The Role of Anifrolumab in Improving Markers of Vascular Risk in Patients With Systemic Lupus Erythematosus (SLE) - IFN-CVD

Background: People with systemic lupus erythematosus (SLE) are at risk of developing complications in their blood vessels. This can increase the risk of heart attacks or stroke. No medications have been effective at reducing this risk in people with lupus. Objective: To test whether a drug (anifrolumab) can improve blood vessel function and reduce blood vessel inflammation in people with SLE. Eligibility: People aged 18 to 80 years with SLE. Design: Participants will undergo screening. They will have a physical exam. They will have blood and urine tests. They will have a test of their heart function and a chest X-ray. They will answer questions about their SLE symptoms. Participants will visit the clinic 9 times in 8 months. After screening, visits will be 4 weeks apart. Each visit may take up to 4 hours. Participants will receive infusions from a tube attached to a needle inserted into a vein in the arm (IV). Some will receive anifrolumab. Others will receive a placebo treatment. They will not know which one they are getting. At some visits they will have additional tests: CAVI (cardio-ankle vascular index) tests blood vessel function. Participants will lie still for 20 minutes. Small electrodes will be placed on both wrists with stickers. A microphone will be placed on their chest. Blood pressure cuffs will be wrapped around their ankles and arms. FDG-PET/CT is an imaging procedure. Participants will receive a substance through an IV line. They will lie on a table for 110 minutes while a machine captures images of their body.

* INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged 18-80 years 4. In good general health as evidenced by medical history or diagnosed with SLE diagnosed per American College of Rheumatology 1997 revised SLE classification criteria. 5. Prednisone \< or equal to 10 mg/day for at least 2 weeks before screening and maintained throughout randomization (day 1) 6. Stable standard of care lupus therapies for at least 4 weeks before screening and maintained through randomization (day 1) 7. Abnormal cardio-ankle vascular index (CAVI) (based on 2 SD above median of healthy controls based on historical data from our own patient cohorts AND/OR 8. Abnormal Pulse wave velocity (PWV) using Sphygmocor. AND/OR 9. Abnormal target to background ratio (TBR) in various aortic territories and total aorta using FDG PET CT scan. 10. Stable medications for diabetes, hypertension and/or statins for at least the previous 3 months. No changes of these medications or immunosuppressive drugs will be allowed during trial. 11. For females and males of reproductive potential: use of highly effective contraception from screening and agreement to use such a method during study participation and for an additional 16 weeks after the end of study medication administration. For the purpose of this study abstinence will be considered as an effective form of contraception. 12. Subjects must confirm receipt of prior vaccination against COVID-19 and Varicella Zoster. Verbal confirmation of vaccination receipt AND detectable antibodies in serum is acceptable in the absence of vaccine records. EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: * Any condition that, in the opinion of the Investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results. * Concurrent enrolment in another clinical study with an investigational product * Major surgery within 8 weeks before signing the ICF or elective major surgery planned during the study period. * Any of the following found at Screening: * Aspartate aminotransferase (AST) \>2.5 x upper limit of normal (ULN). * Alanine aminotransferase (ALT) \>2.0 x ULN. * Total bilirubin \>ULN (unless due to Gilbert's syndrome) * Serum creatinine \>2.5 mg/dL (or \>181 micromol/L) * Urine protein/creatinine ratio \>2.0 mg/mg (or \>226.30 mg/mmol) * Neutrophil count \