Inclusion Criteria:
* Diagnosis of SLE.
* Must be receiving at least one of the following SoC regimens for ≥ 4 weeks: oral glucocorticoids (≤1.0 mg/kg/day or ≤ 40 mg/day prednisone equivalent), antimalarials (hydroxychloroquine, chloroquine, or quinacrine), or a single permitted immunosuppressant (azathioprine, mycophenolate mofetil/mycophenolic acid, methotrexate, mizoribine, or tacrolimus) within specified dose limits.
* Participant must have moderate to severe active SLE disease defined as Systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) ≥ 6 total points.
* Body weight ≥ 15 kg.
* Participants must agree to follow study specific contraception requirements as per local regulations.
Exclusion Criteria:
* Known diagnosis of an IFN mediated autoinflammatory interferonopathy.
* History of, or current diagnosis of, clinically significant non-SLE related vasculitides.
* Active, severe SLE-driven renal disease with significant proteinuria.
* Active severe or unstable neuropsychiatric SLE including but not limited to aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; status epilepticus; cerebellar ataxia; and mononeuritis multiplex.
* In participants ≥ 11 years of age, a history or evidence of suicidal ideation (severity of 4 \[active: method and intent, but no plan\] or 5 \[active: method, intent, and plan\]) within the past 6 months; or any suicidal behavior within the past 12 months or recurrent suicidal behavior in the lifetime of the participant based on an assessment with the Columbia suicide severity rating scale (C-SSRS).
* History of, or current diagnosis of, catastrophic antiphospholipid syndrome (APS).
* History of recurrent or opportunistic infection requiring hospitalization and intravenous (IV) antibiotics.
* Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection, or a positive result for human immunodeficiency virus (HIV) infection.
* Active hepatitis B and C infection.
* Any active or recent herpes zoster (HZ) infection that has not completely resolved within 12 weeks prior to study entry or that emerges between screening and Day 1.
* Any history of severe or recurrent HZ, including non-cutaneous HZ, herpes encephalitis, ophthalmic herpes, or 2 or more prior HZ episodes.
* Any cytomegalovirus (CMV) or Epstein Barr virus (EBV) infection that has not completely resolved.
* History of cancer.
* Prior receipt of anifrolumab.
* Prior treatment with directly acting cytotoxic B-cell depleting therapeutics.
* A known history of allergy or reaction to any component of the study intervention formulation or history of anaphylaxis to any human gamma globulin therapy, human proteins, or monoclonal antibodies (mAbs).
