Association Between Severe Nonadherence to Hydroxychloroquine and Systemic Lupus Erythematosus Flares, Damage, and Mortality in 660 Patients From the SLICC Inception Cohort

Author:

Nguyen Yann1ORCID,Blanchet Benoît2ORCID,Urowitz Murray B.3ORCID,Hanly John G.4ORCID,Gordon Caroline5ORCID,Bae Sang‐Cheol6ORCID,Romero‐Diaz Juanita7,Sanchez‐Guerrero Jorge8,Clarke Ann E.9ORCID,Bernatsky Sasha10ORCID,Wallace Daniel J.11,Isenberg David A.12ORCID,Rahman Anisur12ORCID,Merrill Joan T.13,Fortin Paul R.14ORCID,Gladman Dafna D.3ORCID,Bruce Ian N.15,Petri Michelle16ORCID,Ginzler Ellen M.17,Dooley Mary Anne18,Ramsey‐Goldman Rosalind19ORCID,Manzi Susan20,Jönsen Andreas21,Alarcón Graciela S.22ORCID,Van Vollenhoven Ronald F.23,Aranow Cynthia24,Le Guern Véronique25,Mackay Meggan24,Ruiz‐Irastorza Guillermo26ORCID,Lim S. Sam27ORCID,Inanc Murat28,Kalunian Kenneth C.29,Jacobsen Søren30,Peschken Christine A.31,Kamen Diane L.32,Askanase Anca33ORCID,Buyon Jill34,Costedoat‐Chalumeau Nathalie1

Affiliation:

1. National Referral Centre for Rare Autoimmune and Systemic Diseases, Hôpital Cochin, AP‐HP Centre and Université Paris Cité and Centre de Recherche en Epidémiologie et Statistiques (CRESS), Unité Inserm 1153, Université de Paris Cité Paris France

2. Biologie du médicament‐Toxicologie, AP‐HP Centre–Hôpital Cochin, Université Paris Cité, and UMR8038 CNRS, U1268 INSERM, Université Paris Cité, PRES Sorbonne Paris Cité, CARPEM Paris France

3. Toronto Western Hospital, University of Toronto Toronto Ontario Canada

4. Queen Elizabeth II Health Sciences Centre and Dalhousie University Halifax Nova Scotia Canada

5. Institute of Inflammation and Ageing, University of Birmingham Birmingham United Kingdom

6. Hanyang University Hospital for Rheumatic Diseases, Hanyang University Institute for Rheumatology, and Hanyang University Institute of Bioscience and Biotechnology Seoul Korea

7. Instituto Nacional de Ciencias Médicas y Nutrición Mexico City Mexico

8. Mount Sinai Hospital and University Health Network, University of Toronto Toronto Canada

9. Cumming School of Medicine University of Calgary Calgary Alberta Canada

10. McGill University Health Centre Quebec Canada

11. University of California Los Angeles

12. University College London UK

13. Oklahoma Medical Research Foundation Oklahoma City

14. CHU de Québec–Université Laval Québec City Canada

15. NIHR Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Center and Centre for Epidemiology Versus Arthritis, The University of Manchester Manchester UK

16. Johns Hopkins University School of Medicine Baltimore Maryland

17. State University of New York Downstate Medical Center Brooklyn

18. Thurston Arthritis Research Center, University of North Carolina Chapel Hill

19. Northwestern University and Feinberg School of Medicine Chicago Illinois

20. Allegheny Health Network Pittsburgh Pennsylvania

21. Lund University Lund Sweden

22. University of Alabama at Birmingham Marnix E. Heersink School of Medicine

23. University of Amsterdam Amsterdam Noord‐Holland The Netherlands

24. Feinstein Institute for Medical Research Manhasset New York

25. National Referral Centre for Rare Autoimmune and Systemic Diseases, Hôpital Cochin, AP‐HP Centre, Université Paris Cité Paris France

26. BioCruces Bizkaia Health Research Institute, University of the Basque Country Barakaldo Spain

27. Emory University School of Medicine Atlanta Georgia

28. Istanbul University Istanbul Turkey

29. University of California San Diego School of Medicine La Jolla

30. Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark

31. University of Manitoba Winnipeg Manitoba Canada

32. Medical University of South Carolina Charleston

33. Hospital for Joint Diseases and, Seligman Centre for Advanced Therapeutics, New York University New York City

34. New York University School of Medicine New York City

Abstract

ObjectiveThe goals of this study were to assess the associations of severe nonadherence to hydroxychloroquine (HCQ), objectively assessed by HCQ serum levels, and risks of systemic lupus erythematosus (SLE) flares, damage, and mortality rates over five years of follow‐up.MethodsThe Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort is an international multicenter initiative (33 centers throughout 11 countries). The serum of patients prescribed HCQ for at least three months at enrollment were analyzed. Severe nonadherence was defined by a serum HCQ level <106 ng/mL or <53 ng/mL for HCQ doses of 400 or 200 mg/day, respectively. Associations with the risk of a flare (defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/American College of Rheumatology Damage Index [SDI] increase ≥1 point) and mortality with separate Cox proportional hazard models.ResultsOf the 1,849 cohort participants, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/mL (244–566); 48 patients (7.3%) had severe HCQ nonadherence. No covariates were clearly associated with severe nonadherence, which was, however, independently associated with both flare (odds ratio 3.38; 95% confidence interval [CI] 1.80–6.42) and an increase in the SDI within each of the first three years (hazard ratio [HR] 1.92 at three years; 95% CI 1.05–3.50). Eleven patients died within five years, including 3 with severe nonadherence (crude HR 5.41; 95% CI 1.43–20.39).ConclusionSevere nonadherence was independently associated with the risks of an SLE flare in the following year, early damage, and five‐year mortality.image

Funder

Arthritis Research UK

Canadian Institutes of Health Research

Gigtforeningen

LUPUS UK

National Institutes of Health

National Research Foundation of Korea

NIH Clinical Center

Novo Nordisk Fonden

Sandwell and West Birmingham Hospitals NHS Trust

Publisher

Wiley

Subject

Immunology,Rheumatology,Immunology and Allergy

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