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Objectives Type I interferon (IFN) signalling is a central driver of systemic lupus erythematosus (SLE). Anifrolumab, an anti-IFNAR1 monoclonal antibody, improves outcomes in moderate–severe, trial-eligible patients, however, pivotal trials excluded severe organ-threatening phenotypes and advised against initiation during clinically significant active infection. Herein, we describe the use of anifrolumab in fulminant, refractory mucocutaneous SLE with respiratory compromise and recurrent infections.Methods A 45-year-old woman with known SLE (ANA/dsDNA-positive, hypocomplementaemic) previously manifesting with diffuse ulcerative mucocutaneous disease, alopecia, serositis, pulmonary/mesenteric vasculitis, inflammatory arthritis with Jaccoud’s and shrinking-lung syndrome presented with life-threatening disease despite recent Euro-Lupus cyclophosphamide and rituximab. She presented with haemodynamic compromise (SLEDAI-2K 15) with diffuse ulcerative mucocutaneous lesions (CLASI-A 28; figure 1). Her shrinking lung syndrome progressed and resulted in significant hypercapnia. Admission serology showed dsDNA >400 IU/mL (NR <10), C3 0.37 g/L (NR 0.70-1.65) and C4 0.04 g/L (NR 0.16-0.54). High-dose IV glucocorticoids and re-induction cyclophosphamide were initated but stopped for severe, recurrent infections requiring multiple ICU admissions, rendering further cytotoxic therapy unsafe. Serology showed markedly elevated CXCL10 (1,788 pg/mL, NR 38-316) indicated IFN-driven disease, providing rationale for IFN blockade and anifrolumab 300 mg IV monthly was initiated.Results Within two months of initiation of anifrolumab, her mucocutaneous disease improved and over time hair fully regrew. SLEDAI-2K improved to 2 (mildly elevated DNA binding only). After 309 successive inpatient days, more than seven ICU admissions and consideration of palliation, the patient was discharged home and is now fully independent. Clinical and serological responses were rapid and durable, dsDNA fell from >400 to 17 IU/mL and complement levels normalised over the following 18 months. She remains on monthly Anifrolumab and continues in sustained clinical remission (having weaned off all other immunosuppressive agents and glucocorticoids) with a CLASI of 0.Abstract PT4:07 Figure 1Conclusions In severe, organ-threatening SLE complicated by infection and refractory to cyclophosphamide and rituximab, anifrolumab achieved profound clinical and serological recovery, concordant with CXCL10-flagged IFN-driven biology. This extends real-world use beyond trial populations and underscores biomarker-guided selection when cytotoxic options are unsafe. Clinically, anifrolumab warrants consideration as rescue therapy for high-risk, IFN-driven SLE with contraindications to further cytotoxic treatment.