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Received Date : 05-Feb-2014
Accepted Date : 20-Mar-2014
Article type : Regular Article

Cardiovascular biomarkers in patients with psoriasis

Sascha Gerdes MD
1
, Swetlana Osadtschy
2
, Norbert
Buhles
2
, Hansjoerg Baurecht
3
and Ulrich Mrowietz MD
1

1
Psoriasis-Center at the Department of Dermatology, University Medical Center Schleswig-
Holstein, Campus Kiel, Kiel, Germany
2
Asklepios-Nordseeklinik, Westerland/Sylt, Germany
3
Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel,
Kiel, Germany

Key words: Psoriasis, cardiovascular disease, fetuin-A, sCD40L, MGP



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Sascha Gerdes, MD
Dept. of Dermatology
University Medical Center
Schittenhelmstr. 7
24105 Kiel
Germany
Phone +49-431-5971512
Fax +49-431-5971543
Mail sgerdes@dermatology.uni-kiel.de

Abbreviations:
AT: Adipose tissue
BMI: Body mass index
CD: Cluster of differentiation
CRP: C-reactive protein
CVD: cardiovascular disease
IL: Interleukin
LDL: Low density lipoprotein
MGP: Matrix Gla-protein
ox-LDL: oxidized low-density lipoprotein
PASI: Psoriasis Area and Severity Index
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PsA: Psoriatic arthritis
PsO: Psoriasis vulgaris
RA: Rheumatoid arthritis
sCD40L: soluble CD40 ligand
TNF: Tumor necrosis factor alpha
VAT: Visceral adipose tissue
WHR: Waist to hip ratio

Abstract
Psoriasis is a systemic inflammatory disease of the skin with associated comorbidity. Severe
forms of psoriasis are associated with increased mortality which might be due to
cardiovascular comorbidity. In this study we investigated in 79 patients with psoriasis
compared to 80 healthy volunteers different biomarkers that play a role in vascular disease
and inflammation such as C-reactive protein (CRP), human soluble CD40 ligand (sCD40L),
oxidized low-density lipoprotein (ox-LDL), human matrix gla-protein (MGP) and fetuin-A. Our
results showed that CRP (p<0.0001), sCD40L (p<0.0001) and MGP (p<0.0001) were
elevated in the patient cohort. Fetuin-A showed decreased serum levels in patients with
psoriasis (p<0.0001), whereas ox-LDL did not show any significant difference. In multivariate
analyses controlling for sex, age and BMI these findings were confirmed.
Thus, cardiovascular biomarkers are altered in patients with psoriasis. If the decrease of
fetuin-A as well as the increase of sCD40L can be proven in further studies, these
biomarkers may help to characterize a subgroup of patients who are at risk to develop
cardiovascular disease and/or monitor the effect of therapeutic anti-psoriatic strategies on
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concomitant diseases. This knowledge may be useful in the management of high-need
patients with psoriasis.

Introduction
Psoriasis is a systemic inflammatory disease with concomitant comorbidity. The most
prominent associated disease of plaque-type psoriasis is psoriatic arthritis (PsA) with an
estimated prevalence of 20% (1). Besides this, metabolic as well as cardiovascular diseases
(CVD) are of major importance. It was shown that patients with severe forms of psoriasis
have a reduced life expectancy which might be due to cardiovascular complications such as
myocardial infarction or stroke (2;3). How exactly psoriasis and its comorbidity are
pathophysiologically linked is poorly understood. From a genetic point of view psoriasis and
associated diseases such as metabolic syndrome and coronary heart disease do not share
the same genetic susceptibility loci, thus it has been hypothesized that environmental factors
may play a more important role in the association of comorbidity with psoriasis (4;5). From a
pathophysiological point of view an underlying systemic inflammation present in psoriasis
might contribute to the development and/or progression of comorbidity. In particular
atherosclerosis that itself is linked to inflammation could be triggered by pro-inflammatory
stimuli. This concept was developed and named as psoriatic march (6). It describes the
development of atherosclerosis as a consequence of systemic inflammation on the basis of
psoriasis that leads to insulin resistance followed by atherosclerosis and its complications
such as myocardial infarction.
Therefore, we investigated different biomarkers that play a role in vascular disease and
inflammation such as C-reactive protein (CRP), human soluble CD40 ligand (sCD40L) and
oxidized low-density lipoprotein (ox-LDL) (7-9).
Furthermore, we investigated human matrix gla-protein (MGP) that has a protective local
function in vascular calcification and fetuin-A, which is a potent systemic inhibitor of vascular
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calcification. Fetuin-A is also known to have an association with a higher cardiovascular
mortality in dialysis when degraded (10).
We hypothesised that these biomarkers are altered in patients with psoriasis when compared
to healthy volunteers and may be related to the Psoriasis Area and Severity Index (PASI)
and/or correlated to CRP.

To ensure an integrated management of severely affected patients with psoriasis the
knowledge of concomitant diseases and their pathophysiological interplay is of great
importance. If serum biomarkers could help to characterize the subgroup of patients who are
at risk to develop CVD and vascular complication this would directly influence the
management of these patients. Furthermore, cardiovascular serum biomarkers could be
used to monitor the effect of therapeutic anti-psoriatic strategies on concomitant disease.

Materials and Methods
For the analyses of sCD40L, MGP, ox-LDL, CRP and fetuin-A 79 serum samples of patients
with plaque-type psoriasis were used. Samples were taken from a serum bio bank that has
been collected at two different centres (University Medical Center Kiel and Asklepios-
Nordseeklinik, Westerland/Sylt) from psoriasis patients admitted to hospital for in- or
outpatient treatment. As controls we used samples from 80 matched healthy volunteers
taken from the same bio bank. All subjects have signed informed consent prior to
participation. The ethics committee of the University of Kiel approved the sample collection.
The same set of samples has been used in earlier analyses of adipokines that was already
published by our group (11).
For sample preparation 20 ml of venous blood were collected in serum tubes (Sarstedt S-
Monovette, Sarstedt, Nmbrecht, Germany) and centrifuged after clotting at 2000g for 10
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minutes at room temperature. Serum samples were stored at -80C until further investigation.
Epidemiological data such as age, sex, height, weight, waist and hip circumference, severity
of psoriasis using the Psoriasis Area and Severity Index (PASI) and nicotine consumption
were documented using a standardized questionnaire at both centres.
For the data analyses we grouped the patients in (a) all patients (n=79), (b) all patients with a
documented concomitant PsA (n=15) and (c) all patients with a documented absence of PsA
(n=38). Therefore, subgroups (b) and (c) were used to differentiate between patients with
and without PsA.
Statistical analyses were performed using GraphPad Prism version 3.00 for Windows
(GraphPad Software, San Diego, Ca, USA). Mean, median and standard deviation where
calculated for describing demographic data. Biomarker measurements were normalized by
log-transformation and subsequently analysed by the unpaired t-test. However,
transformation of MGP did not resemble a symmetric distribution, and it was therefore
analysed using the Mann-Whitney U-test. For calculating correlations we used
untransformed data to perform Spearman correlation analyses.

In order to adjust for the influence of known confounders such as sex, age and body mass
index (BMI) a multivariate analyses was performed using a linear regression model on the
log-transformed biomarker serum concentration. For MGP a median regression analysis was
applied, because transformation did not shape the data distribution towards normality. All
multivariate analysis were carried out with R 3.0.1 (R Foundation for Statistical Computing,
Vienna, Austria) and for median regression the package quantreg (Quantile Regression. R
package version 5.05.) was used (R Foundation for Statistical Computing, Vienna, Austria).
P-values of less than 0.05 were rated as statistically significant.
For quantifying the above mentioned biomarkers highly sensitive ELISA-based assays were
used. Each experiment was carried out with one sample of the patient and one sample of the
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control group. Positive and negative controls as well as standard solutions were used in
duplicate. ELISAs were carried out in accordance with manufacturers instructions. For
detection of ox-LDL (analytical-sensitivity: 4.13 ng/ml) and CRP (analytical-sensitivity: 0.124
ng/ml) commercially available ELISA kits from Immunodiagnostik AG, Bensheim, Germany
were used. Human sCD40L (analytical-sensitivity: 0.06 ng/ml) was detected with an ELISA
kit from Bender MedSystems GmbH, Vienna, Austria; MGP (analytical-sensitivity: 0.3 nmol/l)
with an ELISA kit from Biomedica Medizinprodukte GmbH & Co KG, Vienna, Austria and
fetuin-A (analytical-sensitivity: 5.0 ng/ml) with an ELISA kit from Epitope Diagnostics Inc.,
San Diego, CA, USA.

Results:
The demographic characteristics of patients and controls were comparable as well as the
demographic characteristics of the patient subgroups with and without PsA (Supplementary
table S1 online). Thus, the results from our study represent data from well matched groups.
In 48 of 79 patients a PASI was documented. The mean PASI value was 14.3 (SD 12.6) with
a tendency of higher PASI values in patients with concomitant PsA (Supplementary table S1
online).

Univariate analyses
Mean serum concentration of ox-LDL did not show statistically significantly differences
between both groups (psoriasis patients: 564.9 ng/ml; SD 1766 vs. controls: 350.1 ng/ml; SD
592.5; p: 0.1137). Regarding information from the manufacturer of the ELISA for ox-LDL
abnormal high levels of ox-LDL may be detected if patients have increased levels of
interfering proteins for example rheumatoid factor, which could explain the high standard
deviation of our results. As we observed abnormal high levels of ox-LDL in some patients of
both groups we performed a second analysis of ox-LDL. In this analysis we excluded the four
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patients with the highest results for ox-LDL of each group. The results did not change,
statistically significant differences could not be observed between the groups (psoriasis
patients: 222.1 ng/ml; SD 299.4 vs. controls: 248.7 ng/ml; SD 393.1; p: 0.1623).
Fetuin-A serum concentrations were decreased in all patients with psoriasis (0.88 g/l; SD
0.34 g/l; p < 0.0001) compared to controls (1.17 g/l; SD 0.35 g/l) (Figure 1b). There was no
statistically significantly difference between patients with and without PsA (data not shown).
CRP, sCD40L and MGP were elevated in the patient cohort. The most prominent increase
was found for CRP in the patient group (21.2 mg/l; SD 23.4 mg/l; p<0.0001) compared to the
control group (1.8 mg/l; SD 2.97 mg/l) (Figure 1a). Although there was no statistically
significantly difference between the subgroup of patients with PsA compared to patients
without PsA the CRP showed a tendency towards higher values in patients with concomitant
PsA (27.3 mg/l; SD 22.5 mg/l) compared to patients without PsA (18.1 mg/l; SD 20.3 mg/l;
p=0.0635).

The mean value of sCD40L in all patients was increased (2.43 ng/ml; SD 1.4 ng/ml; p <
0.0001) compared to the control group (1.16 ng/ml (SD 0.92 ng/ml). This increase was higher
in patients without PsA (2.77 ng/l; SD 1.47 ng/l; p<0.0001) compared to healthy controls than
in patients with PsA (2.01 ng/ml; SD 1.30; p=0.0036) compared to healthy controls (`ure 1d).
The same results were found for MGP. MGP was elevated in the patient group (11.49 nmol/l;
SD 9.69 nmol/l; p < 0.0001) compared to the control group (5.49 nmol/l; SD 3.93 nmol/l). This
elevation was stronger in patients without concomitant PsA (13.4 nmol/l; SD 12.1 nmol/l;
p<0.0001) compared to healthy controls than in patients with PsA (8.19 nmol/l; SD 7.42
nmol/l; p = 0.04) compared to controls (Figure 1c).

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Our study revealed slight differences between the patient and the control group for BMI,
waist to hip ratio (WHR) and waist circumference, with a tendency towards higher values in
the patient group (Supplementary table S1 online). To rule out any bias due to potential
confounders we carried out multivariate analyses, adjusting for age, sex and BMI.

Multivariate analyses
The multivariate analysis substantiated the findings from the univariate approach. All
biomarkers except ox-LDL showed statistically significantly differences between the patient
group (n=79) and the control group (n=80). No influence of sex, age and BMI was observed
on the tested biomarkers.

Correlation analyses
All biomarkers did not show any correlation to PASI as an indicator for disease severity or to
CRP as an inflammatory marker (Table 1).

Discussion
In our study we analyzed data of patients with moderate-to-severe plaque-type psoriasis with
a mean PASI of 14.3. Patients with PsA showed a tendency of higher PASI (mean 17.3)
compared to patients without PsA (mean 14.8). This difference was not statistically
significant but it could indicate that patients with concomitant PsA present with a stronger
inflammation than patients with psoriasis of the skin only. All patients showed elevated CRP
values that were highly statistically significant and the patients with concomitant PsA showed
a tendency towards higher CRP levels,.reflecting a high inflammatory burden of the
investigated patients. An increase of CRP in moderate-to-severe plaque-psoriasis is found in
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many studies as published in a recent meta-analysis (12). Data on the correlation with PASI
is conflicting and not always statistically significant (12;13). A correlation of CRP with PASI
was not seen in the patients of our study.
The role of CRP in the pathogenesis of atherosclerosis is still under debate and a causal role
of CRP in CVD as an atherothrombotic factor is not evident yet (9). Although causality of
CRP in the pathogenesis of CVD has not been proven, many studies and guidelines from
leading professional organizations consider hsCRP as a predictive marker for cardiovascular
(CV) events (9). We used CRP in our study as a central indicator for systemic inflammation
and correlated CRP with the other tested biomarkers.

The two biomarkers we found to be elevated in the serum of patients with psoriasis
compared to healthy controls were MGP und sCD40L. For both proteins the mean serum
concentration was even higher in the subgroup of psoriasis patients without PsA. In none of
the patient groups a correlation with CRP could be detected.
MGP is a mineralization inhibitor that protects vascular smooth muscle cells from calcification
(14;15). The role of vascular calcification and calcification inhibitors in cardiovascular disease
is still controversially discussed (10). For inflammatory conditions it is proposed that
osteogenic activities in vascular calcification can be triggered by inflammation and could be
improved by anti-inflammatory treatment (16). Another possible therapeutic approached to
prevent or reduce vascular calcification is to increase the activity of calcification inhibitors
such as MGP (15). As cardiovascular disease is associated with psoriasis and psoriasis is
associated with systemic inflammation the increase of MGP in our study population could be
a local protection mechanism of smooth vascular muscle cells to prevent vascular
calcification.
In contrast, we found a significant reduction of fetuin-A in patients with psoriasis with and
without PsA. Fetuin-A is a potent systemic inhibitor of ectopic calcification (15). In humans
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low levels of fetuin-A were found in patients with chronic kidney disease, dialysis patients
and patients with end-stage renal disease with evidence of inflammation (15;17). In
hemodialysis patients low levels of fetuin-A were associated with increased cardiovascular
and all-cause mortality (18). Furthermore, fetuin-A is known as a negative acute phase
protein that is down-regulated by acute inflammation. In rat liver it was shown that TNF- can
reduce fetuin-A gene expression and in humans this was shown for IL-6 and IL-1 (19).
Therefore, it might be possible that the inflammatory stage of our study patients let to a
reduction of systemic fetuin-A levels that increases the risk of vascular calcification and could
possibly link the systemic inflammation of psoriasis to its cardiovascular comorbidity.
Furthermore, the increase of MGP as a local calcification inhibitor could be a protective
reaction of smooth vascular muscle cells to the systemic decrease of fetuin-A.

Critically it has to be discussed, that fetuin-A also plays a role in metabolic diseases such as
insulin resistance, type 2 diabetes mellitus and obesity (20), all of which are known to be
associated with psoriasis. Fetuin-A can inhibit insulin receptor tyrosine kinase activity and
therefore leads to insulin resistance in liver and skeletal muscle (20). In several studies an
increased risk for diabetes was associated with high fetuin-A levels (19). Therefore, high
levels of fetuin-A may also be linked to atherosclerosis and vascular disease in particular in
association with metabolic diseases (20;21).
The other biomarker that was up-regulated in our study was sCD40L. The soluble ligand of
CD40L (sCD40L) is mainly secreted from activated platelets and has autocrine, paracrine
and endocrine activities contributing to the pathophysiology of the atherosclerotic process
from initiation until plaque rupture (22;23). In cardiovascular disease sCD40L has been
reported as a biomarker with predictive value to assess the risk of future cardiovascular
events such as myocardial infarction and cardiovascular death (22).
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The atherosclerotic involvement of sCD40L is of importance in psoriasis. The increase of
serum levels of sCD40L in our study population was significant in all subgroups of patients
but stronger in patients with only plaque-type psoriasis. The increase of sCD40L could
contribute to the understanding on how psoriasis interacts with its comorbidity. In a smaller
study with 39 topically treated patients with psoriasis the same increase of sCD40L in the
serum of the study population compared to a control group of 10 healthy subjects was found
(24). In this study a two weeks topical treatment with dithranol showed no effect on serum
levels of sCD40L. Interestingly in a group of 20 patients with PsA compared to 20 healthy
controls no significant difference of sCD40L between the groups was found but sCD40L was
positively correlated with CRP levels and sCD40L was significantly higher in active PsA
compared to inactive PsA (25). In rheumatoid arthritis an increase of serum sCD40L levels
have been found, too (26). In our study the elevation of sCD40L in serum was less prominent
in the PsA subgroup compared to the subgroup without PsA. In a case-control study from
Greece comparing 198 patients with psoriasis with 400 controls an association of a CD40
gene polymorphism with psoriasis but not with PsA was shown (27). One could speculate
that the involvement of the CD40/CD40L pathway is stronger in patients with skin symptoms
only and more independent of the inflammatory activity as in PsA.
As increased levels of sCD40L can predict future cardiovascular events in patients with
atherosclerosis this might also be the case in patients with psoriasis.
Oxidized LDL is of great importance in the development and progression of atherosclerosis.
During the initial stage of atherosclerosis ox-LDL can activate endothelial cells through the
lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) leading to an up-regulation of
many different signaling pathways including the CD40/CD40L pathway (8;28). In our study
we were not able to show differences in the serum levels of ox-LDL in the patient groups.
This is in contrast to other studies that were able to show increased levels of ox-LDL in
patients with PsA in particular in association with an increased intima media thickening (29).
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Little is known about an increase of ox-LDL in the serum of psoriasis patients but an
accumulation of ox-LDL in lesional skin biopsies was shown (30).
In conclusion our study shows that cardiovascular biomarkers are altered in patients with
psoriasis. In particular the decrease of fetuin-A as well as the increase of sCD40L could be of
interest for further studies. A longitudinal observation on serum level changes of these
biomarkers in response to treatment as well as a correlation of these markers with the
development of concomitant diseases or cardiovascular events in patients with moderate-to-
severe psoriasis should be initiated.

Acknowledgements
This study was supported by an unrestricted educational grant from the CoMorb Study
Initiative. The CoMorb Study Initiative consisted of Abbvie (former Abbott), Biogen Idec, and
Merck/Serono. Furthermore, the study was supported by the German Psoriasis Association.
UM and SG have designed the study concept. SG, SO and NB have collected and SG and
SO have analysed the serum samples. HB has performed the statistical analysis. All authors
analysed and discussed the data and wrote the manuscript.

Conflict of Interest
The authors declare no conflict of interest.

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Table 1:

Correlation with CRP
(all patients, n = 79;
controls, n=80)
Correlation with CRP
(Patients with documented
psoriatic arthritis, n = 15)
Correlation with CRP
(patients with documented
absence of psoriatic arthritis,
n = 38)
Patients

Fetuin A r = -0.13; p = 0.271
(95% CI: -0.34 to 0.11)
r = 0.12 p = 0.680
(95% CI: -0.43 to 0.60)
r = -0.31; p = 0.057
(95% CI: -0.58 to 0.02)
Matrix gla protein r = -0.04; p = 0.727
(95% CI: -0.27 to 0.19)
r = -0.33; p = 0.237
(95% CI: -0.73 to 0.24)
r = 0.25; p = 0.125
(95% CI: -0.08 to 0.54)
sCD40L r = 0.13; p = 0.266
(95% CI: -0.10 to 0.34)
r = 0.43; p = 0.110
(95% CI: -0.12 to 0.78)
r = 0.23; p = 0.174
(95% CI: -0.11 to 0.52)


Controls

Fetuin A r = 0.07; p = 0.540
(95% CI: -0.16 to 0.29)

Matrix gla protein r = 0.07; p = 0.555
(95% CI: -0.16 to 0.29)

sCD40L r = 0.17; p = 0.142
(95% CI: -0.06 to 0.38)

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Correlations of CRP with fetuin-A, Matrix gla-protein and sCD40L separated for all patients,
patients with documented psoriatic arthritis and patients with documented absence of
psoriatic arthritis. r = spearman correlation coefficient; CI = confidence interval; statistically
significant: p-value < 0.05.

Figure legend 1:
Serum concentrations of CRP and fetuin-A in healthy volunteers (Controls; n=80) compared
with all patients with psoriasis (Patients; n=79), as well as Matrix Gla-protein and sCD40L in
healthy volunteers (Controls; n=80), all patients with psoriasis (Patients; n=79), patients with
documented concomitant psoriatic arthritis (PsA; n=15) and patients with documented
absence of psoriatic arthritis (PsO; n=38).
a: Log transformed serum concentration distribution of CRP was statistically significantly
higher in the patient group compared with the control group.
b: Log transformed serum concentration distribution of fetuin-A was statistically significantly
lower in the patient group compared with the control group.
c: Mean serum concentration of Matrix Gla-protein was statistically significant higher in all
patient subgroups compared with the control group. Patients with concomitant PsA showed a
tendency to have lower serum concentrations of Matrix Gla-protein than patients without
PsA.
d: Log transformed serum concentration distribution of sCD40L was statistically significant
higher in all patient subgroups compared with the control group. Patients with concomitant
PsA showed a tendency to have lower log transformed serum concentration distribution of
sCD40L than patients without PsA.
Statistically significant: p<0.05.
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