A reasonable approach in the management of geriatric patients with rheumatic disease is to screen patients for ASCVD risk factors and treat targets closer to those recom- mended to other high risk groups (diabetes mellitus, etc.). A retrospective study evaluating the Toronto SLE cohort dem- onstrated that patients with classic cardiovascular risk fac- tors were suboptimally managed [78]. On the other hand, (aggressive) risk modifications may have limited impact on ASCVD risk reduction since traditional risk factors may not be the strongest risk in patients with rheumatic disease. In this context, the treatment of systemic inflammation has a potential to improve atherosclerosis.
NSAiDS and Selective Cox-2 inhibitors
Both nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors reduce systemic inflammation, but there are concerns about the potential increased risk of ASCVD. This group of drugs inhibits pros- taglandin metabolism, including athero-protective prostacy- clins [79]. Furthermore, this group of drugs decreases the effect of low-dose daily aspirin. Since the withdrawal of two COX-2 inhibitors, rofecoxib and valdecoxib, which showed about twofold increased risk of ASCVD events, the US Food and Drug Administration placed a black-box warning on all COX-2 inhibitors and nonselective NSAIDs [80, 81].
Subsequent pharmacoepidemiologic studies reassure that many nonselective NSAIDs and selective COX-2 inhibitors are not associated with an increased risk of ASCVD events [82]. However, several patient characteristics (age ³80 years, hypertension, prior cardiovascular event, RA, chronic renal disease, and chronic pulmonary disease) may increase the risk of ASCVD events when using specific agents (rofecoxib, ibuprofen) [83].
Corticosteroids
The undesirable effects of corticosteroids on blood pres- sure, insulin resistance, lipid profile, body weight, fat distri- bution, and coagulation proteins may significantly increase the risk of ASCVD [84]. The role of corticosteroids in the promotion of ASCVD in patients with RA has been contro- versial for decades [85, 86]. In patients with SLE, corticos- teroid treatment was suggested to reduce the risk of atherosclerosis [39].
Statins
HMG-CoA reductase inhibitors, originally used to treat hypercholesterolemia, have shown anti-inflammatory and immunomodulating effects and reduce ASCVD morbidity and mortality [87]. More recently, in healthy persons without hyperlipidemia but with elevated high-sensitivity CRP, rosu- vastatin significantly reduced the incidence of major cardio- vascular events and all cause mortality [88]. Statins can mediate clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high- grade autoimmune inflammation. Trial of atorvastatin in rheumatoid arthritis (TARA) showed significant reduction in CRP and erythrocyte sedimentation rate (ESR) as well as in the swollen joint count and the disease activity score in
patients treated with atorvastatin [89], even though a prevention trial among SLE patients was terminated because of inadequate recruitment [90].
Methotrexate
Treatment with methotrexate reduces markers of inflamma- tion and has been associated with decreased cardiovascular mortality. A retrospective study of 1,240 patients with RA reported lower all-cause mortality and cardiovascular mor- tality in patients treated with methotrexate than in those with no methotrexate use, independent of folic acid use [91].
Antimalarial Agents
Hydroxychloroquine has immunomodulatory effects without immune suppression. It inhibits the activation of intracellular toll-like receptors (TLRs) (TLR-3, -7, and -9) by targeting microsomes, stabilizing the microsomal membrane, disrupting proper endosomal maturation and acidic pH, and blocking TLR interaction with nucleic acid ligands [92]. It has been shown to reduce cholesterol levels in cohort studies [93–96]. A recent observational study showed 38% reduction of developing diabetes mellitus among patients with RA [97]. A reduction in the frequency of thrombosis was shown in both patients with SLE and patients with APS [98–101]. Two prospective observational cohorts showed a reduction in mortality in SLE patients [102]. Subclinical atherosclerosis is observed less frequently in patients who take hydroxychloroquine than those who have never taken it [39].
Biological Therapies
Treatment with TNF antagonists appears to significantly reduce the rate of first ever ASCVD [103] and survival ben- efit [104, 105], although this has not been confirmed by other studies. A study in the UK showed that there was no overall reduction in ASCVD event risk in patients treated with anti- TNF drugs, but there was a marked reduction in the risk of myocardial infarction among patients whose RA responded well to the treatment [106]. In contrast, increased mortality was associated with the administration of high dose of inflix- imab in patients with severe congestive heart failure (CHF) [107]. Since TNF inhibition in RA does not lead to an increased risk of developing CHF in RA patients [108], a contraindication for TNF blockers can be confined to patients already suffering from severe established CHF.
Mycophenolate Mofetil
Mycophenolate mofetil (MMF) has a strong cytostatic effect on T lymphocytes by interfering with DNA synthesis in activated T cells. MMF has been shown to inhibit plaque formation in animal studies [109].
Conclusion
Patients with autoimmune rheumatic disease have an increased risk of ASCVD morbidity and mortality. SLE and RA have been studied the most, but other autoimmune diseases may confer the risk of ASCVD as well. In addition to traditional risk factors, systemic inflammation likely contributes to ASCVD risk. Atherosclerosis is considered an inflammatory process, and may be accelerated by systemic inflammation. ASCVD risk reduction can be targeted by aggressive management of ASCVD risk factors and the primary rheumatic disease.
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