Background: Psoriatic arthritis (PsA) is a common chronic inflammatory disease with a prevalence up to 670 every 100,000 subjects. Patients with PsA has an increased risk of cardiovascular disease (CVD) which is one of the major causes of death. The investigators hypothesize that metformin in combination of a treat-to-target (T2T) strategy aiming at tight disease control is more effective in preventing progression of subclinical arthrosclerosis than T2T strategy alone in non-diabetic PsA patients.

Objective: To investigate the vascular effects of metformin in PsA patients without diabetes mellitus. The metabolic and anti-inflammatory roles of metformin will also be explored.

Study design: This is a 1-year, single-centered, pilot, open-labelled, randomized controlled trial. A total of 24 enrolled patients with PsA being followed at the Prince of Wales Hospital rheumatology clinics will be recruited and randomized to either metformin group or control group in a 1:1 ratio. Participants randomized to the metformin group will be instructed to take 500 mg metformin daily for 1 week before titrating up to twice a day (one with the morning meal, one with the evening meal) to reduce gastro-intestinal adverse events.

Expected outcomes: The data from this study will support that there will be significant difference in the proportion of subjects with carotid plaque progression between the metformin group and control group over a period of 1 year.

Psoriatic arthritis (PsA) is a common chronic inflammatory disease with a prevalence up to 670 every 100,000 subjects. Patients with PsA has an increased risk of cardiovascular disease (CVD) which is one of the major causes of death. The investigators hypothesize that metformin in combination of a treat-to-target (T2T) strategy aiming at tight disease control is more effective in preventing progression of subclinical arthrosclerosis than T2T strategy alone in non-diabetic PsA patients.

All participants will be followed up at the Prince of Wales Hospital and receive tight-control treatment aiming at achieving minimal disease activity (MDA). It will be adjusted according to a standardized protocol based on the European League Against Rheumatism (EULAR) recommendation and the Hong Kong guideline on the use of biologics. Patients will be treated with methotrexate monotherapy and then other conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) or biologic DMARDs if they fail to achieve the pre-determined target. Assessment of efficacy will be performed every 3-6 months. If a patient does not achieve the desired treatment goal within 3-6 months of therapy, therapy will be stepped up, unless the patient declines or a toxic effect precludes this approach. Prednisolone at a dose ≤10mg/day will be allowed during the study period. Intra-articular steroid or local steroid injection to enthesitis and dactylitis are allowed during the study but will be forbidden in the 4 weeks before assessment. The details of the treatments received will be recorded.

Participants randomized to the metformin group will be instructed to take 500 mg metformin daily for 1 week before titrating up to twice a day (one with the morning meal, one with the evening meal) to reduce gastro-intestinal adverse events. Although the minimum effective dose for cardiovascular protection with metformin has not been determined, relatively low dose metformin has been shown to be effective for blood glucose control with reduced risk of gastrointestinal side-effects in the Asian population. Patients will be given the necessary number of metformin at each visit. At the following visits, surplus medication will be returned to the investigator. Compliance is calculated as a percentage, based on the number of tablets returned. Anti-hypertensive, anti-platelet and lipid-lowering medications can be initiated or titrated at the discretion of the treating physicians. The details of their usage will be documented.

The following clinical and laboratory variables will be assessed at each visit: erythrocyte sedimentation rate, C-reactive protein, bone profile, number of swollen joints (0-66), number of tender joints (0-68), visual analogue scale (VAS) for pain (0-100 mm, 100 mm=most pain), VAS for patient's global assessment (0-100 mm, 100 mm=worst score) and VAS for physician's global assessment (0-100 mm, 100 mm=worst score). The Maastricht Ankylosing Spondylitis Enthesitis Score, the Leeds Enthesitis Index, the Spondyloarthritis Research Consortium of Canada Enthesitis Index, number of digits with dactylitis, Bath ankylosing spondylitis disease activity index (for patients with axial involvement), body surface area and Psoriasis Activity and Severity Index are used to measure joint and skin disease activity, and will be recorded every visit. The number of damaged joints will be assessed yearly. Functional disability is assessed by the Health Assessment Questionnaire (HAQ) Disability Index (0-3=most functional disability) every visit.

Minimal disease activity (MDA) will be employed as the treatment target of PsA. The MDA criteria assess 7 domains, with the following cutoffs: tender joint count ≤1, swollen joint count ≤1, enthesitis count ≤1, skin score ≤1 (or body surface area ≤3%), function score ≤0.5 (measured by the HAQ), patient's global assessment ≤20 on a 100-mm VAS, and patient-reported pain ≤15 on a 100-mm VAS. If 5 of the 7 cutoffs for these domains are met, then the patient is classified as having MDA. Achieving MDA results in significant benefits in articular disease and can distinguish clearly active treatment from placebo. The investigators have previously shown that achieving sustained MDA, which is believed to be more stringent, but not other composite target, was associated with a protective effect in subclinical atherosclerosis and arterial stiffness progression.

Inclusion Criteria:

1. fulfill the ClASsification criteria for Psoriatic ARthritis (CASPAR),
2. are over 18 years old,
3. have a Framingham Risk Score ≥ 10% (i.e. moderate to high CV risk) and
4. have carotid plague on previous ultrasound.

Exclusion Criteria:

1. have prior therapy with metformin during the last 6 months;

2. have pre-existing diabetes as defined by the World Health Organization (WHO) criteria:

   • fasting plasma glucose values of ≥ 7.0 mmol/L,
   • 2-h post-load plasma glucose ≥ 11.1 mmol/L,
   • HbA1c ≥ 6.5% or
   • a random blood glucose ≥ 11.1 mmol/L);

3. have liver impairment: ALT more than or equal to 2.5×upper limits of normal;

4. have renal impairment: serum creatinine levels more than or equal to 135µmol/L in males and more than or equal to 110µmol/L in females;

5. have had ACS within the previous 3 months;

6. have New York Heart Association functional class 3 or 4 heart failure;

7. have uncontrolled angina;

8. have 70% or more stenosis on initial CCTA;

9. have clinically relevant current malignancy;

10. are pregnant; breastfeeding or of childbearing potential but unwilling to use adequate contraception;

11. are unable to give written informed consent;

12. patients with moderate to heavy alcohol intake.

Anonymized clinical data can be shared upon reasonable request

After publication of the final manuscript

For research purpose