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Objectives The skin, musculoskeletal, hematological (cytopenias) manifestations of SLE are considered mild to moderate and may respond to corticosteroids, antimalarials, and immunosuppressive drugs, but often in clinical practice, there are moderate to severe cases may require additional therapy. Anifrolumab, a human monoclonal antibody against the type I interferon receptor subunit 1, blocks interferon-mediated signaling a key pathway in SLE immunopathogenesis.To describe real-world effectiveness, glucocorticoid-sparing effects, and safety of anifrolumab in SLE at a national referral center.Methods Consecutive adults fulfilling the 2019 EULAR/ACR SLE criteria who received anifrolumab for longer 6 months (December 2024–October 2025) at the Department of Rheumatology, Clinical Center of Montenegro, were analyzed. Follow-up occurred every three months. Parameters included demographics, disease activity indices (SLEDAI-2K, SLE-DAS, CLASI), and glucocorticoid (GC) dose. Safety and treatment persistence were assessed descriptively.Results Twelve patients (91.7% female, mean age 47.4 ± 11.6 years) with mean disease duration 10.9 years were included. The main reasons for initiating anifrolumab were cutaneous manifestations in 5 patients (41.7%), articular involvement in 4 (33.3%), hematologic manifestations in 8 (66.7%), and steroid-related sequelae in 7 (58.3%), often overlapping.Mean SLEDAI-2K decreased from 18.3 at baseline to 3.3 at 6 months (-81.8%) and 0.8 at 9 months (-95.9%). Mean SLE-DAS declined from 8.5 to 2.7 (-68.8%), and CLASI from 6.1 to 1.8 (-71.2%) and 0.4 (-93.8%) at 6 and 9 months, respectively (figure 1). GC dose was reduced from 16.7 mg/day at baseline to 6.5 mg (-61.3%) and 4.4 mg (-73.8%) at 6 and 9 months (figure 2). By month 6, 83% of patients achieved SLEDAI-2K lower than 4, and 50% reached SLEDAI = 0 by month 9. There was only one adverse event, herpes zoster infection paravertebral, but there was no discontinuation of therapy in none of patients.Abstract PO:11:289 Figure 1–2Conclusions In this real-world cohort, anifrolumab induced rapid and sustained improvement in systemic, musculoskeletal and cutaneous disease activity with marked glucocorticoid sparing and excellent safety. These findings support anifrolumab as a valuable and well-tolerated therapeutic option for difficult-to-treat SLE in routine clinical practice.