Abstract Background/Aims Advances in rational drug design and recent clinical trials are leading to emergence of a range of novel therapies for SLE and therapeutic options in clinical practice are expected to broaden rapidly. The optimal real-world place of emerging and established agents will be guided by understanding their differential efficacy on specific SLE manifestations as well as efficacy for more resistant disease. Anifrolumab, a type-I interferon receptor blocking monoclonal antibody, showed efficacy in SLE in phase III trials with a notable effect on mucocutaneous disease although specific lesion subtypes and chroncicity were not explored. Severe refractory mucocutaneous SLE such as scarring discoid lesions are an important and common clinical challenge in current practice. We therefore prospectively evaluated the real-world efficacy and quality of life impact of anifolumab for active mucocutaneous SLE, recalcitrant to multiple biologic and immunosuppressant therapies. Methods Seven patients commenced anifrolumab (300 mg by monthly iv infusion) following application to the manufacturer’s early access programme (NCT 04750057). Prior biologic therapies were discontinued at least 5 half-lives in advance. Mucocutaneous disease activity was captured by Cutaneous Lupus Disease Area and Severity Index (CLASI) activity score and medical photography. Patient reported health-related quality of life comprising the Dermatology Life Quality Index (DLQI); Lupus-QoL and EQ5D-5L were evaluated at baseline, three and six months. Results Seven female patients with active mucocutaneous SLE (Discoid LE n = 5, chilblain LE n = 1, subacute cutaneous LE n = 1) and median disease duration of 17 years were evaluated. Median baseline CLASI activity score was 17 (range 10-26; higher scores indicating severe disease). Median number of previously failed therapies was 7 and included rituximab in 6/7, belimumab in 2/7 and thalidomide in 4/7. Rapid resolution of scale and erythema in DLE was established within 1 month of anifrolumab treatment. Improvements to chilblain lupus were evident by three months. CLASI activity score was improved ≥75% in all patients at 3 months. Clinical responses were associated with significant improvements in DLQI (p < 0.001) and EQ5D-VAS (p = 0.002) by three months. Lupus-QoL trended toward improvement across all domains but most strongly for fatigue (p = 0.01) and pain (p = 0.002) by 6 months. One patient discontinued treatment after 4 months due to polydermatomal shingles complicated by sensorineural hearing loss. Infection coincided with background prednisolone dose >15 mg daily, recent COVID-19 infection and new on-treatment hypogammaglobulinaemia (IgG <5 g/L). Prolonged aciclovir treatment was required for lesion resolution. Conclusion We report rapid real-world efficacy and quality of life impact of anifrolumab on highly refractory mucocutaneous SLE, which exceeded that anticipated from existing clinical trial data. Findings suggest a unique role for emerging interferon targeting therapies in management of mucocutaneous SLE but emphasize need for enhanced VZV precautions among higher risk patients. Disclosure L. Carter: Consultancies; UCB. Z. Wigston: None. P. Laws: Consultancies; Amgen, Celgene, Janssen, Leo, Lilly and Sanofi. Member of speakers’ bureau; AbbVie, Actelion and BMS. Grants/research support; UCB, Almirall, and Novartis. E.M. Vital: Consultancies; Roche, GSK, AstraZeneca, Aurinia Pharmaceuticals, Lilly and Novartis. Grants/research support; Roche, AstraZeneca and Sandoz.