Centrally Acting ACE Inhibition in SLE

Prior treatment

• Current use of anxiolytic, anticonvulsant, antidepressant or antipsychotic medications other than specific serotonin reuptake inhibitors (SSRIs) and gabapentin. SSRIs are allowed if the subject is on a stable dose for 12 weeks prior to the screening FDG-PET scan and is expected to remain on the same SSRI throughout the trial. Gabapentin is allowed if used on a PRN basis for pain or reason other than seizure disorder and the subject is willing not to take it for a minimum of 2 weeks prior to brain imaging or neuropsychological assessments.
• Use of a centrally acting ACE inhibitor (Lisinopril, fosinopril, ramipril, captopril, perindopril, prinivil, monopril, trandolapril) or angiotensin receptor blocker for more than 4 weeks within the past 1 year. Non-centrally acting ACE inhibitors are allowed if the subject is willing to be randomized to Lisinopril or benazepril instead of their non-centrally acting ACE inhibitor.
• Known intolerance to ACE inhibitors.

Other illness

• History of neurological diseases including, but not limited to, severe head injury or history of brain surgery, stroke, seizure, toxic exposure, mental retardation, multiple sclerosis, dementia, encephalitis.
• History of documented transient ischemic attacks within 6 months of screening.
• Addition of belimumab or rituximab within 3 months of screening and/or addition of disease modifying drugs (such as mycophenolate, methotrexate, azathioprine, leflunomide, voclosporin, tacrolimus) within 3 months of screening.
• History of illicit drug or alcohol dependence/abuse within the past 12 months.
• Increased disease activity within 4 weeks of screening defined by an increase in SLEDAI by 3 points or more, exclusive of points from serologies, which prompts an increase in or new addition of SLE medications.
• History of a diagnosis of a primary psychiatric disorder requiring medication that preceded the diagnosis of SLE.
• Current active acute infections requiring antibiotics within 2 weeks of screening and chronic known infections (eg. hepatitis B, C, and/or HIV).
• Co-existing other autoimmune disease(s) other than autoimmune thyroid disease or secondary Sjogren's Syndrome.
• The presence of uncontrolled, severe hypertension, diabetes or heart disease.
• History of hereditary or idiopathic angioedema.
• Presence of any active medical condition that in the opinion of the investigator may contribute to cognitive and/or behavioral disturbances.

Lab values

• Impaired renal function with an eGFR\< 60%.
• Use of investigational drugs within 30 days or 5 half-lives before Visit 1 (Day 1), whichever is longer.
  • Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
  • 23\. A systolic blood pressure less than 100 mmHg at screening. If the investigator feels that the patient is insufficiently hydrated, the patient may be re-evaluated for blood pressure within the screening period.
  • 24\. Current treatment with Cyclophosphamide. 25. The presence of suicidal ideation on the Beck Depression Inventory at screening or sufficient depressive symptoms to warrant intervention with pharmacologic therapy and/or referral for treatment.
  • 26\. For subjects consenting to the MRI scans: the presence of ferromagnetic implants or devices that cannot be removed and/or a history of claustrophobia or intolerance of MRI.

Other

• Inability or unwillingness of a participant to give written informed consent or comply with study protocol.
• Current and/or chronic use of narcotic analgesia for \> 3 weeks within the last 3 months.
• Pregnant and/or lactating women and/or women unwilling to use an acceptable form of contraception.
• Current use of aliskiren in diabetic patients.
• Current use of naltrexone or chronic minocycline use; both are agents also known to alter microglia activation.

• Subject must be able to understand and provide informed consent
• Subjects must be ≥18 and ≤65 years of age: subjects with age \> 65 will be excluded to avoid confounding effects of age on cognitive testing.
• Subjects must fulfill the 1997 American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE or the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) Criteria or the EULAR/ ACR 2019 criteria for SLE.
• Subjects must have stable disease activity and medication doses for 4 weeks prior to screening. Stable disease activity is defined as no increase in disease activity requiring an increase or addition of immunosuppressive medications.
• If on corticosteroids, subjects must be on a dose that is ≤ prednisone 10 mg daily, or the equivalent.
• Must have increased resting metabolism in the posterior putamen/GP/thalamus on the screening FDG-PET scan that is
  • \> 1.647 for non-Black SLE subjects and
  • \> 1.699 for Black SLE subjects.