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ORIGINAL ARTICLE
Circulating adipokine levels in Portuguese patients withpsoriasis vulgaris according to body mass index, severityand therapy
S Coimbra,†,‡,§,* H Oliveira,– F Reis,†† L Belo,†,‡ S Rocha,†,‡ A Quintanilha,‡,‡‡ A Figueiredo,–
F Teixeira,†† E Castro,†,‡ P Rocha-Pereira,‡,§§ A Santos-Silva†,‡
†Faculdade de Farmacia, Servico de Bioquımica, Universidade do Porto, Porto, ‡Instituto de Biologia Molecular e Celular (IBMC),
Universidade do Porto, Porto, §Centro de Investigacao das Tecnologias da Saude (CITS) – Instituto Politecnico da Saude Norte,
CESPU, Gandra-Paredes, –Servico de Dermatologia, Hospitais da Universidade de Coimbra, Coimbra, ††Instituto de
Farmacologia e Terapeutica Experimental, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, ‡‡Instituto de
Ciencias Biomedicas Abel Salazar (ICBAS), Universidade do Porto, Porto, and §§Centro de Investigacao em Ciencias da Saude
(CICS), Universidade da Beira Interior, Covilha, Portugal
*Correspondence: S Coimbra. E-mail: [email protected]
AbstractBackground Psoriasis vulgaris is associated with overweight ⁄ obesity and with increased C-reactive protein (CRP),
tumour necrosis factor (TNF)-a, interleukin (IL)-6, leptin and resistin levels and decreased adiponectin levels.
Objectives To understand the role ⁄ relationship of adipokines, as well as CRP, in a Portuguese psoriatic population,
by assessing the relationship of their levels with psoriasis severity, defined by Psoriasis Area and Severity Index
(PASI), with obesity, defined by body mass index (BMI), and psoriasis therapy.
Methods A cross-sectional (n = 66) and longitudinal study (before and after 12 weeks of therapy; n = 44) was
performed; 10 patients started topical treatment, 17 narrow-band ultraviolet B (NBUVB) and 17 psolaren associated
with UVA (PUVA).
Results Patients presented significantly higher BMI, leptin, resistin, TNF-a, IL-6 and CRP and significantly lower
adiponectin values. CRP and IL-6 correlated with PASI. Adiponectin and leptin were more altered in patients with
higher BMI. Concerning severity, CRP, resistin and adiponectin were more altered in the severer forms. After
treatment, a significant reduction in PASI, CRP, resistin, TNF-a and IL-6, and a significant rise in adiponectin were
observed. Nonetheless, CRP and adiponectin remained different from those of control. Concerning therapies, topical
therapy was not associated with any significant change, except for TNF-a. After NBUVB, a significant reduction was
observed in TNF-a and in CRP. For PUVA, we observed a significant reduction in TNF-a, IL-6 and CRP, and a
significant increase in adiponectin.
Conclusion In psoriatic patients, increased overweight ⁄ obesity was associated with raised leptin levels and decreased
adiponectin levels. Leptin may contribute to enhance the inflammatory process in overweight ⁄ obese psoriatic patients.
Resistin, IL-6, CRP and adiponectin levels appear to be dependent on psoriasis severity. CRP, together with IL-6,
appears to be a useful marker of psoriasis severity. Both NBUVB and PUVA were effective; however, PUVA results seem
to be more successful. Nonetheless, after NBUVB and PUVA, a low-grade inflammation still persists.
Received: 7 December 2009; Accepted: 5 February 2010
Keywordsadipokines, body mass index, C-reactive protein, psoriasis therapy, psoriasis vulgaris, severity
Conflict of interestThe authors have no financial or other relationships that could lead to conflict of interest; all authors state no conflict
of interest.
FundingThis study was supported by FCT (POCI ⁄ SAU – OBS ⁄ 58600 ⁄ 2004) and by FEDER and by CITS (01 ⁄ 09 ⁄ CITS ⁄ CESPU).
ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
DOI: 10.1111/j.1468-3083.2010.03647.x JEADV
IntroductionPsoriasis vulgaris is associated with several risk factors for cardio-
vascular diseases (CVD) namely, increased oxidative stress,1–3 dis-
lipidaemia,1–8 inflammation,3,9–11 and more recently, with
overweight and obesity.3,12–16 Obesity is a pro-inflammatory state,
usually presenting a low-grade chronic inflammation, with
increased levels of tumour necrosis factor (TNF)-a, C-reactive
protein (CRP) and interleukin (IL)-6 that are positively related to
the body mass index (BMI).17,18
Body mass index may provide, however, a surrogate informa-
tion, as more important than the BMI value is the degree of
intra-abdominal fat visceral obesity.13,19 The adipose tissue has
been recognized as a metabolically active organ, secreting numer-
ous cytokines, referred as adipokines, that are important in the
inflammatory and atherosclerotic processes,20,21 namely, IL-6 and
TNF-a, that are significantly higher in plasma of obese patients.22
These two cytokines mediate the acute phase response.23 CRP, a
positive acute phase protein, is released in response to increased
levels of cytokines, such as IL-6 and TNF-a.
Adiponectin is known to inhibit the inflammatory response and
to protect against metabolic diseases and CVD.21,24 Adiponectin
seems to play an important role in atherogenesis,25 as high levels
are associated with high concentrations of high-density lipoprotein
cholesterol (HDLc), low triglyceride26,27 and oxidized low-density
lipoprotein levels28 and with low BMI values.3Moreover, adipo-
nectin reduces the production of TNF-a, IL-6, interferon-c, the
monocyte cell adhesion, the macrophage phagocytic activity and
increases insulin sensitivity and the repair of damaged vascula-
ture.13,29 Plasma concentrations of adiponectin are decreased in
obese subjects, particularly when obesity is mainly abdominal.
Overweight, obesity and, more recently, psoriasis have been associ-
ated with reduced adiponectin levels.3,30–33
Leptin and resistin may also play an important role in psoriasis
pathogenesis, at least in the obese patients. Serum leptin levels
seem to reflect the body fat mass. High levels of leptin seem to
enhance Th1 immune responses, and increase macrophage activ-
ity, with production of different cytokines, namely, TNF-a.31,34,35
Resistin is expressed by cells in the stromal compartment of the
adipose tissue, particularly, by the macrophages, and by peripheral
monocytes.34 It seems that there is a correlation, although weak,
between BMI and serum resistin levels.36 High resistin levels are
reported to be associated with the atherosclerotic process and, like
leptin, resistin has been shown to increase the expression of several
pro-inflammatory cytokines, including TNF-a and IL-6.37 Hyper-
leptinaemia and hyperresistinaemia have been already reported in
psoriatic patients.31,32,34,35,38,39
There are few studies evaluating simultaneously several circulat-
ing adipokine levels at the exacerbation phase of psoriasis vulgaris,
before starting a treatment and after the therapy. Indeed, some
studies evaluated only the levels of some adipokines at the active
stage of the disease31,32 and others studied only the changes in
those values after UVB therapy.34
We have previously shown3 that the risk changes in lipid profile
seem to be independent of the severity and duration of psoriasis,
although a trend towards lower values of HDLc was observed with
increasing Psoriasis Area and Severity Index (PASI) and that CRP
is enhanced in psoriasis and correlated with its severity. Cytokines,
such as adiponectin, leptin, resistin, IL-6 and TNF-a, apparently
crucial in obesity and inflammatory processes, may play an impor-
tant role in the pathogenesis of psoriasis. A study in psoriasis vul-
garis patients about the blood levels of those cytokines, recognized
as important in obesity and CVD and their relationship with the
severity of the disease, with obesity and with the type of therapy,
may contribute to highlight the role of those cytokines in the path-
ogenesis of psoriasis.
Our aim was to understand the role and the relationship of
adiponectin, leptin, resistin, IL-6, TNF-a and of CRP, in a Portu-
guese psoriatic population, by assessing the relationship of their
circulating levels with psoriasis severity, as defined by PASI and
with obesity, as defined by BMI. We also aimed to study the rela-
tionship of these cytokines with psoriasis therapy efficacy, by
studying psoriatic patients before and after treatment, searching
for a relationship with the commonly used therapies [topical ther-
apy, narrow-band ultraviolet B (NBUVB) and psolaren associated
with UVA (PUVA) therapy].
Materials and methods
Subjects and therapies
The protocol used was approved by the Committee on Ethics of
the University Hospital of Coimbra, and all the 66 psoriasis
vulgaris patients (31 women ⁄ 35 men) gave informed consent to
participate in the study. Psoriasis severity was evaluated by the
PASI Score.40 To diminish subjectivity, PASI was evaluated by the
same dermatologist. A PASI Score below 10 defined psoriasis as
mild, between 10 and 20 as moderate and above 20 as severe.41
Psoriasis was diagnosed between 2 months and 55 years before the
present study. All patients were clinically and analytically studied
in the active phase of the disease, before starting a therapy, and 44
patients were also evaluated after 12 weeks of treatment. Ten
patients (five women ⁄ five men) started topical treatment (calci-
potriol and betamethasone dipropionate, in combination or alter-
natively), 17 patients were treated with NBUVB (10 women ⁄ seven
men) and 17 patients received PUVA therapy (nine women ⁄ eight
men). The type of treatment was decided by the patients’ derma-
tologist, according to disease severity and the clinical and thera-
peutic history of the patients.
The NBUVB irradiation (311 ± 2 nm) was administered using
a Waldmann 7001 K cabin (UVA ⁄ UVB-TL01; Waldmann Medi-
zintechnik, Villigen-Schwenningen, Germany); the initial dose,
dependent on the phototype of the patient, was 0.1–0.3 J ⁄ cm2; an
increasing dose schedule based on an increase of 0.1 J ⁄ cm2 was
used in every session (thrice weekly) until a maximum dose of
2.5 J ⁄ cm2 was reached. UVA irradiation (320–400 nm) was
ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
Adipokine levels in Portuguese psoriatic patients 1387
administered using the same cabin; 2 h earlier, 8-methoxipsoralen
was administered (0.6 mg ⁄ kg body weight); the initial dose was 2–
3 J ⁄ cm2, according to the phototype; an increasing dose schedule
based on an increase of 0.5 J ⁄ cm2 was used in every session (thrice
weekly), until a maximum dose of 12 J ⁄ cm2 was reached. Eyes
and genital were shielded during the irradiation procedures.
The control group included 37 apparently healthy volunteers
(16 females ⁄ 21 males) with normal haematological and biochemi-
cal values that were matched with patients for age (Table 1) and
smoking habits.
Controls and patients presenting other skin diseases, diabetes
mellitus, inflammatory or infectious diseases, cardiovascular, liver
or kidney diseases, were excluded from the study. None of the
patients received any treatment for at least 1 month prior to inclu-
sion. Controls and patients were not under any dietary restriction
or therapy that could interfere with our results.
Assays
Blood sample was collected from non-fasting subjects in tubes
without and with anticoagulant (ethylenediaminetetraacetic acid)
and centrifuged to obtain serum and plasma respectively.
Plasma adiponectin and serum leptin, resistin, IL-6 and TNF-alevels were evaluated using enzyme-immunoassay (Human Adipo-
nectin; R&D Systems, Minneapolis, MN, USA; Leptin ELISA,
Mercodia, Uppsala, Sweden; Human Resistin ELISA, Human IL-6
ELISA and Human TNF-a ELISA; Bender MedSystems, Vienna,
Austria).
Serum CRP levels were evaluated by immunoturbidimetry [CRP
(latex) High-Sensitivity; Roche Diagnostics, Basel, Switzerland].
Statistical analysis
We used the Statistical Package for Social Sciences (SPSS, version 16
for Windows; SPSS, Chicago, IL, USA). To compare control with
patients before starting a therapy (T0), and after treatment (T12),
we used the Mann–Whitney test; to evaluate the differences
between T0 and T12, we used the Wilcoxon test. A P-value <0.05
was considered statistically significant. For analysis of confounding
factors, we used analysis of covariance (ANCOVA) after transforma-
tion of variables. The correlation analysis was performed by calcu-
lating the Spearman coefficient correlation.
ResultsWe observed that in the active stage of the disease (Table 1),
before starting a therapy, patients presented statistically signifi-
cantly higher leptin, resistin, TNF-a, IL-6 and CRP levels and sig-
nificantly lower adiponectin values. Patients, compared with
controls, presented a significantly higher BMI (Table 1). All the
statistical significances observed persisted after adjustment for
BMI (by performing analysis of covariance (ANCOVA), after trans-
formation of variables, using the SPSS).
As leptin values seemed to differ between genders,38 we evalu-
ated leptin for female and male patients and controls. Thus, we
found higher leptin values for female patients (P < 0.001). The
same difference was observed between women and men in control
(P = 0.001). Female patients presented significantly higher leptin
levels than female controls, which persisted after adjustment for
BMI, while male patients showed a trend towards higher values
compared with male controls (Table 1). No differences were
observed between genders for all the other parameters studied,
namely, for adiponectin.
We found that both CRP and IL-6 correlated significantly with
PASI (Fig. 1a–b) and that they correlated with each other
(r = 0.343; P = 0.005); CRP also correlated with resistin
(r = 0.301; P = 0.014). Confirming our previous data,3 adiponec-
tin correlated negatively with BMI (r = )0.379; P = 0.002). BMI
correlated with leptin (r = 0.314; P = 0.010) and this correlation
was also observed when considering female patients (r = 0.485;
P = 0.006), but not male patients.
To analyse our results in accordance with BMI, we divided the
patients into three groups: BMI lower than 25 (n = 19), BMI
Table 1 Characteristics of control and psoriatic patients
Control (n = 37) Psoriatic patients (n = 66) P-value
Leptin (ng ⁄ mL) 10.40 (5.45–16.05) 14.25 (7.58–29.60) 0.018
Men 6.55 (4.20–11.73) 9.30 (5.30–11.80) 0.147
Women 15.30 (8.60–25.30) 24.10 (18.10–43.40) 0.030
Resistin (pg ⁄ mL) 2150 (1688–3075) 3090 (2313–4808) 0.004
Adiponectin (ng ⁄ mL) 6122 (4116–7668) 4104 (3433–5948) <0.001
Tumour necrosis factor-a (pg ⁄ mL) 0.80 (0.40–1.65) 1.85 (0.70–4.80) <0.001
Interleukin-6 (pg ⁄ mL) 0.67 (0.35–1.00) 1.07 (0.66–2.22) <0.001
C-reactive protein (mg ⁄ L) 1.50 (0.60–2.58) 4.50 (1.54–8.91) <0.001
Age (years) 50.0 (35.0–58.0) 42.5 (32.8–57.0) 0.417
Duration of disease (years) – 18.0 (10.0–28.3) –
Body mass index (kg ⁄ m2) 24.06 (22.55–25.04) 27.49 (23.81–29.74) <0.001
Psoriasis Area and Severity Index – 18.8 (10.9–29.9) –
Cytokines and C- reactive protein values. Values expressed as median values (interquartile ranges).
ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
1388 Coimbra et al.
between 25 and 30 (n = 35) and BMI higher than 30 kg ⁄ m2
(n = 12). These three groups presented similar age, PASI and
duration of disease (data not shown). The group with BMI > 30
presented significantly higher leptin values than those presented
by BMI 25–30 and BMI < 25 groups, and higher than those pre-
sented by the control group (Fig. 2a); however, 58% (n = 7) of
the BMI > 30 patients were women. In women (Fig. 2a1), the
BMI < 25 group presented lower values than those of the other
two groups, and these two differed significantly from control
female group. Considering men (Fig. 2a2), BMI > 30 group pre-
sented significantly higher leptin values than those presented by
the group BMI 25–30 and by the control group men. Considering
adiponectin (Fig. 2b), the BMI > 30 group presented significantly
lower values than those presented by the BMI < 25 group, and
lower than those presented by the control group; the adiponectin
in the group 25–30 BMI also presented a significantly lower value
than the control, and a trend towards lower adiponectin levels
than the BMI < 25 group (Fig. 2b). We did not find any statisti-
cally significant difference in the other studied parameters among
the three groups.
According to PASI, 17% of the patients (n = 11) presented mild
psoriasis, 36% (n = 24) presented moderate psoriasis and 47%
(n = 31) presented severe psoriasis. These three groups presented
similar age, BMI and duration of disease (data not shown). Con-
cerning adiponectin, we confirmed our previous results,3 a trend
towards lower values of adiponectin was observed in moderate and
severe forms of psoriasis (Fig. 3a); these forms also presented
significantly lower values as compared with the control group.
Concerning resistin (Fig. 3b), the severe forms presented signifi-
cantly higher values when compared with moderate forms and
with control. The degree of inflammation, suggested by IL-6 and
CRP, showed that IL-6 (Fig. 3c) was significantly higher in the
severe form compared with the mild one and moderate and severe
forms presented higher values than the control group; CRP
(Fig. 3d) was significantly higher in the severe form, when com-
pared with moderate forms of psoriasis, and higher, although not
significant, with the mild form; all psoriasis forms differed signifi-
cantly from control. We did not find any statistically significant
difference in the other studied parameters among the three groups.
The weight of the patients did not change during and after
treatment, as they did not alter their nutritional habits, did not
receive any medication that could interfere with their weight and
did not perform a different physical exercise activity during the
treatment. As expected, a significant decrease in psoriasis severity,
as defined by PASI, was recorded after treatment (Table 2). At
T12 (Table 2), a significant reduction in resistin, TNF-a and IL-6,
and a significant rise in adiponectin were observed. Nonetheless,
adiponectin values remained lower than those of the control. Con-
sidering CRP, a significant reduction was found; yet, CRP values
remained higher from those observed in controls. IL-6 levels
remained higher than those of controls, but significance was lost
after BMI adjustment.
Analysing the results according to the used therapies (Table 3),
we found that topical therapy was not associated with any signifi-
cant change, except for TNF-a that was significantly reduced; at T0
and at T12, TNF-a values were higher than those of the control.
(a) (b)60.00
r = 0.301P = 0.014
r = 0.283P = 0.021
15.00
12.00
9.00
6.00
3.00
0.00
50.00
40.00
30.00
CR
P (
mg/
L)
IL6
(pg/
mL)
20.00
10.00
0.00
0.0 10.0 20.0 30.0 40.0PASI
50.0 60.0 70.0 0.0 10.0 20.0 30.0 40.0PASI
50.0 60.0 70.0
Figure 1 Correlations observed for patients between: (a) C-reactive protein (CRP) and Psoriasis Area and Severity Index (PASI);
(b) interleukin-6 and PASI.
ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
Adipokine levels in Portuguese psoriatic patients 1389
After NBUVB treatment (Table 3), a significant reduction was
observed in TNF-a and in CRP values. The resitin and CRP levels,
at T0, were significantly higher than those of the control and CRP
remained significantly higher.
For PUVA therapy (Table 3), we observed a significant reduc-
tion in TNF-a, IL-6 and CRP, and a significant increase in adipo-
nectin values. The adiponectin, TNF-a, IL-6 and CRP were
significantly different from control at T0 and they maintained
these differences at T12 (except for TNF-a).
DiscussionIn the present study, we demonstrated that Portuguese psoriatic
patients showed an incidence of overweight ⁄ obesity as 71% of
them presented a BMI ‡ 25 kg ⁄ m2, which is in accordance with
previous results42 that found for Caucasians a positive association
between obesity and psoriasis. We also observed, compared with
controls, higher leptin, resistin, TNF-a and IL-6 levels, and lower
adiponectin levels. As visceral adipose tissue is the major source of
adiponectin and leptin, it is possible to conclude that also a high
60.0
50.0
40.0
30.0
Lept
in (
ng/m
L)
20.0
10.0
0.0
10 000
8000
6000
4000
Adi
pone
ctin
(ng
/mL)
2000
0
Control Less 25 25–30BMI (kg/m2)
Above 30
Control < 25 25–30
BMI (kg/m2)> 30
Control < 25 25–30
BMI (kg/m2)> 30
Control Less 25 25–30BMI (kg/m2)
Above 30
P < 0.001
P = 0.018P = 0.052
P = 0.001P = 0.001
P = 0.003P = 0.015
100.0
Females
Males
P = 0.003
P = 0.025
P = 0.006 P = 0.017
P = 0.002
P = 0.002
80.0
60.0
Lept
in (
ng/m
L)Le
ptin
(ng
/mL)
40.0
20.0
0.0
30.0
20.0
10.0
0.0
(a) (a1)
(a2)
(b)
Figure 2 Values for control and for patients, according to body mass index, of: (a) leptin; (b) adiponectin.
ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
1390 Coimbra et al.
incidence of adiposity is observed in the Portuguese psoriatic
patients studied. Obesity is referred as having an adverse effect on
psoriasis,43 which, thus, could be a consequence of the enhance-
ment in the production of resistin, leptin, IL-6 and TNF-a, and of
the decreased synthesis of adiponectin.
Visceral adipose tissue increases the secretion of cytokines, such
as IL-6 and TNF-a, known to mediate the acute phase response.23
CRP is released in response to increased levels of circulating cyto-
kines, namely, IL-6 and TNF-a. Psoriasis, as an inflammatory con-
dition, is also associated with increased levels of CRP, IL-6 and
TNF-a.11,23 Our results are consistent with this, showing raised
levels of CRP, IL-6 and TNF-a. Furthermore, we found a positive
correlation of IL-6 and of CRP values with psoriasis severity, as
defined by PASI, suggesting that they may be useful as markers of
psoriasis severity.
Considering leptin, we found, as expected, and in accordance
with Chen et al. study,38 higher levels in female psoriatic patients.
Leptin serum levels seemed to reflect the body fat mass and consis-
tent with this, we detected for female patients that increased levels
of leptin were correlated with higher BMI. Moreover, the
BMI < 25 female group presented significantly lower values of lep-
tin compared with other two groups with higher BMI (Fig. 2a1);
in men, the BMI > 30 group presented higher values than the
BMI 25–30 and the control group (Fig. 2a2). Thus, hyperleptina-
emia in psoriatic patients seems to be related to patient over-
weight ⁄ obesity. As leptin can promote Th1 immune response and
10 000
8000
6000
4000
Adi
pone
ctin
(ng
/mL)
2000
0
6.00 30.00
25.00
20.00
15.00
10.00
0.00
5.00
5.00
4.00
3.00
IL-6
(pg
/mL)
CR
P (
mg/
L)
2.00
1.00
0.00
Control Under 10
P = 0.339P = 0.002
P = 0.001
P = 0.044
P = 0.076
P = 0.008
P = 0.016P = 0.010 P < 0.001
P = 0.011P < 0.001
P = 0.028P = 0.002
P = 0.019
10–20PASI
Above 20
Control Under 10 10–20PASI
Above 20 Control Under 10 10–20PASI
Above 20
Control Under 10 10–20PASI
Above 20
8000
6000
4000
Res
istin
(pg
/mL)
2000
0
(a) (b)
(c) (d)
Figure 3 Values for control and for patients, according to Psoriasis Area and Severity Index (PASI), of: (a) adiponectin; (b) resistin;(c) interleukin-6; (d) C-reactive protein.
ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
Adipokine levels in Portuguese psoriatic patients 1391
suppress type 2 cytokine production,34 leptin may play an impor-
tant role in psoriasis pathogenesis, at least in women and in over-
weight ⁄ obese psoriatic patients. In relation to adiponectin, lower
values were observed in psoriasis. Pro-inflammatory factors, such
as IL-6 and TNF-a, are known to suppress adiponectin production
by adipose tissue,29 thus the elevation observed in IL-6 and TNF-ain psoriatic patients might cause a decrease in the production of
adiponectin, explaining the lower levels detected. Furthermore,
adiponectin correlated inversely with BMI, and adiponectin values
were lower in the patients with higher BMI (Fig. 2b). Therefore, in
the present study, increasing BMI in psoriatic patients is associated
with higher leptin and lower adiponectin levels.
Increasing psoriasis severity (Fig. 3) was associated with a signif-
icantly higher inflammatory degree, as suggested by CRP and IL-6
values. In our study, we found higher CRP and IL-6 values in the
more severe forms of psoriasis vulgaris (Fig. 3c–d) and, moreover,
a significantly positive correlation between CRP and PASI and IL-
6 and PASI (Fig. 1a–b). CRP in combination with IL-6 values may
therefore be useful in monitoring the evolution of the disease and
the therapeutic response.
Moderate and severe forms of psoriasis presented a trend
towards lower values of adiponectin (Fig. 3a). The lower adipo-
nectin levels found for psoriatic patients seem to be dependent on
the overweight ⁄ obesity of the patient and also appear to be related
to the severity of psoriasis.
Consistent with the study of Johnston et al.34 that found a cor-
relation between resistin and psoriasis severity, we found that resi-
stin levels were higher in the more severe forms (Fig. 3c); thus
resistin levels appear to be associated with the severity of psoriasis.
Resistin, known to induce the production of pro-inflammatory
cytokines, such as IL-6 and TNF-a, that in turn can stimulate
more resistin synthesis,34 presented higher levels in psoriatic
patients, which may suggest a pathogenic role for resistin in psori-
asis, especially related to psoriasis severity.
The analytical changes observed after treatment, linked to a sig-
nificant reduction in PASI, seem to reflect the inhibition of cellular
proliferation and of release of cell activation products, including
pro-inflammatory mediators. In accordance, resistin, adiponectin,
TNF-a, IL-6 and CRP presented a significant improvement after
treatment. However, and independent of the therapy used, it
seems that a low-grade of inflammation persists.
We found no significant change in the analytical parameters
studied with topical therapy, except for TNF-a that was significantly
reduced, confirming that the reduction in the hyperproliferative
process within the lesions is important for inflammatory response.
Actually, this is a common finding in the course of the three thera-
pies. We must refer that, at T0, these patients showed milder psoria-
sis, as defined by PASI, and did not present significant differences
from the control group, except for TNF-a, which, although reduced
after treatment, was still significantly higher than in controls, further
strengthening the role of inflammation in psoriasis.
Patients treated with NBUVB, presenting a PASI higher than
the latter group, showed resistin and CRP values higher than con-
trols. After NBUVB treatment, CRP was still higher than in the
control group; a significant TNF-a and CRP reduction was
observed. The differences observed at T0 seem to be mostly related
to the more severe disease presentation. The therapy was successful
as defined by PASI; however, CRP still presented higher values
than controls, reflecting a persistently increased inflammatory risk.
In PUVA group (T0), with the highest PASI, higher values than
controls were observed for TNF-a, IL-6 and CRP, and lower values
for adiponectin. The reduction in inflammation seems to be more
effective with PUVA, as TNF-a, IL-6, CRP and adiponectin pre-
sented a significant improvement, although sustaining values that
are still different from those of the control (except for TNF-a).
In summary, in psoriatic patients, increased overweight ⁄ obesity
is associated with raised levels of leptin and decreased levels of
adiponectin. Leptin, by promoting activation of T cells, induces
Table 2 Cytokines and C-reactive protein (CRP) values in psoriatic patients, before starting (T0) and after 12th weeks of treatment
(T12), and in a control group
Control (C) (n = 37) Psoriatic patients (n = 44)
Starting (T0) 12th week (T12) P-value (T0 vs. T12)
Leptin (ng ⁄ mL) 10.40 (5.45–16.05) 17.90‡‡ (9.35–30.60) 16.15†† (8.00–29.75) 0.058
Men 6.55 (4.20–11.72) 10.00 (6.60–11.80) 8.10 (6.30–11.20) 0.214
Women 15.30 (8.60–25.30) 24.00 (17.90–46.85) 21.50 (16.50–48.55) 0.216
Resistin (pg ⁄ mL) 2150 (1688–3075) 2991‡ (2090–4690) 2688 (1896–4039) 0.039
Adiponectin (ng ⁄ mL) 6122 (4116–7668) 4097‡‡‡ (3387–6083) 4805†† (3156–6408) 0.011
TNF-a (pg ⁄ mL) 0.80 (0.40–1.65) 1.55‡‡ (0.70–3.35) 1.15 (0.53–1.95) <0.001
IL-6 (pg ⁄ mL) 0.67 (0.35–1.00) 1.09‡‡‡ (0.61–2.14) 1.03*,† (0.37–1.74) 0.010
CRP (mg ⁄ L) 1.50 (0.60–2.58) 3.11‡‡‡ (1.26–6.75) 2.46†† (1.12–5.60) 0.012
PASI – 15.8 (10.4–26.9) 2.9 (1.5–5.1) <0.001
Psoriasis severity was evaluated by Psoriasis Area and Severity Index (PASI). Values expressed as median (interquartile ranges).
TNF-a, tumour necrosis factor-a; IL-6, interleukin-6.
*Loss of significance when adjusted for BMI.‡P(C vs. T0) < 0.05; ‡‡P(C vs. T0) £ 0.01; ‡‡‡P(C vs. T0) £ 0.001; †P(C vs. T12) < 0.05; ††P(C vs. T12) £ 0.01; †††P(C vs. T12) £ 0.001.
ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
1392 Coimbra et al.
production of IL-6 and TNF-a and may contribute to enhance the
inflammatory process in overweight ⁄ obese psoriatic patients. Resi-
stin, IL-6, CRP and also adiponectin levels appear to be dependent
on psoriasis severity. CRP, together with IL-6 values, appears to be
a useful marker of psoriasis severity, allowing the monitorization
of the evolution of the disease and of the therapeutic response.
Both NBUVB and PUVA were effective; however, the reduction in
inflammation seems to be more successful with PUVA. Nonethe-
less, after NBUVB and PUVA effective treatments, a low-grade
inflammatory process still persists.
AcknowledgementsThis study was supported by FCT (POCI ⁄ SAU–OBS ⁄ 58600 ⁄2004) and by FEDER, and by CITS (01 ⁄ 09 ⁄ CITS ⁄ CESPU).
We thank the Departamento de Analises Clınicas of Instituto
Politecnico da Saude Norte. But, they had no role in the
design and conduct of the study, in the collection, analysis and
interpretation of data or in the preparation, review or approval
of the manuscript. We are indebted to FCT (POCI ⁄ SAU – OBS ⁄58600 ⁄ 2004), to FEDER and to CITS (01 ⁄ 09 ⁄ CITS ⁄ CESPU).
References1 Rocha-Pereira P, Santos-Silva A, Rebelo I et al. Dislipidemia and oxida-
tive stress in mild and in severe psoriasis as a risk for cardiovascular
disease. Clin Chim Acta 2001; 303: 33–39.
2 Vanizor Kural B, Orem A, Cimsit G et al. Evaluation of the atherogenic
tendency of lipids and lipoprotein content and their relationships with
oxidant–antioxidant system in patients with psoriasis. Clin Chim Acta
2003; 328: 71–82.
3 Coimbra S, Oliveira H, Reis F et al. Circulating levels of adiponectin,
oxidized LDL and C-reactive protein in Portuguese patients with psori-
asis vulgaris, according to body mass index, severity and duration of
the disease. J Dermatol Sci 2009; 55: 202–204.
4 Pietrzak A, Lecewicz-Torun B. Activity of serum lipase [EC 3.1.1.3] and
the diversity of serum lipid profile in psoriasis. Med Sci Monit 2002; 8:
CR9–CR13.
5 Uyanik BS, Ari Z, Onur E et al. Serum lipids and apolipoproteins in
patients with psoriasis. Clin Chem Lab Med 2002; 40: 65–68.
6 Piskin S, Gurkok F, Ekuklu G et al. Serum lipid levels in psoriasis.
Yonsei Med J 2003; 44: 24–26.
7 Reynoso-von Drateln C, Martinez-Abundis E, Balcazar-Munoz BR et al.
Lipid profile, insulin secretion, and insulin sensitivity in psoriasis. J Am
Acad Dermatol 2003; 48: 882–885.
8 Mallbris L, Granath F, Hamsten A et al. Psoriasis is associated with
lipid abnormalities at the onset of skin disease. J Am Acad Dermatol
2006; 54: 614–621.
9 Rocha-Pereira P, Santos-Silva A, Rebelo I et al. The inflammatory
response in mild and in severe psoriasis. Br J Dermatol 2004; 150: 917–
928.
10 Chodorowska G, Juszkiewicz-Borowiec M, Czelej D et al. Activity of
tumor necrosis factor-alfa (TNF-alpha) and selected acute phase pro-
teins in plasma of psoriatic patients receiving local treatment. Ann Univ
Mariae Curie Sklodowska [Med] 2001; 56: 165–169.
11 Chodorowska G, Wojnowska D, Juszkiewicz-Borowiec M. C-reactive
protein and alpha2-macroglobulin plasma activity in medium-severe
and severe psoriasis. J Eur Acad Dermatol Venereol 2004; 18: 180–183.
12 Sommer DM, Jenisch S, Suchan M et al. Increased prevalence of the
metabolic syndrome in patients with moderate to severe psoriasis. Arch
Dermatol Res 2006; 298: 321–328.
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ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
Adipokine levels in Portuguese psoriatic patients 1393
13 Sterry W, Strober BE, Menter A. Obesity in psoriasis: the metabolic,
clinical and therapeutic implications. Report of an interdisciplinary con-
ference and review. Br J Dermatol 2007; 157: 649–655.
14 Setty AR, Curhan G, Choi HK. Obesity, waist circumference, weight
change, and the risk of psoriasis in women: nurses’ Health Study II.
Arch Intern Med 2007; 167: 1670–1675.
15 Clark L, Lebwohl M. The effect of weight on the efficacy of biologic
therapy in patients with psoriasis. J Am Acad Dermatol 2008; 58: 443–
446.
16 Naldi L, Chatenoud L, Linder D et al. Cigarette smoking, body mass
index, and stressful life events as risk factors for psoriasis: results from
an Italian case-control study. J Invest Dermatol 2005; 125: 61–67.
17 Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in
adipose tissue. J Clin Invest 2003; 112: 1785–1788.
18 Panagiotakos DB, Pitsavos C, Yannakoulia M et al. The implication of
obesity and central fat on markers of chronic inflammation: the
ATTICA study. Atherosclerosis 2005; 183: 308–315.
19 Calabro P, Yeh ET. Intra-abdominal adiposity, inflammation, and car-
diovascular risk: new insight into global cardiometabolic risk. Curr
Hypertens Rep 2008; 10: 32–38.
20 Meier CA, Thalmann S. [White adipose tissue, inflammation and
atherosclerosis]. Bull Acad Natl Med 2007; 191: 897–908.
21 Takemura Y, Walsh K, Ouchi N. Adiponectin and cardiovascular
inflammatory responses. Curr Atheroscler Rep 2007; 9: 238–243.
22 Rondinone CM. Adipocyte-derived hormones, cytokines, and media-
tors. Endocrine 2006; 29: 81–90.
23 Arican O, Aral M, Sasmaz S et al. Serum levels of TNF-alpha, IFN-
gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psori-
asis and correlation with disease severity. Mediators Inflamm 2005;
2005: 273–279.
24 Tilg H, Moschen AR. Role of adiponectin and PBEF ⁄ visfatin as regula-
tors of inflammation: involvement in obesity-associated diseases. Clin
Sci (Lond) 2008; 114: 275–288.
25 Aguilera CM, Gil-Campos M, Canete R et al. Alterations in plasma and
tissue lipids associated with obesity and metabolic syndrome. Clin Sci
(Lond) 2008; 114: 183–193.
26 Rothenbacher D, Brenner H, Marz W et al. Adiponectin, risk of coro-
nary heart disease and correlations with cardiovascular risk markers.
Eur Heart J 2005; 26: 1640–1646.
27 Owecki M, Miczke A, Pupek-Musialik D et al. Serum adiponectin
concentrations and their relationship with plasma lipids in obese
diabetic and non-diabetic Caucasians. Neuro Endocrinol Lett 2007; 28:
901–907.
28 Lautamaki R, Ronnemaa T, Huupponen R et al. Low serum adiponec-
tin is associated with high circulating oxidized low-density lipoprotein
in patients with type 2 diabetes mellitus and coronary artery disease.
Metabolism 2007; 56: 881–886.
29 Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin
Immunol 2005; 115: 911–919.
30 Shibata S, Saeki H, Tada Y et al. Serum high molecular weight adipo-
nectin levels are decreased in psoriasis patients. J Dermatol Sci 2009; 55:
62–63.
31 Takahashi H, Tsuji H, Takahashi I et al. Plasma adiponectin and leptin
levels in Japanese patients with psoriasis. Br J Dermatol 2008; 159:
1207–1208.
32 Takahashi H, Tsuji H, Takahashi I et al. Prevalence of obesity ⁄ adiposity
in Japanese psoriasis patients: adiposity is correlated with the severity of
psoriasis. J Dermatol Sci 2009; 55: 74–76.
33 Kaur S, Zilmer K, Kairane C et al. Clear differences in adiponectin level
and glutathione redox status revealed in obese and normal-weight
patients with psoriasis. Br J Dermatol 2008; 159: 1364–1367.
34 Johnston A, Arnadottir S, Gudjonsson JE et al. Obesity in psoriasis: lep-
tin and resistin as mediators of cutaneous inflammation. Br J Dermatol
2008; 159: 342–350.
35 Wang Y, Chen J, Zhao Y et al. Psoriasis is associated with increased lev-
els of serum leptin. Br J Dermatol 2008; 158: 1134–1135.
36 Utzschneider KM, Carr DB, Tong J et al. Resistin is not associated with
insulin sensitivity or the metabolic syndrome in humans. Diabetologia
2005; 48: 2330–2333.
37 Bokarewa M, Nagaev I, Dahlberg L et al. Resistin, an adipokine with
potent proinflammatory properties. J Immunol 2005; 174: 5789–5795.
38 Chen YJ, Wu CY, Shen JL et al. Psoriasis independently associated with
hyperleptinemia contributing to metabolic syndrome. Arch Dermatol
2008; 144: 1571–1575.
39 Cerman AA, Bozkurt S, Sav A et al. Serum leptin levels, skin leptin and
leptin receptor expression in psoriasis. Br J Dermatol 2008; 159: 820–
826.
40 Frederiksson TPU. Severe psoriasis – oral therapy with a new retinoid.
Dermatologica 1978; 157: 238–244.
41 Naldi L, Gambini D. The clinical spectrum of psoriasis. Clin Dermatol
2007; 25: 510–518.
42 Gisondi P, Tessari G, Conti A et al. Prevalence of metabolic syndrome
in patients with psoriasis: a hospital-based case-control study.
Br J Dermatol 2007; 157: 68–73.
43 Sakai R, Matsui S, Fukushima M et al. Prognostic factor analysis for
plaque psoriasis. Dermatology 2005; 211: 103–106.
ª 2010 The Authors
JEADV 2010, 24, 1386–1394 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
1394 Coimbra et al.