OPEN Research Support

Torkell Ellingsen
Department of Rheumatology, Odense University Hospital

Projekt styring
Projekt status    Sampling ongoing
Data indsamlingsdatoer
Start 01.10.2016  
Slut 01.08.2018  

Prognostic value of vitamin D metabolite levels for 10 year cardiovascular events and mortality in rheumatoid arthritis patients from the CIMESTRA study

Short summary

Cardiovascular disease is a major burden in Rheumatoid Arthritis (RA), and mortality in RA patients is elevated due to cardiovascular disease. Low levels of vitamin D are common in RA patients, and in non-RA subjects, low vitamin D is associated to cardiovascular disease. The aim of the study is to test the pre-specified hypothesis that low levels of vitamin D at the time of diagnosis is associated to cardiovascular events in the 10- year period following diagnosis.


Rheumatoid arthritis (RA) is a systemic autoimmune condition, characterized by joint inflammation and several co-morbidities. Cardiovascular disease is a major burden in RA patients; the risk of cardiovascular events has been estimated to be the same size as the risk in patients with type II diabetes, whereas infections, interstitial lung-fibrosis and osteoporosis are other well-known co-morbidities in RA, both because of the disease itself as well as the treatment. Despite increasing inflammatory control, the expected lifespan in RA patients is still 10 year shorter than in the background-population, mostly because of comorbidities.

Because of its´ immunomodulatory potentials, the role of vitamin D and autoimmunity receives rising attention, and several studies show association between low vitamin D levels and incidence as well as disease activity in established RA. 

Association between osteoporosis and vitamin D is well-known due to the pivotal role of vitamin D in calcium- and bone-metabolism, whereas in the last decades, associations between vitamin D and cardiovascular disease, infections and lung disease in non-RA populations have shown possible associations.

To our knowledge, association between low levels of vitamin D and associations to several co-morbidities in RA patients in a long-time prospective set-up has not been investigated. The objective of this study is to evaluate the association between critical low vitamin Dtotal levels at diagnosis (defined as Dtotal < 50 nmol/l) and hospitalisation due to co-morbid reasons, in the 10 year period following diagnosis, to evaluate the pre-specified hypothesis that low baseline Dtotal levels predict co-morbid event in RA patients.

The study is a prospective closed cohort study in 160 early diagnosed RA patients participated in the CIMESTRA Study (CIclosporine, MEthotrexate, STeroid in RA). Patients are allocated in two groups according to baseline levels of vitamin D; those with low levels and those with sufficient levels. The primary outcome; any cardiovascular event, will be based on systematic evaluation of patient journals. 

This study is a sub-study of a PhD-project. You can read about another sub-study here: OP_297 Baseline vitamin D metabolite levels as predictor of progression of cardiovascular and pulmonic comorbidity in newly diagnosed Rheumatoid Arthritis patients.

Description of the cohort

The CIMESTRA study is a prospective, baseline-allocated, closed, blinded endpoint cohort study in 160 early diagnosed RA patients, included 1998-2002 from five Danish University Clinics. The patients participated in the CIMESTRA Study, a multi-centre, randomized, double-blind, parallel-group, placebo-controlled study. Inclusion criteria were fulfilling ACR1987 criteria for RA, disease duration < 6 months, 2 or more swollen joints and age between 18 and 75 years. Exclusion criteria: Glucocorticoid treatment 4 weeks prior to inclusion, previous use of DMARDs, malignancy, diastolic blood pressure > 90 mm Hg, elevated serum creatinine, infections with parvovirus B19, Hepatitis B, C and HIV, and any condition contraindicating the study medication. All patients initiated oral methotrexate (MTX); 7.5 mg/week at inclusion, and were randomized to double-blinded treatment with ciclosporine or placebo. Intra-articular glucocorticoid injections were performed in the case of joint swelling and MTX doses was increased, aiming at clinical remission: no swollen joints. Comorbidities occurring during the study period was treated according to national Danish guidelines. All patients were recommended daily supplements of oral vitamin D3 (400 IU 10 mg) and calcium (500 mg). 

Data and biological material

Data concerning baseline disease activity and vitamin metabolite D levels is already present. Data upon co-morbide events in the 10 year period following diagnosis will be indsamlet using systematic evaluations of patient records.

Collaborating researchers and departments

Department of Rheumatology, Centre of Cancer and Inflammation, Institute of Clinical Medicine, Aarhus University Hospital

  • Professor Kristian Stengaard-Pedersen, MD, DMSc
King Christian 10 th Hospital for Rheumatic Diseases, Southern University of Denmark

  • Professor Kim Hørslev-Petersen, MD, DMSc
Department of Rheumatology, COPECARE, Glostrup, Copenhagen University Hospital

  • Professor Magnus Lie Hetland, MD, DMSc
  • Professor Mikkel Østergaard

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

  • Professor Robin Christensen, BSc, MSc, PhD
Department of Cardiology, Aarhus University Hospital

  • Brian Bridal Løgstrup, MD, PhD
Departments of Clinical Medicine and Endocrinology, Aalborg University

  • Professor Peter Vestergaard, MD, PhD
Department of Rheumatology, Gentofte, Copenhagen University Hospital

  • John Pødenphant, MD, DMSc
Department of Rheumatology, Odense University Hospital

  • Professor Emeritus Peter Junker, MD PhD