Defining Optimally Safe and Effective Blood Levels of Hydroxychloroquine in Lupus: An Important Step Toward Precision Drug Monitoring

Shivani Garg^{1

2}, Benoît Blanchet³, Yann Nguyen⁴, Fauzia Hollnagel¹, Ada Clarke⁴, Michelle Petri⁵, Murray B Urowitz⁶, John G Hanly⁷, Caroline Gordon⁸, Sang-Cheol Bae⁹, Juanita Romero-Diaz¹⁰, Jorge Sanchez-Guerrero¹¹, Ann E Clarke¹², Sasha Bernatsky¹³, Daniel J Wallace¹⁴, David A Isenberg¹⁵, Anisur Rahman¹⁵, Joan T Merrill¹⁶, Paul R Fortin¹⁷, Dafna D Gladman⁶, Ian N Bruce^{18

19}, Ellen M Ginzler²⁰, Mary Anne Dooley²¹, Rosalind Ramsey-Goldman²², Susan Manzi²³, Andreas Jönsen²⁴, Graciela S Alarcón²⁵, Ronald F Van Vollenhoven²⁶, Cynthia Aranow²⁷, Véronique Le Guern⁴, Meggan Mackay²⁷, Guillermo Ruiz-Irastorza²⁸, S Sam Lim²⁹, Murat Inanc³⁰, Kenneth C Kalunian³¹, Søren Jacobsen³², Christine A Peschken³³, Diane L Kamen³⁴, Anca Askanase³⁵, Jill Buyon³⁶, Julie Chezel³⁷, Alicja Puszkiel³⁸, Nathalie Costedoat-Chalumeau⁴

Affiliations

¹ University of Wisconsin School of Medicine and Public Health, Madison.
² Yale University, New Haven, Connecticut.
³ Biologie du Médicament-Toxicologie, Hôpital Cochin, Institut du Cancer Paris CARPEM, AP-HP Centre and Université de Paris, CNRS, INSERM, CiTCoM, U1268, Paris, France.
⁴ 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, Unité Inserm 1153, Université de Paris Cité, Paris, France.
⁵ Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁶ Division of Rheumatology, University of Toronto and Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada.
⁷ Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
⁸ Department of Inflammation and Ageing, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom.
⁹ Hanyang University Hospital for Rheumatic Diseases, Hanyang University Institute for Rheumatology, and Hanyang Institute of Bioscience and Biotechnology, Seoul, Korea.
¹⁰ Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico.
¹¹ Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, Ontario, Canada.
¹² Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹³ McGill University Health Centre, Montreal, Quebec, Canada.
¹⁴ University of California, Los Angeles.
¹⁵ University College London, London, United Kingdom.
¹⁶ Oklahoma Medical Research Foundation, Oklahoma City.
¹⁷ Centre ARThrite-UL, CHU de Québec-Université Laval, Quebec City, Quebec, Canada.
¹⁸ Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
¹⁹ Centre for Public Health, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
²⁰ State University of New York Downstate Medical Center, Brooklyn, New York City.
²¹ Thurston Arthritis Research Center, University of North Carolina at Chapel Hill.
²² Northwestern University Feinberg School of Medicine, Chicago, Illinois.
²³ Allegheny Health Network, Pittsburgh, Pennsylvania.
²⁴ Lund University, Lund, Sweden.
²⁵ University of Alabama at Birmingham Marnix E. Heersink School of Medicine.
²⁶ University of Amsterdam, Amsterdam, the Netherlands.
²⁷ Feinstein Institute for Medical Research, Manhasset, New York.
²⁸ Biobizkaia Health Research Institute, University of the Basque Country, Barakaldo, Spain.
²⁹ Emory University School of Medicine, Atlanta, Georgia.
³⁰ Istanbul University, Istanbul, Turkey.
³¹ University of California San Diego School of Medicine, La Jolla.
³² Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³³ University of Manitoba, Winnipeg, Manitoba, Canada.
³⁴ Medical University of South Carolina, Charleston.
³⁵ Hospital for Joint Diseases and Seligman Centre for Advanced Therapeutics, New York University, New York City.
³⁶ New York University School of Medicine, New York City.
³⁷ Bichat University Hospital, AP-HP, Paris, France.
³⁸ Biologie du Médicament - Toxicologie, Cochin University Hospital, AP-HP and Université Paris Cité, INSERM, Optimisation thérapeutique en neuropharmacologie U1144, Paris, France.

PMID: 41367131
DOI: 10.1002/art.70010

Defining Optimally Safe and Effective Blood Levels of Hydroxychloroquine in Lupus: An Important Step Toward Precision Drug Monitoring

Shivani Garg et al. Arthritis Rheumatol. 2025.

. 2025 Dec 9.

doi: 10.1002/art.70010. Online ahead of print.

Authors

Affiliations

¹ University of Wisconsin School of Medicine and Public Health, Madison.
² Yale University, New Haven, Connecticut.
³ Biologie du Médicament-Toxicologie, Hôpital Cochin, Institut du Cancer Paris CARPEM, AP-HP Centre and Université de Paris, CNRS, INSERM, CiTCoM, U1268, Paris, France.
⁴ 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, Unité Inserm 1153, Université de Paris Cité, Paris, France.
⁵ Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁶ Division of Rheumatology, University of Toronto and Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada.
⁷ Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
⁸ Department of Inflammation and Ageing, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom.
⁹ Hanyang University Hospital for Rheumatic Diseases, Hanyang University Institute for Rheumatology, and Hanyang Institute of Bioscience and Biotechnology, Seoul, Korea.
¹⁰ Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico.
¹¹ Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, Ontario, Canada.
¹² Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹³ McGill University Health Centre, Montreal, Quebec, Canada.
¹⁴ University of California, Los Angeles.
¹⁵ University College London, London, United Kingdom.
¹⁶ Oklahoma Medical Research Foundation, Oklahoma City.
¹⁷ Centre ARThrite-UL, CHU de Québec-Université Laval, Quebec City, Quebec, Canada.
¹⁸ Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
¹⁹ Centre for Public Health, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
²⁰ State University of New York Downstate Medical Center, Brooklyn, New York City.
²¹ Thurston Arthritis Research Center, University of North Carolina at Chapel Hill.
²² Northwestern University Feinberg School of Medicine, Chicago, Illinois.
²³ Allegheny Health Network, Pittsburgh, Pennsylvania.
²⁴ Lund University, Lund, Sweden.
²⁵ University of Alabama at Birmingham Marnix E. Heersink School of Medicine.
²⁶ University of Amsterdam, Amsterdam, the Netherlands.
²⁷ Feinstein Institute for Medical Research, Manhasset, New York.
²⁸ Biobizkaia Health Research Institute, University of the Basque Country, Barakaldo, Spain.
²⁹ Emory University School of Medicine, Atlanta, Georgia.
³⁰ Istanbul University, Istanbul, Turkey.
³¹ University of California San Diego School of Medicine, La Jolla.
³² Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³³ University of Manitoba, Winnipeg, Manitoba, Canada.
³⁴ Medical University of South Carolina, Charleston.
³⁵ Hospital for Joint Diseases and Seligman Centre for Advanced Therapeutics, New York University, New York City.
³⁶ New York University School of Medicine, New York City.
³⁷ Bichat University Hospital, AP-HP, Paris, France.
³⁸ Biologie du Médicament - Toxicologie, Cochin University Hospital, AP-HP and Université Paris Cité, INSERM, Optimisation thérapeutique en neuropharmacologie U1144, Paris, France.

PMID: 41367131
DOI: 10.1002/art.70010

Abstract

Objective: Using a hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust the HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring.

Methods: This observational study included patients (N = 2,010) across the Systemic Lupus International Collaborating Clinics, Wisconsin, international, and French studies who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified an HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for the Systemic Lupus Erythematosus Disease Activity Index 2000 [score ≥6]). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels.

Results: Among 1,842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ-related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1,150 ng/mL and 1.7-fold higher with the cumulative HCQ dose per 1,000-g increase. Blood levels ≥1,150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1,150 ng/mL).

Conclusion: The therapeutic reference range for HCQ blood level monitoring is 750 to <1,150 ng/mL. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.

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References

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Defining Optimally Safe and Effective Blood Levels of Hydroxychloroquine in Lupus: An Important Step Toward Precision Drug Monitoring

Affiliations

Defining Optimally Safe and Effective Blood Levels of Hydroxychloroquine in Lupus: An Important Step Toward Precision Drug Monitoring

Authors

Affiliations

Abstract

References

Grants and funding

LinkOut - more resources

Full Text Sources