Short summary

The objective of the Uri Cor Intervention (URICORI) trial is to evaluate the effectiveness of a one-year intervention of modifiable risk factor for CVD administered in a rheumatology outpatient clinical setting, compared with conventional (GP) treatment for modifiable risk factors for CVD in people with gout.

Rationale

Gout is the most common inflammatory arthritis among men and postmenopausal women with prevalence between 2-4% in the United States. The prevalence of hyperuricaemia (precurser to gout) is more than 21.3%. A recent register based study in Denmark reported gout prevalence of 0.68 in 2015 and an increase of the annual incidence rate of 80% between 1995 and 2015. Gout is characterised by deposition of monosodium urate crystals in tissues and fluids. The response to these crystals results in an acute inflammatory arthritis that is characterised by sudden and severe attacks of red, swollen and painful joints. Gout usually affects only one joint at a time but eventually it can become chronic and affect several joints. It is considered to be one of the most painful forms of arthritis and is a source of disability for many in accordance with the high prevalence. Gout has been associated with a number of comorbidities including the cardiovascular disease (CVD). Mounting evidence suggests that hyperuricaemia and gout are associated with a high risk for CVD. Hyperuricaemia as a predisposing factor for gout is closely related to hypertension, dyslipidaemia, obesity and the metabolic syndrome, all well-known factors contributing to the development of CVD. The exact nature of the association between hyperuricaemia and CVD remains unclear and it is yet to be determined whether the relationship is causal or whether urate is indirectly related to CVD through other established risk factors. A large number of prospective cohort studies have addressed this issur, but no consensus about the relation between CVD, hyperuricaemia and gout has been stated. Mendelian randomisation studies have reported conflicting results regarding adverse cardiovascular outcomes with one reporting hyperuricaemia being casually related to adverse cardiovascular outcomes, particularly sudden cardiac death and the other reporting no association. Prospective clinical research regarding treatment of comorbidities in gout is sparse. A meta-analysis of six studies including people with gout reported a risk of CVD related mortality HR 1.29 (95% CI, I.14-1.44). This was based upon 4 studies (comparing patients with gout to those without gout). Coronary heart disease related mortality was based upon 3 studies (comparing people with gout to those without gout); HR 1.42 (95% CI, 1.22-1.63) and in conclusion these results point to an icnreased mortality in gout patients due to CHD and CVD. Research in this area has focused on how common CVD and coronary heart disease (CHD) is in people with gout, however no studies have focused on the management and the effect of managing CVD risk factors in people with gout. There is an unmet need for elaborating on the comorbidities and their management in a clinical setting in view of the increasing incidence of gout worldwide. Currently, there is no international consensus on how to manage risk factors for CVD in a gout population. The American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) and the Evidence, Expertise and Exchange Initiative (3E Initiative) all agree that comorbidity screening is relevant and recommend screening and managementof comorbidities is an important aspect of gout management with treatment to established CVD risk targets. While the acknowledgement of the close relation of gout and a number of comorbidities the URICORI trial focuses on the management of comorbidities. No randomised trials addressing the effect of treating the risk factors for CVD exists and the need for rigorous designs in this research area is needed. We aim to answer the following question: Does the management of CVD risk factors in people with gout, in a rheumatalogic outpatient clinical setting, versus primary care (GP setting as currently) result in better CVD risk factor control and therefore over time fewer CVD events?

Description of the cohort

The participants will be diagnosed with gout by their treating rheumatologist as defined by the ACR/EULAR gout classification criteria. Inclusion criteria: - Age over 18 - Gout according to current EULAR/ACR gout classification criteria - Plasma LDL > 3.0 mmol/L - Agreeable to start treatment for CVD risk factors if indicated - Ability to give informed consent - Ability to communicate via telephone Exclusion criteria: - Other inflammatory diseases requiring immunosuppressant therapy - Age > 70 years - Active cancer (in active treatment) - Chronic kidney disease (eGFR < 30 ml/min/1.73m2) - People whose behaviour or lifestyle would render them less likely to comply with the study protocol (i.e. alcohol abuse, substance misuse or debilitating psychiatric conditions) - Familial hypercholesterolemia The patients should be willing to remain in the study throughout the one year trial period and participate in the closeout visit five years from randomisation.

Data and biological material

Demographic and clinical features: - Age - Sex - Duration of gout, years - Height, cm - Body weight, kg - Body mass index, kg/m2 - Gout flares in the preceeding year - History of kidney stone - Cardiovascular disease - Diabetes - Hypertension - Dyslipidaemia Gout assessments: These are the outcomes in Rheumataology Clinical Trials (OMERACT) endorsed Core Outcome domains for studies of chronic gout. Domain Instrument/measure Serum urate: mmol/L Gout flares: self-reported Tophus burden: tophus count Health related quality of life (HRQOL): SF-36 Functional disability/activity limitation: HAQ-DI Pain: VAS Patient global assessment: VAS Assessment of gout flare frequency: number of flares in the last month. Gout flares will be self-reported and defined as flares requiring treatment. This definition has been used in other studies of gout. Biochemical Measurements The following groups of tests will be performed as indicated in sections describing outcomes. These are standard biochemical measurements taken routinely at the department of rheumatology and at the general practitioner. Biochemical measurements will not be collected and stored in a biobank. - Lipids: triglycerides, HDL-, LDL-, VLDL-, and total cholesterol - Haemoglobin, white cell count and platelet count - Serum biochemistry for safety monitoring - creatinine liver function tests (ASAT, GGT, ALP), creatinine kinase - Serum urate - HbA1c - Microalbuminuria - Blood pressure (Systolic and Diastolic) - Smoking status (never smoker, former smoker, smoker, new smoker) - Alcohol (women: more than 7 drinks per week y/n, men: more than 14 drinks per week y/n)

Collaborating researchers and departments

Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark. Odense University Hospital

• Professor Torkell Ellingsen

Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg and Frederiksberg Hospital

• Professor, BSc, MSc, PhD Robin Christensen

Department of Internal Medicine, Vejle Hospital

• MD, PhD Tine Lottenburger

Department of Rheumatology, Rigshospitalet Glostrup

• MD, PhD Annemarie Lyng Svensson

Department of Medicine, University of Otago, Christchurch, New Zealand

• Professor, FRACP, PhD Lisa Stamp

Department of Cardiology, Aarhus University Hospital

• Associate Professor, MD, PhD, DM.Sci Brian Bridal Løgstrup