Lupus Highlights
Adnan N Kiani M.D., MPH
- Abstract 664: PiHDL is a Stronger Predictor of Atherosclerosis Than Other High-Risk Inflammatory Lipids, and is Associated with a 17- Fold Increased Risk of Subclinical Atherosclerosis in SLE
- Abstract 666: SLE, OPG, RANKL, and Cardiovascular Disease
- Abstract 669: Carotid Intima-Media Thickness and Plaque Predict Future Cardiovascular Events in Women with Systemic Lupus Erythematosus
- Abstract 1258: Fatigue and Oxidative Stress in SLE
- Abstract 1924: Neutrophil Gelatinase Associated Lipocalin (NGAL) In Urine Predicts the Course of Nephritis in Pediatric Systemic Lupus Erythematosus (pSLE)
- Abstract 1259: Progressive Multifocal Leukoencephalopathy - A National Estimate of Frequency in SLE and Other Rheumatic Diseases
Abstract 664: PiHDL is a Stronger Predictor of Atherosclerosis Than Other High-Risk Inflammatory Lipids, and is Associated with a 17- Fold Increased Risk of Subclinical Atherosclerosis in SLE
Authors:
MA. McMahon, JM. Grossman, L Sahakian, BJ. Skaggs, JD. FitzGerald, C. Charles-Schoeman, N. Ragavendra, DJ. Wallace, M. Weisman, J. Witztum, BH. Hahn.
Background:
Patients with SLE are at increased risk of atherosclerosis. SLE patients have a 7-10 fold risk of an M.I or stroke compared to controls even after adjusting for traditional cardiovascular risk factors. In one previous study of 285 SLE patients with documented atherosclerosis 64% of patients had normal standard lipid profiles. In a study of 20 non-SLE patients with documented atherosclerosis 90% of patients with normal lipid profile had pro-inflammatory HDL i.e. HDL with an abnormal protective function. Therefore, it is hypothesized that piHDL might be a risk factor for atherosclerosis. Paraoxonase and apoA-1, two anti-oxidant components of HDL have been reported to be decreased in SLE, however, it has been yet to find out if these two are surrogate measures of piHDL. HDL in several different ways helps in preventing formation of atherosclerotic plaque. Normal HDL helps efflux of cholesterol out of foam cells, out of vessel lumen and finally transported to the liver. HDL also helps prevent oxidation of LDL thereby inhibiting this inflammatory cascade of atherosclerosis. HDL normally has several anti-inflammatory protective components including the afore-mentioned paraoxonase and apoA-1. During an acute phase reaction both paraoxonase and apoA-1 are down regulated and inflammatory components are up regulated including serum amyloid A and oxidized phospholipids. Previously it has been reported by the same group that piHDL levels are as high as 45% in SLE patients versus 20% in RA versus 4.5% controls in SLE. This study looked at 171 SLE patients and 85 controls and the associations between paraoxonase and apoA-1 and atherosclerotic plaque and carotid IMT in these patients and controls as wells as with piHDL.
Methods:
Female SLE and healthy age- matched subjects not taking statins were studied (since statins affect HDL function). B-mode and Doppler scanning of carotid arteries was performed to measure plaque and intima media thickness. Antioxidant function of HDL was measured as the change in fluorescence intensity caused by oxidation of DCFH by LDL in the presence or absence of test HDL. Values greater than 1.0 after the addition of HDL indicated piHDL. PON activity was assessed by quantification of nitrophenol formation by spectophotometry. ApoA-1 and Lp (a) levels were measured using ELISA. OxLDL/apo B ratio was measured using the EO6 antibody.
Results:
171 SLE and 85 controls were enrolled. Baseline characteristics were similar for both groups including lipid profile (normal in both groups). However, SLE patients had a higher cerebrovascular disease as well as hypertension. hs-CRP levels were also similar in both groups. Overall, 50.3% of SLE patients had piHDL vs. 7.1% of controls (p<0.0001). Among the 30 SLE patients with plaque, 25 (83.3%) had piHDL, compared to 43.3% of SLE patients without plaque (p=0.0001). In the control population 44% with plaque had piHDL versus 10% without plaque had piHDL. Next an association was sought between levels of piHDL and IMT. Patients were divided into quartiles. Patients with highest quartile (>0.67 mm²) had higher mean piHDL levels compared to patients in the lowest quartile. After multivariate analysis including traditional and SLE risk factors, the only significant factors predictive of plaque in SLE were the presence of piHDL, with an OR of 16.6 (95% C.I. 1. 82 - 151.5, p=0.013), age (OR 1.12; 95% C.I. 1.04 - 1.20, p=0.002), and higher LDL levels (OR 1.02, 95% C.I. 1.00 - 1.04, p=0.024). PON activity was significantly lower in SLE patients than in controls (p=0.001); however, there was no association between HDL function and PON or apoA-1 levels. There were also no associations between the presence of plaque and PON activity or apoA-1, nor were there associations between plaque and other inflammatory lipids, including oxidized LDL and Lp(a).
Conclusions:
PiHDL has become apparent as a strong predictor for the presence of plaque on carotid ultrasound. Measurement of HDL components, such as paraoxonase and apoA-1, could not be demonstrated as surrogate measures of HDL function. PiHDL was a stronger predictor of plaque than other inflammatory lipids such as oxidized LDL and Lp (a).
Editorial:
Traditional cardiovascular risk factors (CVRF), including hypertension, hyperlipidemia, obesity and homocysteine are associated with CAD in SLE, but do not explain the entire increased risk of atherosclerosis. HDL has long been considered to be protective against CAD, due to inhibition of oxidation of LDL and promotion of cholesterol efflux. However, abnormalities in HDL composition are well recognized. Acute and chronic inflammation lead to a transformation of anti-inflammatory HDL to pro-inflammatory Acute Phase-HDL (AP-HDL). The pro-inflammatory AP-HDL then leads to increased oxidation of LDL. Navab and colleagues have shown that HDL is pro-inflammatory in murine diet-induced atherosclerosis, apolipoprotein E knock out mice, and in humans and rabbits with an acute-phase response. Pro-inflammatory HDL may be one of the mechanisms leading to abnormal lipid function and atherosclerosis in SLE. McMahon and group has provided valuable insight in understanding atherosclerosis in SLE. The identification of risk factors will help clinicians select patients who require screening and intervention, and also help to jump-start research into the novel pathogenetic pathways important in lupus atherosclerosis. However, this study has its limitations including the inability by another group to reproduce this assay and to see role of piHDL in different SLE populations.
Abstract 666: SLE, OPG, RANKL, and Cardiovascular Disease
Authors:
S Tambar, E Rhew, D Dunlop, J Song, O Almagor, P Eksarko, K Sutton-Tyrrell, DD. McPherson, W Pearce, D Edmundowicz, GT. Kondos, RM. Pope, R Ramsey-Goldman
Background:
A bimodal mortality curve in SLE has been identified earlier, with early deaths due to active disease and infection, and “late” deaths (patients over 40) due to cardiovascular disease. Subsequent epidemiologic studies have further heightened concern about cardiovascular disease in SLE. Compared to an age-matched general population, the risk of coronary artery disease (CAD) was increased 9-fold in SLE patients in Sweden. Female SLE patients in Pittsburgh were 50 times more likely to have a myocardial infarction than age-specific rates in Framingham offspring study controls. Authors examined two novel markers osteoprotegrin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL). These two cytokines are elevated in the general population with cardiovascular disease and in patients with diabetes and with diabetic microvascular manifestations. In this cross sectional study authors examined the frequency of subclinical cardiovascular disease measured by coronary artery calcification (CAC) for SLE patients and compared to age-race-zip code matched controls and the relationship of serum OPG and RANKL to elevated CAC.
Methods:
119 SLE patients and 119 non-SLE patients (controls) were matched by age (+/- 5 yrs), race, and zip code. Demographic and laboratory assessments of traditional CVD risk factors, inflammatory markers, OPG, and RANKL were collected as well as SLEDAI and SLICC damage index (SLE specific disease activity indices). CAC score was measured by EBCT.
Results:
Mean age for SLE patients was 43.9 ± 9.9 years and controls 46.4 ± 9.9. For traditional CVD risk factors, SLE vs controls had lower total cholesterol [difference -9.53 (-19.05, -0.01)] and LDL [-9.83 (-18.11, -1.54)], but higher lipoprotein (a) [13.86 (4.21, 23.51)], homocysteine [2.29 (1.36, 3.22)], and history of cardiovascular events [24.4% vs. 6.7%, OR 4.47 (1.90, 10.53)]
Conclusions:
SLE patients had higher levels of CAC along with lipoprotein(a), increased age, BMI and presence of SLE being significant factors. OPG and OPG/RANKL were higher in both groups if CAC >10, while RANKL was only lower in SLE patients if CAC >10.
Editorial:
In developed countries, cardiovascular and renal disease remains the major cause of death in SLE and contributes importantly to morbidity. Traditional risk factors do not explain the entire risk. Atherosclerosis in SLE is multi-factorial, with immune/inflammatory endothelial damage, traditional and novel cardiovascular risk factors, and prothrombotic factors all playing important roles. Osteoprotegrin (OPG), a member of the tumor necrosis factor (TNF) receptor family, has been identified as a regulator of bone resorption. Recently, it has been demonstrated that OPG is produced by a variety of tissues, including the cardiovascular system (heart, arteries, veins), lung, kidney, and immune tissues, as well as bone. Authors have shown an important association with CAC. Our recent work (in press) has shown that OPG is also associated with lupus specific disease activity indices including LAI and SLEDAI. In addition in our study OPG was associated with urine pr/cr ratio as well as renal biopsy. Our previous work has also shown that CAC is associated with age and BMI as shown by the investigators in this study. Since OPG has been identified a regulator of bone resorption, therefore, a correlation with bone mineral density would have greatly strengthened the study. These exciting results still show the potential of this marker as a future predictor of atherosclerosis and renal damage. However, larger studies are warranted before these be used in clinical practice.
Abstract 669: Carotid Intima-Media Thickness and Plaque Predict Future Cardiovascular Events in Women with Systemic Lupus Erythematosus
Authors:
JR. Elliott, S. Manzi, A. Sattar, LC. Santelices, Z.Avram, P. Shaw, T. Thompson, KC. Sutton-Tyrrell, AH. Kao
Background:
Recent studies have also shown a high burden of sub-clinical atherosclerosis in SLE measured as carotid plaque or intima media thickness. Author and colleagues, in a previous cross sectional study of 214 female lupus patients without clinical cardiovascular disease, found 32% had carotid plaque. The risk of hospitalization for atherosclerotic events was 2.27 times higher in SLE patients ages 18-44 years than in non-SLE controls in a California based study. Authors have for the first time examined whether subclinical carotid vascular disease detected by B-mode ultrasound predicts future cardiovascular events.
Methods:
A total of 224 women with no prior CV events were included from a cohort of 289 SLE women enrolled in 1995 to examine CVD and risk factors longitudinally. At baseline, traditional CV risk factors, SLE-specific factors and B-mode carotid ultrasound [intima-media thickness (IMT) and plaque] were assessed. Incident CV events were defined as angina, MI, PTCA, CABG, fatal cardiac arrest, TIA and CVA.
Results:
Patients had a mean age of 44 and majority Caucasian (90.2%) with a median length of follow-up of 10.1 years.
Baseline characteristics |
|
Lupus disease duration |
8.2 years |
Mean SLAM score |
6 |
Patients on steroids |
42% |
Hypertensive |
37% |
Hypercholesterolemia |
65% |
Current smokers |
14% |
Prevalence of carotid plaque at baseline was 29% (n=64) with a median IMT of 0.68 mm.
Since baseline enrollment, 30 (13.4%) women experienced 73 events (32 angina, 10 MI, 12 PTCA, 5 CABG, 3 fatal cardiac arrest, 3 TIA and 8 CVA).
In the first multivariable model, which included IMT, traditional CV and SLE-specific risk factors, only carotid IMT (HR 1.24, 95% CI 1.04-1.48, every 0.05 mm increment in IMT), age, SLAM score and years of steroid use remained independently predictive of time to any incident CV event. In the second multivariable model, which included plaque, traditional CV and SLE-specific risk factors, only presence of plaque (HR 5.97, 95% CI 1.52-23.38), fasting glucose and HDL/cholesterol ratio remained independently predictive of time to any incident CV event.
Conclusions:
This study for the first time has shown that even after adjusting for cardiovascular and SLE- specific factors, carotid IMT and plaque are independent predictors of future CV events.
Editorial:
Coronary artery disease (CAD) remains the major cause of mortality in SLE. Accelerated atherosclerosis in SLE is attributed both to an increase in traditional cardiovascular risk factors, and to the inflammatory effect of SLE itself. This study suggests that carotid ultrasound may provide an important tool for CVD risk stratification in SLE especially when drugs like statins have shown to be beneficial in reducing carotid IMT and plaque.
Abstract 1258: Fatigue and Oxidative Stress in SLE
Authors:
B Segal, M Slater, E Baechler, M Gross
Background:
Little is known about physiology of lupus related fatigue in SLE. Aerobic capacity is severely reduced in SLE. Peak oxygen consumption in SLE is below that is required to do light household chores. Maximum aerobic capacity in lupus is reduced to a level similar to reported in severe cardiovascular, pulmonary and other metabolic disorders. Authors examined the hypothesis that oxidative stress as measured by F2 isoprostane is associated with symptoms of fatigue in SLE.
Methods:
Sixty two SLE patients (mean age 41) and thirty nine healthy age and gender matched controls were evaluated with validated instruments to assess pain (BPI), sleep (PSQI), depression (CES-D), helplessness (RAI) and fatigue severity: FSS (effects of fatigue on physical activity); somatic fatigue, the PROF-S domain (perception of physical tiredness, muscle fatigue, inability to do work); and mental fatigue; Prof-M (difficulty with memory and attention). Exclusion criteria was a recent hospitalization with infection, change in immunosuppressive drugs in the last 3 months, obvious cardiac and pulmonary causes of fatigue e.g. pulmonary HTN and fibrosis. Phlebotomy was performed for measurement of plasma F2 isoprostane with gas chromatography/mass spectroscopy, the most reliable index of oxidative stress in vivo. Clinical data, a brief physical exam and cardiovascular risk factors were also recorded.
Results:
SLE patients and controls were comparable with respect to age and BMI. SLE patients were more likely to work disabled (.003), report shortness of breath (.0001) and to have HBP (.008) compared to their counter parts. Depression, severe pain, helplessness and poor sleep quality were associated with fatigue. Mean F2 isoprostane was significantly higher (p=.011) in fatigued patients. Pain and F2 isoprostane (adjusted for BMI) were independent predictors of FSS and of somatic fatigue. Depression was predictor of “mental fatigue”.
Conclusions:
This study for the first time has demonstrated a relationship between fatigue in SLE and plasma F2 isoprostane.
Editorial:
Authors have demonstrated that lipid peroxidation is increased in SLE patients with fatigue and F2 isoprostane is predictive of physical fatigue. It is important to look at the consequences of oxidative stress in patients with chronic fatigue. Authors will next be investigating oxidative metabolism during exercise and assessing the relationship between oxidative stress and endothelial function in patients with exercise impairment. This might lead to new effective treatments for chronic fatigue and new strategies for reducing cardiovascular risk.
Abstract 1924: Neutrophil Gelatinase Associated Lipocalin (NGAL) In Urine Predicts the Course of Nephritis in Pediatric Systemic Lupus Erythematosus (pSLE)
Authors:
CH. Hinze, M. Suzuki, M. Klein-Gitelman, M H. Passo, J. Olson, NG. Singer, KA. Haines, K. Onel, KM. O'Neil, ED. Silverman, LB. Tucker, J. Ying, P. Devarajan, HI. Brunner
Background:
Lupus nephritis is a very common manifestation of pediatric SLE patients with a prevalence of up to 80%. Despite advances and improvement in therapy it causes severe disease related morbidity and mortality. Currently available means of diagnosing lupus nephritis early and to recognize worsening of disease have poor predictive value. Gold standard to diagnose lupus nephritis is via kidney biopsy but is not practical in a clinical setting and to screen for worsening of LN either. Therefore, it is desirable to have a reliable non-invasive biomarker which either predicts Lupus Nephritis or worsening of LN. Authors explored the predictive properties of Neutrophil Gelatinase Associated Lipocalin (NGAL) and its potential to predict future course of LN.
Methods:
Plasma NGAL (P-NGAL) and U-NGAL by ELISA were measured on 150 pSLE patients every 3 months. MD assessment of global/renal pSLE, SELENA-SLEDAI, and BILAG were also recorded.
Results:
P-NGAL levels increased by as much as 45% prior to severe global flares and by by 77% and 19% prior to worsening of extra renal pSLE disease activity as measured by the extra renal domains of the SELENA-SLEDAI (p<0.001) and BILAG (p<0.01). U-NGAL though not associated with extra renal disease activity correlated with current LN activity and was also found predictive of future LN flares.
Instrument |
Category at time |
% change of U-NGAL levels from -6 to -3 months |
|||
Average (95% CI) |
p |
Average (95% CI) |
p |
||
MD assessment |
Better |
-29.6 (-67.2 to 51.0) % |
0.367 |
40.6 (-0.3 to 98.2) % |
0.052 |
No change |
27.1 (-12 to 83.3) % |
0.201 |
28.2 (-2.9 to 69.3) % |
0.080 |
|
Worse |
73.3 (5.8 to 183.9) % |
0.029 |
60.0 (-1.9 to 161.1) % |
0.060 |
|
SELENA -SLEDAI |
Better |
-15.8 (-63.9 to 96) % |
0.689 |
29.9 (-19.9 to 110.8) % |
0.289 |
No change |
21.2 (-15.2 to 73.3) % |
0.291 |
35.9 (7.1 to 72.4) % |
0.011 |
|
Worse |
67.0 (2.9 to 171.1) % |
0.038 |
55.9 (-1.4 to 146.6) % |
0.057 |
|
BILAG |
Better |
5.8 (-55.7 to 152.7) % |
0.899 |
-6.6 (-54.6 to 92) % |
0.852 |
No change |
24.3 (-10.6 to 72.9) % |
0.196 |
37.7 (8.9 to 74.2) % |
0.008 |
|
Worse |
104.1 (16.1 to 258.8) % |
0.013 |
92.8 (13.3 to 228) % |
0.015 |
|
p-values < 0.05 indicate significant increase (or decrease) of U-NGAL levels between two consecutive visits. |
|||||
Conclusions:
U-NGAL has a predictive validity for the course of LN where as P-NGAL helps predicting global and extra-renal disease activity.
Editorial:
NGAL is a small soluble protein synthesized in various endothelial tissues. Levels are increased in multiple other diseases including vasculitis and MS. Urine NGAL levels increase immediately and remarkably following acute kidney injury. Authors have previously demonstrated that it is a valid biomarker of concurrent renal disease activity in pSLE patients. Similar results have been shown in adult SLE patients as well. Lupus nephritis has a prevalence of as high as 50% among adult SLE population and is frequently associated with a poor long-term prognosis. In the last decade a few potential novel lupus biomarkers have been identified, though not yet adequately validated. There is an immediate need of non-invasive markers which associate with renal activity and carry minimal risk to the patient. Since U-NGAL levels increase prior to the occurrence of renal flares they provide opportunities for intervention, treatment and thus help reducing mortality and morbidity due to LN in both pSLE and adult SLE population. This study though gives compelling data but further larger studies in both adult and pSLE are warranted before these biomarkers can be used in routine clinical settings.
Abstract 1259: Progressive Multifocal Leukoencephalopathy - A National Estimate of Frequency in SLE and Other Rheumatic Diseases
Authors:
ES. Molloy, LH. Calabrese
Background:
PML is a rare demyelinating disease of central nervous system that results from reactivation of JC virus. It is typically fatal with a few survivors left with severe neurological sequel. PML generally occurs in immunosuppressed patients especially due to HIV, which constitutes large majority of PML cases. PML also occurs in cancer patients getting immunosuppressive therapy. PML is also associated with rheumatic diseases and case reports suggest that in rheumatic disease PML has been associated with immunosuppressive therapy. Authors tried to set up a national estimate of PML frequency among patients with SLE and other rheumatic diseases.
Methods:
Authors used US Nationwide Inpatient Sample database (1998-2005). Cases of PML, SLE and other rheumatic diseases were identified by ICD-9 diagnostic codes with no information available on immunosuppressive therapy.
Results:
A total of 9675 cases of PML were identified with majority being attributable to HIV (82%), hematologic (8.4%), solid cancers (2.8%). 0.44% were associated with SLE, 0.25% with RA, and 0.26% with other connective tissue diseases (CTDs). This equates to a rate of 4, 1, and 5 per 100,000 admissions for SLE, RA and other CTDs. Surprisingly none of SLE patients with PML were coded with other risk factors for PML like HIV or malignancy.
Conclusions:
PML occurred more commonly in SLE versus other rheumatic diseases and was less associated with other risk factors for PML like bone marrow or organ transplantation.
Editorial:
This study though limited by the lack of information regarding immunosuppressive therapy and data limited to inpatient admission only still provides important information. PML was highly prevalent in SLE compared to other rheumatic diseases. Lack of risk factors associated with PML in SLE patients highlights the need for a better understanding of pathophysiology of PML in relation to SLE.
