Role of PPAR-y Agonists in Immunomodulation and Vascular Prevention in SLE (PPAR-SLE)

Systemic lupus erythematosus (SLE) is an autoimmune disease of unclear cause that affects primarily women of childbearing age. Patients with lupus have a significantly increased risk of developing complications of their blood vessels due to accelerated hardening of the arteries (atherosclerosis). These complications include heart attacks and stroke. No drug to date has proven to prevent this type of complication in lupus and premature vascular disease significantly impacts the quality of life of these patients and enhances their risk of death.

The thiazolidinediones (TZD) are a class of drugs approved for the treatment of patients with type 2 diabetes mellitus (DM); they belong to the family of drugs that activate the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). They have been proposed to have strong anti-atherogenic and anti-inflammatory effects even in patients without diabetes. Recent work from our group and others indicates that TZDs significantly improve vascular damage, dysfunction of blood vessels and disease activity in mouse models of lupus and abrogate atherosclerosis. We recently identified the TZD pioglitazone as an effective drug in modulation of vascular function and disease activity in patients with rheumatoid arthritis. In addition, we have found in mouse models of lupus and in in vitro experiments with human lupus cells, that pioglitazone has important roles in modulating immune function and vascular manifestations. Furthermore, this drug is not immunosuppressive, adding an additional advantage when compared to other medications used in this disease.

We propose that TZDs could significantly improve blood vessel function and play a role in atherosclerosis prevention in human SLE, in addition to modifying lupus disease activity. The major goal of the proposed research is to assess the effects of the PPAR-gamma agonist pioglitazone in SLE on vascular function and inflammation and on SLE disease activity. The results of the study may lead to the characterization of a new therapeutic target with dual effects on lupus and its associated blood vessel damage

-INCLUSION CRITERIA:

• For females and males 18 years old or older: females should be on adequate contraception if they are of child-bearing potential, which should be documented by a clinician, unless patients or their spouse/partner(s) have previously undergone a sterilization procedure. Adequate contraception will be considered:

• Intrauterine device (IUD),
• Hormone implants,
• Injectable contraceptives,
• Oral contraceptives plus a barrier method (male condom, female condom or diaphragm),
• Abstinence, or
• A vasectomized partner.
• Meet revised ACR criteria and 2012 SLICC criteria for SLE and have: a) a baseline SLEDAI-2K greater than or equal to 4 and <20 or a clinical SLEDAI-2K greater than or equal to 2 (not considering anti-dsDNA or complement levels) and b) lack of BILAG A flare at baseline.
• Stable doses of immunosuppressants and/or antimalarials for at least 3 months, and/or corticosteroids for at least 2 weeks. The prednisone dose may be increased after screening visit as long as the total dose is less than 20 mg of prednisone or equivalent per

day and the subject is on stable dose for at least 2 weeks prior to their Day 1 visit. If on statins, should have been on stable doses for at least 6 months.

• Allowed concomitant lupus-related medications

Antimalarials,

Prednisone greater than or equal to 20mg daily or equivalent doses of other corticosteroids;

Immunosuppressants:

• Mycophenolate mofetil, up to 3000 mg/day,
• Methotrexate, up to 30 mg/week,
• Azathioprine, up to 3 mg/kg/day,
• Leflunomide, up to 20 mg/day,
• Cyclosporine, up to 5 mg/kg/day
• Tacrolimus, up to 0.1 mg/kg/day

NSAIDS and aspirin

Note: While it would be highly desirable to maintain corticosteroid dosage at constant level for trial duration, it is impractical to anticipate that all patients with active SLE can be maintained without therapy modification for an 8-month period. Because corticosteroids are acceptable agents for treatment of the vast majority of minor lupus flares, and patients with major flares (BILAG 2004 A or recent change in medications) will be excluded, this will provide standardized treatment across study population that can be easily analyzed. An increase in prednisone dose of less than or equal to <10 mg/day from their prednisone dose at study entry will be permitted during the trial for increased disease activity with a standardized taper allowable in small monthly decrements to the patient s baseline dose or 5 mg/day, whichever is less.

Exclusion criteria

• Pregnant or lactating women
• Expected need for major surgery during trial.
• Current or previous diagnosis of malignant disease, except for basal cell or squamous cell carcinoma of the skin with complete excision and clear borders or adequately treated in situ carcinoma of the cervix.
• Acute infections identified during screening that require antibiotics. These subjects would be eligible to participate following resolution of infection before Day 1 visit within the allowed 46 days screening period. The subject will re-screen if it extends beyond the

allowed 46 days screening period.

• Chronic infections such as hepatitis B, hepatitis C, HIV or Tuberculosis.
• Current use of cyclophosphamide or having received cyclophosphamide within the last year.
• Prior history of hemorrhagic cystitis or hematuria while receiving cyclophosphamide that could not be explained by other causes.
• Current use (within 3 months) of tocilizumab, rituximab, belimumab, intravenous gammaglobulin or other biologic.
• History of poor compliance with medical care, study visits and/or medication use.
• Receipt of any investigational new drug or device within 30 days prior to screening or 5 half-lives of the agent <TAB>(whichever is longer), or any investigational new drug with known long-term effects.
• Pioglitazone is not recommended in patients with symptomatic heart failure. Patients with current heart failure (NYHA class II, III or IV) and/or a left ventricular ejection fraction of <45% by echocardiogram at screening will be excluded.
• Significant impairment of major organ function (lung, heart, liver, kidney) or any condition that, in the opinion of the Investigator, would jeopardize the subject s safety following exposure to the study drug.
• Known hypersensitivity to TZDs
• Serum hepatic transaminase levels > 2 times upper normal limit, or clinical evidence of active liver disease at screening. The only exception is patients with confirmed non-alcoholic fatty liver disease (NAFLD) where pioglitazone has been reported to have a therapeutic role.
• Diagnosis of DM or meeting DM criteria at screening visit, as established by new classification criteria: Patients with diabetes are excluded because diabetes by itself will induce profound changes in endothelial function and we want to assess the effects of PPAR agonists in vascular risk beyond changes in insulin resistance.
• Known latex allergy for EndoPAT test
• Patients with severe Raynaud's phenomenon, history of finger ulcers or finger gangrene will not undergo Endopat testing.
• Patients with severe SLE at baseline, as quantified as SLEDAI-2K >20.
• Patients with active lupus nephritis or active CNS lupus at baseline even if SLEDAI-2K <20. Active disease will be considered as CNS or renal disease that require aggressive immunosuppression. Active CNS disease will be diagnosed based on clinical presentation and physical exam, exclusion of other conditions that could explain symptomatology and, when warranted, ancillary tests (imaging) that support the diagnosis.

Patients that are not on induction therapy for lupus nephritis and have chronic (more than 6 months), stable proteinuria <750 mg/gram in protein:creatinine ratio but otherwise considered to have no evidence of active lupus nephritis (e.g. no cellular casts and stable serum creatinine < 2 mg/dL) over the last 6 months, will be included in the study.

In selected patients with potentially confounding clinical factors, consults will be requested to help clarify the nature of any underlying renal disease that may affect inclusion.

• Postmenopausal women who have not undergone a DEXA scan over the last year will undergo a DEXA scan at screening. Patients with a better than -2.5 will be included. Postmenopausal women who have undergone a DEXA scan during the last year and have a T score better than -2.5 will be included without repeating the DEXA scan prior to enrollment. If the T score is worse than -2.5, they will be excluded from participating unless the subject is willing to begin appropriate treatment for osteoporosis by Visit Day 1. Postmenopausal women who have undergone a DEXA scan during the last year, have a T score worse than -2.5 and are not on bisphosphonates or other appropriate therapy will be excluded.