Elsevier

Autoimmunity Reviews

Volume 9, Issue 12, October 2010, Pages 835-839
Autoimmunity Reviews

Review
The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases

https://doi.org/10.1016/j.autrev.2010.07.018Get rights and content

Abstract

The higher mortality rate among rheumatoid arthritis (RA) patients in comparison with the general population is largely attributable to cardiovascular (CV) disease, particularly coronary atherosclerosis, but also non-fatal myocardial infarction and heart failure. It may be due to RA-specific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia or vascular inflammation, or morbidity related to high levels of cytokines such as tumour necrosis factor (TNF) and RA medications.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most important in rheumatology, but many are associated with CV disease. A number of randomised control trials have shown that, although exposure to low doses of corticosteroids for 1–3 years does not significantly increase CV risk, longer exposure can increase CV events. The use of disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate, increases homocysteinemia, reduces inflammation and improves lipid profiles, thus reducing the development of atherosclerosis and clinically overt CVD. Although contraindicated in RA patients with severe heart failure, biological agents such as anti-TNF agents delay and even reverse the progression of endothelial dysfunction and atherosclerosis. Tocilizumab leads to changes in lipid profiles without increasing adverse vascular events.

The effects on the CV system depend on the drug itself, the dose and the period of exposure, and so CV risk should be evaluated before starting treatment with any drug.

Introduction

Inflammatory rheumatic diseases are associated with a substantial increase in accelerated atherosclerosis [1]. Studies have demonstrated that mortality is higher in patients with rheumatoid arthritis (RA) than in the general population, and most of the excess mortality is due to accelerated atherosclerosis. Although RA and atherosclerotic cardiovascular (CV) disease share risk factors such as smoking and poor diet, the increased risk of CV disease in RA patients cannot be explained by traditional risk factors alone. Various disease-related mechanisms may be involved in the development of premature vascular damage, including an increased synthesis of pro-inflammatory mediators (cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors [1], [2].

Section snippets

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are a large number of compounds that act by non-selectively inhibiting the cyclo-oxygenase isoenzymes COX-1 and/or COX-2. Two main classes are currently on the market: classic NSAIDs, which consist of various sub-classes that block both COX-1 and COX-2 (e.g. enolic, acetic, propionic and fenamic acid derivates), and the COXIBs that act selectively on inducible COX-2 (e.g. celecoxib and etoricoxib).

The CV toxicity of these drugs is a relatively

Corticosteroids

Corticosteroids (CTs) are powerful anti-inflammatory agents used for the symptomatic treatment of RA. They may have cardioprotective effects mediated by their anti-inflammatory and anti-proliferative action on vessel walls, but their long-term use at high doses can affect blood pressure, insulin resistance, lipid profiles, body weight and fat distribution, all of which may significantly increase the risk of CV disease [2]. A recent systematic review of the literature has revealed a weak

Statin treatment

Statins (3-hydroxy-3-methylglutarylcoenzyme-A reductase inhibitors) reduce CVD morbidity and mortality [18]. Different mechanisms are responsible for this result: effects on lipid levels, anti-inflammatory and immunomodulating effects include suppression of leukocyte cytokine release, reduction of MHC class II expression and reduction of production of reactive oxygen species [18]. Moreover, in RA patients apart from reducing lipid levels, treatment with statins, as it was demonstrated on

Methotrexate

There are some indications that disease-modifying antirheumatic drugs (DMARDs) can alter CV risk by influencing atherosclerotic processes directly through inflammation or indirectly by affecting CV risk factors.

However, few studies have investigated their effects on the occurrence of CV disease in RA patients, with methotrexate (MTX, a DMARD that inhibits dihydrofolate reductase and reduces folate levels) being the most widely studied [20].

A first observational study of MTX found that it led to

Anti-TNF agents infliximab, etanercept and adalimumab

The increased mortality of patients with RA may be due to RA-specific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia, vascular inflammation, drug-related morbidity, or high levels of cytokines such as tumour necrosis factor (TNF). TNF, an inflammatory cytokine released by activated monocytes, macrophages and T lymphocytes, favours the inflammatory responses that are important in the pathogenesis of RA [2]. It also promotes dyslipidemia and insulin resistance, both of

Conclusions

The role of antirheumatic drugs in the development of CV involvement in RA patients is controversial. As RA is itself a risk factor for CV events, physicians should stop corticosteroids as soon as possible and screen all patients for CV disease before administering NSAIDs. Biological drugs act not only on disease activity, but also on endothelial dysfunction and the progression of atherosclerosis, thus preventing CV complications and possibly reducing mortality.

Take-home messages

  • Users of COXIBs and classic NSAIDs (particularly diclofenac and ibuprofen) are at increased risk of acute myocardial infarction.

  • Short (1–3 year) exposures to low corticosteroid doses does not significantly increase CV risk, but longer exposure may increase the risk of major CV events.

  • The use of statins improves lipid profile and acts modestly on arthritis.

  • The use of DMARDs (particularly MTX) potently suppresses inflammation and improves the lipid profile, thus reducing the development of

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