OBJECTIVES: DORIS remission, based on clinical activity, and Lupus Low Disease Activity State (LLDAS), which includes serological markers, are protective targets in SLE. However, it remains unclear whether their prognostic impact is influenced by serum anti-dsDNA and complement levels. METHODS: We analysed data from five phase III trials (BLISS-52, BLISS-76, BLISS-SC, BLISS-NEA, EMBRACE) totalling 45 254 monthly visits. Generalized linear models evaluated the effects of DORIS/LLDAS -with or without active serology- on the risk for severe (BILAG ≥1A/2B) and renal (BILAG A/B) flares. Organ damage was also assessed. RESULTS: Normal serology occurred in 544/1871 (29.1%) DORIS and 1879/4760 (39.5%) LLDAS visits. Using no-DORIS as reference, DORIS with anti-dsDNA(-) or normal/high C3/C4 demonstrated stronger protection against severe flares (odds ratios[ORs] 0.042
95% CI 0.005-0.331 and 0.216
95% CI 0.094-0.494, respectively) compared with DORIS with anti-dsDNA(+) or low C3/C4 (ORs 0.511
95% CI 0.284-0.919 and 0.528
95% CI 0.261-1.067). Similarly, LLDAS with normal serology showed greater risk-reduction in severe flares compared with LLDAS with active serology, especially low C3/C4. For renal flares, DORIS with serological activity carried ∼6-fold higher risk compared with combined clinical/serological remission (OR 5.94
95% CI 1.26-28.04). Damage accrual was lowest in patients with sustained DORIS and ≥1 visit showing anti-dsDNA(-) (0.8%) or normal C3/C4 (1.8%). CONCLUSION: Normal serology enhances the protection of DORIS and LLDAS against severe and renal SLE flares, possible reflecting deeper states of disease control. Patients with recently active disease who meet clinical targets but have persistently abnormal serology may require close monitoring to minimize flare-risk.