Extra-renal disease patterns in lupus nephritis: clinical and serological activity confers increased risk of renal flares and damage accrual

OBJECTIVE: To explore patterns of extra-renal disease activity following renal response in lupus nephritis (LN) and evaluate their association with renal flares and organ damage accrual. METHODS: Multicenter retrospective cohort study of patients with biopsy-proven LN who achieved renal response. Latent class analysis (LCA) was applied to identify patterns of extra-renal activity. Associations with adverse outcomes were examined using Cox proportional hazards models. RESULTS: A total of 168 patients were included. Over a median follow-up of 4.0 years, 92.3% of patients exhibited extra-renal activity at least once. Serological activity (anti-dsDNA positivity and/or hypocomplementemia) was the most frequent active domain, followed by mucocutaneous and musculoskeletal involvement. Clinically significant extra-renal flares occurred in 37.5% of patients. Higher non-renal SLEDAI-2K scores were independently associated with increased risk of subsequent renal flares (aHR 1.18, 95% CI 1.07-1.30) and damage accrual (aHR 1.23, 95% CI 1.13-1.35), while BILAG-A extra-renal flares were strongly associated with damage accrual (aHR 10.56, 95% CI 4.63-24.06). LCA identified three classes of extra-renal activity: (1) mucocutaneous/musculoskeletal, (2) combined serological-clinical activity, and (3) predominant hypocomplementemia. Only the combined phenotype was independently associated with renal flares (aHR 2.66, 95% CI 1.34-5.30) and damage accrual (aHR 2.37, 95% CI 1.07-5.25). In exploratory analyses stratified by anti-dsDNA status, clinical extra-renal activity was associated with adverse outcomes among anti-dsDNA positive visits. CONCLUSIONS: Extra-renal activity in LN following renal response is common. Anti-dsDNA positivity is the main factor associated with adverse outcomes, while concomitant clinical extra-renal activity may further increase risk among serologically active patients.