MANAGEMENT OF LIPID DISORDERS

GENERAL MEDICAL CARE OF THE PATIENT WITH RHEUMATIC DISEASE

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MANAGEMENT OF LIPID DISORDERS Christopher A. Friedrich, MD, PhD, and Daniel J. Rader, MD

Patients with rheumatologic diseases often have adverse lipid profiles, either because of the nature of the underlying disease or the side effects of medication. This may place them at increased risk for atherosclerotic cardiovascular diseases, such as coronary artery disease, cerebral vascular disease, and peripheral vascular disease. Patients with rheumatologic diseases should be screened for dyslipidemia. Treatment begins with modifications of diet and lifestyle but often lipid-lowering medications are required to reduce the risk of atherosclerosis. The selection of lipid-lowering agents depends on the lipid profile, side effects, concurrent medications, and patient acceptability. Lipoprotein disorders are important and common risk factors for atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral vascular disease.15 Clinical trials have definitively established that reduction of plasma cholesterol significantly reduces the risk of cardiovascular events, revascularization procedures, and total mortality in patients with and without established ASCVD.16 Lipoprotein metabolism is often influenced by rheumatologic conditions or by medications used to treat these disorders and, therefore, many of these patients have hypercholesterolemia or other associated lipoprotein abnormalities. Furthermore, many rheumatologic conditions are associated with an increased risk of premature ASCVD. The identification and appropriate treatment of lipoprotein disorders in rheumatology patients thus has substantial implications for reducing the burden of ASCVD in this population.

From the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 25 * NUMBER 3 AUGUST 1999

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FRIEDRICH & RADER

Lipoproteins are large, macromolecular complexes that transport cholesterol and triglycerides within the blood.40The five major families of lipoproteins are chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL), and high density lipoproteins (HDL). Chylomicrons are the largest and most lipid-rich lipoproteins, whereas HDL are the smallest lipoproteins and contain the least amount of lipid. The major metabolic pathways of lipoproteins are shown in Figures 1-3 and described in the accompanying legends. Apolipoproteins are the major protein components of lipoproteins; they are required for the structural integrity of lipoproteins and direct their metabolic interactions with enzymes, lipid transport proteins, and cell surface receptors. Quantifying certain apolipoproteins may be useful in the diagnosis of some lipid disorders and in the assessment of cardiovascular risk.42Lipoprotein receptors mediate cellular interactions with lipoproteins. The best understood lipoprotein receptor is the LDL receptor, which is responsible for catabolizing chylomicron and VLDL remnants and LDL, and is defective in the inherited disorder familial hypercholesterolemia? Finally, lipid-modifying enzymes and lipid transport proteins play a major role in lipoprotein metabolism. One focus of this article is to review the pathophysiology of lipoprotein metabolism in selected rheumatologic disorders. The Adult Treatment Panel I1 of the National Cholesterol Education Program (NCEP) updated its guidelines for management of hypercholesterolemia in 1993.13A summary of these guidelines is shown in Table 1. Muscle Adipose

Chol Liver Intestine

Figure 1. Exogenous pathway of lipid transport. Dietary fat is absorbed into chylomicrons, which have the major structural protein apoB-48. Chylomicrons bind to lipoprotein lipase (LPL) on the luminal surface of the capillary endothelium of tissues, especially muscle and adipose tissue. The LPL hydrolyzes the triglycerides (apoC-ll on the chylomicron is a required co-factor for LPL). The free fatty acids enter the tissue and the smaller chylomicron remnant (CMR) is released. CMRs are taken up by the liver by the binding of apoE to the LDL receptor and the LDL receptor related protein (LRP). (From Rader DJ: Lipid disorders. In Topol EJ (ed): Textbook of Cardiovascular Medicine. Philadelphia, Lippincott-Raven, 1998; with permission.)

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LLJ Peripheral

LDL Receptor

/

Receptor -iver

LPL

@ :' Chol 1-1

VLDL

IUL

LDL

Figure 2. Endogenous pathway of lipid transport. The liver synthesizes triglyceride (TG) and cholesteryl (Chol) esters and packages them into very low density lipoproteins (VLDL), which have the major structural protein apoB-100. VLDL triglycerides are hydrolyzed by LPL to form intermediate density lipoproteins (IDL). IDL can be taken up by the liver by the binding of apoE to the LDL receptor or LRP, or the triglyceride and phospholipid in IDL can be hydrolyzed by hepatic lipase within the hepatic sinusoids to form low density lipoproteins (LDL). LDL can be taken up by LDL receptors in peripheral cells or by the liver by the binding of apoB-100 to the LDL receptor. (From Rader DJ: Lipid disorders. In Topol EJ (ed): Textbook of Cardiovascular Medicine. Philadelphia, Lippincott-Raven, 1998; with permission.)

The focus of these guidelines is on reduction of the LDL cholesterol level. The intensity with which LDL cholesterol is treated depends on the presence of existing ASCVD and, if absent, the presence and number of other cardiovascular risk factors. Traditional risk factors include age greater than 45 for men or greater than 55 for women, current cigarette smoking, hypertension, diabetes mellitus, a family history of premature ASCVD, or an HDL cholesterol level less than 35 mg/dL. An HDL cholesterol level greater than 60 mg/dL is considered protective against atherosclerosis and can be used to offset the effect of one risk factor. Patients with established ASCVD or two or more risk factors are treated most aggressively, including frequent use of drug therapy, whereas lowrisk patients are generally managed with nonpharmacologic measures. This article also reviews the nonpharmacologic and pharmacologic approaches to reduction of LDL cholesterol in patients with rheumatologic disorders. Although the NCEP guidelines and current clinical practice are focused primarily on reducing LDL cholesterol, there is growing interest in the role of other lipoprotein-related cardiovascular risk factors. These include HDL,14 trig1ycerides:O small dense LDL; and lipoprotein(a) [ L ~ ( a ) ]Evidence .~l strongly suggests that each of these are independently associated with cardiovascular risk, although little clinical trial data exist demonstrating reduction in risk with therapy specifically directed against these risk factors. A third focus of this article is to review, when known, abnormalities of these additional lipid-related risk factors in rheumatologic conditions.

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_____________.------.__.-.--

___---_____-----(Bile) ..-__.-...-

Intestine

LDL

0 Peripheral Cell Figure 3. HDL metabolism and the reverse cholesterol transport pathway. High density lipoproteins (HDL) and their major apolipoprotein apoA-l are synthesized by the intestine and the liver; a second HDL protein, apoA-ll, is made only by the liver. The metabolism of HDL cholesterol and HDL apolipoproteins is divergent. Nascent discoidal HDL interacts with peripheral cells to faciliate the removal of excess free cholesterol. This cholesterol is esterified to cholesteryl ester on the HDL particle by the action of lecithin: cholesterol acyltransferase (LCAT) and the nascent HDL particle becomes the larger HDL,. HDL, can acquire further cholesteryl ester by continued LCAT action and eventually becomes HDL,. HDL, can selectively transfer its cholesteryl ester to the liver by way of a cell-surface HDL receptor in the liver called SR-BI (not shown). Cholesteryl ester can also be transferred from HDL, to apoB-100 containing lipoproteins such as VLDL and LDL by the cholesteryl ester transfer protein (CETP). Subsequently, by way of uptake of LDL by the LDL receptor, these cholesteryl esters can then be returned to the liver. HDL, phospholipid can be hydrolyzed by hepatic lipase (HL) to recycle it into HDL,. Cholesteryl esters derived from HDL contribute to the hepatic cholesterol pool used for bile acid synthesis. Cholesterol derived from the periphery is eventually excreted from the body either as bile acid or as free cholesterol in the bile. HDL apolipoproteins apoA-l and apoA-ll are catabolized by the liver and the kidneys through poorly defined processes. (From Rader DJ: Lipid disorders. In Topol EJ (ed): Textbook of Cardiovascular Medicine. Philadelphia, Lippincott-Raven, 1998; with permission.)

DYSLlPlDEMlA IN SELECTED RHEUMATOLOGIC DISORDERS Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is associated with a significantly increased risk of premature ASCVD.5,18, 31, 47 Although this undoubtedly has several contributing factors, dyslipidemia is common in SLE39 and probably contributes to the increased cardiovascular risk.

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Table 1. INITIAL CLASSIFICATION BASED ON TOTAL AND HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVELS Total Cholesterol

Classification

Action

<200 mg/dL Desirable HDL >35 mg/dL Repeat in 5 years Fasting lipoprotein profile HDL <35 mg/dL 200-240 mg/dL Borderline-high HDL >35 and fewer Dietary information and repeat in 1 than 2 risk factors year HDL <35 or 2 other Fasting lipoprotein profile risk factors >240 mg/dL High Fasting lipoprotein profile Treatment Decisions Based on Low Density Lipoprotein Cholesterol Level Initiate Dietary Initiate Drug Patient Category Therapy Therapy LDL Goal

With CHD or other arterosclerosis Without CHD but with 2 risk factors Without CHD and fewer than 2 risk factors Selected low-risk individuals

>lo0 mg/dL

>130 mg/dL

4 0 0 mg/dL

>130 mgdL

>160 mg/dL

<130 mg/dL

>160 mg/dL

>190 mg/dL

<160 mg/dL

>160 mg/dL

>220 mg/dL

4 6 0 mg/dL

~

HDL

=

~

~

~~~~~~~

high density lipoproteins; LDL = low density lipoprotein; CHD

=

coronary heart disease.

The causes of dyslipidemia in SLE are not well established. They can be grouped into factors related to the underlying disease itself and those related to its treatment. SLE itself seems to directly affect lipoprotein metabolism. For example, children and adolescents with SLE were noted to have dyslipidemia before exposure to corticosteroids.22These abnormalities include elevated VLDL cholesterol and triglycerides and decreased levels of HDL cholesterol. In two studies, patients with SLE also had elevated levels of Lp(a).2,25 Autoantibodies to proteins involved in lipoprotein metabolism could be one cause of dyslipidemia in patients with SLE. One potential example of this phenomenon was reported by Merrill et a132Serum from an SLE patient with low HDL cholesterol was used to screen an expression library; one clone was found to be homologous to human apolipoprotein A-I (apoA-I),the major HDL apolipoprotein. The protein product of this clone reacted with antiserum to apoA-I, suggesting that, in this patient, an autoantibody to apoA-I may have led to increased catabolism of apoA-I and low levels of HDL. Other evidence that SLE directly influences lipoprotein metabolism comes from the MRL/lpr mouse, an established mouse model for SLE that is known to have elevated lipid levels compared with wild-type mice. One group reported that hepatic lipase activity was one third that of age-matched controls,3° suggesting reduced hepatic lipase as one factor responsible for the abnormal lipids in these mice.

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FRIEDRICH & RADER

A second factor in SLE that contributes to dyslipidemia is renal disease. Both chronic renal insufficiency and nephrotic syndrome are associated with specific lipoprotein abnormalities. Both of these topics have been the subject of comprehensive reviews.17,36 Mild hypertriglyceridemia is common in chronic renal failure, with up to 50% of patients having triglyceride levels greater than 150 mg /dL. Reduced lipolysis of triglycerides by lipoprotein lipase (LPL) and decreased plasma clearance of lipoproteins are the major cause of hyperlipidemia in renal insuffi~iency.5~ In contrast to chronic renal failure, nephrotic syndrome is characterized by increased total and LDL cholesterol levels, with elevated triglycerides less common and HDL levels in the low-normal range. The causes of hyperlipidemia in nephrotic syndrome include increased hepatic production of VLDL and decreased clearance of VLDL and 50 chylomi~rons.~~~ Finally, the therapy of SLE can contribute to the dyslipidemia. Prednisone has been associated with elevations of total cholesterol and triglycerides. Of 24 children with SLE, 4 developed a lipid disorder only after initiation of treatment with corticosteroids and 3 others had substantial worsening of their lipid profile after initiation of therapy.22 Ettinger et all2 noted that corticosteroid treatment in SLE patients was associated with higher levels of triglycerides, total cholesterol, VLDL cholesterol, and LDL cholesterol than in those patients not receiving corticosteroids. In a study of 264 patients with SLE, a regression model predicted an increase in cholesterol of 7.5 mg/dL for each increase of 10 mg of p r e d n i ~ o n e . ~ ~ Treatment with hydroxychloroquine (HCQ) may be associated with beneficial effects on lipids. Wallace et a1 found that patients treated with HCQ had lower total cholesterol (181 mg/dL) and LDL cholesterol (101 mg/dL) than those treated with steroids (213 mg/dL and 120 mg/dL, respectively), steroids and HCQ together (186 mg/dL and 102 mg/dL, respectively), or neither HCQ nor steroids (205 mg/dL and 128 mg/dL, re~pectively).~~ Eighteen women with inactive or mild SLE were studied by Hodis et al.I9 Nine were taking HCQ and had levels of triglycerides 46% lower than those in the remaining patients after being matched for corticosteroid dose and severity of disease. A larger study of 3027 visits by 264 patients with SLE determined the effects of prednisone and HCQ on lipid levels.37,38 Longitudinal regression analysis showed treatment with HCQ was associated with a lower total cholesterol level (8.9 mg/ dL lower in HCQ group). As with all patients, the initial approach to dyslipidemia in SLE should be nonpharmacologic. A Step I American Heart Association (AHA) diet was evaluated in 11 pediatric SLE subjects and found to lower triglyceride levels significantly.22Fish oil capsules also have been found to reduce triglyceride levels in some SLE but relatively high doses (at least 6 g/day) are required. Approximately one half of SLE patients do not respond adequately to nonpharmacologic interventions (including fish oils). Therefore, drug therapy is frequently a consid-

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513

eration in patients with SLE. Specific issues regarding drug therapy are provided in more detail later in the discussion. Rheumatoid Arthritis Although cardiovascular disease has been reported to account for about half of all deaths in patients with rheumatoid arthritis (RA),15 there have been relatively few comprehensive studies of plasma lipids and lipoproteins in patients with RA. In active RA, levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides are usually reduced when compared with inactive disease or control s~bjects,2~, 43, 48, 49 although not always.28Levels of Lp(a) are elevated in RA.43,46 When Lp(a) levels, normally less than 30 mg/dL, exceeded 48 mg/dL there was a significant correlation between Lp(a) levels and erythrocyte sedimentation rate (ESR) and platelet In patients with RA, an inverse relationship has been shown between inflammatory status and preheparin plasma levels of LPL, although triglyceride levels were not significantly different than in control subjects.51This finding is of unknown clinical significance. Children with juvenile rheumatoid arthritis (JRA) had high levels of VLDL and triglycerides with decreased levels of total cholesterol, HDL and LDL. The most extreme changes occurred in patients with active arthritis and in those with systemic-onset disease.23In a study of 18 girls and 19 boys with juvenile chronic arthritis, 19 of whom had active disease, apolipoprotein A-I levels were significantly lower in those with active disease when compared with healthy controls or inactive patients.l The reasons for this difference could be nutritional or related to active inflammation or other medications; however, no patient had taken steroids for at least 1 year. Although LDL cholesterol levels were lower in active or inactive patients when compared with control subjects, there were no differences found in levels of triglycerides, total cholesterol, HDL cholesterol, or apolipoprotein B. They did not investigate the possible effect of decreased nutritional intake in those with active disease, or report on the use of medications or objective measurement of inflammatory response. The authors are unaware of any similar studies performed in children with other inflammatory diseases. As in SLE, corticosteroid therapy can cause dyslipidemia in patients with RA. Hydroxychloroquine and chloroquine has been shown to have beneficial effects on lipid levels in patients with RA, similar to those reported for patients with SLE.49,52 In a prospective randomized trial of 100 patients with RA who were treated with intramuscular gold or oral hydroxychloroquine (HCQ), the lipid profiles worsened slightly in those treated with gold, whereas those treated with HCQ had a significant improvement in their lipids.35The HDL rose a median of 15% in the HCQ group whereas in the group treated with gold there was a 12% decrease after 12 months. Triglycerides increased 31% over 12 months in the gold group and remained stable in the HCQ group. There was no change in the total cholesterol in either group. Because of the frequency

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of ASCVD in patients with RA, an aggressive approach to management of dyslipidemia in these patients should be taken (see later discussion). Other Rheumatologic Disorders

Relatively little data exist concerning dyslipidemia in other rheumatologic disorders. A study of 40 patients with psoriatic arthritis (PA) showed similar patterns of dyslipidemia as seen in patients with RA, with a similar correlation between lipid levels and disease activity.29 Some patients with systemic sclerosis have been reported to have dyslipidemia; but this has not been systematically studied. There is a need for more investigation of the prevalence and cause of lipid disorders in rheumatologic conditions. CLINICAL APPROACH TO DIAGNOSIS AND TREATMENT OF LIPID DISORDERS IN RHEUMATOLOGIC PATIENTS Screening

Given the prevalence of dyslipidemia and ASCVD in patients with rheumatologic disorders, it is appropriate to obtain a fasting (12 hour) lipid profile in all patients with rheumatologic disease. Triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol should be measured. Total cholesterol levels over 200 mg/dL, LDL cholesterol levels over 160 mg/dL, triglyceride levels over 400 mg/dL, or HDL cholesterol levels less than 35 mg/dL warrant a repeat analysis of a second fasting specimen. Treatment

In the presence of known ASCVD, an attempt should be made to reduce the LDL cholesterol below 100 mg/dL as recommended by the NCEP.13 In the setting of two or more risk factors but without known ASCVD, the treatment goal is to reduce the LDL cholesterol level below 130 mg/dL. If triglycerides are greater than 400 mg/dL, a primary attempt to reduce triglycerides is usually necessary before LDL cholesterol can be effectively reduced. Nonpharmacologic Therapy The AHA Step I diet recommends limiting total caloric intake to the degree needed to lose weight or maintain the desired weight in adults or to promote growth in children, which is limiting fat intake to 30% of daily calories, limiting saturated fat to 10% of daily calories, and limiting

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515

dietary cholesterol to 300 mg per day. Patients with elevated lipids are recommended to start a Step I1 diet, which differs by limiting total fat to 20% of daily calories, limiting saturated fat to 7% of daily calories, and limiting dietary cholesterol to 200 mg per day. Step I diets have been shown to lower triglyceride levels significantly in pediatric patients with SLE.22If dietary changes coupled with regular exercise do not allow the patient to achieve the recommended results within 3 to 6 months, a formal dietary consultation may be of value. In many cases, however, drug therapy may be required. Pharmacologic Therapy

The choice of drugs is guided by the assessment of the type of lipid disorder, the presence of other risk factors, and the potential for side effects and drug-drug interactions. A list of the lipid-lowering drugs currently available is provided in Table 2. One useful method for deciding on which drug to use is to stratify patients based on fasting triglyceride levels. Levels greater than 1000 mg/dL are associated with risk of acute pancreatitis and, in general, triglyceride levels greater than about 400 mg/dL require a specific approach directed initially toward the triglycerides. The drug class known as the fibric acid derivatives (Table 2) are generally considered to be the first-line treatment for patients with severe hypertriglyceridemia. The most effective fibrate available in the United States is micronized fenofibrate and the dose is 200 mg once a day. The dose may need to be decreased in patients with renal insufficiency. If fenofibrate or another fibrate is not tolerated or does not adequately reduce the fasting triglycerides (to less than about 400 mg/ dL), consideration can be given to adding either fish oils or niacin (Table 2). Fish oil capsules containing omega-3 polyunsaturated fatty acids are very effective triglyceride-reducing agents but must generally be taken at a dose of at least 6 gm/day. Both fish oils and niacin can be associated with unpleasant or unacceptable side effects. A controlled-release form of niacin called Niaspan is now available for once-nightly use and causes significantly less flushing than regular niacin.34Niaspan (KOS, Miami, FL) differs from classic sustained-release niacin in its pharmacokinetics and once-daily dosing and does not seem to be associated with the risk of hepatoxicity that is associated with classic sustained-release niacin. After the triglycerides have been adequately controlled, some patients may still require further treatment, such as a statin, for reducing the LDL cholesterol level. When triglycerides are less than 400 mg/dL, the LDL cholesterol can be calculated, with treatment to reduce the LDL cholesterol level as the primary objective. The three major options for reducing LDL cholesterol (Table 2) are niacin, bile acid sequestrants (resins), and HMG CoA reductase inhibitors (statins). Niacin lowers LDL cholesterol, triglycerides, and Lp(a) while raising HDL levels. Bile acid sequestrants lower LDL cholesterol levels but triglyceride levels often increase them. Statins effectively reduce LDL cholesterol but have modest effects on triglycer-

12 g daily

3 g daily

Elevated triglycerides

Fish oils

HMG = hydroxymethylglutaryl; CoA = coenzyme A, LDL = low density lipoprotein; qhs twice a day; VLDL = very low density lipoprotein; TG = triglycerides.

=

Decrease TG synthesis, enhance TG catabolism

Stimulate lipoprotein lipase, may decrease VLDL synthesis

Decreases VLDL synthesis

Promote bile acid excretion and increase LDL receptors in liver

Inhibit cholesterol synthesis and upregulate LDL receptors in liver

Mechanism

~

Common Side Effects

=

every day; bid

=

Bloating, constipation, elevated triglycerides Cutaneous flushing, GI upset, elevated glucose, uric acid, and liver function tests Myositis, GI upset, gallstones, elevated liver function tests Diarrhea, GI upset, fishy odor to breath

Myositis, arthralgias, GI upset, elevated liver function tests

every hour of sleep; tid = three times a day; qd

200 mg qd 600 mg bid

200 mg qd 600 mg bid

Elevated triglycerides

meals

1 g tid after

32 g daily 40 g daily

80 mg daily 40 mg qhs 80 mg qhs 40 mg qhs 80 mg qhs 0.4 mg qhs

Maximal Dose

Fibric acid derivatives fenofibrate gemfibrozil

100 mg tid after meals

4 g daily 5 g daily

20 mg daily 10 mg qhs 10 mg qhs 20 mg qhs 20 mg qhs 0.2 mg

Starting Dose

Elevated LDL, triglycerides

Elevated LDL

Elevated LDL

Major Indications

Nicotinic acid

HMG CoA reductase inhibitors lovastatin pravastatin simvastatin fluvastatin atorvastatin cerivistatin Bile acid sequestrants cholestyramine colestipol

Drug

Table 2. MAJOR DRUGS USED FOR THE TREATMENT OF HYPERLlPlDEMlA

MANAGEMENT OF LIPID DISORDERS

517

ides and relatively little effect on HDL. Statins are by far the most commonly used lipid-lowering class because of their efficacy in LDL cholesterol reduction, abundant outcome data demonstrating reduction in clinical cardiovascular events, and relatively low incidence of side effects.15Statins are generally administered at bedtime because of some evidence of increased efficacy compared with other times of day.

Side Effects and Drug-Drug Interactions There is a small risk of myalgias or frank myositis associated with the use of HMG CoA reductase inhibitors.15Dermatomyositis also has been reported in association with statin use.26Patients on statins should be asked about musculoskeletal symptoms, and new occurrence of muscle pain may be an indication for discontinuation of the medication. Monitoring of serum creatine phosphokinase (CPK) is not generally advised because statin-induced muscle symptoms can occur in the absence of a rise in CPK and, conversely, asymptomatic CPK elevations are common but do not require discontinuation of the drug. Musclerelated side effects are idiosyncratic, so another statin can be tried that frequently will not cause the same problem. Anecdotally, patients with underlying musculoskeletal symptoms may be more sensitive to the myopathic effects of statin drugs. Overall, the incidence of frank myositis associated with statin monotherapy is extremely low; however, some statins are metabolized with the cytochrome P450 enzyme 3A4, which is responsible for the metabolism of many other drugs and can be inhibited by several different classes of compounds. Therefore, inhibition of 3A4 by another drug, such as cy~losporin,4~ could result in elevated levels of certain statins and could substantially increase the risk of myositis. Nevertheless, there is now a substantial experience with the use of statins in combination with cyclosporin in patients after solid organ transplantation, and the risk of myositis seems to be very low.” The use of fibrates in combination with statins further increases the risk of severe myositis and rhabdomyolysis, but this is also rare.ll Limited data exist, however, regarding the use of this combination in patients with underlying rheumatic conditions or on other drugs metabolized with cytochrome P450. The bile acid sequestrants cholestyramine and colestipol are known to affect the absorption of many medications. It is generally recommended that concurrent medications be taken 1 hour before a bile acid sequestrant or 4 hours after to minimize interference with absorption. Cholestyramine has been shown to accelerate the elimination of the nonsteroidal anti-inflammatory drug (NSAID) meloxicam, similar to its effect on piro~icam.~ Cholestyramine also decreases the bioavailability of the immunosuppressive agent mycophenolic Cholestyramine8-loand colestipo19have significant drug interactions with NSAIDs such as ibuprofen, diclofenac, and sulindac that may decrease the clinical effectiveness of the NSAIDs in persons taking these drugs.

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SUMMARY

ASCVD is common in patients with rheumatologic disorders. Reduction of LDL cholesterol and treatment of lipid disorders is proved to reduce the risk of ASCVD and its associated clinical events. Therefore, plasma lipids should be obtained in all patients with rheumatologic disorders and lipid disorders should be aggressively treated in an attempt to reduce cardiovascular risk. The clinical approach is similar to other patients, but care should be taken to avoid side effects and drugdrug interactions, which may be somewhat more likely to occur in patients with rheumatologic disorders. References 1. Bakkaloglu A, Kirel 8, Ozen S, et al: Plasma lipids and lipoproteins in juvenile chronic arthritis. Clin Rheumatol 15:341-345, 1996 2. Borba EF, Santos RD, Bonfa E: Lipoprotein(a) levels in systemic lupus erythematosus. J Rheumatol 21:220-223, 1994 3. Brown MS, Goldstein J L A receptor-mediated pathway for cholesterol homeostasis. Science 2 3 2 9 4 7 , 1986 4. Brunzell JD, Austin M, Deeb S, et al: Familial combined hyperlipidemia and genetic risk for atherosclerosis. In Woodford XFP, Davignon J, Sniderman A (eds): Atherosclerosis. New York, Elsevier, 1995, pp 624-627 5. Bulkley BH, Roberts WC: The heart in systemic lupus erythematous and the changes induced in it by corticosteroid therapy: A study of 36 necropsy patients. Am J Med 58943-264, 1975 6. Bunce TD, Black CM, Bruckdorfer KR: Systemic sclerosis, plasma antioxidants and lipids. Biochem SOCTrans 23(suppl):274S, 1995 7. Busch U, Heinzel G, Narjes H The effect of cholestyramine on the pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID) in man. Eur J Clin Pharmacol48269-272, 1995 8. Davies N M Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin Pharmacokinet 34:lOl-154, 1998 9. Davies NM, Anderson KE: Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clin Pharmacokinet 33:184-213, 1997 10. Davies NM, Watson M S Clinical pharmacokinetics of sulindac. A dynamic old drug. Clin Pharmacokinet 32437459,1997 11. Ellen RLB, McPherson R Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol 81(suppl):60B-65B, 1998 12. Ettinger WH, Goldberg AP, Applebaum-Bowden D, et al: Dyslipoproteinemia in systemic lupus erythematosus. Effect of corticosteroids. Am J Med 83503-508,1987 13. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Summary of the second report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel 11).JAMA 269:20-23, 1993 14. Gordon DJ, Rifkind BM: High-density lipoproteins-the clinical implications of recent studies. N Engl J Med 321:1311-1316, 1989 15. Gotto AM: Cholesterol management in theory and practice. Circulation 96:44244430, 1997 16. Gould LA, Rossouw JE, Santanello NC, et al: Cholesterol reduction yields clinical benefit Impact of statin trials. Circulation 97946-952, 1998 17. Grundy SM: Management of hyperlipidemia of kidney disease [editorial]. Kidney Int 37847-853, 1990 18. Haider VS, Roberts WC: Coronary arterial disease in systemic lupus erythematosus:

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Qualification of degrees of narrowing in 22 necropsy patients (21 women) aged 16-37 years. Am J Med 70:775-781, 1981 19. Hodis HN, Quismorio FP, Wickham E: The lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus. J Rheumatol 20:661465, 1993 20. Hokanson JE, Austin MA: Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: A meta-analysis of population based prospective studies. J Cardiovasc Risk 3:213-219, 1996 21. Homcy CJ, Liberthson RP, Fallon J T Ischemic heart disease in systemic lupus erythematosus in the young patient: Report of six cases. Am J Cardiol49:478-484, 1982 22. Ilowite NT, Copperman N, Leicht T Effects of dietary modification and fish oil supplementation on dyslipoproteinemia in pediatric systemic lupus erythematosus. J Rheumatol221347-1351, 1995 23. Ilowite N, Samuel P, Beseler L: Dyslipoproteinemia in juvenile rheumatoid arthritis. J Pediatr 114:823-826, 1989 24. Joven J, Vilella E: Hyperlipidemia of the nephrotic syndrome-the search for a nephrotic factor. Nephrol Dial Transplant 103314-316, 1995 25. Kawai S, Mizushima Y, Kaburaki J: Increased serum lipoprotein(a) levels in systemic lupus erythematosus myocardial and cerebral infarction. J Rheumatol 221210-1211, 1995 26. Khattak FH, Morris IM, Branford WA: Simvastatin-associated dermatomyositis. Br J Rheum 33:199, 1993 27. Kobashigawa JA, Kasiske EL: Hyperlipidemia in solid organ transplantation. Transplantation 63:331-338, 1997 28. Lakatos J, Harsagyi A Serum total, HDL, LDL cholesterol and triglyceride levels in patients with rheumatoid arthritis. Clin Biochem 21:93-96, 1988 29. Lazarevic MB, Vitic J, Mladenovic V, et al: Dyslipoprotein in the course of active rheumatoid arthritis. Semin Arthritis Rheum 22172-178, 1992 30. Magilavy DB, Zhan R, Black DD: Modulation of murine hepatic lipase activity by exogenous and endogenous Kupffer-cell activation. Biochem J 292:255,1993 31. Meller J, Condel CA, Deppisch LM. Myocardial infarction due to coronary atherosclerosis in three young adults with systemic lupus erythematosus. Am J Cardiol 35:309314, 1975 32. Merrill JT, Rivkin E, Shen C: Selection of a gene for apolipoprotein A1 using autoantibodies from a patient with systemic lupus erythematosus. Arthritis Rheum 38:16551659, 1995 33. Mignat C: Clinically significant drug interactions with new immunosuppressive agents. Drug Safety 16:267-278, 1997 34. Morgan JM, Capuzzi DM, Guyton JR, et al: Treatment effect of Niaspan, a controlledrelease niacin, in patients with hypercholesterolemia: A placebo-controlled trial. Journal of Cardiovascular Pharmacology and Therapy 1:195-202, 1996 35. Munro R, Morrison E, McDonald AG: Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis 56:374-377, 1997 36. Orth SR, Ritz E: The nephrotic syndrome. N Engl J Med 338:1202-1211, 1998 37. Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: Effects on lipids, glucose and thrombosis. Lupus 5(suppl):s16-s22, 1996 38. Petri M, Lakatta C, Magder L: Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: A longitudinal data analysis. Am J Med 96954-259, 1994 39. Petri M, Perez-Guttham S, Spence D, et al: Risk factors for coronary artery disease in patients with systemic lupus erythematosus. Am J Med 93:513-519, 1992 40. Rader DJ, Brewer HB: Lipids, apolipoproteins and lipoproteins. In Genetic Factors in Coronary Heart Disease. Boston, Kluwer, 1994, pp 83-103 41. Rader DJ, Brewer HB Jr: Lipoprotein(a): Clinical approach to a unique atherogenic lipoprotein. JAMA 2671109-1112, 1992 42. Rader DJ, Hoeg JM, Brewer HE Jr: Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Medicine 120:1012-1025, 1994

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