HUNTER HEART-RA-2 (HHRA-2) STUDY A Randomised Controlled Trial Evaluating the Effects of Humira Upon Cardiovascular Risk as Measured by Endothelial Function in patients with Rheumatoid Arthritis who Test Positive for Anti-CCP Antibodies as well as those who Test Negative for Anti-CCP Antibodies.

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Introduction Rheumatoid arthritis is a severe destructive inflammatory arthritis that affects 1.5% of the population. They have a 50% increased risk of cardiovascular events that is directly related to the disease process although the mechanisms of this remain unclear. New effective treatments for rheumatoid arthritis called the "Biologics" have become widely available over the last decade. This has resulted in dramatic improvements in the treatment of the arthritis. However, it remains unclear whether these treatments influence the risk of cardiovascular events. Pooled analyses of the large trials have not had sufficient power and are of insufficient duration to answer this question. Meta-analysis of the combined registry data found dramatic differences in the TNF-inhibitor treated group but these effects may be explained by confounding. Studies using assessments of pre-clinical vascular disease using imaging and physiological assessments of arterial stiffness seem more likely to show treatment effects but have thus far been inconclusive. Based upon studies in hypertension it is likely that studies utilising assessments of arterial stiffness and carotid artery wall thickness would require randomised controlled trials of considerable size and duration to detect treatment effects. Earlier pathological processes in vascular disease such as endothelial dysfunction are more likely to change quickly and detectably in response to treatment. However, studies have been inconclusive possibly due to the small sample sizes, insufficient study duration and because the studies evaluated subject with established and possibly irreversible disease. The Australian PBS funds Biologic drugs for patients with rheumatoid arthritis only after they have failed to respond to 6 months conventional DMARD therapy. This 6 month period presents an opportunity to evaluate the effects of TNF-inhibition (with adalimumab) upon vascular function in a randomised controlled trial while at the same time enhancing patient care. Our consortium have already conducted a small phase 2 study (Hunter HEART-RA has already evaluating the effect of adalimumab in anti-CCP antibody positive RA. This phase 2, single-centre, double-blind randomised, placebo-controlled study will evaluate the effects of adalimumab upon endothelial function anti-CCP positive and NEGATIVE rheumatoid arthritis. Methods 1. 36 subjects with Anti-CCP Positive Rheumatoid Arthritis and ; 2. 34 subjects with Anti-CCP Negative Rheumatoid Arthritis (age>18 years) Subjects within each group will be randomised 1:1 to receive adalimumab / placebo for 24 weeks in addition to "usual care”. During the 24-week trial subjects will undergo assessments of vascular function, rheumatoid arthritis disease activity, functional impairment and work disability. Assessments will occur at 0 (baseline), 12 and 24 weeks. The primary response variable will be peripheral endothelial function as measured by EndoPAT. Secondary response variable will include: 1. Arterial stiffness (Carotid-femoral pulse wave velocity, Central Aortic Augmentation Index as measured from the radial pulse wave analysis) 2. Carotid artery ultrasound (carotid initmal medial thickness, carotid plaque score and carotid wall elasticity) 3. Disease activity (ESR, CRP, joint counts, DAS28, SDAI) 4. Functional Ability (HAQ Questionnaire) 5. Work Disability (RA-WIS Questionnaire) 6. Australian Quality of Life (AQoL) Questionnaire 7. 40-joint musculoskeletal ultrasound.