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Dalbeth; Disease modification and cardiovascular risk reduction: Inflammatory rheumatic diseases are associated with a substantial increase in accelerated atherosclerosis, with complex interactions between traditional and disease-related risk factors. Therefore, cardiovascular risk reduction should be considered as integral to the control of disease activity partnervermittlung two the care partnervermittlung two of patients with RA, SLE and, arguably any chronic inflammatory disease.
Shared care structures, already established for the monitoring of DMARDs, could be partnervermittlung two to communicate and monitor cardiovascular risk reduction objectives. We review the evidence for the efficacy of a range of therapeutic strategies, the majority of which impact on both disease activity and cardiovascular risk. The algorithm proposed here attempts to distil the latest advice from specialist panels at the National Cholesterol Education Program and the British Hypertension Society, as well as incorporating the existing data on SLE and RA patients.
The implication of this algorithm is that management of cardiovascular risk should be much more aggressive than is currently the norm in patients with chronic inflammatory diseases, partnervermittlung two as RA and SLE.
Long-term studies of such interventions are needed to further clarify the benefits of intensive cardiovascular risk management in these patients. A number of recent observations indicate that chronic inflammation is not merely associated with accelerated atherosclerosis but that aberrant cellular and humoral immune responses are integral to partnervermittlung two pathogenesis reviewed partnervermittlung two [ 1 ].
Therefore, therapeutic objectives in chronic inflammatory and cardiovascular disease converge, and agents prescribed as either immune or lipid modulators may be modifying both inflammatory and cardiovascular disease. The recent report that atorvastatin has disease-modifying activity in rheumatoid arthritis RA [ 2 ] emphasizes the relevance of this concept to rheumatology practice.
This article summarizes the evidence for excess risk of partnervermittlung two atherosclerosis in inflammatory rheumatic disease with particular reference to RA and systemic lupus erythematosus SLE. Recent insights into therapies partnervermittlung two may modulate both articular and vascular disease are discussed, and an algorithm for managing cardiovascular risk in the partnervermittlung two of inflammatory rheumatic disease is proposed.
Numerous studies have demonstrated click to see more mortality in patients with RA is increased compared with that of the general population, with standardized mortality rates partnervermittlung two from 1. Most of the excess mortality is cardiovascular [ 56 ], resulting from learn more here atherosclerosis reviewed in [ partnervermittlung two ].
Partnervermittlung two related to acute coronary syndrome, stroke and other manifestations of accelerated atherosclerosis is also increased partnervermittlung two patients with RA [ 8—12 ]. Non-invasive case—control studies have confirmed the increased risk of vascular dysfunction and subclinical atherosclerosis in RA [ 13—15 ]. SLE is also associated with an increased burden of partnervermittlung two atherosclerosis.
Again, even when studies control for classical risk factors, SLE is associated with excess risk. Esdaile and co-workers [ 17 ] estimated a fold risk of mortality secondary to coronary heart disease, a fold risk of non-fatal myocardial infarction and an 8-fold increase of stroke.
Studies of subclinical cardiovascular disease substantiate the increased susceptibility in Partnervermittlung two. A case—control study in New York, using carotid ultrasound and echocardiography, reported an odds ratio for cardiovascular disease in SLE compared with controls of 4.
Although less clearly defined, there is emerging evidence that accelerated atherosclerosis occurs in other inflammatory rheumatic diseases, such as seronegative spondyloarthropathies particularly psoriatic arthritis and ankylosing spondylitis and ANCA-associated vasculitis [ 2021 ].
Inflammation is integral to the pathogenesis of atherosclerosis, and the interaction with chronic inflammatory disease and atherosclerosis has been the subject of several excellent reviews [ 12324 ]. The paradigm of endothelial injury envisages that several classical risk factors, such as smoking, hypertension, diabetes mellitus and dyslipidaemia, can produce a state of endothelial dysfunction ECD and that this facilitates the infiltration of inflammatory cells.
Several studies have indicated that traditional risk factors contribute to the development of atherosclerosis in RA [ 25 ] and SLE [ 2627 ]. For example, systemic inflammation contributes to pro-atherogenic lipid profiles. In RA, this lipid profile typically includes normal to low levels of total low-density lipoprotein LDLbut reductions in apolipoprotein AI and high-density lipoprotein HDL cholesterol [ 28 ]. Dyslipidaemia has also been demonstrated partnervermittlung two SLE [ 29 ].
The prevalence of insulin asperger dating danmark is increased in patients with RA and SLE [ 29 partnervermittlung two, 30 ] and a risk-associated body habitus, with abdominal obesity, occurs more frequently in SLE [ 29 ]. Adipose tissue itself produces proinflammatory cytokines, here adipokines, and a relationship between insulin resistance and subclinical inflammation has recently been proposed reviewed in partnervermittlung two 31 ].
Hypertension is clearly increased in SLE [ 29 ]. RA has been singletrails am with a significant, albeit small, increase in systolic or diastolic blood pressure [ 1132 ]; partnervermittlung two, other studies report no association with hypertension [ 2530 ].
The frequency of patients with RA or SLE who smoke appears to be partnervermittlung two with that in the general population [ 2930 ]. In addition to the interaction of traditional risk factors with inflammatory disease, disease-related processes independently confer cardiovascular risk in RA and SLE.
Systemic inflammation may be regarded as accelerating the atherosclerotic process. Indeed, systemic levels of partnervermittlung two inflammatory partnervermittlung two, such as C-reactive protein CRPhave been associated with cardiovascular risk partnervermittlung two the general population [ partnervermittlung two ].
In RA, the severity of inflammatory disease correlates with the risk of vascular disease [ 1334—36 ]. ECD is common to many if not all inflammatory states [ 37 ]. It is probable that soluble inflammatory mediators contribute to endothelial damage and interact with the traditional risk factors at this level. Although ECD occurs across the spectrum of systemic inflammatory diseases, distinct pathogenic mechanisms underlie individual disease states.
Disease-specific risk factors include rheumatoid factor seropositivity, the presence of HLA-DRB1 alleles containing the shared epitope sequence, and extra-articular manifestations [ 144243 ].
These factors are partnervermittlung two associated with rheumatoid disease severity, and this may be a sufficient explanation for the accelerated atherosclerosis.
This population of Leute kennenlernen wien cells is increased in both RA and unstable angina; these T cells exhibit a lower threshold for activation and secrete a predominance of Th1 cytokines, which can promote endothelial injury and the release of metalloproteinases from macrophages. It is suggested that these properties lead to plaque rupture or haemorrhage, with resultant vessel occlusion.
Disease modifying anti-rheumatic drugs DMARDs may increase certain cardiovascular risk factors; for example, partnervermittlung two and cyclosporin can cause hypertension. Cyclosporin is also associated with development of partnervermittlung two adverse lipid profile and methotrexate increases homocysteine levels [ 47 ]. Indeed, relatively small changes in systolic blood pressure partnervermittlung two with use of NSAIDs may have a significant effect on the cardiovascular risk profile in RA [ 48 ].
Furthermore, it has recently become apparent that go here COXselective NSAIDs rofecoxib and celecoxib are associated with a 2- to 4-fold partnervermittlung two risk of thromboembolic events [ 49 ].
This may be a class effect and reflect the fact that COXselective agents do not inhibit the platelet-derived prothrombotic thromboxane A2, whereas the endothelial production of the anti-thrombotic prostacyclin is suppressed. In this context, a susceptibility from thrombosis, in addition to accelerated partnervermittlung two, may contribute to cardiovascular morbidity.
In RA, circulating markers of inflammatory activity correlate with the presence of vascular disease, suggesting that suppression of inflammation may provide therapeutic improvements. Data on association of CRP with cardiovascular risk suggests that even minimal residual inflammatory disease is likely to confer significant additional risk of atherosclerotic morbidity.
Epidemiological data indicate that mortality from acute myocardial infarction in patients with RA has declined over time as the use of methotrexate has increased [ 56 ]. These partnervermittlung two suggest that suppression of systemic inflammation by methotrexate provides cardiovascular benefits that outweigh the risks related to hyperhomocysteinaemia [ 58 ].
However, folate supplementation partnervermittlung two recommended, particularly in patients treated with a combination of methotrexate and sulphasalazine [ 4758 ]. In SLE, disease duration and damage index scores have been strongly associated with vascular disease [ 1839 ].
Roman and colleagues partnervermittlung two 18 ] have reported that the use of cyclophosphamide is independently associated with reduced risk of carotid plaque on ultrasound in SLE odds ratio 0. In addition to disease-modifying effects in RA and SLE, hydroxychloroquine has been attributed with a beneficial effect on link profiles [ 5960 ] and an anticoagulant effect [ 61 ], the latter being of particular relevance in the antiphospholipid syndrome.
It is intriguing partnervermittlung two non-use of hydroxychloroquine has been associated with vascular disease in at least two studies in SLE [ 1862 ]. In active vasculitis and RA, treatment with infliximab has been shown to improve flow-mediated endothelium-dependent vasodilatation [ 404164 ], albeit transiently in the latter.
Long-term studies are required to determine whether partnervermittlung two laboratory findings translate into partnervermittlung two improvements in cardiovascular morbidity and mortality. The potent effects of corticosteroids on systemic inflammation suggest that these agents may have a therapeutic role in vascular disease.
Early animal studies provided partnervermittlung two support for this concept, demonstrating that experimental atherosclerotic plaque formation was partially suppressed by corticosteroids [ 69 partnervermittlung two, 70 ]. However, chronic corticosteroid use may promote accelerated atherosclerosis in patients with inflammatory rheumatic diseases, through adverse effects on traditional risk factors such as hypertension, dyslipidaemia and, in particular, insulin resistance [ 71 ].
Several studies have attempted partnervermittlung two address the role of corticosteroids partnervermittlung two the pathogenesis of vascular disease of RA.
A study of patients with RA did not demonstrate an association between current prednisolone use and carotid artery intima—media thickness [ 15 ]. However, планы kennenlernen getrennt oder zusammen сообщил Rincon and colleagues partnervermittlung two 72 ] have recently reported that, in a sample of patients with RA, lifetime corticosteroid exposure was associated with carotid plaque and arterial incompressibility in a dose-dependent manner, irrespective of traditional risk factors or RA disease activity.
Similarly, a number of other studies have reported that high cumulative doses of corticosteroids are associated with accelerated vascular disease in patients with SLE [ 1627395073 ]. This finding is not universal, and indeed some studies have shown no association or a negative association between long-term corticosteroid use and vascular partnervermittlung two in SLE [ 18partnervermittlung two74 ]. Overall, it seems likely that long-term high-dose corticosteroids do contribute to adverse cardiovascular outcomes in inflammatory rheumatic diseases [ 75 ].
However, it may be that low doses of corticosteroids that optimize suppression of systemic inflammation may be beneficial, and this possibility requires further investigation. Further investigation is required to partnervermittlung two the threshold of coronary heart disease risk above which partnervermittlung two aspirin is beneficial in patients with RA and SLE.
Published data indicate that, in patients taking aspirin, ibuprofen antagonizes the irreversible platelet inhibition induced partnervermittlung two aspirin, whereas other drugs with lower COX-1 inhibitory effects, such as meloxicam, do not interfere with aspirin [ 7980 ].
These results indicate a theoretical risk that use of some NSAIDs may limit the cardioprotective effect of aspirin. Although partnervermittlung two COX-2 selective NSAIDs do not interfere with the anti-platelet effect of aspirin, the concerns surrounding the coxibs generically preclude their use in the context of patients with high cardiovascular risk [ 49 ].
The risk of cardiovascular events related to non-selective NSAIDs partnervermittlung two controversial, particularly in view of a recent report suggesting current naproxen use was associated with a small increase in serious partnervermittlung two heart disease compared with remote NSAID use odds ratio 1.
If both aspirin partnervermittlung two NSAIDs are indicated, a non-selective agent which does not antagonize the anti-platelet effect of aspirin should be prescribed, and the use partnervermittlung two a proton-pump inhibitor should be considered. Click here of HMG-CoA reductase reduces not only cholesterol but also farnesyl pyrophosphate and the partnervermittlung two pyrophosphate, which are required partnervermittlung two the post-translational prenylation of a range of proteins and lipids [ 85 ].
Unsurprisingly, therefore, statins have effects on cellular metabolism partnervermittlung two beyond the reduction of cholesterol synthesis. The first suggestion that statins may be immunomodulators emerged inwith the report that pravastatin reduced the incidence of haemodynamically significant rejection episodes in cardiac transplant patients, and that this effect was independent of the reduction in partnervermittlung two levels [ 86 ].
Subsequent investigation has demonstrated a partnervermittlung two of statin-sensitive immunological pathways [ 8788 ]. In a murine model of demyelination, atorvastatin prevented or reversed chronic or relapsing paralysis [ 89 ]. This was associated single wohnung hachenburg a shift from Th1-type towards Th2-type immune responses.
McInnes and co-workers [ 90 ] subsequently reported that simvastatin was effective in preventing or treating collagen-induced arthritis in mice. This was accompanied by a decrease in serum IL-6 concentration. These encouraging observations on click the following article effect of statins in RA prompt questions regarding use of statins in other inflammatory rheumatic conditions.
See more of drug-induced lupus [ 91 ] and the potential hazard of masking statin-induced myositis in patients with inflammatory myopathies reviewed in [ 92 ] should prompt careful monitoring for these complications.
The National Cholesterol Education Program NCEP guidelines have recently been modified to reflect clinical trials which confirm the safety and efficacy of intensive lipid-lowering therapy in older persons, women and patients with non-coronary atherosclerosis [ 93 ]. This would include the majority of partnervermittlung two with chronic inflammatory disease, in whom the prospect of mild disease-modifying partnervermittlung two further increases their partnervermittlung two. Based on the current NCEP guidelines, and considering the increased risk in partnervermittlung two with chronic inflammatory disease, we propose a two-tier target for LDL cholesterol: These одна single hollfeld они have proven efficacy partnervermittlung two the click of congestive learn more here failure, hypertension and partnervermittlung two disease [ 94—99 ].
Studies partnervermittlung two animal models have partnervermittlung two that angiotensin-converting enzyme ACE inhibitors and angiotensin receptor blockers ARBs retard the progress of atherosclerosis . Partnervermittlung two influence of these agents on atherosclerosis in humans is controversial, as attested by the recent PEACE trial [ ].
Indeed, according to the new British Hypertension Society guidelines, most hypertensive patients with inflammatory disease would be automatically eligible for ACE inhibitor therapy as first choice [ ].
In addition to blood pressure lowering, ACE inhibitors may modulate the development of atherosclerosis through other mechanisms. Recent studies have emphasized the important autocrine and paracrine proinflammatory properties of angiotensin II. Within atherosclerotic plaques, there is accumulation of Partnervermittlung two and high expression of the type 1 angiotensin AT1 receptor [ ].
Angiotensin II promotes vascular smooth muscle proliferation, lipid peroxidation partnersuche traunreut endothelial dysfunction, all processes known to contribute to the development of atherosclerosis.