Systemic Lupus Erythematosus (SLE) is an immune-mediated disease associated with inflammation of multiple organ systems. This study will assess how safe and effective upadacitinib is in treating adult participants with moderately to severely active SLE. Adverse events and change in the disease activity will be assessed. Upadacitinib is an approved drug for rheumatoid arthritis, psoriatic arthritis, and axial spondylarthritis and is being developed for the treatment of SLE. This study is "double-blinded", which means that neither the trial participants nor the study doctors will know who will be given upadacitinib and who will be given placebo (does not contain treatment drug) . This study comprised of 4 sub studies. In Study 1 and Study 2, study doctors put the participants in 1 of the 2 groups, called treatment arms. Each group receives a different treatment. There is a 1 in 2 chance that participants will be assigned to placebo. Eligible participants from Study 1 and Study 2 will enter Study 3 at week 52 to receive specific doses of upadacitinib. Study 4 is a 104-week continued extension if participation is likely to provide a benefit to their SLE. Approximately 500 participants diagnosed with SLE will be enrolled in each of the Study 1 and Study 2 in approximately 320 sites across the world. Participants will receive oral tablets of upadacitinib or matching placebo once daily for 52 weeks in Study 1 and Study 2. Eligible participants from Study 1 and Study 2 will receive oral tablets of upadacitinib once daily for 52 weeks in Study 3. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, checking for side effects and completing questionnaires.
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Inclusion Criteria: * Clinical diagnosis of systemic lupus erythematosus (SLE) at least 24 weeks prior to screening as defined by the 2019 European Alliance of Associations for Rheumatology (EULAR)/ American College of Rheumatology (ACR) classification criteria for SLE. * At Screening, must have at least one of the following: * antinuclear antibody (ANA) positive (titer \>= 1:80) * anti-double stranded deoxyribonucleic acid (dsDNA) positive * anti-Smith positive * Hybrid systemic lupus erythematosus disease activity index (hSLEDAI) \>= 6, of which \>= 4 points are clinical (not based on laboratory criteria), independently reviewed by the MCDR at Screening. Clinical hSLEDAI score (not based on laboratory criteria) must be re-confirmed as \>= 4 at the Baseline visit. Lupus headache or organic brain syndrome do not count towards the hSLEDAI points required for eligibility but should be documented on the hSLEDAI if present. * Physician's Global Assessment (PhGA) \>= 1 during screening period. * On stable background treatment for \>= 60 days prior to Baseline (with the exception of oral corticosteroid \[OCS\], which must be at a stable dose for \>=14 days prior to Baseline) with * antimalarial(s) \[hydroxychloroquine \<= 400 mg daily, chloroquine \<= 500 mg daily, quinacrine \<= 100 mg daily\]; * and/or prednisone (or prednisone-equivalent) (\<= 20 mg daily); * and/or no more than 1 of the following: azathioprine (\<= 150 mg daily), 6-mercaptopurine (\<= 150 mg daily), mycophenolate mofetil (\<= 2 g daily), mycophenolate sodium \<= 1,440 mg/day, leflunomide (\<= 20 mg daily), cyclosporine, tacrolimus, voclosporin (\<= 23.7 mg twice daily), methotrexate (\<= 25 mg weekly), or mizoribine (\<= 150 mg daily). Exclusion Criteria: * Class III/IV lupus nephritis that was treated with induction therapy within the 6 months prior to Screening. * Active neuropsychiatric SLE (excluding lupus headache) within the 6 months prior to Screening. * SLE overlap syndromes including, but not limited to, rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, or mixed connective tissue disease (Sjögren's syndrome is permitted). * Antiphospholipid syndrome and prior unprovoked venous or arterial thrombosis who are not on stable and adequate anticoagulation. * Two or more episodes of herpes zoster, or one or more episodes of disseminated herpes zoster or herpes zoster ophthalmicus. * History of malignancy, except for successfully treated non-melanoma skin cancer or localized carcinoma in situ of the cervix. * Pregnancy, breastfeeding, or considering becoming pregnant during the study. * Clinically relevant or significant ECG abnormalities at Screening. * Planned elective surgery that would impact study procedures or assessments through the completion of the Week 52 assessments. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.