Using cardiovascular magnetic resonance to define mechanisms of comorbidity and to measure the effect of biological therapy: the CADERA observational study
Authors: Plein Sven , Erhayiem Bara , Fent Graham , Andrews Jacqueline , Greenwood John , Baxter Paul , Hensor Elizabeth M , Pavitt Sue , Buch Maya H 
Published: March 2021

Background
The VEDERA (Very Early vs. Delayed Etanercept in Rheumatoid Arthritis) randomised controlled trial compared the effect of conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) therapy with biologic DMARD (bDMARD) therapy using the tumour necrosis factor inhibitor etanercept in treatment-naive, early rheumatoid arthritis patients. The CADERA (Coronary Artery Disease Evaluation in Rheumatoid Arthritis) trial was a bolt-on study in which VEDERA patients underwent cardiovascular magnetic resonance imaging to detect preclinical cardiovascular disease at baseline and following treatment.

Objectives
To evaluate whether or not patients with treatment-naive early rheumatoid arthritis have evidence of cardiovascular disease compared with matched control subjects; whether or not this is modifiable with DMARD therapy; and whether or not bDMARDs confer advantages over csDMARDs.

Design
The VEDERA patients underwent cardiovascular magnetic resonance imaging at baseline and at 1 and 2 years after treatment.

Setting
The setting was a tertiary centre rheumatology outpatient clinic and specialist cardiovascular magnetic resonance imaging unit.

Participants
Eighty-one patients completed all assessments at baseline, 71 completed all assessments at 1 year and 56 completed all assessments at 2 years. Patients had no history of cardiovascular disease, had had rheumatoid arthritis symptoms for ≤ 1 year, were DMARD treatment-naive and had a minimum Disease Activity Score-28 of 3.2. Thirty control subjects without cardiovascular disease were approximately individually matched by age and sex to the first 30 CADERA patients. Patients with a Disease Activity Score-28 of ≥ 2.6 at 48 weeks were considered non-responders.

Interventions
In the VEDERA trial patients were randomised to group 1, immediate etanercept and methotrexate, or group 2, methotrexate ± additional csDMARD therapy in a treat-to-target approach, with a switch to delayed etanercept and methotrexate in the event of failure to achieve clinical remission at 6 months.

Main outcome measures
The primary outcome measure was difference in baseline aortic distensibility between control subjects and the early rheumatoid arthritis group and the baseline to year 1 change in aortic distensibility in the early rheumatoid arthritis group. Secondary outcome measures were myocardial perfusion reserve, left ventricular strain and twist, left ventricular ejection fraction and left ventricular mass.

Results
Baseline aortic distensibility [geometric mean (95% confidence interval)] was significantly reduced in patients (n = 81) compared with control subjects (n = 30) [3.0 × 10–3/mmHg (2.7 × 10–3/mmHg to 3.3 × 10–3/mmHg) vs. 4.4 × 10–3/mmHg (3.7 × 10–3/mmHg to 5.2 × 10–3/mmHg), respectively; p < 0.001]. Aortic distensibility [geometric mean (95% confidence interval)] improved significantly from baseline to year 1 across the whole patient cohort (n = 81, with imputation for missing values) [3.0 × 10–3/mmHg (2.7 × 10–3/mmHg to 3.4 × 10–3/mmHg) vs. 3.6 × 10–3/mmHg (3.1 × 10–3/mmHg to 4.1 × 10–3/mmHg), respectively; p < 0.001]. No significant difference in aortic distensibility improvement between baseline and year 1 was seen in the following comparisons (geometric means): group 1 (n = 40 at baseline) versus group 2 (n = 41 at baseline): 3.8 × 10–3/mmHg versus 3.4 × 10–3/mmHg, p = 0.49; combined groups 1 and 2 non-responders (n = 38) versus combined groups 1 and 2 responders (n = 43): 3.5 × 10–3/mmHg versus 3.6 × 10–3/mmHg, p = 0.87; group 1 non-responders (n = 17) versus group 1 responders (n = 23): 3.6 × 10–3/mmHg versus 3.9 × 10–3/mmHg, p = 0.73. There was a trend towards a 10–30% difference in aortic distensibility between (group 1) responders who received first-line etanercept (n = 23) and (group 2) responders who never received etanercept (n = 13): 3.9 × 10–3/mmHg versus 2.8 × 10–3/mmHg, p = 0.19; ratio 0.7 (95% confidence interval 0.4 to 1.2), p = 0.19; ratio adjusted for baseline aortic distensibility 0.8 (95% confidence interval 0.5 to 1.2), p = 0.29; ratio fully adjusted for baseline characteristics 0.9 (95% confidence interval 0.6 to 1.4), p = 0.56.

Conclusions
The CADERA establishes evidence of the vascular changes in early rheumatoid arthritis compared with controls and shows improvement of vascular changes with rheumatoid arthritis DMARD therapy. Response to rheumatoid arthritis therapy does not add further to modification of cardiovascular disease but, within the response to either strategy, etanercept/methotrexate may confer greater benefits over standard methotrexate/csDMARD therapy.

Trial registration
Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151.

Funding
This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 4. See the NIHR Journals Library website for further project information. Pfizer Inc. (New York, NY, USA) supported the parent study, VEDERA, through an investigator-sponsored research grant reference WS1092499.