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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:
[email protected]@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