A Study to Learn About the Safety of Litifilimab (BIIB059) Injections and Whether They Can Improve Symptoms of Adult Participants Who Have Systemic Lupus Erythematosus

In this study, researchers will learn more about a study drug called litifilimab (BIIB059) in participants with systemic lupus erythematosus (SLE). The study will focus on participants who have active disease and are already taking standard of care medications. These may include antimalarials, steroids, and immunosuppressants. The main objective of the study is to learn about the effect litifilimab has on lowering the activity of the disease. The main question researchers want to answer is: \- How many participants have an improvement in their symptoms after 52 weeks of treatment? Researchers will answer this and other questions by measuring the symptoms of SLE over time using a variety of scoring tools. These include the SLE Responder Index (SRI), the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K), the British Isles Lupus Activity Group-2004 index (BILAG-2004), and the BILAG-BASED Combined Lupus Assessment (BICLA), among others. Researchers will also learn more about the safety of litifilimab. They will study how participants' immune systems respond to litifilimab. Additionally, they will measure the effect litifilimab and SLE have on the quality of life of participants using a group of questionnaires. The study will be done as follows: * After screening, participants will be randomized to receive either a high or low dose of litifilimab, or placebo. A placebo looks like the study drug but contains no real medicine. * All participants will receive either litifilimab or placebo as injections under the skin once every 4 weeks. The treatment period will last 52 weeks. Participants will continue to take their standard of care medications. * Neither the researchers nor the participants will know if the participants are receiving litifilimab or placebo. * There will be a follow-up safety period that lasts up to 24 weeks. * In total, participants will have up to 22 study visits. The total study duration for participants will be up to 80 weeks.

The primary objective of the study is to demonstrate the efficacy of litifilimab compared with placebo in participants with active SLE, who are receiving background lupus standard of care (SOC) therapy in reducing disease activity. The secondary objectives of this study are to demonstrate efficacy of litifilimab compared with placebo in participants with active SLE, who are receiving background lupus SOC therapy in reducing disease activity and occurrence of flare up to Week 52; to demonstrate organ-specific efficacy of litifilimab compared with placebo in participants with active SLE, who are receiving background lupus SOC therapy in reducing joint disease activity and skin disease activity; to demonstrate and evaluate effect of litifilimab compared with placebo in reducing oral corticosteroid(s) (OCS) use; to evaluate additional efficacy of litifilimab compared with placebo in reducing disease activity with additional disease activity measures; assess the difference between litifilimab and placebo on participant reported health-related quality of life (HRQoL), symptoms, and impacts of SLE; to evaluate the safety, tolerability and immunogeneicty of litifilimab in participants with active SLE.

Key Inclusion Criteria: * Participant must be diagnosed with systemic lupus erythematosus (SLE) at least 24 weeks prior to screening and must meet the 2019 European League Against Rheumatism (EULAR) / American College of Rheumatology (ACR) classification criteria for SLE at screening by a qualified physician. * Participant has a modified Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score ≥ 6 (excluding alopecia, fever, lupus-related headache, and organic brain syndrome) at screening (adjudicated). * Participant has a modified clinical SLEDAI-2K score ≥ 4 (excluding anti-dsDNA, low complement component 3 (C3) and/or complement component 4 (C4), alopecia, fever, lupus-related headache, and organic brain syndrome) at Screening (adjudicated) and randomization. * Participant has BILAG-2004 grade A in ≥ 1 organ system or BILAG-2004 grade B in ≥ 2 organ systems at Screening (adjudicated) and randomization. * Participant must be treated with one of the following background nonbiologic lupus SOC therapies, initiated ≥ 12 weeks prior to Screening and at stable dose ≥ 4 weeks prior to randomization: 1. Antimalarials as stand-alone treatment 2. Antimalarial treatment in combination with OCS and/or a single immunosuppressant 3. Treatment with OCS and/or a single immunosuppressant Key Exclusion Criteria: * History of or positive test result for human immunodeficiency virus (HIV). * Current hepatitis C infection (defined as positive hepatitis C virus (HCV) antibody and detectable HCV ribonucleic acid \[RNA\]). * Current hepatitis B infection (defined as positive for antibody to hepatitis B surface antigen (HBsAg) and/or positive for total hepatitis antibody to B core antigen \[anti-HBc\] with positive reflex HBV DNA). * History of severe herpes infection. * Presence of uncontrolled or New York Heart Association class III or IV congestive heart failure. * Active severe lupus nephritis where, in the opinion of the Investigator, protocol-specified SOC is insufficient and use of a more aggressive therapeutic approach is indicated, such as adding IV cyclophosphamide and/or high-dose IV pulse corticosteroid therapy or other treatments not permitted in the protocol is indicated; or urine protein-creatinine ratio \> 2.0 or severe chronic kidney disease (estimated glomerular filtration rate \< 30 milliliters per minute per 1.73 meter square \[mL/min/1.73 m\^2\]) calculated using the abbreviated modification of diet in renal disease equation. * Any active skin conditions other than cutaneous lupus erythematosus (CLE) that may interfere with the study assessment of CLE such as but not limited to psoriasis, dermatomyositis, systemic sclerosis, non-LE skin lupus manifestation or drug-induced lupus. * History or current diagnosis of a clinically significant non-SLE-related vasculitis syndrome. * Active neuropsychiatric SLE. * Use of oral prednisone (or equivalent) above 20 mg/day. Note: Other protocol defined Inclusion/Exclusion criteria may apply.