0343: Severe Non-adherence to Hydroxychloroquine Is Associated with Flares, Early Damage, and Mortality in Systemic Lupus Erythematosus: Data from 660 Patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort

Yann Nguyen¹, Benoît BLanchet², Murray Urowitz³, John Hanly⁴, Caroline Gordon⁵, Sang-Cheol Bae⁶, Juanita Romero-Diaz⁷, Jorge Sanchez-Guerrero⁸, Ann E Clarke⁹, Sasha Bernatsky¹⁰, Daniel Wallace¹¹, David Isenberg¹², Anisur Rahman¹³, Joan Merrill¹⁴, Paul R Fortin¹⁵, Dafna Gladman¹⁶, Ian N. Bruce¹⁷, Michelle Petri¹⁸, Ellen M. Ginzler¹⁹, Mary Anne Dooley²⁰, Rosalind Ramsey-Goldman²¹, Susan Manzi²², Andreas Jönsen²³, Graciela Alarcón²⁴, Ronald van Vollenhoven²⁵, Cynthia Aranow²⁶, Veronique Le Guern²⁷, Meggan Mackay²⁶, Guillermo Ruiz-Irastorza²⁸, S. Sam Lim²⁹, Murat Inanc³⁰, Kenneth C Kalunian³¹, Soren Jacobsen³², Christine Peschken³³, Diane Kamen³⁴, Anca Askanase³⁵, Jill Buyon³⁶ and Nathalie Costedoat-Chalumeau³⁷, ¹AP-HP.Centre Universit Paris Cit Hôpital Cochin, Montmorency, France, ²Biologie du médicament-Toxicologie, AP-HP Centre – Hôpital Cochin, Université Paris Cité, Paris, France, Paris, ³University of Toronto, University Health Network, Schroeder Arthritis Institute, Toronto, ON, Canada, ⁴Division of Rheumatology, Queen Elizabeth II Health Sciences Center (Nova Scotia Rehabilitation Site) and Dalhousie University, Halifax, NS, Canada, ⁵Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom, ⁶Hanyang University Medical Center, Seoul, Republic of Korea, ⁷Instituto Nacional de Ciencias Medicas y Nutricion SZ, Ciudad de México, Mexico, ⁸Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON, Canada, ⁹University of Calgary, Division of Rheumatology, Cumming School of Medicine, Calgary, AB, Canada, ¹⁰Research Institute of the McGill University Health Centre, Montréal, QC, Canada, ¹¹Cedars-Sinai Medical Center, Los Angeles, CA, ¹²University College London, London, United Kingdom, ¹³Centre for Rheumatology, Department of Medicine, University College London, London, United Kingdom, ¹⁴Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁵Centre ARThrite - CHU de Québec - Université Laval, Québec, QC, Canada, ¹⁶Toronto Western Hospital, Schroeder Arthritis Institute, Toronto, ON, Canada, ¹⁷Centre for Epidemiology Versus Arthritis, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom, ¹⁸Johns Hopkins University School of Medicine, Division of Rheumatology, Baltimore, MD, ¹⁹SUNY Downstate Health Sciences University, Department of Medicine, Brooklyn, NY, ²⁰Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, ²¹Northwestern University Feinberg School of Medicine, Chicago, USA, Chicago, IL, ²²Allegheny Health Network, Lupus Center of Excellence, Wexford, PA, ²³Lund University, Lund, Sweden, ²⁴The University of Alabama at Birmingham, Oakland, ²⁵Amsterdam University Medical Centers, Amsterdam, Netherlands, ²⁶Feinstein Institutes for Medical Research, Manhasset, NY, ²⁷Hôpital Cochin, Paris, France, ²⁸Autoimmune Diseases Research Unit, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain, ²⁹Emory University, Atlanta, GA, ³⁰Division of Rheumatology, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Istambul, Turkey, ³¹University of California San Diego School of Medicine, La Jolla, ³²Rigshospitalet, Copenhagen, Denmark, ³³University of Manitoba, Winnipeg, MB, Canada, ³⁴Medical University of South Carolina, Charleston, SC, ³⁵Columbia University Medical Center, New York, NY, ³⁶NYU Grossman School of Medicine, New York, NY, ³⁷Inserm DR Paris 5, Paris, France

Background/Purpose: The efficacy of antimalarials, especially hydroxychloroquine (HCQ), in preventing flares of systemic lupus erythematosus (SLE) is well demonstrated, but its effectiveness is impaired by non-adherence to treatment, reported to vary between 3% and 85%. We aimed to assess the associations of baseline severe non-adherence to HCQ, objectively assessed by HCQ serum levels, and risks of SLE flares, damage, and mortality over 5 years of follow-up.

Methods: The SLICC Inception Cohort is a multicentric prospective study of SLE patients from 31 centers in 11 countries. Patients were enrolled within 15 months of recognition of SLE (1997 ACR classification criteria). Serum HCQ levels of patients with HCQ prescription for at least 3 months, sampled at enrollment (or, if unavailable, during the first-year follow-up visits), were centrally measured. Severe non-adherence was defined by a serum HCQ level < 106 ng/mL for a daily prescribed HCQ dose of 400 mg, and < 53 ng/mL for a daily HCQ dose of 200 mg, respectively (1). SLE flare was defined by the occurrence of one of the following events within the first year following serum collection: (a) increase of at least four point in the SLEDAI-2K; (b) new start in prednisone (oral or pulse) or immunosuppressive agent; (c) a new renal involvement (active nephritis, nephrotic syndrome). Association between severe non-adherence and SLE flare was assessed with logistic regression models, further adjusted on potential confounders. Damage was assessed by the time until an increase ≥1 in the SLICC damage index (SDI), within the 5 years following HCQ measurement. Associations between severe non-adherence and either damage or mortality (from all cause) within 5 years following HCQ measurement were assessed with Cox proportional hazard models, adjusted on sex, education, and potential confounders.

Results: Of 1849 cohort subjects, 660 patients (88% women) were included. Median [interquartile range] serum HCQ level was 388 ng/mL (244-566) and 48 patients (7.3%) had severe HCQ non-adherence. No factors were clearly associated with severe non-adherence. A SLE flare occurred in 191 (28.9%) patients within the first year (28 [58.3%] non-adherent patients versus 163 [26.6%] other patients). In multivariate analysis, severe nonadherence was independently associated with the risk of flare (OR= 3.32; 95% CI 1.78-6.28).

Within five years, 167 patients (25.3%) had ≥1 point increase of SDI. Severe on-adherence was associated with an increase in the SDI within each of the first 3 years (HR 1.92 at 3 years; 95% CI 1.05–3.50).

Eleven patients died within 5 years, including 3 with severe non-adherence (unadjusted HR 5.41; 95% CI 1.43–20.39).

Conclusion: In this large multicentric international prospective cohort, severe non-adherence was independently associated with the risk of SLE flare in the following year, with early damage, and 5-year mortality. As severe non-adherence is often unknown by the physician and since no predictive clinical or biological factors were identified, our results suggest the benefits of testing to detect severe non-adherence, to identify the patients at risk.

Figure 1. Kaplan Meier curves for the risk of damage, defined by a ≥1-point increase of SLICC/ACR damage index, according to severe non-adherence. Severe non-adherence was associated with the risk of SDI worsening at 1 (adjusted HR 4.26; 95% CI 1.40–13), 2 (adjusted HR 3.54; 95% CI 1.83–6.86) and 3 years after the HCQ measurement (adjusted HR 1.92; 95% CI 1.05–3.50), with a non-significant trend at 5 years (adjusted HR 1.47; 95% CI 0.86–2.49). *P < 0.05; **P < 0.01; NS: non-significant. Following variables were included in the multivariate models: age, black race, education level (post-secondary; ≤High school), SLEDAI-2000, azathioprine, and severe HCQ non-adherence.
Disclosures: Y. Nguyen, None; B. BLanchet, None; M. Urowitz, None; J. Hanly, None; C. Gordon, UCB, Amgen, Astra-Zeneca, AbbVie, Sanofi, MGP; S. Bae, None; J. Romero-Diaz, Biogen; J. Sanchez-Guerrero, None; A. Clarke, AstraZeneca, Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK); S. Bernatsky, None; D. Wallace, None; D. Isenberg, Merck/MSD, astra zeneca, Eli Lilly, Servier, Amgen; A. Rahman, None; J. Merrill, UCB, GlaxoSmithKline, AbbVie, EMD Serono, Remegen, Celgene/Bristol Myers Squibb, AstraZeneca, Amgen, Janssen, Lilly, Genentech, Aurinia, Astellas, Alexion, Sanofi, Zenas, Proventio; P. Fortin, AstraZeneca, GlaxoSmithKlein(GSK); D. Gladman, AbbVie, Amgen, Eli Lilly, Janssen, Gilead, Novartis, Pfizer, Bristol-Myers Squibb(BMS), Galapagos, UCB Pharma, Celgene; I. Bruce, AstraZeneca, Bristol-Myers Squibb(BMS), Eli Lilly, Aurinia, Janssen, GlaxoSmithKlein(GSK); M. Petri, Exagen, AstraZeneca, Alexion, Amgen, AnaptysBio, Argenx, Aurinia, Biogen, Caribou Biosciences, CVS Health, EMD Serono, Eli Lilly, Emergent Biosolutions, GlaxoSmithKline (GSK), IQVIA, Janssen, Kira Pharmaceuticals, MedShr, Sanofi, SinoMab, Thermofisher, BPR Scientific Advisory Committee; E. Ginzler, Aurinia Pharma; M. Dooley, None; R. Ramsey-Goldman, None; S. Manzi, AstraZeneca, GlaxoSmithKline (GSK), Exagen Diagnostics Inc, AbbVie, HGS, Cugene, Lilly, UCB Advisory Board, Lupus Foundation of America; A. Jönsen, None; G. Alarcón, None; R. van Vollenhoven, Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK), UCB, Merck/MSD, Pfizer, Roche, AbbVie, AstraZeneca, Biogen, Galapagos, Janssen, Miltenyi, R-Pharma; C. Aranow, None; V. Le Guern, None; M. Mackay, None; G. Ruiz-Irastorza, None; S. Lim, None; M. Inanc, None; K. Kalunian, None; S. Jacobsen, None; C. Peschken, None; D. Kamen, None; A. Askanase, AstraZeneca, GlaxoSmithKlein(GSK), Aurinia, Amgen, Pfizer, Idorsia, Eli Lilly, UCB, AbbVie/Abbott, Janssen, Bristol-Myers Squibb(BMS); J. Buyon, None; N. Costedoat-Chalumeau, UCB, Roche.