Coronary Computed Tomography Angiography In Rheumatoid Arthritis Study (COTIRA)

The Coronary Computed Tomography Angiography in Rheumatoid Arthritis study is part of the multinational, prospective, observational Autoimmunity and Atherosclerosis in Rheumatic Diseases cohort (https://atacc-rd.com) that includes comprehensive baseline and follow-up assessments at 3, 5, and 10 years. It comprises a main protocol and several optional modules, including a Cardiac Imaging Module, Biobanking Module, Pulmonary Module, and Anxiety and Depression Module.

The study aims to advance understanding of cardiopulmonary and psychological comorbidities in rheumatoid arthritis, to improve early identification and management, and to enhance insights into underlying disease mechanisms-ultimately refining risk stratification and targeted prevention strategies.

The study includes 4,000 patients with rheumatoid arthritis enrolled through the Cardiac Imaging Module in the main protocol. Participants undergo coronary computed tomography angiography, pulmonary function testing, physical examination, questionnaires, and biobanking, supplemented by genetic, proteomic, metabolomic, and microbiome profiling.

Study Overview

• Status: Enrolling by invitation
• Conditions: Depressive Disorder; Cardiovascular Disease; Pulmonary Disease, Chronic Obstructive; Rheumatoid Arthritis; Anxiety Disorders; Pulmonary Disease; Atherosclerotic Ischemic Disease; Lung Cancer (Diagnosis); COPD (Chronic Obstructive Pulmonary Disease); Interstitial Lung Disease in Patients With Rheumatoid Arthritis; Cardiovascular (CV) Risk; Pulmonary Diseases or Conditions; Cardiovascular Disease (CVD) Risk Factors; Cardiovascular Disease (CKD); Cardiovascular Biomarkers; Cardiovascular and Respiratory Disease; Depressive and Anxiety Disorders

Detailed Description

This prospective, observational study follows individuals with rheumatoid arthritis over time to understand how the disease and its treatment relate to cardiovascular, pulmonary, psychological, and biological outcomes. The study collects standardized clinical data from outpatient rheumatology clinics, complemented by advanced imaging, biological sample collection, and linkage to national health registries.

Study Procedures and Visit Schedule Participants are enrolled during routine or ad-hoc outpatient visits. After informed consent, a baseline evaluation is performed, followed by standardized follow-up visits after approximately 3, 5, and 10 years (± 3-6 months).

At baseline, demographic and lifestyle factors (age, sex, education, smoking, alcohol, physical activity, and family history) are recorded together with anthropometric measures (height, weight, waist circumference) and rheumatoid arthritis characteristics (serologic status, disease duration, erosive disease, and disease activity scores). Concomitant diseases and medications are documented, and vital signs and blood pressure are measured.

Patient-reported outcomes include validated questionnaires on quality of life (Short Form 36, version 1), functional ability (Multidimensional Health Assessment Questionnaire), work productivity (Work Productivity and Activity Impairment - General Health), fatigue and pain visual analogue scales, physical activity (International Physical Activity Questionnaire - Short Form), and shortness of breath (University of California, San Diego Shortness of Breath Questionnaire). Laboratory results, including markers of inflammation and metabolic status, are obtained according to routine standards.

Follow-up visits repeat these assessments to evaluate disease activity, lifestyle changes, and incident comorbidities. Events such as hospitalizations, procedures, and deaths are continuously updated through registry linkage, ensuring complete longitudinal follow-up.

Registry Data Sources All participants are linked to national Danish health and administrative registries to enable comprehensive, long-term follow-up. The study integrates data from the National Patient Registry, the Danish Rheumatology Quality Database, the Civil Registration System, the Danish National Causes of Death Registry, the Western Denmark Heart Registry, the Danish Heart Registry, the Danish Stroke Registry, the Danish National Vascular Registry, the Danish National Database of Reimbursed Prescriptions, the Clinical Laboratory Information System, the Register of Laboratory Results for Research, and the Danish Research Institute for Economic Analysis and Modelling. Linkage across these registries allows continuous capture of clinical events, treatments, and vital status, ensuring complete longitudinal follow-up and verification of outcomes recorded during study visits.

Governance The study is governed by an executive steering committee responsible for overall scientific direction, study design, resource allocation, and regulatory compliance. Supporting boards and advisory groups contribute to patient involvement, methodological quality, and international collaboration. Dedicated centers coordinate site operations, biobanking, cardiac imaging, and data analysis to ensure standardized procedures and data integrity across all participating sites.

All procedures are conducted in accordance with Danish and European data-protection regulations, and data are stored and managed in secure systems compliant with the General Data Protection Regulation.

• Study Type: Observational
• Enrollment (Estimated): 4000

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital
  • Esbjerg, Denmark
    • Esbjerg Hospital
  • Herning, Denmark
    • Regional Hospital Gødstrup
  • Herning, Denmark
    • Silkeborg Regional Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with rheumatoid arthritis from rheumatology outpatient clinics across Denmark.

Description

Inclusion Criteria:

• Fulfill the ACR/EULAR-2010 criteria for rheumatoid arthritis
• Attending or has attended at least one visit during the last two years in rheumatology outpatient clinic for diagnostic or monitoring purposes related to rheumatoid arthritis
• Age 50-75 years

Exclusion Criteria:

• Diagnosed with overlapping systemic autoimmune diseases other than secondary Sjogren's syndrome
• Active cancer
• Prior coronary atherosclerotic symptoms as defined by myocardial infraction, percutaneous coronary intervention, or coronary artery bypass grafting
• Allergy to radiocontrast agents
• Estimated glomerular filtration rate (eGFR) < 30 mL/min
• BMI > 35 kg/m2
• Persistent atrial fibrillation

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with a first occurrence of Major Adverse Cardiovascular Events (MACE)	Cardiovascular death as defined by death from any of the following causes: Ischemic heart disease; Sudden cardiac death; Ventricular tachycardia; Other cardiac arrhythmias; Heart failure; Fatal ischemic stroke; Sudden undefined death; Unwitnessed or unknown cause of death; Hospitalization for non-fatal myocardial infarction, including hospitalization for PCI and CABG; Hospitalization for non-fatal ischemic stroke	3, 5 and 10 years
Number of participants with a first occurrence of any ischemic cardiovascular events, including MACE	Hospitalization for cerebrovascular disease (transient ischemic attack). Hospitalization for peripheral vascular disease. Hospitalization for peripheral vascular surgery. Cardiovascular death as defined by death from any of the following causes: Ischemic heart disease; Sudden cardiac death; Ventricular tachycardia; Other cardiac arrhythmias; Heart failure; Fatal ischemic stroke; Sudden undefined death; Unwitnessed or unknown cause of death. Hospitalization for non-fatal myocardial infarction, including hospitalization for PCI and CABG. Hospitalization for non-fatal ischemic stroke	3, 5 and 10 years
Number of participants with all-cause death (all-cause mortality)	Death from any cause	3, 5 and 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The coronary artery plaque surface extent at baseline evaluated for the percent composition of non-calcified-, mixed-, and calcified plaques	Quantitative plaque measurement	Baseline
The quantitative difference in coronary artery plaque surface extent from baseline to 3 years evaluated for the percent composition of non-calcified-, mixed-, and calcified plaques	Quantitative plaque measurement	Baseline and 3 year
Proteomics concentrations	Blood sample	Baseline, 3, 5 and 10 years
Metabolomics concentration	Blood and stool sample	Baseline, 3, 5 and 10 years
Microbiome profile of stool	Stool sample	Baseline, 3, 5 and 10 years
Genome-, epigenom-, and RNA sequencing	Blood sample	Baseline, 3, 5 and 10 years
Coronary Artery Calcium Score (Agatston score)	Coronary Artery Calcium Score (CACS), Agatston units. Minimum: 0. Maximum: No upper limit. Higher score indicates worse outcome (more coronary artery calcification).	Baseline
Change in Coronary Artery Calcium Score (Agatston units) from baseline to 3 years	Coronary Artery Calcium Score (Agatston score), Agatston units. Change (Δ) in Coronary Artery Calcium Score (CACS) calculated as 3-year CACS minus baseline CACS. Minimum: No lower limit (negative). Maximum: No upper limit (positive). A positive change indicates increasing calcification (worse); a negative change indicates decreasing calcification (better).	Baseline and 3 years
Number of participants with a occurrence of hospitalization for cerebrovascular disease	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a first occurrence of hospitalization for non-fatal myocardial infarction	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization for non-fatal ischemic stroke	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization for peripheral vascular disease	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization for peripheral vascular surgery	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization for thromboembolic events as defined by deep vein thrombosis and pulmonary embolism	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a first occurrence of hospitalization for PCI	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a first occurrence of hospitalization for CABG	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a first occurrence of treatment for stable angina pectoris	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of treatment for atrial fibrillation and flutter	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with sudden death	Source of data: record and registry	3, 5 and 10 years
Number of participants with cardiovascular death	Source of data: record and registry	3, 5 and 10 years
Number of participants with a occurrence of treatment for essential hypertension with/without complications	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of treatment for disorders of lipoprotein metabolism and other lipidemias	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of treatment for diabetes mellitus	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization for respiratory disease	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization or specialist-initiated treatment for interstitial pulmonary diseases	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization or specialist-initiated treatment for chronic lower respiratory diseases	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization or specialist-initiated treatment for anxiety disorders, including generalized anxiety disorder	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization or specialist-initiated treatment for a depressive episode or recurrent major depressive disorder	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of general practitioner-initiated treatment for anxiety disorders	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of general practitioner-initiated treatment for depression	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of referral to a psychologist or psychiatrist	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of infection with Mycobacterium tuberculosis	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of opportunistic infections	Source of data: patient, record, registry	3, 5 and 10 years
Number of participants with a occurrence of hospitalization for infections (suspected/confirmed)	Source of data: patient, record, registry	3, 5 and 10 years

Collaborators and Investigators

• Sponsor: Ellen Margrethe Hauge
• Collaborators: Aarhus University Hospital; University of Aarhus; The Danish Rheumatism Association; Alfasigma S.p.A.; Independent Research Fund Denmark; ATACC-RD consortium
• Investigators: Study Chair: Ellen-Margrethe Hauge, MD, PhD, Aarhus University Hospital and Aarhus University; Study Director: Dzenan Masic, MD, PhD, Aarhus University Hospital and Aarhus University

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2024
• Primary Completion (Estimated): December 31, 2038
• Study Completion (Estimated): December 31, 2040

Study Registration Dates

• First Submitted: January 15, 2026
• First Submitted That Met QC Criteria: January 15, 2026
• First Posted (Actual): January 23, 2026

Study Record Updates

• Last Update Posted (Actual): February 3, 2026
• Last Update Submitted That Met QC Criteria: January 29, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Patient reported outcomes; Metabolomics; Biobank; Proteomics; Lipidomics; Patient-reported outcomes; Coronary Computed Tomography Angiography; RNA sequencing; Multi-omics; Genome sequencing; Deep phenotyping; Coronary Artery Calcium Score; Pulmonary function tests; Faecal microbiome; Epigenom sequencing; Disease Activity Score-28 for Rheumatoid Arthritis; Coronary plaque analysis
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Mental Disorders; Pathologic Processes; Neoplasms by Site; Neoplasms; Chronic Disease; Disease Attributes; Arthritis; Joint Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Respiratory Tract Neoplasms; Thoracic Neoplasms; Mood Disorders; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Anxiety Disorders; Lung Neoplasms; Cardiovascular Diseases; Depressive Disorder; Disease; Arthritis, Rheumatoid; Respiration Disorders
• Other Study ID Numbers: 1-10-72-85-23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD collected throughout the study.
• IPD Sharing Time Frame: After completion of the study.
• IPD Sharing Access Criteria: Individuals who obtain approval from the Danish Ethical Review Authority, the authority responsible for personal data, and the COTIRA Steering Committee will be able to access all PIDs as described above.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No