Exploratory, double-blind randomized, placebo-controlled, Phase II study to evaluate the effect(s) of short-term administration of liraglutide, a GLP-1R (glucagon-like peptide-1 receptor) agonist on joint and skin inflammation in patients with active Psoriatic Arthritis.

The primary purpose of this study is to determine whether short-term (12-week) administration of the GLP-1R agonist, liraglutide, will improve joint and skin swelling in patients with active Psoriatic Arthritis compared to placebo.

Background: Psoriatic Arthritis is a systemic inflammatory T-cell disorder affecting the joints and spine, and is associated with an elevated risk for Type 2 Diabetes and Cardiovascular Disease. In addition to classical effects on glycemic-lowering, GLP-1R agonists are anti-diabetes agents which also have anti-inflammatory properties that may be clinically useful for patients with inflammatory diseases, particularly those with co-morbid metabolic disease. While a few small exploratory studies in patients with psoriasis have demonstrated that GLP-1R agonists reduce the severity of skin plaques, dedicated prospective, randomized mechanistic studies evaluating potential mechanisms by which GLP-1R agonists exert anti-inflammatory action(s) in humans with inflammatory disease is lacking.

Objectives: Primary objective is to evaluate the clinical efficacy of short-term liraglutide (GLP-1R agonist) administration on the severity of joint and skin inflammation in patients with active Psoriatic Arthritis. Secondary objectives are to determine whether short-term liraglutide administration in patients with active psoriatic arthritis will 1) modify the degree of impaired glucose tolerance, underlying b-cell function and cardiovascular risk factor profiles, 2) improve patient-centered outcomes such as quality of life and functionality, 3) modify specific sub-populations of T-cells and affect their differentiation and activation, and 4) modify activation of circulating immune cells, pro-inflammatory cytokines, and hormones.

Design: Double-blind, randomized, placebo-controlled trial, Phase II.

Patient population: 34 patients between with active Psoriatic Arthritis meeting CASPAR (ClASsification criteria for Psoriatic ARthritis).

Intervention: Participants will be randomized (1:1) to liraglutide (1.2 mg sc daily) or to placebo (sc daily) for 12 weeks.

Endpoints: The primary endpoint of this study will be the proportion of patients who experience a 20% ACR (American College of Rheumatology) improvement response following liraglutide therapy as compared to placebo.

Inclusion Criteria:

• Patients with active psoriatic arthritis (3 tender and swollen joints) meeting CASPAR study group criteria

Exclusion Criteria:

• BMI > 35 kg/m2
• Uncontrolled diabetes, HbA1c > 10.5%
• Current biological treatment for any inflammatory disorder within the past three months
• renal dysfunction (eGFR < 50 ml/min/1.73m or macroalbuminuria >300mg)
• hepatic dysfunction (AST (aspartate aminotransferase), ALT (alanine aminotransferase), Total bilirubin > 3 times upper limit of normal)
• history of pancreatitis or personal or family history of medullary thyroid cancer, c-cell hyperplasia, or MEN-2 syndrome
• current pregnancy or current breast feeding
• use of DPP-4 (dipeptidyl peptidase-4 inhibitor) or GLP-1 receptor agonist within 2 months (washout is permitted)
• drug or alcohol dependence
• resting tachycardia > 100 bpm or conduction abnormalities associated with tachycardia
• current enrollment in any other clinical trial
• symptomatic gastroparesis
• concomitant serious medical conditions
• all medication for the treatment of Psoriatic Arthritis such as MTX (methotrexate) < 25 mg, LFN (leflunomide) < 20 mg, and NSAIDs (non-steroidal anti-inflammatory drugs) will have been used at stable doses for at least 4 weeks, having been initiated at least 3 months prior to study start (8 weeks before screening, 4 weeks before baseline) for MTX and LFN and at least 4 weeks for NSAIDs