ReviewThe effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases
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
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Users of COXIBs and classic NSAIDs (particularly diclofenac and ibuprofen) are at increased risk of acute myocardial infarction.
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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.
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The use of statins improves lipid profile and acts modestly on arthritis.
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The use of DMARDs (particularly MTX) potently suppresses inflammation and improves the lipid profile, thus reducing the development of
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2017, Handbook of Systemic Autoimmune DiseasesCitation Excerpt :Folate supplementation to SASP therapy may reduce homocysteine production and thus it may also be vasculoprotective in arthritis (Baskan et al., 2009). Today, SASP is mainly used in combination, therefore it is very difficult to determine the net CV effects of this compound (Atzeni et al., 2010). The vascular effects of methotrexate (MTX) may also be somewhat controversial.