Rheumatology 2009;48:497–501 doi:10.

1093/rheumatology/kep030
Advance Access publication 5 March 2009

Adipokines as novel biomarkers in paediatric systemic lupus

erythematosus
Marjon Al1, Lawrence Ng1, Pascal Tyrrell1, Joanne Bargman2, Timothy Bradley3 and Earl Silverman1

Objectives. Patients with SLE are at risk for premature atherosclerosis and metabolic syndrome. Cytokines produced by adipocytes,
adipokines, are important in glucose/lipid metabolism and the development of atherosclerosis. The objectives of this study were to evaluate
leptin, adiponectin and ghrelin concentrations in paediatric SLE (pSLE) and to correlate these concentrations with measures of disease
activity, serum lipid concentrations, measures of insulin resistance and serum homocysteine concentrations.
Methods. Two hundred and eight samples from 105 patients with pSLE and 77 samples from 77 healthy paediatric controls were evaluated
by ELISA to measure leptin, adiopnectin and ghrelin. Students’ t-test was used for analysis. Concentrations of adipokines were correlated
with disease activity, serum lipids, insulin resistance and homocysteine.
Results. Overall 35 SLE patients (34%) had an abnormally elevated leptin level. The only significant correlation of leptin concentrations was

Downloaded from rheumatology.oxfordjournals.org by guest on November 19, 2010

with homocysteine concentrations but not disease activity, prednisone dose, lipids or insulin resistance. There was no difference in the mean
adiponectin concentrations between the control and patient groups and none of the patient samples were below the normal lower limit while
seven were elevated. There was a significant correlation of adiponectin concentrations with prednisone dose, lipid concentrations and insulin
resistance but not with disease activity or homocysteine. Elevated ghrelin concentrations were found in 20% of the pSLE patients. The only
correlation of ghrelin concentrations was with homocysteine.
Conclusions. Adipokines are novel biomarkers in pSLE. They may represent cardiovascular risk and are not just surrogate markers for
disease activity, therapy or serum lipids. Their correlation with atherosclerosis needs to be explored.

KEY WORDS: Paediatric SLE, Atherosclerosis, Leptin, Ghrelin, Adiponectin, Paediatric rheumatology, Biomarkers.

Introduction plays a role in regulation of insulin secretion. Ghrelin has been

SLE is a chronic autoimmune disease characterized by the pro-
duction of autoantibodies and chronic inflammation. It has been
recognized since the early 1970s that patients with SLE are at
risk for premature atherosclerosis [1]. It has been postulated that
the chronic inflammation of SLE, the production of autoanti-
bodies and the presence of metabolic syndrome (characterized
by elevated blood pressure, central obesity, dyslipidaemia and
glucose intolerance) are important in the development of pre-
mature atherosclerosis in SLE [2]. Adipose tissue secretes a variety
of cytokines with autocrine/paracrine and endocrine functions
that influence body weight and glucose/lipid metabolism. These
cytokines which include leptin, adiponectin, IL-6, TNF-
and
resistin, are collectively known as adipocytokines or adipokines.
Leptin and adiponectin are the two major insulin-sensitizing adi-
pokines secreted from adipose tissue.
Adiponectin acts mainly on skeletal muscle and liver, and
increases insulin sensitization. It has been suggested that adipo-
nectin may have an important protective role in the development
of atherosclerosis as adiponectin inhibits the production of pro-
inflammatory cytokines and can render macrophages resistant to
pro-inflammatory stimuli [3–7]. Leptin, a second important adi-
pokine, is important in energy balance. Serum concentrations of
leptin have been positively correlated to adipose tissue mass with
higher concentrations in women than in men. Adult patients with
SLE have been shown to have elevated serum leptin concentra-
tions [8–10]. A third cytokine, ghrelin, which is secreted mainly
from the stomach, acts as an appetite-stimulating hormone and
1
Division of Rheumatology, Department of Pediatrics, SickKids Hospital, 2Division
of Nephrology, Department of Medicine, University Health Network and 3Division of
Cardiology, Department of Pediatrics, SickKids Hospital, University of Toronto,
Toronto, Ontario, Canada.
Submitted 12 August 2008; revised version accepted 22 January 2009.
Correspondence to: Earl Silverman, Division of Rheumatology, Department of
Pediatrics, Hospital for Sick Children, 555 University Ave., Toronto, Ontario,
Canada M5G 1X8. E-mail: earl.silverman@sickkids.ca
497
ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
shown to have beneficial cardiovascular actions by decreasing
vascular calcification and inhibiting endothelial cell cytokine
production [11, 12].
The primary aim of this study was to evaluate leptin, adipo-
nectin and ghrelin concentrations in a large cohort of paediatric
patients with SLE. Additional aims were to correlate these con-
centrations with measures of disease activity, treatment, serum
lipid concentrations, measures of insulin resistance and serum
homocysteine concentrations.
Materials and methods
Subjects and samples
Following informed consent 208 fasting serum samples were col-
lected from 105 patients with paediatric SLE (pSLE). The cohort
consisted of 21 males (20%) and 84 females (80%) with a mean
age of 14.98
2.46 years who attended the Lupus Clinic at
SickKids Hospital, Toronto and were enrolled in a prospective
study of examining non-invasive measurements of atherosclero-
sis (Table 1). All children fulfilled at least 4/11 of the ACR criteria
for the diagnosis of SLE and were between the ages of 10 and 18
years at the time of the study [13]. This work was approved by the
Research Ethics Board of SickKids Hospital.
Serum samples were collected from 127 otherwise healthy chil-
dren (50 males and 77 females) with mean age of 10.04
3.48
years (range 3–18 years). It has been recognized that leptin and
adiponectin concentrations may vary with age and we found
that this was true up to the age of 9 years in our healthy controls.
As >95% of patient samples were from patients 59 years of age,
we used 9 years as the cut-off for both patients and the control
group. This left 77 individuals (21 males and 56 females) in the
control group. Peripheral venous blood samples were collected
between 1999 and 2006. The blood samples were centrifuged
for 12 min at 800 g; plasma was extracted and stored at 808C
until testing which may have been up to 7 years. None of the
samples had been previously thawed prior to testing. The
samples were tested for ghrelin, leptin and adiponectin to
498 Marjon Al et al.

establish a normal range. The healthy serum control samples NH, USA). The absorbance was measured at 405 nm with an
were obtained from children seen in the Rheumatology Clinic at ELISA plate reader (Versamax ROM v3.13). The concentration
SickKids Hospital and were found not to have a rheumatological was determined using computer program SoftMax Pro 4.3. The
or any other acute or chronic illness. assay had a sensitivity of 0.6 pg/ml.

ELISA
Leptin. A direct sandwich assay was used to measure leptin
according to instructions outlined by the manufacturer with
patient serum or control serum diluted 1 : 4 (ELISA Kit, Linco
Research, MO, USA). The absorbance was measured by 450 nm
with an ELISA plate reader (Versamax ROM v3.13; Molecular
Devices, Sunnyvalle, CA, USA). The concentration was deter-
mined using computer program SoftMax Pro 4.3 (SoftMax,
San Diego, CA, USA). The assay had a sensitivity of 0.50 ng/ml.
Statistics
The data are reported as means
S.D. A two-tailed Student’s
t-test was used to compare control and study groups. When indi-
cated, z-score transformation was performed prior to analysis.
A P-value of <0.05 was considered as statistically significant.
Statistical analyses were performed using standard computer soft-
ware (Microsoft Excel Statistical Addin, Microsoft Corporation,
Seattle, Washington, USA).

Adiponectin. Direct sandwich ELISA assay for adiponectin was

performed according to the method outlined by the manufacturer
(ELISA Kit, Linco Research). However, when measuring adipo- Results

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nectin serum samples were pre-diluted 1 : 500 prior to adding to Leptin
the ELISA plate. The absorbance was measured at 450 nm with an
ELISA plate reader (Versamax ROM v3.13). The concentration As expected, we found a significant correlation of leptin concen-
was determined using computer program SoftMax Pro 4.3. The trations and height, weight and BMI in controls (data not shown).
assay had a sensitivity of 0.78 ng/ml. All data for pSLE patients are reported for the initial sample
only unless otherwise indicated as serial measurements. This is
Ghrelin. Direct sandwich ELISA assay for unacylated ghrelin was true for adiponectin, ghrelin as well as for leptin concentrations.
performed according to the method outlined by the manufacturer When compared with controls, mean serum leptin concentra-
with serum samples diluted 1 : 2 (ALPCO Diagnostics, Salem, tions were elevated in the SLE cohort (22.4
18.2) as well as for
female patients (24.3
19.2 vs 10.2
7.7; P < 0.0001) with a trend
for elevated concentrations in males (14.6
13.2 vs 8.6
11.0;
TABLE 1. pSLE patient demographic data P ¼ 0.08) (Table 2). Overall 35 patients (34%) had an abnormally
elevated leptin concentration (33.3% of males and 33.7% of
Male Female females). We did not find a statistically significant difference in
Number of patients 21 84
the serial leptin concentrations when we compared the initial
Age, mean
S.D., years 14.43
2.20 (8–18) 14.32
2.67 (7–18) sample to a sample repeated 6–24 months later (103 samples
(age range 7–18 years) from 85 patients) (data not shown). Unlike the results seen in
Weight, mean
S.D. 63.2
12.5 (42.3–94.3) 58.4
18.1 (24.1–109) controls, we did not find a statistically significant correlation
(range), kg
Height, mean
S.D. 159.78
11.04 (143–185) 157.03
12.64 (112–183)
of leptin concentrations with height for both sexes while there
(range), cm was a statistically significant correlation with weight for female
BMI, mean
S.D. 24.07
3.57 (18.23–29.94) 23.76
5.32 (15.61–38.87) (r ¼ 0.640; P < 108) but not male patients. There was a significant
(range), kg/m2 correlation with BMI only (r ¼ 0.762; P < 1013 for females and
ECLAM score, 1.79
2.04 (0–7) 3.66
2.06 (0–9)
mean
S.D. (range) r ¼ 0.725; P ¼ 0.001 for males). When we attempted to correlate
SLEDAI score, 2.89
3.09 (0–10) 3.66
3.89 (0–16) leptin concentrations with active SLE, we did not find any
mean
S.D. (range) significant correlation of leptin concentrations with ECLAM or
Prednisone dose, 19.88
18.05 (0–60) 12.37
11.82 (0–60)
mean
S.D. (range), mg
SLEDAI scores (data not shown). The mean SLEDAI score was
3.51
3.54 (range 0–16) and mean ECLAM score was 2.25
2.06.

TABLE 2. Leptin, adiponectin and ghrelin concentrations

SLE group Control group

Male Female Male Female

Patients/controls, n 21 84 21 56
Leptin concentrations, 14.6
13.2a (0–44.3) 24.3
19.2a (1.7–100.6) 8.6
11.0a (0–49.8) 10.2
7.7a (0–43.8)
mean
S.D. (range), ng/ml
pSLE patients with abnormally 7 (33.3) 28 (33.7)
elevated leptin concentrations, n (%)
a
Adiponectin concentrations, 14.7
9.6 (8.1–42.9) 15.1
7.6a (2.2–43.1) 15.7
6.7a (4.1–33.0) 15.5
7.7a (3.9–46.0)
mean
S.D. (range), mg/ml
pSLE patients with abnormally 0 (0) 0 (0)
decreased adiponectin concentrations
in patients, n (%)
pSLE patients with abnormally elevated 3 (7.5) 12 (7.1)
adiponectin concentrations, n (%)
Ghrelin concentrations, mean
S.D. 96.6
158.2 (0–812.5) 109.1
111.1 (0–789.6) 69.5
123.4 (0–892.7) 46.5
51.0 (0–275.3)
(range), pg/ml
pSLE patients with abnormally elevated 4 (19) 17 (20.5)
ghrelin concentrations, n (%)

a
Mean and S.D. of concentrations from patients 9 years of age only.
 Adipokines in paediatric SLE 499

Adiponectin
There was no difference in the mean adiponectin concentrations
between the control and patient groups (15.6
7.3 vs 15.4
8.2).
None of the patient samples were below the normal lower limit
while seven adiponectin measurements from seven patients were
elevated (Table 2). None of the controls had elevated adiponectin
concentrations. We did not find a statistically significant differ-
ence in adiponectin concentrations when we compared the initial
sample to a sample repeated 6–24 months later in the patients who
had repeated samples (103 samples from 85 patients) (data not
shown). There was no correlation of adiponectin concentrations
with height, or BMI for both sexes although there was a negative
correlation of adiponectin concentrations with weight in male
(r ¼ 0.56; P ¼ 0.013) but not female patients. There was no cor-
relation of adiponectin concentrations and ECLAM or SLEDAI
scores.
Ghrelin
for males (r ¼ 0.862; P < 0.001) but not for females (P ¼ 0.18).
There was no correlation of adiponectin concentration with
apolipoprotein (Apo) A1 or ApoB in males or females. We did not
find any significant correlation of ghrelin or leptin concentration
with any of the lipids measured.
Correlation with homocysteine concentrations
There was a statistically significant negative correlation of homo-
cysteine concentrations with ghrelin in males (r ¼ 0.772;
P ¼ 0.04) and a significant positive correlation with leptin
concentrations in males (r ¼ 0.788; P ¼ 0.04). There were no
correlations of homocysteine concentrations with ghrelin or leptin
concentrations in females (P ¼ 0.278 and P ¼ 0.137, respectively)
or with adiponectin concentrations for males (P ¼ 0.51) or females
(P ¼ 0.22).
Correlation with measures of insulin resistance
There was no significant correlation of leptin or ghrelin concentra-

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When compared with controls, the mean ghrelin concentrations tions with measures of insulin resistance (insulin concentrations,
for the total SLE group as well as for both male and female insulin C-peptide or haemoglobin A1C concentrations). However,
patients were not significantly elevated (Table 2). Elevated ghrelin there was a statistically significant correlation of adiponectin
concentrations were found in 20/99 patients (20%) (19% of the concentrations with insulin C-peptide concentrations (r ¼ 0.938;
males and 20% of the females). We did not find a statistically P ¼ 0.002) for males with a trend for a significant association
significant difference in ghrelin concentrations when we compared with insulin concentrations (P ¼ 0.06). In contrast, there was no
the initial sample to a sample repeated 6–24 months later in the statistically significant association of either insulin C-peptide or
patients who had repeated samples (103 samples from 85 patients) insulin concentrations with adiponectin concentrations in females
(data not shown). There was no statistically significant correlation (P ¼ 0.64 and P ¼ 0.99, respectively).
of ghrelin concentrations with height, weight, BMI, SLEDAI or
ECLAM concentrations (data not shown). Discussion
The development of atherosclerosis in patients with SLE is the
Associations with prednisone dose result of a complex interaction of traditional risk factors, chronic
There was a statistically significant correlation of adiponectin inflammation, the production of autoantibodies and therapies
concentrations and prednisone dose in both males (r ¼ 0.655; used to treat the disease. Recent evidence has suggested that the
P ¼ 0.0017) and females (r ¼ 0.413; P ¼ 0.0001) but there was no adipokines leptin and adiponectin and the appetite-stimulating
correlation of prednisone dose with leptin or ghrelin concentra- hormone ghrelin may be important in the development of athero-
tions (data not shown). sclerosis in otherwise healthy individuals and in disease states.
In this study, we examined how these cytokines/adipokines inter-
Correlation with lipid concentrations act with each other and the association with these adipokines and
serum lipids, insulin resistance, homocysteine concentrations and
We next correlated adiponectin, leptin and ghrelin with serum measures of disease activity in a large cohort of patients with
lipid concentrations (Table 3). The only significant correlations we pSLE.
found were a correlation of adiponectin concentrations in pSLE Adiponectin has been shown to be important in the regulation
patients with total cholesterol for both males (r ¼ 0.296; P ¼ 0.01) of insulin sensitivity, energy homeostasis and more recently in the
and females (r ¼ 0.554; P ¼ 0.008); with high-density lipoprotein development of atherosclerosis. It has been reported that low
(HDL) in females (r ¼ 0.700; P ¼ 0.0009) but not males (P ¼ 0.32); serum adiponectin concentrations may be a risk factor for ath-
with low-density lipoprotein (LDL) in males (r ¼ 0.288; erosclerosis in patients with metabolic syndrome and renal dis-
P ¼ 0.01) but not in females (P ¼ 0.22); and with lipoprotein A ease [14, 15]. In patients with type 1 diabetes mellitus, it has been
suggested that adiponectin concentrations are increased in an
TABLE 3. Lipid, homocysteine and insulin measurements in pSLE patients attempt to decrease endothelial and vascular damage [16]. In our
study, similar to what has been reported in type 1 diabetes melli-
Male Female tus, we found that some SLE patients had elevated adiponectin
concentrations. Similar to a previous observation in adults with
Number of patients 21 84
Cholesterol, mean (range), 4.50
1.09 (2.5–8.17) 4.19
1.09 (0.79–8.3) SLE, we did not find decreased adiponectin concentrations in any
mmol/l of our patients with pSLE [17]. Adiponectin concentrations were
Triglycerides, mean (range), 1.19
0.37 (0.69–1.83) 1.27
0.48 (0.37–3.15) positively associated with multiple lipid concentrations: total
mmol/l cholesterol (both sexes), HDL (females only), lipoprotein A (males
HDL, mean (range), mmol/l 1.42
0.71 (0.61–3.72) 1.22
0.60 (0.70–2.21)
LDL, mean (range), mmol/l 2.52
0.88 (1.14–4.03) 2.44
0.86 (0.70–5.55) only) and negatively associated with LDL (males only). These
Number of samples 7 28 results are consistent with previous studies in healthy individuals
Insulin, mean (range), pmol/l 188.5
236.5 (64–494.8) 105.7
66.6 (41.2–220) which found a positive association of serum adiponectin concen-
Insulin C-peptide, 4.1
3.2 (2–10.5) 3.2
1.7 (1–7.5) trations with HDL demonstrating that high adiponectin concen-
mean (range), pmol/l
Apo1A, mean (range), mmol/l 1.5
0.8 (0.7–3.3) 1.3
0.2 (0.9–1.7) trations are associated with a low-risk lipid profile [3, 4, 14,
Apo1B, mean (range), mmol/l 0.9
0.3 (0.7–1.4) 0.8
0.3 (0.5–1.8) 18–21]. However, we did not find a correlation with triglyceride
Lipoprotein, mean (range), 24.4
22.3 (9.4–32.2) 26.5
30.0 (9.4–131) concentrations, or with ApoA1 and ApoB concentrations as pre-
mg/dl viously reported in healthy individuals, suggesting that in patients
Homocysteine, mean (range), 10.5
1.7 (8.2–11.7) 9.2
3.6 (5.5–19.9)
mol/l with SLE the association of adiponectin with serum lipids is more
complex than that found in the general population. Of impor-
All results are listed as mean
S.D. tance, there was an association of adiponectin with insulin
500 Marjon Al et al.
C-peptide and a trend for an association with insulin concentra-
tions suggesting that in patients with SLE adiponectin concentra-
tions are not decreased in the presence of insulin resistance as
found in the general population. Of importance, adiponectin
concentrations were significantly associated with prednisone in
both male and female patients but not with disease activity. We
suggest that this may be a biomarker for the metabolic syndrome
phenotype seen in SLE patients.
Our findings of high serum leptin concentrations in one-third of
the patients with pSLE are in agreement with previous studies in
adults with SLE [8–10]. This is in contrast with studies in juvenile
idiopathic arthritis and adult RA which have shown either normal
or low concentrations [8–10, 22–25]. Similar to previous studies in
healthy individuals, we found that leptin concentrations correlated
with height, weight and BMI in controls. In contrast, in SLE
patients, we found that leptin concentrations correlated with only
BMI in both sexes. These results suggest that in patients with SLE
other factors in addition to height, weight and BMI control leptin
concentrations. Similar to previous studies in adults with SLE, we
did not find an association with global measures of disease activity
suggesting that leptin concentrations reflect a different process
than disease activity [8–10]. We did not find an association of
leptin concentrations with any of the lipids measured including
triglyceride or HDL concentrations, although in healthy adults
and children, leptin concentrations have been correlated with
serum lipid measurements [26, 27]. Although dexamethasone has
been shown to induce hyperleptinaemia, we did not find an asso-
ciation of leptin concentrations with prednisone dose at the time
of leptin measurement or with mean prednisone dose in the
3 months prior to leptin measurement. Therefore, the hyperlepti-
naemia seen in SLE is likely not secondary to prednisone therapy.
This lack of association of leptin concentrations and prednisone
dose has been previously reported in adults with SLE [8, 9].
Lastly, we have found for the first time an association of leptin
concentrations with homocysteine concentrations. Future studies
are required to determine the control of leptin secretion in SLE.
Ghrelin has recently been shown to have an inhibitory effect on
the production of pro-inflammatory cytokines [28–30]. The ghrelin
concentrations were inversely correlated to leptin concentrations,
a finding previously reported in healthy adults and seen in our
healthy paediatric controls [31, 32]. Despite this inverse correla-
tion with leptin concentrations, we did not find significant differ-
ence between ghrelin concentrations in pSLE patients and controls
and there was no association of ghrelin concentrations with height,
weight or BMI. These results confirm the findings in healthy indi-
viduals that these two cytokines function independently of each
other. We did not find the previously demonstrated association of
ghrelin concentrations with HDL concentrations [28]. However,
similar to what we found with leptin, we did find a significant
association of ghrelin concentrations with homocysteine although,
as may be expected, the association of ghrelin concentrations with
homocysteine concentrations was negative. There was no asso-
ciation of ghrelin concentrations with prednisone treatment. Our
study suggests that measuring ghrelin does not add additional
information to measuring leptin concentrations in SLE.
In this study, we have shown that leptin, adiponectin and, to
a lesser extent ghrelin, cytokines which are important in energy
homeostasis, may be important biomarkers in SLE. We suggest
that adiponectin may be an important counter-regulatory mole-
cule in SLE which is secreted in response to chronic inflammation
or prednisone therapy to down-regulate the negative effects of
pro-inflammatory cytokines, and therefore elevated concentra-
tions may be protective. In contrast, elevated leptin concentra-
tions may be an additional biomarker of the risk of metabolic
syndrome or atherosclerosis. However, a limitation of our study
was our inability to measure long-term cardiovascular outcome
or all cardiovascular risk factors in our cohort, and therefore
additional studies are required to not only confirm our results
but to test the correlation of these biomarkers with markers of
subclinical atherosclerosis.
Rheumatology key messages
 The adipokines leptin and adiponectin are novel biomarkers which
may be predictive of cardiovascular risk in pSLE.
 Circulating leptin concentrations are increased in approximately
one-third of the patients with pSLE.
 Adiponectin concentrations are increased and not decreased in
pSLE.
Disclosure statement: The authors have declared no conflicts of
interest.
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