Autoimmune diseases and cardiovascular risk: a population-based study on 19 autoimmune diseases and 12 cardiovascular diseases in 22 million individuals in the UK

Summary

Background

Some autoimmune diseases are associated with an increased risk of cardiovascular disease. We aimed to determine whether or not this is true, and to what extent, for a broad range of autoimmune conditions.

Methods

In this population-based study, we used linked primary and secondary care records from the Clinical Practice Research Datalink (CPRD), GOLD and Aurum datasets, to assemble a cohort of individuals across the UK who were newly diagnosed with any of 19 autoimmune diseases between Jan 1, 2000, and Dec 31, 2017, younger than 80 years at diagnosis, and free of cardiovascular diseases up to 12 months after diagnosis. We also assembled a matched cohort with up to five individuals matched on age, sex, socioeconomic status, region, and calendar year, who were free of autoimmune disease and free of cardiovascular diseases up to 12 months after study entry. Both cohorts were followed up until June 30, 2019. We investigated the incidence of 12 cardiovascular outcomes and used Cox proportional hazards models to examine differences in patients with and without autoimmune diseases.

Findings

Of 22 009 375 individuals identified from the CPRD databases, we identified 446 449 eligible individuals with autoimmune diseases and 2 102 830 matched controls. In the autoimmune cohort, mean age at diagnosis was 46·2 years (SD 19·8), and 271 410 (60·8%) were women and 175 039 (39·2%) were men. 68 413 (15·3%) people with and 231 410 (11·0%) without autoimmune diseases developed incident cardiovascular disease during a median of 6·2 years (IQR 2·7–10·8) of follow-up. The incidence rate of cardiovascular disease was 23·3 events per 1000 patient-years among patients with autoimmune disease and 15·0 events per 1000 patient-years among those without an autoimmune disease (hazard ratio [HR] 1·56 [95% CI 1·52–1·59]). An increased risk of cardiovascular disease with autoimmune disease was seen for every individual cardiovascular disease and increased progressively with the number of autoimmune diseases present (one disease: HR 1·41 [95% CI 1·37–1·45]; two diseases: 2·63 [2·49–2·78]); three or more diseases: 3·79 [3·36–4·27]), and in younger age groups (age <45 years: 2·33 [2·16–2·51]; 55–64 years: 1·76 [1·67–1·85]; ≥75 years: 1·30 [1·24–1·36]). Among autoimmune diseases, systemic sclerosis (3·59 [2·81–4·59]), Addison's disease (2·83 [1·96–4·09]), systemic lupus erythematosus (2·82 [2·38–3·33]), and type 1 diabetes (2·36 [2·21–2·52]) had the highest overall cardiovascular risk.

Interpretation

These findings warrant targeted cardiovascular prevention measures, in particular in younger patients with autoimmune diseases, and further research into pathophysiological mechanisms underlying these complications.

Funding

Horizon 2020 Marie Skłodowska-Curie Actions and European Society of Cardiology.

Introduction

Select autoimmune diseases, such as rheumatoid arthritis, are associated with increased cardiovascular morbidity and mortality.¹ Chronic and systemic inflammation, largely attributed to the presence of proinflammatory cytokines and autoantibodies, is thought to underlie these observed associations. Rheumatoid arthritis is not the only nor the most common autoimmune disease with inflammatory pathophysiology. A range of autoimmune diseases also have this pathophysiology, such as multiple sclerosis and psoriasis, and many of the over 100 known autoimmune diseases, which collectively affect 5–9% of the global population.2, 3 However, the contribution of individual diseases to cardiovascular risk, interactions with traditional cardiovascular risk factors, and exact underlying biological mechanisms are still subject to much debate.⁴

To date, a particular challenge has been the relatively small sized cohorts available to study, their relatively short duration of follow-up, and small numbers of cardiovascular events.⁵ Consequently, biomarkers or other surrogates have been relied on to probe disease mechanisms and inform the development of treatments.⁴ Some investigations have been done into the association between selected inflammatory conditions and specific cardiovascular events,1, 6, 7 but the effect of different conditions on various cardiovascular diseases has not been compared on a large scale. As a result, there is insufficient evidence for cardiovascular prevention guidelines to specifically address autoimmunity,⁸ and, of all autoimmune diseases, only rheumatoid arthritis and systemic lupus erythematosus are typically used to predict cardiovascular risk in routine clinical practice.9, 10 Importantly, the contribution of autoimmune diseases to cardiovascular disease in the population might extend beyond atherosclerotic diseases, such as myocardial, valvular, conduction, and other cardiac complications and venous-thromboembolic problems, and the potential effect of autoimmune diseases on the broader spectrum of cardiovascular diseases is unknown.

Research in context

Evidence before this study

We searched PubMed, Embase, and Web of Science for reports published between Jan 1, 2000, and Dec 30, 2021, in English, related to autoimmune disorders (any of the 19 individual conditions investigated) and cardiovascular risk (any of the 12 individual conditions investigated), reviewed references of clinical practice guidelines, and consulted with experts for relevant studies. Most studies investigated one autoimmune disorder at a time, and generally more common autoimmune disorders, such as rheumatoid arthritis or psoriasis. Cardiovascular outcomes were largely focused on coronary heart disease and stroke. Studies frequently referred to comparatively small sample sizes and insufficiently assessed independence from classic atherosclerotic cardiovascular risk factors, rendering adequate synthesis of the findings difficult. Evidence was particularly scarce for rarer autoimmune disorders and for non-atherosclerotic heart diseases. We found no study that reported associations between autoimmune disorders as a group of conditions and a broad range of cardiovascular outcomes. With the exception of rheumatoid arthritis, inflammatory bowel disease, lupus, and psoriasis, we found that evidence was insufficient to achieve consensus in the latest cardiovascular prevention guidelines or for risk estimators used in routine clinical practice.

Added value of this study

In this large observational population-based study, we found that patients with autoimmune disorders have an approximately 1·4–3·6 times higher risk of developing cardiovascular disease than people without an autoimmune disorder, depending on their autoimmune disorder; an order of magnitude that is similar to the risk caused by type 2 diabetes. Excess risk was particularly high in the young (<45 years) and was not explained by traditional cardiovascular risk factors, such as age, sex, socioeconomic status, blood pressure, BMI, smoking, cholesterol, or type 2 diabetes. The 19 autoimmune disorders investigated in our study accounted for a population attributable fraction of cardiovascular disease of 6·3%. We found that, among 19 of the most common autoimmune disorders, all conditions were associated with increased cardiovascular risk, indicating a pattern that affects autoimmune disorders as a group of diseases, rather than individually. Excess cardiovascular risk also affected rates of hospital admissions and death due to cardiovascular causes. Furthermore, increased cardiovascular risk was visible across the whole cardiovascular disease spectrum, beyond classic atherosclerotic disease, including infection-related heart disorders, heart inflammation, and thromboembolic and degenerative heart disorders.

Implications of all the available evidence

Cardiovascular risk prevention should be considered as an integral part of the management of autoimmune diseases. Further research is needed to design and assess the effectiveness of cardiovascular prevention measures for patients with autoimmune disorders, such as screening programmes and early use of preventive treatments.

To address these knowledge gaps, we used a large longitudinal database of linked primary and secondary care data that provides information on millions of individuals’ diagnoses with several years of follow-up,¹¹ and assessed the association between 19 of the most common autoimmune diseases and a broad range of cardiovascular outcomes accounting for known cardiovascular risk factors.