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INTERVAL-CENSORED OUTCOMES AND FLARE RISK AFTER HYDROXYCHLOROQUINE TAPERING/CESSATION: SENSITIVITY ANALYSES OF SYSTEMIC LUPUS INTERNATIONAL COLLABORATING CLINICS (SLICC) INCEPTION COHORT DATA
Abstract   Peer reviewed

INTERVAL-CENSORED OUTCOMES AND FLARE RISK AFTER HYDROXYCHLOROQUINE TAPERING/CESSATION: SENSITIVITY ANALYSES OF SYSTEMIC LUPUS INTERNATIONAL COLLABORATING CLINICS (SLICC) INCEPTION COHORT DATA

Rima Kaddoura, Celline Almeida-Brasil, John Hanly, Murray Urowitz, Ann Clarke, Guillermo Ruiz-Irastorza, Caroline Gordon, Rosalind Ramsey-Goldman, Michelle Petri, Ellen Ginzler, …
Journal of rheumatology, v 52(Suppl 1), pp 46-47
21 May 2025
DOI: https://doi.org/10.3899/jrheum.2025-0390.O052
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https://doi.org/10.3899/jrheum.2025-0390.O052View
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Abstract

Background/Purpose We previously evaluated hydroxychloroquine (HCQ) tapering/cessation and risk of systemic lupus erythematosus (SLE) flare in the SLICC Inception cohort. However, in our approach we did not account for potential bias due to interval-censored (IC) outcomes, where exact timing of events are unknown. Our objective was to address this, with alternative approaches to defining timing of IC events, including the Simulation Extrapolation (SIMEX) approach. Methods We evaluated 1,543 members of the SLICC Inception cohort (January 1999 to January 2019). Adults (18+) with SLE were enrolled in this cohort within 15 months of diagnosis and followed annually with questionnaires and physician assessment. In our time-to-event analyses, time-zero was defined as cohort entry if a subject was taking HCQ at the time, or the first prescription of HCQ otherwise. HCQ tapering/cessation was defined as the first cessation or decreased dose of HCQ and modeled as a binary time-varying exposure. Multivariable proportional hazard regression assessed associations between HCQ tapering/cessation and time to SLE flare, controlling for demographics (age, sex, race/ethnicity, region, education), baseline medication (steroids, immunosuppressives, biologics), enrollment year, time between diagnosis and cohort entry, smoking status, end-stage renal disease, and body mass index. Lupus flare was defined as the earliest of: A. Increase (from prior score) of at least 4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), B. Increase/initiation of SLE therapy (prednisone, immunosuppressive, or biologic), or C. SLE-related hospitalization. Since exact date of increased SLEDAI-2K was unknown, these represented IC events. We compared alternative analyses, imputing the IC event time at either the end- or the mid-point of the interval between the previous clinic visit and the visit when the outcome was reported. In sensitivity analyses we used SIMEX, a more sophisticated method based on simulations that allowed us to assess how the HR of interest changes with increasing time interval between adjacent visits. By extrapolating observed trends between the original and simulated data, we could correct the bias estimated to be within the original data, due to IC events.[1] Results Out of the total 1,543 subjects, 398 (25.8%) decreased or stopped their HCQ at some point during their follow-up and 1,187 experienced a disease flare (76.9%). When IC event times were imputed at the end of the relevant time interval, the adjusted HR for flare related to HCQ decrease/cessation was 1.43 (95% confidence interval, CI 1.24-1.66). When IC event times were imputed at the mid-point, the point estimate for the adjusted HR was slightly higher (1.53, 95% CI1.32-1.78). SIMEX correction yielded an even higher point estimate for the adjusted HR (1.68, bootstrapped 95% CI 1.44-2.02). Conclusions HCQ tapering/cessation was associated with greater flare risk regardless of how IC events were handled. Correcting imprecise timing of IC events tended to increase the strength of estimated associations, although confidence intervals overlapped. Limitations of these analyses include failure to account for disease status and/or other concomitant drug changes at tapering/cessation. Future analyses will address these issues (and stratify outcomes according to whether HCQ was tapered vs stopped).

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