Antimalarial use and extra-renal damage accrual in lupus nephritis: a longitudinal cohort study

OBJECTIVES: Antimalarial agents, particularly hydroxychloroquine, are fundamental in SLE management. While their renal benefits in lupus nephritis (LN) are recognized, their corresponding role in reducing extra-renal damage is less defined. This study examined the association between antimalarial use and extra-renal damage accrual in biopsy-confirmed LN. METHODS: This was a retrospective analysis of a prospectively followed cohort of patients with biopsy-confirmed LN enrolled in the University of Toronto Lupus Clinic (1970-2024). Extra-renal damage was defined as any increase (≥1) in the extra-renal SLICC/ACR Damage Index (SDI). Antimalarial use was analyzed as a time-dependent variable. Associations were assessed using multivariable Cox proportional hazards models. RESULTS: Among 352 patients, the median age was 34.1 years, 14.5% were male, and the median follow-up was 9.6 years [IQR 4.9-16.6]. Antimalarials were used by 47.7% at baseline, 58.5% during the first year, and 67.9% by year 5. Among 327 patients with complete SDI data, extra-renal damage occurred in 151 patients (46.2%) with a median time of 4.1 years [1.8-8.9]. In multivariable models, antimalarial use was independently protective against extra-renal damage accrual (HR 0.51, 95% CI 0.37-0.72). This protective effect remained significant across all baseline extra-renal SDI subgroups, including in patients with SDI=0 and those with SDI ≥1. CONCLUSIONS: Extra-renal damage is common in patients with LN. In this population, antimalarial therapy was associated with a significant protective effect against extra-renal damage. These findings extend the benefits of antimalarials beyond renal protection and reinforce their essential role in reducing damage accrual in SLE patients with LN.