PsA T2T Statin Trial on Carotid and Coronary Atherosclerosis
PsA T2T Statin Trial on Carotid and Coronary Atherosclerosis
Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with an increased risk
 of myocardial infarction (MI). Using coronary computer tomography angiogram (CCTA), it is
 found that a significantly higher prevalence of high-risk coronary plaque (non-calcified
 plaque [NCP]), supporting the notion that more aggressive cardiovascular (CV) evaluation
 strategy should be considered in these patients.

 Carotid ultrasound screening in this population may be a better alternative than traditional
 risk score to identify patients at high CV risk as the latter underestimated CV risk.
 Previous study from our group have demonstrated that achieving treatment target (minimal
 disease activity [MDA]) can prevent progression of carotid atherosclerosis. Nevertheless, 38%
 of this Treat to Target (T2T) cohort still had carotid plaque progression.

 Project description

 it is hypothesized that combination of a T2T stratgy together with high-intensity
 rosuvastatin treatment (Group 1: T2T-statin group) is more effective in preventing
 progression of coronary and carotid atherosclerosis than T2T stratgy alone (Group 2: T2T-only
 group) in high-risk PsA patients with carotid plaque.

 The primary outcome is to ascertain the effect of T2T strategy with high-intensity
 rosuvastain (Group 1: T2T-statin group) on the change in CIMT over a period of 12 months
 compared with T2T strategy alone (Group 2: T2T-only group)
Treatment protocol This is a 1-year prospective, hospital-based, open-label, randomized,
 controlled trial. The trial comprised two arms. Group 1 will receive T2T strategy together
 with rosuvastain 20mg daily (T2T-statin group). Group 2 will receive T2T strategy only
 (T2T-only group). The method of concealed random allocation will be used. Simple
 randomization will be conducted by a computer-generated random list.

 Use of statins The patients will be given the necessary number of rosuvastatin tablets 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.

 No trials to date that have evaluated effects on CVD events have tested any medication in
 combination with statins or treatment to specific LDL-C goals, therefore we do not intensify
 the regimen for any particular level of LDL-C response. Measuring LDL-C response after
 initiating therapy in this study is mainly to assess adherence. In this primary prevention
 trial, in patients who do not tolerate statins, no lipid-lowering therapy will be
 administered. Potential interventions include lifestyle modification.

 Use of DMARDs All participants will receive a 1-year protocolized treatment with the aim to
 achieve MDA. A predefined treatment protocol is developed based on the EULAR recommendations
 and the Hong Kong guideline for the use of bDMARDs. Patients fulfilling the criteria for
 bDMARDs can either pay out of pocket or can apply for the Samaritan Fund for financial
 assistance, provided they must pass a household-based financial assessment
 (http://www.ha.org.hk/visitor/ha_visitor_index.asp?content_id=212020). When patient cannot
 achieve treatment goal within 3-6 months of therapy, the treatment therapy will be escalated
 to the next step according to the protocol, unless the patient declined or toxic effects
 preclude this approach. For the introduction of DMARD only joint involvement is taken into
 account. The participants with active disease who failed non-steroidal anti-inflammatory drug
 (NSAID) or those with poor prognostic factor will start with methotrexate monotherapy, which
 is increased to 20mg/week or maximum tolerated dose. Subsequent steps for patients who fail
 to achieve treatment goal include switching to other conventional synthetic DMARDs
 (csDMARDs), combination csDMARD therapy or TNFi, ustekinumab, secukinumab or tofacitinib.
 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.

 Clinical Assessment Assessment performed at each visit include pain, physicians' and
 patients' global assessments, number of tender joints count (TJC) and swollen joints count
 (SJC) (using the 68 tender/66 SJC), Maastricht Ankylosing Spondylitis Enthesitis Score
 (MASES), number of digits with dactylitis; ankylosing spondylitis disease activity score
 (ASDAS), modified health assessment questionnaire (M-HAQ); Disease Activity index for
 Psoriatic Arthritis (DAPSA), Psoriasis Area (BSA), Psoriasis Activity and Severity Index
 (PASI) were used to measure joint and skin disease activity.(31) MDA was used for assessment
 of treatment efficacy endpoint. The MDA criteria assess 7 domains [TJC ≤ 1, SJC ≤ 1,
 enthesitis count ≤ 1, skin (≤ 1 or BSA ≤ 3%), function (measured by the Health Assessment
 Questionnaire), ≤ 0.5, patient's global VAS on a 100-mm scale ≤ 20, and patient pain VAS on a
 100 mm scale ≤ 15]. If 5 of 7 of the cutoffs for these domains are met, then the patient is
 deemed to be in MDA.

 Cardiovascular assessments The following anthropomorphic assessment will be performed at each
 visit. Anthropomorphic measurements include body heights, body weight, waist and hip
 circumferences, two consecutive blood pressure readings in sitting position and heart rate.
 Hypertension status is defined as systolic blood pressure (SBP) ≥140mmHg or diastolic blood
 pressure (DBP) ≥90mmHg or the use of antihypertensive agents. Other data include menopausal
 status, smoking and drinking habits, history of DM, hypertension, hypercholesterolemia, overt
 CVD, and family history of CVD, DM in first-degree male relatives <55 years of age or
 first-degree female relatives <65 years of age. Drug history is retrieved from case notes or
 elicited during the clinical assessment.

 Laboratory assessments and inflammatory markers Laboratory assessments at each visit include
 complete blood count, liver and renal function tests, creatine kinase (CK), ESR and
 C-reactive protein (CRP), fasting blood glucose, lipid profile (total cholesterol [TC],
 LDL-C, high-density lipoprotein-cholesterol [HDL-C], triglycerides), fibrinogen and uric
 acid.

 Carotid intima-media thickness (CIMT) and plaque CIMT and plaque will be assessed at baseline
 and 12 months.CIMT will be measured using a high-resolution B-mode ultrasound machine
 (Philips EPIQ7) by an experienced sonographer blinded to all clinical information using a
 30-MHz linear vascular probe (Philips L12-3 broadband linear array transducer). The CIMT will
 be measured offline in the distal common carotid artery, bulb, and proximal internal carotid
 artery using dedicated software (Philips Xcelera Cardiology Enterprise Viewer Client 4). The
 mean and maximal IMT values of 6 arterial segments will be calculated for further analysis.
 Plaque is defined as a localized thickening >1.2 mm that do not uniformly involve the whole
 artery. Progression of plaque is defined as an increase in region harboring plaque or number
 of plaque. Reproducibility of IMT was 0.97. Total plaque area (TPA) will be measured as
 described before. The plane for measurement of each plaque will be chosen by reviewing the
 video of the scan to find the largest extent of plaque as seen on the longitudinal view. TPA
 will be recorded as the sum of the areas of all plaques in the right and left carotid
 arteries. Reading of the ultrasound scans obtained at baseline and follow-up will be
 performed concurrently by a single reader (ITC) who is aware of the temporal order of the
 images but is blinded to all clinical data. The change in TPA will be calculated by
 subtracting the baseline TPA from the follow-up TPA. The intraobserver intraclass correlation
 coefficient for TPA was 0.94.

 Coronary atherosclerosis assessment CCTA scans will be performed at baseline and 12 months
 256-rows multidetector CT (General Electric (GE) Revolution CT) in accordance with the
 protocol employed in the ACCURACY trial, and will be analysed by an experienced radiologist
 blinded to clinical data (PT). Coronary artery calcium score (CAC) will be quantified by the
 Agatston method. The presence, site, stenosis level of plaques will be recorded. Coronary
 arteries will be standardised to American Heart Association 15-segment model. Segment
 involvement score (SIS) represented the total number of segments harbouring plaque. Lesions
 rendering over 50% stenosis of the lumen will be considered as obstructive. For multiple
 plaques, the most stenotic one will be recorded. Voxels with attenuation less than 130 HU
 will be assigned to the non-calcified volume of the plaque. For each segment, the presence or
 absence of 4 coronary artery high risk plaque features will be assessed: positive remodeling,
 low attenuation plaque, spotty calcification, and the "napkin ring" sign. Positive remodeling
 is defined as an outer vessel diameter that is 10% greater than the mean of the diameter of
 the segments immediately proximal and distal to the plaque. Low-attenuation plaque is defined
 as a focal central area of plaque with an attenuation density of <30 HU. Spotty calcification
 is defined as focal calcification within the coronary artery wall <3 mm in maximum diameter.
 The "napkin ring" sign is defined as a central area of low attenuation plaque that had a
 peripheral rim of high attenuation. Observer agreement for the assessment of coronary artery
 plaque characteristics has overall been shown to be fair. Plaque volume will be measured
 automatically based on attenuation (CardIQ Xpress 2.0 Reveal, General Electic).

 Toxicity monitoring To monitor the possible side effect of the statin and DMARDs, complete
 blood count, CK, liver and renal function tests will be performed every visit. Chest X-rays
 will be obtained at baseline and at the end of the study. The treating physician record all
 adverse events and serious adverse events and, if necessary, make treatment adjustments in
 accordance with the protocol. Serious adverse events are defined as any adverse reaction
 resulting in any of the following outcomes: a life-threatening condition or death, a
 significant or permanent disability, a malignancy, hospitalization or prolongation of
 hospitalization, a congenital abnormality, or a birth defect.
Inclusion Criteria:

 1. Fulfilled the Classification of Psoriatic Arthritis (CASPAR) criteria

 2. With asymptomatic carotid plaques with <50% stenosis

 Exclusion Criteria:

 1. History of overt CVD (including myocardial infarction, angina, stroke, and transient
 ischemic attack)

 2. Currently on antiplatelet agents (including aspirin, Clopidogrel etc), or HMG-CoA
 reductase inhibitors (statins);

 3. FRS > 10% at screening visit who are indicated to start statins;

 4. had contraindication for statin medication (hypersensitivity to statins, liver disease
 with transaminase levels of ≥ 2 times the upper limit of normal [ULN], previous
 statin-induced myopathy or severe hypersensitivity, reactions to other statins

 5. Female of childbearing potential who are unwilling to use adequate contraception

 6. Pregnant or breastfeeding women

 7. Cyclosporine treatment

 8. Treatment with medicinal products that have a known interaction with rosuvastatin

 9. Uncontrolled hypothyroidism defined as thyroid-stimulating hormone level of >1.5 times
 the ULN at the first visit [due to the connection between myopathy and hypothyroidism
 with statin treatment]

 10. Secondary hyperlipidemia (primary hypothyroidism, nephrotic syndrome, creatinine level
 of > 120µmol/l], uncontrolled diabetes mellitus [DM] [glycated hemoglobin >10%], or
 plasma triglyceride level of >6.8 mmoles/liter [602.3 mg/dl])

 11. Other diseases or treatment that reduces the safety of rosuvastatin or treatment that
 would interfere with use of rosuvastatin (gastrointestinal disease/treatment that may
 cause malabsorption of rosuvastatin, cancer, severe psychiatric disease,
 life-threatening ventricular arrhythmias, other medication that increases the risk of
 rhabdomyolysis, known alcohol abuse, or participation in other studies).

 12. Currently on glucocorticoids at a dose >10mg/day.