein at Kiel, Kiel, Germany
  29. 29 Department of Medicine, Division of Rheumatology, University of California at San Francisco and the VA Medical Center, San Francisco, California, USA
  30. 30 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
  31. 31 Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Zagreb School of Medicine and University Hospital Centre Zagreb, Zagreb, Croatia
  32. 32 INSERM UMR 1163, Université Paris Sud, Hôpitaux Universitaires Paris-Sud, AP-HP, INSERM UMR 1184, Paris, France
  33. 33 Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong
  34. 34 Division of Rheumatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  35. 35 Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, New York, USA
  36. 36 Department of Rheumatology and Immunology, University of Pécs, Pécs, Hungary
  37. 37 Division of Rheumatology, University of Padova, Padova, Italy
  38. 38 Internal Medicine, Medical University of Graz, Graz, Austria
  39. 39 Lupus Clinical Research Program, Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
  40. 40 Rheumatology, New York University School of Medicine, New York, New York, USA
  41. 41 Rheumatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux universitaires Paris-Sud – Hôpital Bicêtre, Le Kremlin Bicêtre, France
  42. 42 Université Paris-Sud, Center for Immunology of Viral Infections and Auto-immune Diseases (IMVA), Institut pour la Santé et la Recherche Médicale (INSERM) UMR 1184, Université Paris-Saclay, Le Kremlin Bicêtre, France
  43. 43 Department of Rheumatology, University Hospital of Vigo, IRIDIS Group, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Spain
  44. 44 Rheumatology, Doctor Negrín University Hospital, Las Palmas de Gran Canaria, Las Palmas, Spain
  45. 45 Université Paris Sud, Hôpitaux Universitaires Paris-Sud, AP-HP, INSERM UMR 1184, Le Kremlin-Bicêtre, France
  46. 46 First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
  47. 47 Medical School, National and Kapodistrian University of Athens, Athens, Greece
  48. 48 Centro Hospitalar do Porto, ICBAS, UMIB, University of Porto, Porto, Portugal
  49. 49 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
  50. 50 NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  51. 51 Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  52. 52 Rheumatology, Istanbul Bilim Universitesi, Istanbul, Turkey
  53. 53 Clinical Immunology and Rheumatology Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy
  54. 54 Fcaulty of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  55. 55 McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  56. 56 Department of Medicine, Division of Rheumatology, Toronto Western Hospital, Toronto, Ontario, Canada
  1. Correspondence to Professor Martin Aringer, University Medical Center and Faculty of Medicine, Department of Medicine III, Division of Rheumatology, TU Dresden, 01062 Dresden, Sachsen, Germany; martin.aringer{at}uniklinikum-dresden.de; Dr Sindhu R Johnson; Sindhu.Johnson{at}uhn.ca

Abstract

Background/objectives The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria.

Methods We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE.

Results Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement.

Conclusions Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

  • lupus erythematosus
  • systemic
  • antibodies
  • antiphospholipid
  • autoantibodies
  • synovitis

Data availability statement

All data relevant to this study are included in this manuscript (including the supplementary information) or the previous two manuscripts on the EULAR/ACR classification criteria.

https://doi.org/10.1136/annrheumdis-2020-219373

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    Data availability statement

    All data relevant to this study are included in this manuscript (including the supplementary information) or the previous two manuscripts on the EULAR/ACR classification criteria.

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    Footnotes

    • Handling editor David S Pisetsky

    • Twitter @none, @edvital

    • Deceased Ray Naden deceased on 16 August 2020

    • Contributors All authors were involved in the EULAR/ACR classification criteria exercises, contributed to the manuscript and critically read and approved the final version. This final version could unfortunately not be read and approved any more by RN, who died in early autumn of 2020, as referred to on the title page. He was intimately involved in the study and had been up to date with the manuscript until a few days before his death.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient and public involvement statement SLE patient representatives were involved at every stage of the EULAR/ACR classification criteria project.

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

    • Author note We mourn Prof Ray Naden, who passed away on August 16th 2020. The authors wish to dedicate this article to his memory as a friend and colleague, and to highlight his efforts for these and other criteria.

    • 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.