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Objectives To assess clinical effectiveness, safety and in vivo effects on cytokines, chemokines and low-density neutrophils (LDNs) in patients with active systemic lupus erythematosus (SLE) treated with anifrolumab over a 12-month real-world follow-up.Methods We established a longitudinal, multicentre, observational cohort of adult patients with active SLE receiving anifrolumab 300 mg intravenously every 4 weeks. Patients with active lupus nephritis or central nervous system involvement were excluded. Clinical and laboratory measures were recorded at baseline and at months 3, 6, 9 and 12. Chemokines, cytokines, LDNs and neutrophil extracellular trap degradation products were assessed at the respective time points. Longitudinal changes were analysed using generalised additive models with patient-level random intercepts.Results Twenty patients were recruited. Baseline mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) was 10.9±5.0, with frequent musculoskeletal, immunological and cutaneous involvement. Over 12 months, mean SLEDAI-2K declined to 3.1 (95% CI 1.1 to 5.1; p<0.001). SLE Responder Index-4 response rates were 64.7% at month 12 in intention-to-treat analyses with non-responder imputation. By month 12, 86% of patients reached Lupus Low Disease Activity State and 50% achieved Definition of Remission in SLE remission. Physician Global Assessment improved from 1.6 to 0.2 (95% CI 0.0 to 0.5; p<0.001). Daily prednisolone equivalents were significantly reduced (p=0.036); a dose ≤5 mg/day was achieved in 11/13 patients receiving glucocorticoids at baseline, including three who discontinued glucocorticoids. Drug persistence at 12 months was 65%. Fifty-five adverse events were recorded, of which four were serious. Anifrolumab significantly reduced circulating LDNs (p=0.032), interferon-driven chemokines and inflammatory cytokines.Conclusion This real-world cohort provides clinical and mechanistic evidence that anifrolumab improves clinical outcomes, enables glucocorticoid tapering and reduces LDNs as well as interferon-driven chemokines in patients with active SLE. Safety and drug persistence were consistent with clinical trial data.Trial registration number DRKS00024360.