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The Effect of Inflammation and Infection on Lipids and Lipoproteins

, MD and , MD, PhD.

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Last Update: June 12, 2015.

ABSTRACT

Chronic inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis and infections, such as periodontal disease and HIV, are associated with an increased risk of cardiovascular disease. Patients with these disorders also have an increase in coronary artery calcium measured by CT and carotid intima media thickness measured by ultrasound. Inflammation and infections induce a variety of alterations in lipid metabolism that may initially dampen inflammation or fight infection, but if chronic could contribute to the increased risk of atherosclerosis. The most common changes are decreases in serum HDL and increases in triglycerides. The increase in serum triglycerides is due to both an increase in hepatic VLDL production and secretion and a decrease in the clearance of triglyceride rich lipoproteins. The mechanisms by which inflammation and infection decrease HDL levels are uncertain. There is also a consistent increase in lipoprotein (a) levels due to increased apolipoprotein (a) synthesis. LDL levels are frequently decreased but the prevalence of small dense LDL is increased due to cholesterol ester transfer protein (CETP) mediated exchange of triglycerides from triglyceride rich lipoproteins to LDL followed by triglyceride hydrolysis. In addition to affecting serum lipid levels, inflammation also adversely effects lipoprotein function. LDL is more easily oxidized as the ability of HDL to prevent the oxidation of LDL is diminished. Moreover, there are a number of steps in the reverse cholesterol transport pathway that are adversely affected during inflammation. The greater the severity of the underlying inflammatory disease, the more consistently these abnormalities in lipids and lipoproteins are observed. Treatment of the underlying disease leading to a reduction in inflammation results in the return of the lipid profile towards normal. The changes in lipids and lipoproteins that occur during inflammation and infection are part of the innate immune response and therefore are likely to play an important role in protecting the host. The guidelines for the management of lipid disorders and the standard risk calculators for predicting cardiovascular disease (ACC/AHA and Framingham) underestimate the risk in patients with inflammation. It has been recommended to increase the calculated risk by approximately 50% in patients with severe inflammatory disorders. The treatment of lipid disorders in patients with inflammatory disorders is similar to patients without inflammatory disorders. Of note statins, fibrates, and fish oil have anti-inflammatory properties and have been reported to have beneficial effects on many of these inflammatory disorders.

INTRODUCTION

A number of chronic inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, and psoriasis are associated with an increased risk of cardiovascular disease [1-4]. For example, in a meta-analysis of twenty-four studies comprising 111,758 patients with 22,927 cardiovascular events it was observed that there was a 50% increased risk of CVD death in patients with rheumatoid arthritis [5]. Similarly, women with systemic lupus erythematosus in the 35- to 44-year age group were over 50 times more likely to have a myocardial infarction than were women of similar age in the Framingham Offspring Study [6]. As a final example, a meta-analysis of 14 studies reported that in individuals with severe psoriasis the risk for cardiovascular mortality was 1.37, the risk for myocardial infarction was 3.04, and the risk for stroke was 1.59 times higher than the general population [7]. It should be noted that the pathology in psoriasis is localized to the skin but nevertheless even this disorder by inducing systemic inflammation is associated with an increased risk of cardiovascular disease.

Further, supporting the link of rheumatoid arthritis, systemic lupus erythematosus, and psoriasis with atherosclerosis are studies showing that patients with these disorders have an increase in coronary artery calcium measured by CT and carotid intima media thickness measured by ultrasound [8-14]. Finally, even children and adolescents with systemic lupus erythematosus have an increase in carotid intimal-medial thickness [15]. Thus it is clear that patients with a number of different chronic inflammatory diseases have an increased risk of atherosclerotic cardiovascular complications.

In addition, chronic infections are also associated with an increased risk of atherosclerosis [16-18]. Since the development of effective anti-viral agents it has been widely recognized that a major cause of morbidity and mortality in HIV infected patients is due to cardiovascular disease (see chapter on the effect of HIV infection on lipid and lipoprotein metabolism for details). Moreover, numerous studies have demonstrated an association of periodontal infections with an increased risk of atherosclerotic vascular disease [19]. Additionally, carotid intima-media thickness is increased in patients with periodontal disease [20-23]. The link between various chronic infections, such as HIV, dental infections, Helicobacter pylori, chronic bronchitis, and urinary tract infections with cardiovascular disease is presumably due to the chronic inflammation that accompanies these infections [24]. For certain infections such as chlamydia pneumonia and cytomegalovirus it is possible that the association with cardiovascular disease is due to a direct role in the vessel wall.

The mechanisms by which chronic inflammation and infection increase the risk of atherosclerotic cardiovascular disease are likely multifactorial. As will be discussed below inflammation and infection induce a variety of alterations in lipid and lipoprotein metabolism that could contribute to the increased risk of atherosclerosis.

LIPID AND LIPOPROTEIN ABNORMALITIES IN PATIENTS WITH INFLAMMATORY DISORDERS AND INFECTIONS

Rheumatoid arthritis

The most consistent abnormality in patients with rheumatoid arthritis is a decrease in HDL and apolipoprotein A-I levels [25-28]. In particular, small HDL particles are decreased in patients with rheumatoid arthritis [29]. Patients with more severe rheumatoid arthritis have the greatest reductions in HDL [25-28, 30]. There is an inverse correlation of CRP levels with HDL levels (i.e. higher CRP levels are associated with lower HDL levels). With regards to total cholesterol and LDL, there is more variability with many studies showing a decrease, other studies showing no change, and some studies showing an increase in patients with rheumatoid arthritis [25-28, 30]. The more severe the rheumatoid arthritis the greater the likelihood that the LDL levels will be decreased. Serum triglyceride levels and small dense LDL levels tend to be increased in patients with rheumatoid arthritis [25-28, 30]. Levels of lipoprotein (a) are characteristically elevated in patients with rheumatoid arthritis and correlate with CRP levels [31-33].

Systemic lupus erythematosus

The changes in serum lipids and lipoproteins seen in patients with systemic lupus erythematosus are very similar to those observed in patients with rheumatoid arthritis [34-36]. Specifically there is a decrease in HDL levels and an increase in serum triglyceride levels. LDL cholesterol levels are variable and maybe increased, normal, or low but small dense LDL levels tend to be increased. Lipoprotein (a) levels are also increased [37]. Similar to rheumatoid arthritis the more severe the disease state the greater the alterations in serum lipid levels.

Psoriasis

A large number of studies have compared serum lipid levels in controls and patients with psoriasis [38]. However, many of these studies included only a small number of subjects and the results have therefore been extremely variable with some studies showing alterations in serum lipid levels in patients with psoriasis and other studies showing no changes. In general, there is a tendency for an increase in serum triglycerides and a decrease in HDL in patients with psoriasis [39-42]. Additionally, a number of studies showed an increase in LDL and lipoprotein (a) levels in patients with psoriasis [39, 40, 42]. This variability between studies is most likely due to differences in the severity of the psoriasis with more severe disease demonstrating more robust alterations in lipid levels. The prevalence of other abnormalities that affect lipid metabolism such as obesity and abnormalities in glucose metabolism could also account for the variability in results.

Periodontal Disease

Differences exist between studies but in general patients with periodontitis tend to have increased LDL and triglyceride levels and decreased HDL levels [43-46]. Additionally, the prevalence of small dense LDL is increased in patients with periodontitis [46, 47]. The severity of the periodontitis correlated with the changes in the in the lipid profile with patients with increased periodontal disease having higher triglyceride levels, lower HDL levels, and smaller LDL particle size [48]. Moreover, treatment of periodontitis improved the dyslipidemia, with the HDL levels increasing and the LDL levels decreasing [46, 49, 50].

Acute Infections

Patients with a variety of different infections (gram positive bacterial, gram negative bacterial, viral, tuberculosis) have similar alterations in plasma lipid levels. Specifically, total cholesterol, LDL cholesterol, and HDL cholesterol levels are decreased while plasma triglyceride levels are elevated or inappropriately normal for the poor nutritional status [24, 51-57]. As expected apolipoprotein A-I, A-II, and B levels are reduced [51, 56, 57]. While LDL levels were decreased, the concentration of small dense LDL has been found to be increased during infections [58-60].That plasma cholesterol levels decrease during infection has been known for many years as it was described by Denis in 1919 in the Journal of Biological Chemistry (JBC 29: 93, 1919). The alterations in lipids correlate with the severity of the underlying infection i.e. the more severe the infection the more severe the alterations in lipid and lipoprotein levels [61, 62]. The decreases in plasma cholesterol levels can be quite profound and a recent case report described HDL cholesterol levels < 10mg/dl and LDL cholesterol levels < 3mg/dl in sepsis [63].

Of note studies have demonstrated that the degree of reduction in total cholesterol, HDL cholesterol, and apolipoprotein A-I are predictive of mortality in patients with severe sepsis [64-67]. Moreover, epidemiologic studies have suggested that low cholesterol and HDL levels increase the chance of developing an infection [68, 69]. During recovery from the infection plasma lipid and lipoprotein abnormalities return towards normal. The changes in lipid and lipoproteins that occur during infection can be experimentally reproduced in humans and animals by the administration of endotoxin and lipoteichoic acid [24, 70].

Thus, in these different inflammatory disorders and infectious diseases, the alterations in plasma lipid and lipoprotein levels are very similar with decreases in plasma HDL being consistently observed. Also of note is the consistent increase in lipoprotein (a) levels and small dense LDL [24, 71]. There is also a tendency for plasma triglyceride levels to be elevated. The greater the severity of the underlying disease the more consistently these abnormalities in lipids are observed. Additionally, treatment of the underlying disease leading to a reduction in inflammation results in a return of the lipid profile towards normal. This is best illustrated in periodontal disease where intensive dental hygiene can reverse the abnormalities in the lipid profile [49, 50]. Of note, these changes are very similar to the changes in lipid and lipoproteins seen during chronic HIV infection (see chapter on HIV for additional details).

EFFECT OF ANTI-INFLAMMATORY DRUGS ON LIPID LEVELS

As noted above, treatments that reduce inflammation will return the lipid profile towards normal resulting in an increase in plasm HDL levels. If LDL levels were reduced at baseline, treatment that reduces inflammation will result in an increase in LDL levels (i.e. a return towards “normal” levels) [72, 73]. Many of the drugs used for the treatment of rheumatoid arthritis, systemic lupus erythematosus, and psoriasis decrease inflammation and have been shown to increase both HDL and LDL levels [72-74]. The increase in HDL tends to be more robust. In a few instances drugs used to treat inflammatory disorders have effects on lipid metabolism that are independent of the reduction in inflammation.

Methotrexate

While the results vary from study to study the most consistent effect of methotrexate treatment of patients with rheumatoid arthritis is an increase in HDL cholesterol levels [26, 74-78]. In addition, several studies have also observed an increase in LDL levels [75-77]. These changes were frequently associated with decreases in inflammation and improvement in disease activity. Methotrexate may also increase triglyceride levels but the mechanism is not clear [75-77].

Hydroxychloroquine

Hydroxychloroquine has been reported to lower total cholesterol, LDL, and triglycerides in patients with rheumatoid arthritis and systemic lupus erythematosus [79-81], an effect that is not simply due to reducing inflammation (a reduction in inflammation would have the opposite effect increasing total cholesterol and LDL levels). Additionally, hydroxychloroquine increases HDL levels, which is thought to be secondary to improvement in disease activity. In cultured hepatocytes studies have shown that chloroquine decreases hepatic cholesterol synthesis while in fibroblasts this drug increases the number of LDL receptors [82, 83]. These changes could contribute to the decrease in total cholesterol and LDL levels independent of the effect of chloroquine on inflammation.

Glucocorticoids

In patients without inflammatory disorders high dose glucocorticoids have an adverse effect on the lipid profile [84-86]. High dose glucocorticoid treatment results in an increase in serum triglyceride and LDL levels due to the increased production and secretion of VLDL by the liver [84-86]. If severe insulin resistance develops, a decrease in lipoprotein lipase activity can also occur resulting in the decreased clearance of triglyceride rich lipoproteins, further increasing triglyceride levels. HDL levels are more variable, but increases in HDL with glucocorticoid treatment are frequently observed [84-86].

In patients with inflammatory diseases the effect of glucocorticoids on lipids is confounded by the marked anti-inflammatory effects, which can reduce inflammation and therefore affect the lipid response. Also the dose of glucocorticoids used can be an important variable, as low doses often having minimal effects on triglyceride and LDL levels.

TNF-alpha Blocking Therapy

There have been several meta-analyses of the effect of TNF inhibitors on lipid and lipoprotein levels in patients with rheumatoid arthritis [87-89]. In general, TNF blocking agents increase total cholesterol, triglycerides, and HDL cholesterol levels. LDL levels were not consistently altered by treatment with TNF inhibitors. In patients with psoriasis, treatment with TNF inhibitors did not have a major impact on the lipid profile [90, 91].

Tofacitinib

Tofacitinib is a dual JAK1 and JAK3 inhibitor. In patients with rheumatoid arthritis, treatment with tofacitinab increased LDL and HDL levels [92-97]. A similar increase was observed in patients with ulcerative colitis treated with tofacitinib [98]. The effect of treatment with either tofacitinab or adalimumab, a TNF inhibitor, was compared in a study by van Vollenhoven et al [97]. Despite a similar effect on disease activity, LDL cholesterol and HDL cholesterol levels increased by 18% and 10% respectively with tofacitnib therapy and only 3.6% and 5.6% with adalimumab therapy. In a comparison of tofacitnib vs. methotrexate, Lee et al reported that LDL levels increased by 22% and HDL levels by 17% with tofacitnib [95]. In contrast, methotrexate treatment increased LDL levels by only 3.9% and HDL levels by only 7%. It should be noted that methotrexate was not as effective in reducing disease activity. Nevertheless these two studies indicate that tofacitnib has effects on serum lipoprotein levels beyond decreasing inflammation. It should be noted that treatment with atorvastatin can inhibit the increase in LDL induced by tofacitinib therapy [99].

Tocilizumab

Tocilizumab is a monoclonal antibody against the IL-6 receptor. Treatment of patients with rheumatoid arthritis with tocilizumab increases HDL, LDL, and triglyceride levels [73, 96, 100, 101]. LDL levels have been reported to increase by as much as 20% [102]. In vitro studies have shown that IL-6 receptor antagonists decrease the expression of LDL receptors in cultured hepatocytes [102]. A decrease in hepatic LDL receptors could account for the increase in LDL levels with tocilizumab treatment. Finally, studies have also demonstrated that treatment with tocilizumab decreases lipoprotein (a) levels [103].

Rituximab

Rituximab is a monoclonal antibody that decreases B-lymphocytes. In patients with rheumatoid arthritis four studies have examined the effect of rituximab on plasma lipid levels [104-107]. The results were variable with some studies showing an increase in LDL, HDL, and triglycerides, while other studies showed no significant changes in these parameters. An increase in HDL was the most consistent observation and was seen in three of the four studies. An increase in LDL and triglycerides levels was observed in two of the four studies. Interestingly in patients with systemic lupus erythematosus rituximab decreased plasma triglyceride levels but had no significant effect on LDL or HDL levels [108].

Retinoids

Retinoids are analogues of vitamin A that are used to treat psoriasis. These drugs can cause marked increases in serum triglyceride levels and have been reported to cause pancreatitis [109, 110]. Individuals with preexisting hypertriglyceridemia, obesity, metabolic syndrome, or a family history of hypertriglyceridemia are at increased risk of developing serious hypertriglyceridemia with retinoid therapy. In addition retinoids frequently increase LDL and decrease HDL levels [109, 110]. Retinoids increase apolipoprotein C-III production and serum levels, which may account for the increase in plasma triglycerides [110]. Before initiating therapy with retinoids, it is important to check plasma lipid levels and a markedly elevated plasma triglyceride level is a contraindication to treatment with retinoids. After initiating therapy with retinoids lipid levels should be measured periodically.

Cyclosporine

Cyclosporine is an immunosuppressant agent used in the treatment of psoriasis. It increases plasma cholesterol, triglycerides, and LDL levels [111-115]. The effect of cyclosporine on HDL is more variable with either no change or an increase being reported. The mechanism by which cyclosporine treatment induces changes in plasma lipids is not fully understood but studies have shown that cyclosporine induces a number of changes in lipid metabolism that could account for the alterations in plasma lipid and lipoprotein levels. The increase in plasma cholesterol and LDL levels induced by cyclosporine could be due to a decrease in LDL receptor expression and a decrease in cholesterol 7 alpha hydroxylase, a key enzyme in the conversion of cholesterol to bile acids [116, 117]. The increase in plasma triglyceride levels induced by cyclosporine could be due to the inhibition of lipoprotein lipase, the key enzyme that metabolizes circulating triglyceride rich lipoproteins [117].

PATHOPHYSIOLOGY OF THE DYSLIPIDEMIA OF INFLAMMATION AND INFECTION

Inflammation and infections increase the production of a variety of cytokines, including TNF, IL-1, and IL-6, which have been shown to alter lipid metabolism [24]. Many of the changes in plasma lipids and lipoproteins that are seen during chronic inflammation and infections are also observed following the acute administration of cytokines [24].

Increased Triglyceride Levels

Multiple cytokines increase serum triglyceride and VLDL levels (TNF, IL-1, IL-2, IL-6, etc.) [24]. Following a single administration of a cytokine or LPS (a model of gram negative infections), which stimulates cytokine production, an increase in serum triglyceride and VLDL levels can be seen within 2 hours and this effect is sustained for at least 24 hours. The increase in serum triglycerides is due to both an increase in hepatic VLDL production and secretion and a decrease in the clearance of triglyceride rich lipoproteins (figure 1) [24]. The increase in VLDL production and secretion is a result of increased hepatic fatty acid synthesis, an increase in adipose tissue lipolysis with the increased transport of fatty acids to the liver, and a decrease in fatty acid oxidation in the liver. Together these changes provide an increased supply of fatty acids in the liver that stimulate an increase in hepatic triglyceride synthesis [24]. The increased availability of triglycerides leads to the increased formation and secretion of VLDL. The decrease in the clearance of triglyceride rich lipoproteins is due to a decrease in lipoprotein lipase, the key enzyme that metabolizes triglycerides in the circulation [24]. A variety of cytokines have been shown to decrease the synthesis of lipoprotein lipase in adipose and muscle tissue [24]. Recent studies have shown that inflammation also increases angiopoietin like protein 4, an inhibitor of lipoprotein lipase activity, which would further block the metabolism of triglyceride rich lipoproteins [118]. In systemic lupus erythematosus, antibodies to lipoprotein lipase have been reported and are associated with increased triglyceride levels [119, 120].

Figure 1: Pathogenesis of Hypertriglyceridemia

Figure 1Pathogenesis of Hypertriglyceridemia

Production of Small Dense LDL and HDL

The elevation in triglyceride rich lipoproteins in turn has effects on other lipoproteins [24]. Specifically, cholesterol ester transfer protein (CETP) mediates the exchange of triglycerides from triglyceride rich VLDL and chylomicrons to LDL and HDL. The increase in triglyceride rich lipoproteins per se leads to an increase in CETP mediated exchange, increasing the triglyceride content of both LDL and HDL. The triglyceride on LDL and HDL is then hydrolyzed by hepatic lipase and lipoprotein lipase leading to the increased production of small dense LDL and HDL. The affinity of Apo A-I for small HDL particles is reduced leading to the disassociation of Apo A-I and the consequent accelerated clearance and breakdown of Apo A-I by the kidneys. These changes, along with other factors described below, result in a reduction in the levels of Apo A-I and HDL in patients with inflammation.

Decreased HDL Levels

In addition to a decrease in HDL, inflammation can also lead to structural changes in this lipoprotein [24]. During inflammation HDL particles tend to be larger with a decrease in cholesterol ester and an increase in free cholesterol, triglycerides, and free fatty acids. Furthermore, there are marked changes in HDL associated proteins and the enzymes and transfer proteins involved in HDL metabolism and function (figure 2 and 3).

Figure 2: Changes in HDL Protein Composition During Inflammation

Figure 2Changes in HDL Protein Composition During Inflammation

Figure 3: Changes in Enzymes and Transfer Proteins During Inflammation

Figure 3Changes in Enzymes and Transfer Proteins During Inflammation

The precise mechanism by which inflammation and infection decrease HDL levels is uncertain and is likely to involve multiple mechanisms [24]. Decreases in apolipoprotein A-I synthesis in the liver occur during inflammation and would result in the decreased formation of HDL. However, in acute infection and inflammation HDL decreases faster than would be predicted from decreased synthesis of apolipoprotein A-I. Increased serum amyloid A (SAA) production by the liver and other tissues occurs during inflammation and infection and the SAA binds to HDL displacing apolipoprotein A-I, which can accelerate the clearance of HDL. However, the overexpression in SAA in the absence of the acute phase response does not result in a decrease in HDL levels [121]. Inflammation results in a decrease in LCAT leading to decreased cholesterol ester formation, which would prevent the formation of normal HDL, leading to decreased cholesterol carried in HDL. Elevations in triglyceride rich lipoproteins that accompany inflammation and infection can lead to the enrichment of HDL with triglycerides that can accelerate the clearance of HDL. Finally, cytokine induced increases in enzymes such as secretory phospholipase A2 (sPLA2) and endothelial cell lipase, which metabolize key constituents of HDL, could alter the stability and metabolism of HDL. Given the complexity of HDL metabolism it is not surprising that multiple pathways could be affected by inflammation, which together may account for the decrease in HDL levels.

Increased Lipoprotein (a)

The mechanism accounting for the increase in lipoprotein (a) during inflammation is likely due to increased apolipoprotein (a) synthesis, as apolipoprotein (a) is a positive acute phase protein whose expression is up-regulated during inflammation [24, 122]. The apolipoprotein (a) gene contains several IL-6 responsive elements that enhance transcription [123].

FUNCTIONAL CHANGES IN LIPOPROTEINS THAT INCREASE THE RISK OF ATHEROSCLEROSIS

LDL

While the levels of LDL do not consistently increase and may even decrease with inflammation and infection, many studies have indicated that inflammation and infection are associated with small dense LDL [24]. These small dense LDL particles are believed to be more pro-atherogenic for a number of reasons. Small dense LDL particles have a decreased affinity for the LDL receptor resulting in a prolonged period of time in the circulation. Additionally, they more easily enter the arterial wall and bind more avidly to intra-arterial proteoglycans, which traps them in the arterial wall. Finally, small dense LDL particles are more susceptible to oxidation, which could result in an enhanced uptake by macrophages.

Several markers of lipid peroxidation, including conjugated dienes, thiobarbituric acid-reactive substances, malondialdehyde, and lipid hydroperoxides are increased in serum and/or circulating LDL during inflammation and infection [24, 48, 124-126]. Moreover, LDL isolated from LPS-treated animals is more susceptible to oxidation in vitro [24]. Oxidized LDL is taken up very efficiently by macrophages and is thought to play a major role in foam cell formation in the arterial wall. Additionally, antibodies to oxidized LDL are present in patients with systemic lupus erythematosus and could facilitate the uptake of an antibody LDL complex via the Fc-receptor in macrophages [124]. Finally, studies have shown that LDL isolated from patients with periodontal disease leads to enhanced uptake of cholesterol esters by macrophages [48]

HDL

In addition to a decrease in serum HDL, inflammation and infection affects the anti-atherogenic properties of HDL [24, 127, 128]. Reverse cholesterol transport plays a key role in preventing cholesterol accumulation in macrophages thereby reducing atherosclerosis. Most steps in the reverse cholesterol transport pathway are adversely affected during inflammation and infection (figure 4) [30, 129]. First, cytokines induced by inflammation and infection decrease the production of Apo A-I, the main protein constituent of HDL. Second, pro-inflammatory cytokines decrease the expression of ABCA1, ABCG1, SR-B1, and apolipoprotein E in macrophages, which will lead to a decrease in the efflux of phospholipids and cholesterol from the macrophage to HDL. Third, the structurally altered HDL formed during inflammation is a poor acceptor of cellular cholesterol and in fact may actually deliver cholesterol to the macrophage [30, 129-135]. HDL isolated from patients with rheumatoid arthritis, systemic lupus erythematosus, psoriasis, periodontal disease, and acute sepsis are poor facilitators of cholesterol efflux [130-135]. Similarly, the experimental administration of endotoxin to humans also results in the formation of HDL that is a poor facilitator of the efflux of cholesterol from macrophages [136]. Of note treatments that reduce inflammation in patients with rheumatoid arthritis, psoriasis, or periodontitis can restore towards normal the ability of HDL to remove cholesterol from cells [76, 135, 137, 138]. Fourth, pro-inflammatory cytokines decrease the production and activity of LCAT, which will limit the conversion of cholesterol to cholesterol esters in HDL. This step is required for the formation of a normal spherical HDL particle and facilitates the ability of HDL to transport cholesterol. Fifth, pro-inflammatory cytokines decrease CETP levels, which will decrease the movement of cholesterol from HDL to Apo B containing lipoproteins, an important step in the delivery of cholesterol to the liver. Sixth, pro-inflammatory cytokines decrease the expression of SR-B1 in the liver. SR-B1 plays a key role in the uptake of cholesterol from HDL particles into hepatocytes. Finally, inflammation and infection decrease both the conversion of cholesterol to bile acids and the secretion of cholesterol into the bile, the two mechanisms by which cholesterol is disposed of by the liver.

Figure 4: Effect of Inflammation on Reverse Cholesterol Transport (from reference 61)

Figure 4Effect of Inflammation on Reverse Cholesterol Transport (from reference 61)

Figure 4b

Another important function of HDL is to prevent the oxidation of LDL. Oxidized LDL is more easily taken up by macrophages and is pro-atherogenic. Paraoxonase is an enzyme that is associated with HDL and plays a key role in preventing the oxidation of LDL. Inflammation and infection decrease the expression of paraoxonase 1 in the liver resulting in a decrease in circulating paraoxonase activity [24]. Plasma paraoxonase levels are decreased in patients with patients rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and infections [139-147] Studies have shown that HDL isolated from patients with rheumatoid arthritis and systemic lupus erythematous have a diminished ability to protect LDL from oxidation and in fact may facilitate LDL oxidation [127]. Moreover, in patients with rheumatoid arthritis, reducing inflammation and disease activity with methotrexate treatment restored HDL function towards normal [148]. Additionally, treatment with atorvastatin 80mg improved the function of HDL in patients with rheumatoid arthritis [149].

Thus, it should be recognized that in patients with inflammatory disorders and infections the absolute levels of lipids and lipoproteins may not be the only factor increasing the risk of atherosclerosis [24, 38, 125, 127-129]. Rather functional changes in LDL and HDL maybe pro-atherogenic and thereby contribute to the increased risk of atherosclerosis in inflammatory disorders and infections. Additionally, the increase in lipoprotein (a) may also play a role.

Table 1Pro-Atherogenic Changes During Inflammation

Increased triglycerides
Decreased HDL
Increased small dense LDL
Increased Lp(a)
Oxidized LDL
Dysfunctional HDL

BENEFICIAL EFFECTS OF LIPIDS DURING INFECTIONS AND INFLAMMATION

The changes in lipids and lipoproteins that occur during inflammation and infection are part of the innate immune response and therefore are likely to play an important role in protecting from the detrimental effects of infection and inflammatory stimuli [24, 150-152]. Some of the potential beneficial effects are listed in Table 2. Thus the changes in lipid and lipoprotein metabolism that occur during inflammation may initially be protective but if chronic can increase the risk of atherosclerosis.

Table 2Beneficial Effects of Lipoproteins

Redistribution of nutrients to immune cells that are important in host defense
Lipoproteins bind endotoxin, lipoteichoic acid, and other biological agents and prevent their toxic effects
Lipoproteins bind urate crystals
Lipoproteins bind and target parasites for destruction
Apolipoproteins neutralize viruses
Apolipoproteins lyse parasites

LIPID MANAGEMENT IN A PATIENT WITH AN INFLAMMATORY DISEASE

Deciding When to Treat

As noted earlier, patients with inflammatory disorders are at an increased risk for atherosclerosis and this is not totally accounted for by standard lipid profile measurements and other risk factors [1-3]. Some authors have advocated considering inflammatory disorders as a cardiovascular risk equivalent similar to diabetes; however many of the guidelines and risk calculators commonly used for deciding on lipid lowering therapy do not take into account this increased risk in patients with inflammatory disorders [3, 153]. For example both the American College of Cardiology/American Heart Association and National Lipid Association recommendations do not specifically address this patient population [154, 155]. Additionally, the standard risk calculators for predicting cardiovascular disease (ACC/AHA and Framingham) underestimate the risk in this population [156-160]. Even the Reynolds Risk Calculator (http://www.reynoldsriskscore.org/Default.aspx), which uses measurements of hsCRP levels, a marker of inflammation, underestimates the risk of cardiovascular events in patients with inflammatory disorders [156-160]. Thus if one follows the standard protocols one will undertreat patients with inflammatory disorders. It should be noted that the QRISK calculator (http://qrisk.org/) does factor in the presence of rheumatoid arthritis when calculating risk [161].

A reasonable approach is to use the standard approach and calculators but increase the calculated risk by approximately 50% in patients with severe inflammatory disorders. For example, if a patient with rheumatoid arthritis has a 5% ten year risk and 40% lifetime risk one might increase the ten year risk to 7.5% and lifetime risk to 60%. This approach has been recommended by an expert committee who advocated introducing a 1.5 multiplication factor (i.e. 50% increase) in patients with rheumatoid arthritis who meet two of the following criteria; disease duration of more than 10 years, rheumatoid factor positive, or presence of extra-articular manifestations [162]. Alternatively one could carry out imaging studies such as obtaining a coronary artery calcium score to better define risk. Whatever the approach taken it is crucial to recognize that patients with inflammatory diseases have an increased risk of cardiovascular disease and therefore one needs to be more aggressive.

Treatment Approach

As in all patients with lipid abnormalities the initial approach is lifestyle changes. Dietary recommendations are not unique in patients with inflammatory disorders. Exercise is recommended but depending upon the clinical situation the ability of patients with certain inflammatory disorders to participate in an exercise regimen may be limited. Exercise programs will need to be tailored for each patient’s capabilities.

Drug Therapy

This section on drug therapy will focus solely on the studies that are unique to patients with inflammatory diseases. Detailed information on the use of these drugs can be found in the appropriate chapters on these drugs.

Statin Therapy

As expected, studies have demonstrated that statins lower LDL cholesterol levels in patients with inflammatory disorders to a similar degree as patients without inflammatory disorders. For example, in a randomized trial in 116 patients with rheumatoid arthritis with a mean LDL level of 125mg/dl, the effect of atorvastatin 40mg was compared to placebo [163]. Atorvastatin reduced LDL cholesterol by 54mgdl vs. 3mg/dl in the placebo group [163]. Similarly in the IDEAL trial there was a small subgroup of patients with rheumatoid arthritis [164]. The IDEAL trial compared the ability of atorvastatin 80mg vs. simvastatin 20-40mg to reduce cardiovascular events. The lowering of LDL with either simvastatin or atorvastatin was similar in the patients with and without rheumatoid arthritis [164]. Studies have shown similar reductions in LDL levels with statin therapy in patients with systemic lupus erythematosus and psoriasis (see below). The effects of statin treatment on other lipid parameters were also similar in patients with and without inflammatory diseases. Thus, as expected statins improve the lipid profile in patients with inflammatory disorders. In some studies the incidence of statin associated side effects have been increased in the patients with inflammatory disorders. Specifically, in the IDEAL trial rheumatoid arthritis patients reported myalgia more frequently than patients without rheumatoid arthritis (10.4% and 7.7% in rheumatoid arthritis patients vs 1.1% and 2.2% in non-rheumatoid arthritis patients receiving simvastatin and atorvastatin respectively) [164].

A key question is whether statin therapy will reduce cardiovascular events in patients with inflammatory diseases. A number of studies have looked at surrogate markers for events such as changes in carotid intima-media thickness or changes in cardiac calcium scores in patients treated with statins. The results have varied with some studies showing benefits and other studies showing no effects. Rollefstad et al measured changes in carotid plaque size in 86 patients with inflammatory joint disease treated with rosuvastatin for 18 months [165]. The LDL cholesterol levels decreased from 155mg/dl to 66mg/dl and plaque height was significantly reduced [165]. Similarly, Mok et al treated 72 patients with systemic lupus erythematosus with rosuvastatin 10mg or placebo for 12 months and reported that carotid intima-media thickness appeared to decrease [166]. Moreover, Plazak et al treated 60 patients with systemic lupus erythematosus with atorvastatin 40mg or placebo for 1 year and measured changes in coronary calcium score [167]. They observed an increase in coronary calcium in the placebo group while there was no change in the patients treated with statin therapy [167]. In contrast, Petri et al treated 200 patients with systemic lupus erythematosus with atorvastatin 40mg or placebo for 2 years and measured both carotid intima-media thickness and coronary calcium score [168]. In this study no beneficial effects of statin therapy were observed [168]. Similarly, Schanberg et al treated 221 children with systemic lupus erythematosus with atorvastatin 10-20mg or placebo for 36 months and did not observe a beneficial effect of statin treatment on carotid intima-media thickness [169]. Thus, the effect of statin therapy in patients with inflammatory disorders on these surrogate markers of atherosclerosis is uncertain.

There are no large randomized controlled trials evaluating the impact of statin therapy on cardiovascular disease outcomes in patients with inflammatory disease. A subgroup analysis of a small number of patients with systemic lupus erythematosus in the ALERT study has been reported [170]. The ALERT study was a randomized placebo controlled trial examining the effect of fluvastatin 40-80mg on cardiovascular events after kidney transplantation. In this trial fluvastatin therapy reduced the risk of cardiovascular events by 74% in the patients with systemic lupus erythematosus [170]. Additionally, a post hoc analysis of patients with inflammatory arthritis in the IDEAL and TNT trial has been reported [171]. The IDEAL trial compared atorvastatin 80mg vs simvastatin 20-40mg and the TNT compared atorvastatin 80mg vs. atorvastatin 10mg. In these trials, statin therapy resulted in a decrease in lipid levels in the patients with inflammatory arthritis to a similar degree as patients without inflammatory arthritis [171]. Moreover, there was an approximate 20% reduction in the risk of cardiovascular events in patients treated with atorvastatin 80mg compared to moderate dose statin therapy in patients with and without inflammatory arthritis [171]. These results suggest that patients with inflammatory diseases will have a reduction in cardiovascular events with statin therapy but clearly further studies are indicated.

It is well recognized that statins have anti-inflammatory properties and studies have consistently demonstrated a decrease in CRP levels in patients treated with statins. Two meta-analyses have explored the effect of statin therapy on disease activity in patients with rheumatoid arthritis. A meta-analysis by Ly et al included 15 studies with 992 patients and reported that statin therapy decreased erythrocyte sedimentation rate, CRP, tender joint count, swollen joint count, and morning stiffness [172]. Similarly, a meta-analysis by Xing et al included 13 studies with 737 patients [173]. They reported that statin therapy decreased erythrocyte sedimentation rate, CRP, tender joint count, and swollen joint count [173]. Additionally, the disease activity score 28 (DAS28), which focuses on joint pathology, decreased significantly in the patients treated with statin therapy and the patients with the most active disease benefited the most [173].

In contrast to the beneficial effects seen in patients with rheumatoid arthritis, in randomized placebo controlled trials in patients with systemic lupus erythematosus studies by Plazak et al and Petri et al failed to show a decrease in disease activity with statin therapy [167, 168]. In psoriasis treatment with statins has produced mixed results with some studies showing a decrease in skin abnormalities and others showing no significant effect or even an increase in disease activity [174]. Finally, treatment with statins has also been shown to improve periodontal disease and reduce inflammation [175-177]. Thus statins can decrease the clinical manifestations of rheumatoid arthritis, periodontitis, and perhaps psoriasis but has no effect on the clinical manifestations of systemic lupus erythematosus. These differences could be due to the relative severity of the inflammatory response and/or the specific pathways that induce inflammation in these different disorders.

The effect of statins on outcomes in patients with sepsis has been extensively studied. Numerous observational studies have shown that patients treated with statins have a marked reduction in morbidity and mortality [178, 179]. For example, in a meta-analysis by Wan et al of 27 observational studies with 337,648 patients, statins were associated with a relative mortality risk of 0.65 (CI 0.57-0.75) [179]. However, in randomized placebo controlled clinical trials statin administration has not been shown to reduce mortality or improve outcomes [178-180]. For example in a meta-analysis of Wan et al of 5 randomized controlled trials with 867 patients the relative risk was 0.98 [179]. Additionally, a recent study examining the effect of rosuvastatin on sepsis associated acute respiratory distress also failed to demonstrate a benefit of statin therapy [181]. Thus, while observational data suggested that statins may be beneficial the more rigorous randomized placebo controlled trials have not provided evidence of benefit.

Fibrate Therapy

Fibrates, gemfibrozil and fenofibrate, are used to lower triglycerides and raise HDL levels. However, fibrates, by activating PPAR alpha, are well known to have anti-inflammatory effects. Several studies have shown that fibrate therapy improves the clinical manifestations in patients with rheumatoid arthritis. For example Shirinsky et al treated 27 patients with rheumatoid arthritis with fenofibrate and reported a significant reduction in disease activity score (DAS28) [182]. A recent review described 4 randomized trials and 2 observation trials of fibrates in patients with rheumatoid arthritis and in general these studies showed that fibrate therapy decreased disease activity in patients with rheumatoid arthritis [183]. There have been no clinical trials of fibrate therapy In patients with psoriasis, systemic lupus erythematosus, and periodontal disease. Thus, there is a suggestion that the anti-inflammatory properties of fibrates may beneficially impact disease activity, but clearly further studies are required.

Bile Acid Binder Therapy

Bile acid binders are used to lower LDL cholesterol levels. While there are no studies of the effect of bile acid binders in patients with either rheumatoid arthritis, systemic lupus erythematosus, or periodontal disease, there are two studies in patients with psoriasis. Both Roe and Skinner et al reported that the treatment of patients with psoriasis with bile acid binders improved the skin condition [184, 185]. The mechanism for this beneficial effect is unknown.

Ezetimibe Therapy

Ezetimibe is used to lower LDL cholesterol. There is a single six week trial in 20 patients with rheumatoid arthritis that demonstrated that ezetimibe treatment decreased total cholesterol, LDL, and CRP levels [186]. Moreover, ezetimibe treatment reduced disease activity [186]. The mechanism for this beneficial effect is unclear.

Fish Oil Therapy

Fish oil is widely used to reduce serum triglyceride levels and is recognized to have anti-inflammatory properties. There are numerous studies examining the effect of fish oil therapy on inflammatory diseases. A meta-analysis of 17 randomized controlled trials by Goldberg and Katz of the effect of omega3-polyunsaturated fatty acids in patients with rheumatoid arthritis reported that treatment with omega 3 fatty acids reduced joint pain intensity, morning stiffness, number of painful and/or tender joints, and the use of non-steroidal anti-inflammatory medications [187]. Similarly, a meta-analysis by Lee et al also demonstrated that fish oil had beneficial effects in patients with rheumatoid arthritis [188]. In psoriasis, a recent review of 15 trials reported that overall there was a moderate benefit of fish oil supplements with 12 trials showing clinical benefit and 3 trials showing no benefit [189]. In systemic lupus erythematosus two randomized trials have demonstrated clinical benefit with fish oil therapy, while a single trial failed to show disease improvement [190-192]. Finally, there are data suggesting that treatment with fish oil reduces periodontal disease [193-195]. A major limitation of the studies in patients with periodontal disease is that in these trials the experimental group treated with fish oil also was simultaneously treated with aspirin making it difficult to be sure that the beneficial effects were solely due to fish oil supplementation [193, 194]. Taken together these studies indicate that in addition to lowering serum triglyceride levels, fish oil therapy may have beneficial effects on the underlying inflammatory disorder.

Niacin Therapy

Niacin is used to lower LDL and triglycerides and raise HDL. There are no reported clinical trials of niacin in patients with rheumatoid arthritis, systemic lupus erythematosus, psoriasis, or periodontal disease.

Treatment Strategy

The first priority in treating lipid disorders is to lower the LDL cholesterol levels to goal, unless triglycerides are markedly elevated (> 500-1000mg/dl), which increases the risk of pancreatitis. LDL is the usual first priority because the database linking lowering LDL with reducing cardiovascular disease is extremely strong and we now have the ability to markedly decrease LDL cholesterol levels in the vast majority of patients. Dietary therapy is the initial step but in most patients will not be sufficient to achieve the LDL goals. If patients are willing and able to make major changes in their diet it is possible to achieve remarkable reductions in LDL cholesterol levels but this seldom occurs in clinical practice.

Statins are the first choice drugs to lower LDL cholesterol levels and many patients with inflammatory disorders will require statin therapy. Currently four statins are available as generic drugs, lovastatin, pravastatin, atorvastatin, and simvastatin, and these statins are relatively inexpensive. The choice of statin will depend on the magnitude of LDL lowering required and whether other drugs that the patient is taking might alter statin metabolism thereby increasing the risk of statin toxicity. For example, cyclosporine affects the metabolism of many of the statins and in patients taking cyclosporine fluvastatin appears to be the safest statin [196].

If a patient is unable to tolerate statins or statins as monotherapy are not sufficient to lower LDL to goal the second choice drug is ezetimibe. Ezetimibe can be added to any statin and is now available in a combination pill with simvastatin (Vytorin) or atorvastatin (Liptrozet). If additional LDL lowering is required or a patient cannot tolerate ezetimibe one could add a bile acid binder. Both ezetimibe and bile acid binders additively lower LDL cholesterol levels when used in combination with a statin, resulting in a reduction in serum LDL levels. Niacin and the fibrates also lower LDL cholesterol levels.

The second priority should be non-HDL cholesterol (non-HDL cholesterol = total cholesterol – HDL cholesterol), which is particularly important in patients with elevated triglyceride levels (>200mg/dl). Non-HDL cholesterol is a measure of all the pro-atherogenic apolipoprotein B containing particles. Numerous studies have shown that non-HDL cholesterol is a strong risk factor for the development of cardiovascular disease. The non-HDL cholesterol goals are 30mg/dl greater than the LDL cholesterol goals. For example, if the LDL goal is <100mg/dl then the non-HDL cholesterol goal would be <130mg/dl. Drugs that reduce either LDL cholesterol or triglyceride levels will reduce non-HDL cholesterol levels.

The third priority in treating lipid disorders is to increase HDL cholesterol levels. There is strong epidemiologic data linking low HDL cholesterol levels with cardiovascular disease, but whether increasing HDL levels with drugs reduces cardiovascular disease is unknown. Life style changes are the initial step and include increased exercise, weight loss, and stopping cigarette smoking. The role of recommending ethanol, which increases HDL levels, is controversial but in patients who already drink moderately there is no reason to recommend that they stop. The most effective drug for increasing HDL levels is niacin, but studies have not demonstrated a reduction in cardiovascular events when niacin is added to statin therapy [197, 198]. Fibrates and statins also raise HDL cholesterol levels but the increases are modest (usually less than 15%). Additionally, the ACCORD-LIPID trial failed to demonstrate that adding fenofibrate to statin therapy reduces cardiovascular disease [199]. Unfortunately, given the currently available drugs, it is very difficult to significantly increase HDL levels and in many of our patients we are unable to achieve HDL levels in the recommended range. Furthermore, whether this will result in a reduction in cardiovascular events is unknown.

The fourth priority in treating lipid disorders is to decrease triglyceride levels. Fibrates, niacin, statins, and fish oil all reduce serum triglyceride levels. Typically, one will target triglyceride levels when one is trying to lower non-HDL cholesterol levels to goal. Patients with very high triglyceride levels (> 500-1000 mg/dl) are at risk of pancreatitis and therefore lifestyle and drug therapy should be initiated early. Given the beneficial effects of fish oil on disease activity in many patients with inflammatory diseases this drug can be very useful as it both lowers triglyceride levels and may reduce clinical manifestations.

Note that there is very limited evidence that adding drugs that lower triglyceride levels or increase HDL levels will reduce cardiovascular events. However, the recent studies of fibrates or niacin in combination with statins did not specifically target patients with high triglycerides, high non-HDL cholesterol, and low HDL levels. The only drug in combination with statin therapy that has been shown to further reduce cardiovascular events beyond statins alone is ezetimibe.

Many patients with inflammatory diseases have multiple lipid abnormalities. As discussed above life style changes are the initial therapy. If life style changes are not sufficient in patients with both elevations in LDL and triglycerides (and elevations in non-HDL cholesterol) one approach is to base drug therapy on the triglyceride levels (Figure 5). If the serum triglycerides are very high (greater than 500mg/dl), where there is an increased risk for pancreatitis and hyperviscosity syndromes, initial pharmacological therapy is directed at the elevated triglycerides and the initial drug choice is either a fibrate, niacin, or high dose fish oil (3 grams EPA/DHA per day). After lowering triglyceride levels to < 500mg/dl statin therapy should be initiated if the LDL and/or non-HDL cholesterol is not at goal. If the serum triglycerides are less than 500mg/dl, statin therapy to lower the LDL level to goal is the initial therapy (see Figure 5). Studies have clearly demonstrated that statins are effective drugs in lowering triglyceride levels in patients with elevated triglycerides. In patients with low triglyceride levels statins do not greatly affect serum triglyceride levels. If the non-HDLc levels remain above goal after one reaches the LDL goal one should then consider combination therapy to lower triglyceride levels which will lower non-HDLc levels.

Figure 5. Combined Hyperlipidemia. Increased LDL and TG

Figure 5

Combined Hyperlipidemia. Increased LDL and TG

Often monotherapy is not sufficient to completely normalize the lipid profile. For example, with statin therapy one may often lower the LDL to goal but the non HDLc, HDL, and triglycerides remain in the abnormal range. Currently, there are no randomized controlled trials demonstrating that combination therapy with fibrates, fish oil, or niacin reduces cardiovascular disease to a greater extent than statin monotherapy. In fact three recent outcome studies adding either niacin or fenofibrate to statin therapy failed to demonstrate additional benefit [197-199]. However, many experts believe that further improvements in the lipid profile will be beneficial and that the studies completed so far should not be considered definitive as they had flaws such as not treating patients with the appropriate lipid profile.

When using combination therapy one must be aware that the addition of either fibrates or niacin to statin therapy may increase the risk of myositis. The increased risk of myositis is greatest when gemfibrozil is used in combination with statins. Fenofibrate has a much more modest risk and the FDA approved the use of fenofibrate in combination with moderate doses of statins. Additionally, in the ACCORD LIPID trial the combination of simvastatin and fenofibrate was well tolerated [199]. The increased risk with niacin appears to be very modest and there is even a combination pill containing lovastatin and niacin available (Advicor). In the AIM-HIGH trial the risk of myositis was not increased in patients on the combination of niaspan and statin, whereas in the HPS2-Thrive trial myopathy was increased in the group treated with the combination of niacin and statin [197, 198]. The absolute risks of combination therapy are relatively modest if patients are carefully selected; in many patients at high risk for cardiovascular disease combination therapy may be appropriate. Table 3 indicates the type of patient that one should consider the use of combination therapy. As with many decisions in medicine one needs to balance the benefits of therapy with the risks of therapy and determine for the individual patient the best approach. In deciding to use combination therapy a key focus is the non-HDLc level. When the LDL is at goal but the non-HDLc is still markedly above goal it may be appropriate to resort to combination therapy in patients at high risk.

Table 3. When to Use Combination Therapy

  • Clinical Evidence of Arteriosclerosis
  • High Risk Patient
    • Hypertension
    • Family History of CAD
    • Cigarettes
    • Proteinurea
    • Central Obesity
    • Inactivity
    • Elevated CRP
  • No Contraindications
    • Renal or Liver Disease
    • Non-compliant patient
    • Use of other drugs that effect statin metabolism

In summary, modern therapy of patients with inflammatory diseases demands that we aggressively treat lipids to reduce the high risk of cardiovascular disease in this susceptible population and in those with very high triglycerides to reduce the risk of pancreatitis. Furthermore, treatment with lipid lowering drugs may improve the underlying inflammatory disorder.

REFERENCES

  1. Coumbe, A.G., M.R. Pritzker, and D.A. Duprez, Cardiovascular risk and psoriasis: beyond the traditional risk factors. Am J Med, 2014. 127(1): p. 12-8.
  2. Haque, S., H. Mirjafari, and I.N. Bruce, Atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Curr Opin Lipidol, 2008. 19(4): p. 338-43.
  3. John, H., T.E. Toms, and G.D. Kitas, Rheumatoid arthritis: is it a coronary heart disease equivalent? Curr Opin Cardiol, 2011. 26(4): p. 327-33.
  4. Ogdie, A., et al., Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis, 2015. 74(2): p. 326-32.
  5. Avina-Zubieta, J.A., et al., Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum, 2008. 59(12): p. 1690-7.
  6. Manzi, S., et al., Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol, 1997. 145(5): p. 408-15.
  7. Samarasekera, E.J., et al., Incidence of cardiovascular disease in individuals with psoriasis: a systematic review and meta-analysis. J Invest Dermatol, 2013. 133(10): p. 2340-6.
  8. Asanuma, Y., et al., Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med, 2003. 349(25): p. 2407-15.
  9. Chung, C.P., et al., Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors. Arthritis Rheum, 2005. 52(10): p. 3045-53.
  10. Giles, J.T., et al., Coronary arterial calcification in rheumatoid arthritis: comparison with the Multi-Ethnic Study of Atherosclerosis. Arthritis Res Ther, 2009. 11(2): p. R36.
  11. Ludwig, R.J., et al., Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol, 2007. 156(2): p. 271-6.
  12. Roman, M.J., et al., Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med, 2003. 349(25): p. 2399-406.
  13. Wang, S., et al., Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis. J Intern Med, 2009. 266(5): p. 445-52.
  14. Yiu, K.H., et al., Prevalence and extent of subclinical atherosclerosis in patients with psoriasis. J Intern Med, 2013. 273(3): p. 273-82.
  15. Schanberg, L.E., et al., Premature atherosclerosis in pediatric systemic lupus erythematosus: risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort. Arthritis Rheum, 2009. 60(5): p. 1496-507.
  16. Becker, A.E., O.J. de Boer, and A.C. van Der Wal, The role of inflammation and infection in coronary artery disease. Annu Rev Med, 2001. 52: p. 289-97.
  17. Epstein, S.E., Y.F. Zhou, and J. Zhu, Infection and atherosclerosis: emerging mechanistic paradigms. Circulation, 1999. 100(4): p. e20-8.
  18. Leinonen, M. and P. Saikku, Evidence for infectious agents in cardiovascular disease and atherosclerosis. Lancet Infect Dis, 2002. 2(1): p. 11-7.
  19. Lockhart, P.B., et al., Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation, 2012. 125(20): p. 2520-44.
  20. Beck, J.D., et al., Relationship of periodontal disease to carotid artery intima-media wall thickness: the atherosclerosis risk in communities (ARIC) study. Arterioscler Thromb Vasc Biol, 2001. 21(11): p. 1816-22.
  21. Desvarieux, M., et al., Relationship between periodontal disease, tooth loss, and carotid artery plaque: the Oral Infections and Vascular Disease Epidemiology Study (INVEST). Stroke, 2003. 34(9): p. 2120-5.
  22. Desvarieux, M., et al., Periodontal microbiota and carotid intima-media thickness: the Oral Infections and Vascular Disease Epidemiology Study (INVEST). Circulation, 2005. 111(5): p. 576-82.
  23. Soder, P.O., et al., Early carotid atherosclerosis in subjects with periodontal diseases. Stroke, 2005. 36(6): p. 1195-200.
  24. Khovidhunkit, W., et al., Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res, 2004. 45(7): p. 1169-96.
  25. Choi, H.K. and J.D. Seeger, Lipid profiles among US elderly with untreated rheumatoid arthritis--the Third National Health and Nutrition Examination Survey. J Rheumatol, 2005. 32(12): p. 2311-6.
  26. Georgiadis, A.N., et al., Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis: effect of early treatment--a prospective, controlled study. Arthritis Res Ther, 2006. 8(3): p. R82.
  27. Lazarevic, M.B., et al., Dyslipoproteinemia in the course of active rheumatoid arthritis. Semin Arthritis Rheum, 1992. 22(3): p. 172-8.
  28. Steiner, G. and M.B. Urowitz, Lipid profiles in patients with rheumatoid arthritis: mechanisms and the impact of treatment. Semin Arthritis Rheum, 2009. 38(5): p. 372-81.
  29. Chung, C.P., et al., Lipoprotein subclasses determined by nuclear magnetic resonance spectroscopy and coronary atherosclerosis in patients with rheumatoid arthritis. J Rheumatol, 2010. 37(8): p. 1633-8.
  30. Knowlton, N., et al., Apolipoprotein-defined lipoprotein abnormalities in rheumatoid arthritis patients and their potential impact on cardiovascular disease. Scand J Rheumatol, 2012. 41(3): p. 165-9.
  31. Asanuma, Y., et al., Serum lipoprotein(a) and apolipoprotein(a) phenotypes in patients with rheumatoid arthritis. Arthritis Rheum, 1999. 42(3): p. 443-7.
  32. Dursunoglu, D., et al., Lp(a) lipoprotein and lipids in patients with rheumatoid arthritis: serum levels and relationship to inflammation. Rheumatol Int, 2005. 25(4): p. 241-5.
  33. Lee, Y.H., et al., Lipoprotein(a) and lipids in relation to inflammation in rheumatoid arthritis. Clin Rheumatol, 2000. 19(4): p. 324-5.
  34. Borba, E.F. and E. Bonfa, Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus, 1997. 6(6): p. 533-9.
  35. Bruce, I.N., et al., Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum, 2003. 48(11): p. 3159-67.
  36. de Carvalho, J.F., E. Bonfa, and E.F. Borba, Systemic lupus erythematosus and "lupus dyslipoproteinemia". Autoimmun Rev, 2008. 7(3): p. 246-50.
  37. Borba, E.F., et al., Lipoprotein(a) levels in systemic lupus erythematosus. J Rheumatol, 1994. 21(2): p. 220-3.
  38. Feingold, K.R. and C. Grunfeld, Psoriasis: it's more than just the skin. J Lipid Res, 2012. 53(8): p. 1427-9.
  39. Friedewald, V.E., et al., AJC editor's consensus: psoriasis and coronary artery disease. Am J Cardiol, 2008. 102(12): p. 1631-43.
  40. Gottlieb, A.B. and F. Dann, Comorbidities in patients with psoriasis. Am J Med, 2009. 122(12): p. 1150 e1-9.
  41. Langan, S.M., et al., Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom. J Invest Dermatol, 2012. 132(3 Pt 1): p. 556-62.
  42. Tobin, A.M., et al., Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis. J Rheumatol, 2010. 37(7): p. 1386-94.
  43. Bullon, P., et al., Metabolic syndrome and periodontitis: is oxidative stress a common link? J Dent Res, 2009. 88(6): p. 503-18.
  44. Penumarthy, S., G.S. Penmetsa, and S. Mannem, Assessment of serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol in periodontitis patients. J Indian Soc Periodontol, 2013. 17(1): p. 30-5.
  45. Pussinen, P.J. and K. Mattila, Periodontal infections and atherosclerosis: mere associations? Curr Opin Lipidol, 2004. 15(5): p. 583-8.
  46. Schenkein, H.A. and B.G. Loos, Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases. J Periodontol, 2013. 84(4 Suppl): p. S51-69.
  47. Rufail, M.L., et al., Atherogenic lipoprotein parameters in patients with aggressive periodontitis. J Periodontal Res, 2007. 42(6): p. 495-502.
  48. Pussinen, P.J., et al., Severe periodontitis enhances macrophage activation via increased serum lipopolysaccharide. Arterioscler Thromb Vasc Biol, 2004. 24(11): p. 2174-80.
  49. Teeuw, W.J., et al., Treatment of periodontitis improves the atherosclerotic profile: a systematic review and meta-analysis. J Clin Periodontol, 2014. 41(1): p. 70-9.
  50. Buhlin, K., et al., Periodontal treatment influences risk markers for atherosclerosis in patients with severe periodontitis. Atherosclerosis, 2009. 206(2): p. 518-22.
  51. Alvarez, C. and A. Ramos, Lipids, lipoproteins, and apoproteins in serum during infection. Clin Chem, 1986. 32(1 Pt 1): p. 142-5.
  52. Cappi, S.B., et al., Dyslipidemia: a prospective controlled randomized trial of intensive glycemic control in sepsis. Intensive Care Med, 2012. 38(4): p. 634-41.
  53. Gallin, J.I., D. Kaye, and W.M. O'Leary, Serum lipids in infection. N Engl J Med, 1969. 281(20): p. 1081-6.
  54. Gordon, B.R., et al., Low lipid concentrations in critical illness: implications for preventing and treating endotoxemia. Crit Care Med, 1996. 24(4): p. 584-9.
  55. Kerttula, Y. and T.H. Weber, Serum lipids in viral and bacterial meningitis. Scand J Infect Dis, 1986. 18(3): p. 211-5.
  56. Sammalkorpi, K., et al., Changes in serum lipoprotein pattern induced by acute infections. Metabolism, 1988. 37(9): p. 859-65.
  57. van Leeuwen, H.J., et al., Lipoprotein metabolism in patients with severe sepsis. Crit Care Med, 2003. 31(5): p. 1359-66.
  58. Apostolou, F., et al., Persistence of an atherogenic lipid profile after treatment of acute infection with Brucella. J Lipid Res, 2009. 50(12): p. 2532-9.
  59. Apostolou, F., et al., Acute infection with Epstein-Barr virus is associated with atherogenic lipid changes. Atherosclerosis, 2010. 212(2): p. 607-13.
  60. Gazi, I.F., et al., Leptospirosis is associated with markedly increased triglycerides and small dense low-density lipoprotein and decreased high-density lipoprotein. Lipids, 2011. 46(10): p. 953-60.
  61. Deniz, O., et al., Serum total cholesterol, HDL-C and LDL-C concentrations significantly correlate with the radiological extent of disease and the degree of smear positivity in patients with pulmonary tuberculosis. Clin Biochem, 2007. 40(3-4): p. 162-6.
  62. Deniz, O., et al., Serum HDL-C levels, log (TG/HDL-C) values and serum total cholesterol/HDL-C ratios significantly correlate with radiological extent of disease in patients with community-acquired pneumonia. Clin Biochem, 2006. 39(3): p. 287-92.
  63. Palacio, C., et al., Transient dyslipidemia mimicking the plasma lipid profile of Tangier disease in a diabetic patient with gram negative sepsis. Ann Clin Lab Sci, 2011. 41(2): p. 150-3.
  64. Barlage, S., et al., Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation. Intensive Care Med, 2009. 35(11): p. 1877-85.
  65. Chien, J.Y., et al., Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis. Crit Care Med, 2005. 33(8): p. 1688-93.
  66. Gruber, M., et al., Prognostic impact of plasma lipids in patients with lower respiratory tract infections - an observational study. Swiss Med Wkly, 2009. 139(11-12): p. 166-72.
  67. Lekkou, A., et al., Serum lipid profile, cytokine production, and clinical outcome in patients with severe sepsis. J Crit Care, 2014. 29(5): p. 723-7.
  68. Grion, C.M., et al., Lipoproteins and CETP levels as risk factors for severe sepsis in hospitalized patients. Eur J Clin Invest, 2010. 40(4): p. 330-8.
  69. Iribarren, C., et al., Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases. Epidemiol Infect, 1998. 121(2): p. 335-47.
  70. Patel, P.N., et al., Human experimental endotoxemia in modeling the pathophysiology, genomics, and therapeutics of innate immunity in complex cardiometabolic diseases. Arterioscler Thromb Vasc Biol, 2015. 35(3): p. 525-34.
  71. Missala, I., U. Kassner, and E. Steinhagen-Thiessen, A Systematic Literature Review of the Association of Lipoprotein(a) and Autoimmune Diseases and Atherosclerosis. Int J Rheumatol, 2012. 2012: p. 480784.
  72. Choy, E. and N. Sattar, Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis, 2009. 68(4): p. 460-9.
  73. Robertson, J., et al., Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat Rev Rheumatol, 2013. 9(9): p. 513-23.
  74. Park, Y.B., et al., Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study. Am J Med, 2002. 113(3): p. 188-93.
  75. Navarro-Millan, I., et al., Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum, 2013. 65(6): p. 1430-8.
  76. Ronda, N., et al., New anti-atherosclerotic activity of methotrexate and adalimumab: Complementary effects on lipoprotein function and macrophage cholesterol metabolism. Arthritis Rheumatol, 2015.
  77. Saiki, O., et al., Infliximab but not methotrexate induces extra-high levels of VLDL-triglyceride in patients with rheumatoid arthritis. J Rheumatol, 2007. 34(10): p. 1997-2004.
  78. Boers, M., et al., Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis, 2003. 62(9): p. 842-5.
  79. Cairoli, E., et al., Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect. Lupus, 2012. 21(11): p. 1178-82.
  80. Munro, R., et al., Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis, 1997. 56(6): p. 374-7.
  81. Tam, L.S., et al., Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J Rheumatol, 2000. 27(9): p. 2142-5.
  82. Beynen, A.C., A.J. van der Molen, and M.J. Geelen, Inhibition of hepatic cholesterol biosynthesis by chloroquine. Lipids, 1981. 16(6): p. 472-4.
  83. Goldstein, J.L., G.Y. Brunschede, and M.S. Brown, Inhibition of proteolytic degradation of low density lipoprotein in human fibroblasts by chloroquine, concanavalin A, and Triton WR 1339. J Biol Chem, 1975. 250(19): p. 7854-62.
  84. Arnaldi, G., et al., Pathophysiology of dyslipidemia in Cushing's syndrome. Neuroendocrinology, 2010. 92 Suppl 1: p. 86-90.
  85. Ettinger, W.H., Jr. and W.R. Hazzard, Prednisone increases very low density lipoprotein and high density lipoprotein in healthy men. Metabolism, 1988. 37(11): p. 1055-8.
  86. Mihailescu, D.V., A. Vora, and T. Mazzone, Lipid effects of endocrine medications. Curr Atheroscler Rep, 2011. 13(1): p. 88-94.
  87. Daien, C.I., et al., Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with meta-analysis. Ann Rheum Dis, 2012. 71(6): p. 862-8.
  88. Di Minno, M.N., et al., Lipid profile changes in patients with rheumatic diseases receiving a treatment with TNF-alpha blockers: a meta-analysis of prospective studies. Ann Med, 2014. 46(2): p. 73-83.
  89. van Sijl, A.M., et al., The effect of TNF-alpha blocking therapy on lipid levels in rheumatoid arthritis: a meta-analysis. Semin Arthritis Rheum, 2011. 41(3): p. 393-400.
  90. Lestre, S., et al., Effects of etanercept treatment on lipid profile in patients with moderate-to-severe chronic plaque psoriasis: a retrospective cohort study. Eur J Dermatol, 2011. 21(6): p. 916-20.
  91. Wu, J.J., et al., Initiation of TNF inhibitor therapy and change in physiologic measures in psoriasis. J Eur Acad Dermatol Venereol, 2014. 28(10): p. 1380-7.
  92. Fleischmann, R., et al., Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med, 2012. 367(6): p. 495-507.
  93. He, Y., et al., Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis. BMC Musculoskelet Disord, 2013. 14: p. 298.
  94. Kremer, J., et al., Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med, 2013. 159(4): p. 253-61.
  95. Lee, E.B., et al., Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med, 2014. 370(25): p. 2377-86.
  96. Souto, A., et al., Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta-analysis. Arthritis Rheumatol, 2015. 67(1): p. 117-27.
  97. van Vollenhoven, R.F., et al., Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med, 2012. 367(6): p. 508-19.
  98. Sandborn, W.J., et al., Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med, 2012. 367(7): p. 616-24.
  99. McInnes, I.B., et al., Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study. Ann Rheum Dis, 2014. 73(1): p. 124-31.
  100. Singh, J.A., S. Beg, and M.A. Lopez-Olivo, Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev, 2010(7): p. CD008331.
  101. Singh, J.A., S. Beg, and M.A. Lopez-Olivo, Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol, 2011. 38(1): p. 10-20.
  102. Strang, A.C., et al., Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis. Atherosclerosis, 2013. 229(1): p. 174-81.
  103. Schultz, O., et al., Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS One, 2010. 5(12): p. e14328.
  104. Hsue, P.Y., et al., Depletion of B-cells with rituximab improves endothelial function and reduces inflammation among individuals with rheumatoid arthritis. J Am Heart Assoc, 2014. 3(5): p. e001267.
  105. Kerekes, G., et al., Effects of rituximab treatment on endothelial dysfunction, carotid atherosclerosis, and lipid profile in rheumatoid arthritis. Clin Rheumatol, 2009. 28(6): p. 705-10.
  106. Mathieu, S., et al., No significant change in arterial stiffness in RA after 6 months and 1 year of rituximab treatment. Rheumatology (Oxford), 2012. 51(6): p. 1107-11.
  107. Raterman, H.G., et al., HDL protein composition alters from proatherogenic into less atherogenic and proinflammatory in rheumatoid arthritis patients responding to rituximab. Ann Rheum Dis, 2013. 72(4): p. 560-5.
  108. Fernandez-Nebro, A., et al., The effects of rituximab on the lipid profile of patients with active systemic lupus erythematosus: results from a nationwide cohort in Spain (LESIMAB). Lupus, 2014. 23(10): p. 1014-22.
  109. Lilley, J.S., M.F. Linton, and S. Fazio, Oral retinoids and plasma lipids. Dermatol Ther, 2013. 26(5): p. 404-10.
  110. Staels, B., Regulation of lipid and lipoprotein metabolism by retinoids. J Am Acad Dermatol, 2001. 45(5): p. S158-67.
  111. Ellis, C.N., et al., Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med, 1991. 324(5): p. 277-84.
  112. Gisondi, P., et al., Metabolic abnormalities associated with initiation of systemic treatment for psoriasis: evidence from the Italian Psocare Registry. J Eur Acad Dermatol Venereol, 2013. 27(1): p. e30-41.
  113. Grossman, R.M., et al., Hypertriglyceridemia in patients with psoriasis treated with cyclosporine. J Am Acad Dermatol, 1991. 25(4): p. 648-51.
  114. Mathis, A.S., et al., Drug-related dyslipidemia after renal transplantation. Am J Health Syst Pharm, 2004. 61(6): p. 565-85; quiz 586-7.
  115. Stiller, M.J., et al., Elevation of fasting serum lipids in patients treated with low-dose cyclosporine for severe plaque-type psoriasis. An assessment of clinical significance when viewed as a risk factor for cardiovascular disease. J Am Acad Dermatol, 1992. 27(3): p. 434-8.
  116. Rayyes, O.A., A. Wallmark, and C.H. Floren, Cyclosporine inhibits catabolism of low-density lipoproteins in HepG2 cells by about 25%. Hepatology, 1996. 24(3): p. 613-9.
  117. Vaziri, N.D., K. Liang, and H. Azad, Effect of cyclosporine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions. J Pharmacol Exp Ther, 2000. 294(2): p. 778-83.
  118. Lu, B., et al., The acute phase response stimulates the expression of angiopoietin like protein 4. Biochem Biophys Res Commun, 2010. 391(4): p. 1737-41.
  119. de Carvalho, J.F., et al., Anti-lipoprotein lipase antibodies: a new player in the complex atherosclerotic process in systemic lupus erythematosus? Arthritis Rheum, 2004. 50(11): p. 3610-5.
  120. Reichlin, M., et al., Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus. Arthritis Rheum, 2002. 46(11): p. 2957-63.
  121. Hosoai, H., et al., Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice. J Lipid Res, 1999. 40(4): p. 648-53.
  122. Ramharack, R., D. Barkalow, and M.A. Spahr, Dominant negative effect of TGF-beta1 and TNF-alpha on basal and IL-6-induced lipoprotein(a) and apolipoprotein(a) mRNA expression in primary monkey hepatocyte cultures. Arterioscler Thromb Vasc Biol, 1998. 18(6): p. 984-90.
  123. Wade, D.P., et al., 5' control regions of the apolipoprotein(a) gene and members of the related plasminogen gene family. Proc Natl Acad Sci U S A, 1993. 90(4): p. 1369-73.
  124. Borba, E.F., J.F. Carvalho, and E. Bonfa, Mechanisms of dyslipoproteinemias in systemic lupus erythematosus. Clin Dev Immunol, 2006. 13(2-4): p. 203-8.
  125. Esteve, E., W. Ricart, and J.M. Fernandez-Real, Dyslipidemia and inflammation: an evolutionary conserved mechanism. Clin Nutr, 2005. 24(1): p. 16-31.
  126. Frostegard, J., et al., Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations. Arthritis Rheum, 2005. 52(1): p. 192-200.
  127. Hahn, B.H., et al., The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun, 2007. 28(2-3): p. 69-75.
  128. Mehta, N.N. and J.M. Gelfand, High-density lipoprotein cholesterol function improves after successful treatment of psoriasis: a step forward in the right direction. J Invest Dermatol, 2014. 134(3): p. 592-5.
  129. Feingold, K.R. and C. Grunfeld, The acute phase response inhibits reverse cholesterol transport. J Lipid Res, 2010. 51(4): p. 682-4.
  130. Charles-Schoeman, C., et al., Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis. Ann Rheum Dis, 2012. 71(7): p. 1157-62.
  131. Holzer, M., et al., Psoriasis alters HDL composition and cholesterol efflux capacity. J Lipid Res, 2012. 53(8): p. 1618-24.
  132. Mehta, N.N., et al., Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis. Atherosclerosis, 2012. 224(1): p. 218-21.
  133. Ronda, N., et al., Impaired serum cholesterol efflux capacity in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis, 2014. 73(3): p. 609-15.
  134. Annema, W., et al., Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A(2). J Lipid Res, 2010. 51(4): p. 743-54.
  135. Pussinen, P.J., et al., Periodontitis decreases the antiatherogenic potency of high density lipoprotein. J Lipid Res, 2004. 45(1): p. 139-47.
  136. McGillicuddy, F.C., et al., Inflammation impairs reverse cholesterol transport in vivo. Circulation, 2009. 119(8): p. 1135-45.
  137. Holzer, M., et al., Anti-psoriatic therapy recovers high-density lipoprotein composition and function. J Invest Dermatol, 2014. 134(3): p. 635-42.
  138. Liao, K.P., et al., The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. J Am Heart Assoc, 2015. 4(2).
  139. Cheng, Y., et al., Identification of potential serum biomarkers for rheumatoid arthritis by high-resolution quantitative proteomic analysis. Inflammation, 2014. 37(5): p. 1459-67.
  140. Ferretti, G., et al., Correlation between lipoprotein(a) and lipid peroxidation in psoriasis: role of the enzyme paraoxonase-1. Br J Dermatol, 2012. 166(1): p. 204-7.
  141. He, L., et al., Psoriasis decreases the anti-oxidation and anti-inflammation properties of high-density lipoprotein. Biochim Biophys Acta, 2014. 1841(12): p. 1709-15.
  142. Isik, A., et al., Paraoxonase and arylesterase levels in rheumatoid arthritis. Clin Rheumatol, 2007. 26(3): p. 342-8.
  143. Tanimoto, N., et al., Serum paraoxonase activity decreases in rheumatoid arthritis. Life Sci, 2003. 72(25): p. 2877-85.
  144. Tripi, L.M., et al., Relationship of serum paraoxonase 1 activity and paraoxonase 1 genotype to risk of systemic lupus erythematosus. Arthritis Rheum, 2006. 54(6): p. 1928-39.
  145. Usta, M., et al., Serum paraoxonase-1 activities and oxidative status in patients with plaque-type psoriasis with/without metabolic syndrome. J Clin Lab Anal, 2011. 25(4): p. 289-95.
  146. Draganov, D., et al., PON1 and oxidative stress in human sepsis and an animal model of sepsis. Adv Exp Med Biol, 2010. 660: p. 89-97.
  147. Novak, F., et al., Decreased paraoxonase activity in critically ill patients with sepsis. Clin Exp Med, 2010. 10(1): p. 21-5.
  148. Charles-Schoeman, C., et al., Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis. Arthritis Rheum, 2009. 60(10): p. 2870-9.
  149. Charles-Schoeman, C., et al., Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J Rheumatol, 2007. 34(7): p. 1459-64.
  150. Barcia, A.M. and H.W. Harris, Triglyceride-rich lipoproteins as agents of innate immunity. Clin Infect Dis, 2005. 41 Suppl 7: p. S498-503.
  151. Han, R., Plasma lipoproteins are important components of the immune system. Microbiol Immunol, 2010. 54(4): p. 246-53.
  152. Pirillo, A., A.L. Catapano, and G.D. Norata, HDL in infectious diseases and sepsis. Handb Exp Pharmacol, 2015. 224: p. 483-508.
  153. Peters, M.J., et al., Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum, 2009. 61(11): p. 1571-9.
  154. Jacobson, T.A., et al., National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol, 2014. 8(5): p. 473-88.
  155. Stone, N.J., et al., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2014. 129(25 Suppl 2): p. S1-45.
  156. Arts, E.E., et al., Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis. Ann Rheum Dis, 2015. 74(4): p. 668-74.
  157. Crowson, C.S., et al., Usefulness of risk scores to estimate the risk of cardiovascular disease in patients with rheumatoid arthritis. Am J Cardiol, 2012. 110(3): p. 420-4.
  158. Kawai, V.K., et al., The ability of the 2013 American College of Cardiology/American Heart Association cardiovascular risk score to identify rheumatoid arthritis patients with high coronary artery calcification scores. Arthritis Rheumatol, 2015. 67(2): p. 381-5.
  159. Kawai, V.K., et al., Novel cardiovascular risk prediction models in patients with systemic lupus erythematosus. Lupus, 2011. 20(14): p. 1526-34.
  160. Purcarea, A., et al., Utility of different cardiovascular disease prediction models in rheumatoid arthritis. J Med Life, 2014. 7(4): p. 588-94.
  161. Hippisley-Cox, J., et al., Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using QResearch database. BMJ, 2010. 341: p. c6624.
  162. Peters, M.J., et al., EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis, 2010. 69(2): p. 325-31.
  163. McCarey, D.W., et al., Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet, 2004. 363(9426): p. 2015-21.
  164. Semb, A.G., et al., Intensive lipid lowering in patients with rheumatoid arthritis and previous myocardial infarction: an explorative analysis from the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) trial. Rheumatology (Oxford), 2011. 50(2): p. 324-9.
  165. Rollefstad, S., et al., Rosuvastatin induced carotid plaque regression in patients with inflammatory joint diseases: The RORA-AS study. Arthritis Rheumatol, 2015.
  166. Mok, C.C., et al., Effects of rosuvastatin on vascular biomarkers and carotid atherosclerosis in lupus: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken), 2011. 63(6): p. 875-83.
  167. Plazak, W., et al., Influence of atorvastatin on coronary calcifications and myocardial perfusion defects in systemic lupus erythematosus patients: a prospective, randomized, double-masked, placebo-controlled study. Arthritis Res Ther, 2011. 13(4): p. R117.
  168. Petri, M.A., et al., Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis, 2011. 70(5): p. 760-5.
  169. Schanberg, L.E., et al., Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum, 2012. 64(1): p. 285-96.
  170. Norby, G.E., et al., Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: a randomized placebo-controlled study. Arthritis Rheum, 2009. 60(4): p. 1060-4.
  171. Semb, A.G., et al., Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease. Arthritis Rheum, 2012. 64(9): p. 2836-46.
  172. Lv, S., et al., The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol, 2015. 33(1): p. 69-76.
  173. Xing, B., et al., Effect of 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor on disease activity in patients with rheumatoid arthritis: a meta-analysis. Medicine (Baltimore), 2015. 94(8): p. e572.
  174. Mosiewicz, J., et al., Rational for statin use in psoriatic patients. Arch Dermatol Res, 2013. 305(6): p. 467-72.
  175. Fajardo, M.E., et al., Effect of atorvastatin on chronic periodontitis: a randomized pilot study. J Clin Periodontol, 2010. 37(11): p. 1016-22.
  176. Norata, G.D. and A.L. Catapano, Statins and periodontal inflammation: a pleiotropic effect of statins or a pleiotropic effect of LDL-cholesterol lowering? Atherosclerosis, 2014. 234(2): p. 381-2.
  177. Subramanian, S., et al., High-dose atorvastatin reduces periodontal inflammation: a novel pleiotropic effect of statins. J Am Coll Cardiol, 2013. 62(25): p. 2382-91.
  178. Tralhao, A.F., et al., Impact of statins in outcomes of septic patients: a systematic review. Postgrad Med, 2014. 126(7): p. 45-58.
  179. Wan, Y.D., et al., Effect of statin therapy on mortality from infection and sepsis: a meta-analysis of randomized and observational studies. Crit Care, 2014. 18(2): p. R71.
  180. Pasin, L., et al., The effect of statins on mortality in septic patients: a meta-analysis of randomized controlled trials. PLoS One, 2013. 8(12): p. e82775.
  181. National Heart, L., et al., Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med, 2014. 370(23): p. 2191-200.
  182. Shirinsky, I., et al., The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study. Rheumatol Int, 2013. 33(12): p. 3045-8.
  183. van Eekeren, I.C., et al., Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review. Ther Adv Musculoskelet Dis, 2013. 5(1): p. 33-44.
  184. Roe, D.A., The clinical and biochemical significance of taurine excretion in psoriasis. J Invest Dermatol, 1962. 39: p. 537-42.
  185. Skinner, R.B., et al., Improvement of psoriasis with cholestyramine. Arch Dermatol, 1982. 118(3): p. 144.
  186. Maki-Petaja, K.M., et al., Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis. J Am Coll Cardiol, 2007. 50(9): p. 852-8.
  187. Goldberg, R.J. and J. Katz, A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain, 2007. 129(1-2): p. 210-23.
  188. Lee, Y.H., S.C. Bae, and G.G. Song, Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis. Arch Med Res, 2012. 43(5): p. 356-62.
  189. Millsop, J.W., et al., Diet and psoriasis, part III: role of nutritional supplements. J Am Acad Dermatol, 2014. 71(3): p. 561-9.
  190. Bello, K.J., et al., Omega-3 in SLE: a double-blind, placebo-controlled randomized clinical trial of endothelial dysfunction and disease activity in systemic lupus erythematosus. Rheumatol Int, 2013. 33(11): p. 2789-96.
  191. Duffy, E.M., et al., The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. J Rheumatol, 2004. 31(8): p. 1551-6.
  192. Wright, S.A., et al., A randomised interventional trial of omega-3-polyunsaturated fatty acids on endothelial function and disease activity in systemic lupus erythematosus. Ann Rheum Dis, 2008. 67(6): p. 841-8.
  193. Elkhouli, A.M., The efficacy of host response modulation therapy (omega-3 plus low-dose aspirin) as an adjunctive treatment of chronic periodontitis (clinical and biochemical study). J Periodontal Res, 2011. 46(2): p. 261-8.
  194. El-Sharkawy, H., et al., Adjunctive treatment of chronic periodontitis with daily dietary supplementation with omega-3 Fatty acids and low-dose aspirin. J Periodontol, 2010. 81(11): p. 1635-43.
  195. Sculley, D.V., Periodontal disease: modulation of the inflammatory cascade by dietary n-3 polyunsaturated fatty acids. J Periodontal Res, 2014. 49(3): p. 277-81.
  196. Launay-Vacher, V., H. Izzedine, and G. Deray, Statins' dosage in patients with renal failure and cyclosporine drug-drug interactions in transplant recipient patients. Int J Cardiol, 2005. 101(1): p. 9-17.
  197. HPS Thrive Collaborative Group, et al., Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med, 2014. 371(3): p. 203-12.
  198. Aim High Investigators, et al., Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med, 2011. 365(24): p. 2255-67.
  199. Accord Study Group, et al., Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med, 2010. 362(17): p. 1563-74.
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