Atherosclerosis in Systemic Atherosclerosis in Systemic Lupus ErythematosusLupus Erythematosus

Maureen McMahon, MD, MCRMaureen McMahon, MD, MCR

Assistant Professor of MedicineAssistant Professor of Medicine

David Geffen School of Medicine David Geffen School of Medicine UCLAUCLA

Overall Survival in Lupus hasOverall Survival in Lupus has ImprovedImproved

Gabriel, S. et al., Arthritis Rheum 1999;42:46-50.

1950-1979 1980-1992

0

5

10

15

20

25

30

35

40

Active SLE Heart Disease Infection Others

Early Deaths (n = 46) Late Deaths (n = 78)

Abu-Shakra M, et al. J Rheum. 1995;22:1265–1270. [Evidence Level B]

Late Deaths in SLE are due to Late Deaths in SLE are due to Heart Disease (Atherosclerosis)Heart Disease (Atherosclerosis)

There is an Increased Risk for There is an Increased Risk for Atherosclerosis (ATH) in SLEAtherosclerosis (ATH) in SLE

0

10

20

30

40

50

60

Rel

ativ

e R

isk

CAD (Females 35–44 y)

All Patients

MI (Non-Obese)

CAD Death

CVA

CVA = cerebrovascular accident.Esdaile JM, et al. Arthritis Rheum. 2001;44:2331–2337 [Evidence Level B]; Karrar A, et al. Semin Arthritis Rheum. 2001;30:436–443 [Evidence Level C]; Manzi S, et al. Am J Epidemiol. 1997;145:408–415 [Evidence Level B]; Manzi S, et al. Arthritis Rheum. 1999;42:51–60. [Evidence Level B]

Roman MJ, et. al. N Engl J Med. 2003;349:2399–2406. [Evidence Level B]

Prevalence of ATH Plaque Among Prevalence of ATH Plaque Among Control Subjects and Patients With Control Subjects and Patients With SLE, According to Decade of LifeSLE, According to Decade of Life

2.4

13.213.4

33.3

72.5 71.4

45

30

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

Pre

vale

nce

of

Pla

qu

e (%

) Controls Patients

4th 5th 6th 7thDecade of Age

P = .009

P = .01

P = .001 P = .08

Why do SLE patients have an Why do SLE patients have an increased risk of Heart increased risk of Heart

Disease?Disease?

Patients with SLE Do Have Patients with SLE Do Have Traditional Cardiac Risk FactorsTraditional Cardiac Risk Factors

RISK FACTOR High Blood Pressure 41%Family History Heart Disease 41%Smoking 35%Increased Cholesterol 56%Diabetes 7%Sedentary Lifestyle 70%

Petri et al. Medicine 1992

Traditional Risk Factors Do Traditional Risk Factors Do Contribute to ATH in SLEContribute to ATH in SLE

0

5

10

15

20

25

MALEGender

HighBlood

Pressure

Diabetes

PLAQUE

NO Plaque

% o

f pa

tient

s w

ith p

laqu

e, a

ge a

djus

ted

p=0.05

p=0.0001p=0.07

Maksimowicz-McKinnon et al. J Rheum 2006

Posadas-Romero et al. Arthritis Rheum. 2004;50:160-165.

SLE Disease Activity Influences SLE Disease Activity Influences Standard Lipid LevelsStandard Lipid Levels

Influence of treatment on lipid levels Influence of treatment on lipid levels in SLEin SLE

Steroid therapy is associated withSteroid therapy is associated with

– increased total cholesterol, increased total cholesterol, – Increased VLDLIncreased VLDL– increased triglyceridesincreased triglycerides– increased LDLincreased LDL– Increased insulin resistanceIncreased insulin resistance– Increased risk of obesityIncreased risk of obesity

Ettinger Am J Med 1987;

Prevalence and Risk Factors of Prevalence and Risk Factors of Carotid Plaque in SLECarotid Plaque in SLE

–Independent predictors of increased ATH in SLE (multivariate analysis)

Higher amount of damage (SLICC damage index)Longer disease durationLess use of cyclophosphamide (Cytoxan)

–Predictors using univariate analysisPresence of pulmonary hypertensionOlder ageLess use of prednisone and hydroxychloroquine (Plaquenil)Absence of antiphospholipid antibodies

Roman, et al., NEJM 2003;349:25.

Risk Factors for ATH in SLE and RA

SLE and RA patients do appear have an increase in traditional cardiac risk factors

– Age *

– Smoking

– High Blood Pressure

– Elevated cholesterol *

– Diabetes

But these traditional risk factors DO NOT fully explain the increased risk of ATH in SLE or RA!!

* Most consistently associated risks

Traditional Framingham Risk Traditional Framingham Risk Factors Do Not Fully Explain Factors Do Not Fully Explain

Risk of ATH in SLERisk of ATH in SLE

Canadian cohortCanadian cohort– 296 Patients 296 Patients – Even after controlling for age, sex, Even after controlling for age, sex,

cholesterol, HTN, DM, tobacco usecholesterol, HTN, DM, tobacco use 10 x Increased risk for nonfatal MI 10 x Increased risk for nonfatal MI 17 x Increased risk for death due to CAD 17 x Increased risk for death due to CAD 8 x Increased risk for stroke8 x Increased risk for stroke

Esdaile JM, et al. Arthritis Rheum. 2001;44:2331–2337. [Evidence Level B]

Hypothesis Hypothesis

One study in non-SLE patients with ATH One study in non-SLE patients with ATH but no cardiac risk factors found that 90% but no cardiac risk factors found that 90% had “Pro-Inflammatory HDL”, HDL with had “Pro-Inflammatory HDL”, HDL with abnormal protective functionabnormal protective function

Ansell et al. Circulation 2003

Could “Pro-Inflammatory HDL be a factor in SLE??

LDL: the “Bad Cholesterol”LDL: the “Bad Cholesterol”

LDLLDL

Mackness MI et al. Biochem J 1993. Lipids Online 2004 (Baylor)

Blood VesselBlood VesselWhite Blood Cells:White Blood Cells:MonocytesMonocytes

White Blood Cell: White Blood Cell: MacrophageMacrophage

HDL are anti-inflammatoryHDL are anti-inflammatory

Foam Foam CellCell

HDL Remove “Bad Cholesterol”HDL Remove “Bad Cholesterol”

HDL PreventHDL PreventOxidationOxidation

of LDLof LDLOxidized

LDL

PLAQUE

DCFH (chemical that turns

green when oxidized)

LDL

FluorescentSignal

Patient HDL (normal)

--

+

Patient HDL (pro-inflammatory)

Pro-Inflammatory HDL AssayPro-Inflammatory HDL Assay

Values in the absence of test HDL are standardized to 1.0 •“Normal” Anti-Inflammatory HDL is defined as having a value <1.0•“Pro-Inflammatory” HDL is defined as having a value >1.0

ProPro--Inflammatory HDL in CHD patients, Inflammatory HDL in CHD patients, before and after statinbefore and after statin

0 .5 3

1 .1 9

0 .9 1

0

0 .2

0 .4

0 .6

0 .8

1

1 .2

Pro

tec

tiv

e c

ap

ac

ity

sc

ore

CF

A

be

fore

CF

A a

fte

r

C o n tro ls

P a tie n ts

PatientsAnsell et al Circulation 2003Ansell et al Circulation 2003

P=<0.0001

Populations of Women studiedPopulations of Women studied

Not taking medicines for cholesterolNot taking medicines for cholesterol

154 Women with SLE154 Women with SLE 72 Control Subjects72 Control Subjects 48 Female Rheumatoid Arthritis patients48 Female Rheumatoid Arthritis patients

45% of SLE patients have pro-inflammatory HDL

SLE group RA group Control group0

10%

20%

30%

40%

50%

60%p < 0.0001

p=0.001

p=0.039

20.1%

44.7%

4.1%

Pe

rce

nt

wit

h P

ro-i

nfl

am

ma

tory

HD

L

Pro-inflammatory HDL may be Pro-inflammatory HDL may be associated with heart diseaseassociated with heart disease

4 patients with a history of heart attack were included (all patients had SLE):

All 4 had pro-inflammatory HDL!

Populations of Women studiedPopulations of Women studied

No history of statin useNo history of statin use 123 Women with SLE123 Women with SLE 53 Control Subjects53 Control Subjects

All subjects had blood drawn to measure HDL function

All subjects had a carotid artery ultrasound to look for thickening of the arteries, or “plaque”

44% of SLE patients vs. 6.3% of controlshave piHDL

SLE control SLE plaque control plaque

0.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

2.25

2.50

2.75

p<0.0001

p=0.058

HD

L s

core

in

Flo

ure

scen

ce u

nit

s;>

1.0=

piH

DL

86% of SLE patients with ATH have 86% of SLE patients with ATH have piHDLpiHDL

* Chi-squared or Fisher’s Exact

SLE plaque SLE no plaque Control plaque Control no plaque0

10

20

30

40

50

60

70

80

90

100

p<0.0001

14.3%

7.1%

p NS

86%

35%

5.9%

SLE subjects

Perc

en

t S

LE

su

bje

cts

wit

h p

iHD

L

Presence of piHDL Greatly Increases Presence of piHDL Greatly Increases Risk for Carotid Plaque in SLERisk for Carotid Plaque in SLE

Statistical Analysis was performed to take Statistical Analysis was performed to take traditional cardiac risk factors into account traditional cardiac risk factors into account (age, high blood pressure, diabetes, high (age, high blood pressure, diabetes, high cholesterol and current smoking)cholesterol and current smoking)

After taking traditional risk factors into After taking traditional risk factors into account, there was still increased ODDS account, there was still increased ODDS FOR PLAQUE IN piHDL POSITIVE SLE = FOR PLAQUE IN piHDL POSITIVE SLE =

8.88.8

SummarySummary

HDL are abnormal and “Pro-Inflammatory” in a HDL are abnormal and “Pro-Inflammatory” in a substantial proportion of patients with SLE andsubstantial proportion of patients with SLE andRA. RA.

Pro-Inflammatory HDL are significantly associated Pro-Inflammatory HDL are significantly associated with plaque on carotid ultrasound in women with with plaque on carotid ultrasound in women with SLE but not in healthy controls.SLE but not in healthy controls.

Pro-Inflammatory HDL may be one marker that canbe used to predict which patients are at risk for ATH

Future Research DirectionsFuture Research Directions

Future: Develop risk profile including Future: Develop risk profile including piHDL to predict levels of risk for piHDL to predict levels of risk for accelerated ATHaccelerated ATH

Develop new treatments : Anti-oxidant Develop new treatments : Anti-oxidant peptides?peptides?

What Can Lupus Patients Do What Can Lupus Patients Do to Decrease Their Risk of to Decrease Their Risk of

Heart Disease?Heart Disease?

Ways to Improve ATH Risk Factors Ways to Improve ATH Risk Factors Without MedicationsWithout Medications

Reduced intakes of saturated fat and Reduced intakes of saturated fat and cholesterolcholesterol

Increased physical activityIncreased physical activity Weight controlWeight control Stop smokingStop smoking

Control High Blood PressureControl High Blood Pressure

Blood Pressure Targets should be Blood Pressure Targets should be

<130 mm/Hg systolic blood pressure<130 mm/Hg systolic blood pressure<80 mm/Hg diastolic blood pressure<80 mm/Hg diastolic blood pressure

Minimize salt intake Minimize salt intake If borderline, may be helpful to have a home If borderline, may be helpful to have a home

blood pressure cuffblood pressure cuff

NIH CV Risk CalculatorNIH CV Risk Calculator

hp2010.nhlbihin.net/atpiii/calculator.asp

6

LDL Cholesterol Goals:The NCEP guidelines

190 (160–189: LDL-lowering drug

optional)

160<1600–1 Risk Factor

10-year risk 10–20%: 130

10-year risk <10%: 160

130<1302+ Risk Factors

(10-year risk 20%)

130 (100–129: drug

optional)100<100

CHD or CHD Risk Equivalents

(10-year risk >20%)

LDL Level at Which to Consider

Drug Therapy (mg/dL)

LDL Level at Which to Initiate Therapeutic Lifestyle Changes

(TLC) (mg/dL)LDL Goal(mg/dL)Risk Category

Status of Statins in Rheumatic Status of Statins in Rheumatic DiseasesDiseases

RARA: 116 patients treated 6 months with : 116 patients treated 6 months with atorvastatin 40 mg qdatorvastatin 40 mg qd

– Disease activity score was significantly lower in Disease activity score was significantly lower in statin group, statin group, PP=.004 but small change (-0.5)=.004 but small change (-0.5)

– Markers of inflammation (ESR, CRP) Markers of inflammation (ESR, CRP) lower in patients taking statinslower in patients taking statins

McCarey et al. Lancet. 2004;363:2015-2021

Statins in SLEStatins in SLE

• LAPS trial: RCT of Atorvastatin 40 mg vs. placebo LAPS trial: RCT of Atorvastatin 40 mg vs. placebo in 200 SLE patients, followed for 2 yearsin 200 SLE patients, followed for 2 years

No effect on coronary calcium progressionNo effect on coronary calcium progression No significant improvement in disease activityNo significant improvement in disease activityNo significant difference in mean artery thickness No significant difference in mean artery thickness

(IMT) change, although there was a significant (IMT) change, although there was a significant difference in the proportion of patients in whom difference in the proportion of patients in whom IMT improved, stayed the same, or got worse, IMT improved, stayed the same, or got worse, favoring atorvastatinfavoring atorvastatin

• Further long-term studies need to be performed; Further long-term studies need to be performed; for now, treat according to NCEP guidelinesfor now, treat according to NCEP guidelines

Petri et al., Arthritis Rheum 2006; 54: suppl 1246

Summary of Statins in Summary of Statins in Rheumatology PracticeRheumatology Practice

Statins have the expected effects on lipid levelsStatins have the expected effects on lipid levels They lower markers of inflammation (ESR and They lower markers of inflammation (ESR and

CRP)CRP) Effects on disease activity in RA and SLE are not Effects on disease activity in RA and SLE are not

large in doses and preparation studied to date.large in doses and preparation studied to date. They lower piHDL but not to normalThey lower piHDL but not to normal

Antimalarial Drugs and Heart Antimalarial Drugs and Heart disease in SLEdisease in SLE

Antimalarial drugs may have a beneficial Antimalarial drugs may have a beneficial effect on lipid profiles in SLEeffect on lipid profiles in SLE– Compare 160 patients on stable dosage Compare 160 patients on stable dosage

prednisone (mean, 9.7 mg/d) with 180 patients prednisone (mean, 9.7 mg/d) with 180 patients on stable prednisone dosage (mean, 10.2 on stable prednisone dosage (mean, 10.2 mg/d) and antimalarialmg/d) and antimalarial

– Antimalarial patients had 11% reduction in TC Antimalarial patients had 11% reduction in TC when compared with patients on prednisone when compared with patients on prednisone alone (alone (PP <.01) <.01)

Rahman P, et al. J Rheum. 1999;26:325–330. [Evidence Level B]

Hydroxychloroquine in SLEHydroxychloroquine in SLE

Patients treated with hydroxychloroquine Patients treated with hydroxychloroquine were nearly half as likely to increase overall were nearly half as likely to increase overall damage from lupus compared to patients damage from lupus compared to patients not taking the drug.not taking the drug.

Possible decrease in risk of thrombosis may Possible decrease in risk of thrombosis may also contribute to decreased risk of ATHalso contribute to decreased risk of ATH

Patients treated with hydroxychloroquine Patients treated with hydroxychloroquine were less likely to have plaque on carotid were less likely to have plaque on carotid USUS

Fessler BJ et al., Arth Rheum 05; Ho KT et al., Rheumatol 2005; Rahman et al., J Rheum 1999.; Roman et al NEJM 2003

ConclusionsConclusions

Risk of atherosclerotic disease is increased in Risk of atherosclerotic disease is increased in SLESLE– Likely multifactorialLikely multifactorial– Combination of traditional, disease-related risk factorsCombination of traditional, disease-related risk factors

Low threshold to get screened for ATHLow threshold to get screened for ATH Minimize Traditional risk factorsMinimize Traditional risk factors

– BP controlBP control– Diet Diet – ExerciseExercise– Control High CholesterolControl High Cholesterol

If you or a friend are interested in If you or a friend are interested in participating in the carotid participating in the carotid ultrasound /piHDL study:ultrasound /piHDL study:

Contact study coordinator at: 310-825-6452Contact study coordinator at: 310-825-6452

Or email Dr. McMahon:Or email Dr. McMahon:

mmcmahon@mednet.ucla.edummcmahon@mednet.ucla.edu

AcknowledgementsAcknowledgements

UCLA Rheumatology

Bevra Hahn, M.D.

Christina Charles, M.D.

Jennifer Grossman, M.D.

John FitzGerald, M.D., Ph.D.

Weiling Chen, M.S.

UCLA Cardiology

Alan Fogelman, M.D.

Mohamad Navab, Ph.D.

Cedars-Sinai Medical CenterDaniel Wallace, M.D.Michael Weisman, M.D.

UCLA RadiologyNagesh Ragavendra, M.D.

Funding OrganizationsLupus Research InstituteAlliance for Lupus Research The Arthritis Foundation