Psoriasis Therapy and Cardiovascular Risk Factors

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Psoriasis Therapy and Cardiovascular Risk FactorsA 12-Week Follow-Up Study

Susana Coimbra,1,2,3 Hugo Oliveira,4 Flavio Reis,5 Luıs Belo,1,2 Susana Rocha,1,2 Alexandre Quintanilha,2,6

Americo Figueiredo,4 Frederico Teixeira,5 Elisabeth Castro,1,2 Petronila Rocha-Pereira2,7 and Alice Santos-Silva1,2

1 Servico de Bioquımica, Faculdade de Farmacia, Universidade do Porto, Porto, Portugal

2 Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal

3 Centro de Investigacao das Tecnologias da Saude (CITS) – Instituto Politecnico da Saude Norte, Gandra-Paredes, Portugal

4 Servico de Dermatologia, Hospitais da Universidade de Coimbra, Coimbra, Portugal

5 Instituto de Farmacologia e Terapeutica Experimental, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal

6 Instituto de Ciencias Biomedicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

7 Centro de Investigacao em Ciencias da Saude (CICS), Universidade da Beira Interior, Covilha, Portugal

Abstract Background: Psoriatic patients present with an increased frequency of cardiovascular events.

Objective: To study the impact of psoriasis duration and therapy on traditional and new cardiovascular risk

factors.

StudyDesign:A longitudinal study performed between 2005 and the first trimester of 2008. Each patient was

followed up for 12 weeks, and was observed before and 3, 6, and 12 weeks after starting therapy.

Setting: Patients attending the Dermatology Service, University Hospital of Coimbra, Coimbra, Portugal

were enrolled.

Subjects: Thirty-four patients with psoriasis vulgaris and 37 healthy volunteers as controls.

Main Outcome Measures: Psoriasis Area and Severity Index (PASI); lipid profile, oxidized low-density

lipoprotein (oxLDL), oxLDL/low-density lipoprotein (LDL), total antioxidant status, lipid peroxidation,

C-reactive protein (CRP), and circulating levels of adiponectin.

Intervention: Ten patients started therapy with topical treatment, 11 with narrow-band UVB radiation

(NB-UVB), and 13 with psolaren plus UVA (PUVA).

Results: Before starting therapy, psoriatic patients presented with several risk changes in their lipid profiles,

and significantly higher CRP, oxLDL, and oxLDL/LDL, and lower adiponectin levels (vs control subjects),

which may further contribute to inflammation and atherogenesis. After treatment of the patients, although

no significant differences were observed in the lipid profile compared with baseline, some changes suggested

that the treatment could somehow alter lipid metabolism, as the reduction in high-density lipoprotein

cholesterol (HDL-C) and apolipoprotein A and the increase in the atherogenic index cholesterol/HDL-C

maintained an even higher significance (as shown by p-values) when compared with the control group.

After topical therapy, there was a significant reduction in thiobarbituric acid reactivity only, suggesting

that the reduction in the hyperproliferative process within the lesions is important for lipid peroxidation.

After NB-UVB therapy, oxLDL/LDL, cholesterol/HDL-C, lipoprotein (a) [Lp(a)], and CRP remained

higher than in the control subjects, reflecting persistent inflammation and atherogenic risk. After PUVA

treatment, there was a significant reduction in Lp(a), associated with an almost significant increase in

apolipoprotein-B (p = 0.054); these changes were not observed after NB-UVB treatment. However, after

PUVA and NB-UVB treatment, CRP and, in the NB-UVB group, oxLDL/LDL were persistently higher

than controls.

Conclusion: Our data show that psoriatic patients present with several lipid profile changes that seem to be

related to the severity of the disease and/or the treatment used. Mild psoriasis patients receiving topical

treatment presented before starting therapywith a lipid profile similar to controls, whereas those undergoing

NB-UVB and PUVA, who had higher PASI scores, presented with several risk factors. Moreover, PUVA

therapy seems to interact in a different way with lipids that might result from an interaction of psoralen with

ORIGINAL RESEARCH ARTICLEAm J Clin Dermatol 2010; 11 (6): 423-432

1175-0561/10/0006-0423/$49.95/0

ª 2010 Adis Data Information BV. All rights reserved.

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plasma lipids, namely Lp(a). Inflammation, a hallmark of psoriasis, also seems to be related to psoriasis

severity. Both NB-UVB and PUVAwere effective, as shown by the reduction in PASI score, as well as in the

oxidative and inflammatory stressmarkers. However, afterNB-UVB and PUVA, a low-grade inflammatory

process still persisted, which might be related to the duration of remission of the disease.

Introduction

Psoriasis vulgaris is a chronic inflammatory skin disease that

affects approximately 2–3% of theCaucasian population,[1] and

it has been estimated that 1.2–1.4% of individuals in the Iberian

region have psoriasis.[2,3] It is characterized by an abnormal

cycle of epidermal development, with epidermal hyperprolif-

eration, altered maturation of skin cells, vascular changes, and

marked inflammation. Psoriatic patients present with an in-

creased incidence of cardiovascular events that has been asso-

ciated with risk factors for cardiovascular disease (CVD),

including dyslipidemia, oxidative stress, leukocyte activation,

and obesity.[4-9] The worsening of psoriasis has been associated

with enhanced oxidative stress and dyslipidemia, suggesting

that the risk for CVD events might be higher in severe psoria-

sis.[5] Despite extensive studies, the importance of serum lipids

and apolipoproteins in the etiology of psoriasis remains con-

troversial, as lipid abnormalities are often already present at the

onset of psoriasis.[10]

A strong association between psoriasis, obesity, and

cardiovascular co-morbidities has been reported.[11] Psoriatic

patients seem to be more prone to overweight/obesity.[12]

The adipocyte is an important source of cytokines, namely

interleukin-6 and tumor necrosis factor-a, which are found in

significantly higher levels in the plasma of obese patients.[13] It

is known that proinflammatory cytokines may promote the

development of obesity-related features, namely dyslipidemia,

insulin resistance, and endothelial dysfunction, which are all

known risk factors for CVD.[14,15] In contrast to other adipo-

kines, adiponectin, which is adipose tissue specific, has been

noted as an important anti-atherogenic and anti-diabetic pro-

tein and as an anti-inflammatory protein.[16] Also, in contrast to

other cytokines, plasma levels of adiponectin are decreased in

obese subjects, particularly when obesity is mainly due to

abdominal obesity. Overweight/obesity, oxidative stress and,

more recently, psoriasis, were associated with reduced levels of

adiponectin.[7,17-22]

In psoriasis, the products of inflammatory cell activation,

namely oxygen metabolites and proteases, may contribute to

further enhance inflammation and oxidative stress, and lead to

oxidative modifications in plasma constituents and cells. Ac-

cording to the oxidative modification hypothesis for athero-

genesis, oxygen metabolites contribute to atherosclerosis de-

velopment and progression, by oxidatively modifying low-

density lipoprotein (LDL). In psoriasis, oxidized LDL (oxLDL),

besides its pro-atherogenic and proinflammatory role,[23] may

accumulate in skin, triggering immune-inflammatory events

that result in progressive skin damage.[24] Although oxLDL

auto-antibodies have been previously determined in psoria-

sis,[23,25] circulating oxLDL has not, as far as we know, been

prospectively evaluated.

C-reactive protein (CRP) is an acute-phase protein that

rapidly increases in the presence of infection or inflammation.

The new high-resolution CRP assays have allowed clinicians to

explore the potential role of CRP levels in predicting and

diagnosing low-grade inflammatory conditions.

There are several cross-sectional studies that have shown that

both traditional (e.g. lipid profile) and new (e.g. CRP, adipo-

nectin, circulating oxLDL) CVD risk factors are altered in pa-

tients with psoriasis.[4-10,20-23,25-29] However, few longitudinal

studies addressing the changes in these risk factors have been per-

formed, and studies have mainly focused on the clinical efficacy

of therapies. Moreover, few studies have focussed on the rela-

tionship between risk factors and psoriasis duration and therapy.

Corbetta et al.[30] in a longitudinal study of ten patients with

psoriasis vulgaris analyzed the effects of only one type of treatment

(low-dose acitretin) on glucose metabolism, lipid profile, and adi-

ponectin and resistin levels. Chodorowska et al.[28,31] prospectively

evaluated CRP and a2-macroglobulin under different therapies,

but not under narrow-band UVB (NB-UVB) treatment.

Topical agents, appropriate wavelengths of UV radiation,

and systemic medication are three therapeutic modalities used

alone or in combination in psoriasis. Topical preparations are

usually sufficient to control mild psoriasis; moderate to severe

psoriasis usually requires phototherapy and photochemother-

apy, or even systemic agents. However, their potential toxicities

should be considered, as psoriasis is a recurrent, long-term

disease.[32] Therefore, in moderate to severe psoriasis a rotation

of therapies is usually advised.

The aim of our longitudinal study in patients with psoriasis

vulgaris was to evaluate the changes in lipid profile, oxidative

stress/inflammation markers, and circulating levels of adipo-

nectin (before treatment, and 3, 6, and 12 weeks after therapy),

and to search for a relationship between these changes and the

424 Coimbra et al.

ª 2010 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2010; 11 (6)

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three employed therapies (topical therapy, NB-UVB, and

psoralen plusUVA [PUVA]) andwith the duration of psoriasis.

Methods

The study protocol was approved by the Committee

on Ethics of the University Hospital of Coimbra, Coimbra,

Portugal, and all patients gave their informed consent.

Subjects and Therapies

Patients who presented with psoriasis vulgaris to the Derm-

atology Service, University Hospital of Coimbra between

2005 and the first trimester of 2008 were enrolled in this study.

The diagnosis was performed by clinical evaluation and con-

firmed by skin biopsies when necessary. Psoriasis severity was

evaluated by the Psoriasis Area and Severity Index (PASI)

score.[33] To diminish subjectivity, the PASI was evaluated by

the same dermatologist in all patients.

The patients received the therapy that the dermatologist con-

sidered themost appropriate, considering the clinical presentation

of psoriasis and the clinical and therapeutic history of the patient.

Topical treatment consisted of calcipotriene (calcipotriol) or

betamethasone dipropionate, or a combination of the two.

NB-UVB irradiation (311– 2nm) was administered using a

Waldmann 7001K cabin (Waldmann GmbH, Schwenningen,

Germany) [UVA/UVB-TL01]. The initial dosewas 0.1–0.3 J/cm2,

depending on the phototype of the patient; this dose was in-

creased by 0.1 J/cm2 each session (three times weekly), until a

maximum dose of 2.5 J/cm2 was reached.

UVA irradiation (320–400 nm) was administered using the

same cabin. Methoxsalen (8-methoxypsoralen) at a dose of

0.6mg/kg bodyweight was administered 2 hours before UVA.

The initial UVA dose was 2–3 J/cm2, according to the patient’s

phototype; this dose was increased by 0.5 J/cm2 each session

(three times weekly), until a maximum dose of 12 J/cm2 was

reached. The eyes and genital areas were shielded during the

irradiation procedures.

A control group of healthy volunteers with normal hema-

tologic and biochemical values was also recruited.

Patients were divided into three therapeutic groups to study

the effect of topical, NB-UVB, and PUVA treatments. Patients

were also divided into three groups according to the time since

the diagnosis of psoriasis, <10 years, 10–20 years, and more

than 20 years, to study the effect of the disease duration. They

were also studied together as one group, to compare the ana-

lytical evaluations with the control group, and to study the

clinical and analytical changes with treatment.

Individuals presenting with other skin diseases, diabetes

mellitus, or inflammatory, infectious, cardiovascular, liver, or

kidney diseases were excluded from the study. None of the

patients had received any treatment for psoriasis for at least

1 month prior to enrolment.

None of the psoriasis patients or control subjects was under

any dietary restrictions or receiving regular therapies that could

interfere with the results, except for some women who were

taking oral contraceptives; however, there was a similar num-

ber of women in the control group (11 of 16) and the psoriasis

group (14 of 18) taking oral contraceptives.

Assays

Each subject was followed up over a period of 12 weeks.

Patients were observed before starting the treatment and at 3, 6,

and 12 weeks after starting therapy. Blood was collected from

non-fasting subjects into tubes with and without anticoagulant

(edetic acid; EDTA), and centrifuged in order to obtain plasma

or serum, respectively.

Triglyceride (TG) levels were measured using an enzymatic

colorimetric method (Triglycerides; Randox Laboratories,

Crumlin, UK). Total cholesterol, high-density lipoprotein cho-

lesterol (HDL-C), and LDL cholesterol (LDL-C) were measured

using enzymatic assays (Cholesterol, Direct HDL-Cholesterol,

and Direct LDL-Cholesterol; Randox Laboratories, Crumlin,

UK). Apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B),

and Lp(a) were measured using immunoturbidimetric assays

(Apolipoprotein A1 and Apolipoprotein B; Randox Labora-

tories, Crumlin, UK, and Lipoprotein (a); Roche Diagnostics,

Basel, Switzerland).

To study the oxidative stress we evaluated the total anti-

oxidant status (TAS) [TAS colorimetric assay; Randox Labora-

tories, Crumlin, UK] and lipid peroxidation (thiobarbituric acid

[TBA] reactivity estimation assay),[34] and calculated the ratio

between these parameters. To measure the importance of oxi-

dative stress in LDL oxidation, we evaluated the level of oxLDL

in plasma (enzyme immunoassay; oxidized LDL ELISA; Mer-

codia, Uppsala, Sweden). The ratio of oxLDL/LDL was calcu-

lated to measure the LDL oxidation value within LDL particles.

CRP (immunoturbidimetry; CRP [latex] HS; Roche Diag-

nostics, Basel, Switzerland) and adiponectin levels were also

evaluated (enzyme immunoassay; Human Adiponectin; R&D

Systems, Minneapolis, MN, USA).

Statistical Analysis

We used the Statistical Package for Social Sciences (SPSS,

version 16 for Windows, Chicago, IL, USA). To compare

Psoriasis Therapy and CV Risk Factors: A Follow-Up Study 425


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control subjects with patients before starting therapy (T0),

and after treatment (T12), we used the unpaired Student’s t-test

and the Mann-Whitney U test; to evaluate the differences

between T0 and T12 we used the paired Student’s t-test and

the Wilcoxon signed-rank test, according to Gaussian dis-

tribution. A p-value of <0.05 was considered statistically sig-

nificant. For adjustment for confounding factors we used

analysis of covariance, after log transformation of variables

(when necessary).

Results

Subjects

A total of 34 patients (18 women and 16 men) with psoriasis

vulgaris were recruited. Psoriasis had been diagnosed from

2 months to 45 years prior to their attending the Dermatology

Service. Median PASI score at baseline was 14.8. Ten patients

started topical treatment (with calcipotriene or betamethasone

dipropionate, or a combination of the two), 11 patients started

NB-UVB therapy, and 13 patients started PUVA therapy.

All patients completed the 12-week treatment period and all

follow-ups.

The control group included 37 healthy volunteers (16women

and 21 men) with normal hematologic and biochemical values.

Psoriasis patients and control subjects had similar ages (43 – 15

vs 47 – 15 years, respectively; p= 0.223) and smoking habits

(24% vs 21% were smokers).

Assay Results

The lipid profiles of the patients at baseline (T0) were dif-

ferent to those of the healthy volunteers, namely significantly

lower HDL-C, LDL-C, Apo-B, and Apo-A levels and sig-

nificantly higher cholesterol/HDL-C, TG, and lipoprotein (a)

[Lp(a)] values; a trend towards higher total cholesterol values

was also observed (table I). Concerning the oxidative stress

markers, patients, compared with control subjects, had sig-

nificantly higher oxLDL levels and oxLDL/LDL ratios. A

trend towards higher TBA and TBA/TAS was also observed.

At T0, patients presented with significantly lower adiponectin

levels and significantly higher CRP levels compared with

Table I. Follow-up for lipid profile, oxidative stress, and inflammatory markers in the control group of healthy volunteers and in psoriatic patients. Psoriasis

severity was evaluated with the Psoriasis Area and Severity Index (PASI). Values are expressed as median [interquartile ranges]

Parameter Control subjects (n = 37) Psoriatic patients (n = 34)

baseline (T0) wk 3 (T3) wk 6 (T6) wk 12 (T12)

Cholesterol (mg/dL) 207.0 [185.0–230.0] 225.0 [183.0–257.8] 217.5 [194.0–256.5] 222.5 [196.5–259.5] 225.5 [197.0–262.5]*a

HDL-C (mg/dL) 56.0 [51.5–62.0] 49.5 [43.0–56.3]* 50.0 [46.3–54.0] 50.5 [46.0–57.0] 50.5 [44.8–55.3]**

Cholesterol/HDL-C ratio 3.71 [3.03–4.25] 4.48 [3.73–5.44]** 4.59 [3.73–4.89] 4.63 [3.88–4.94] 4.57 [4.07–5.31]***

LDL-C (mg/dL) 135.0 [108.5–166.0] 116.5 [91.3–150.8]*a 129.5 [104.0–144.5] 120.0 [103.0–148.0] 126.0 [99.3–161.0]

TG (mg/dL) 98.0 [70.5–146.0] 139.0 [102.8–207.8]** 128.0 [107.5–182.0] 147.0 [100.3–202.3] 143.0 [100.3–206.0]**

Apo-B (mg/dL) 103.0 [77.5–114.0] 90.0 [76.0–98.0]* 86.5 [82.0–103.0] 87.0 [77.0–105.0] 90.5 [76.8–106.8]

Apo-A (mg/dL) 128.0 [118.0–148.0] 122.5 [114.8–129.5]*a 123.0 [116.0–131.3] 126.0 [113.8–134.3] 120.0 [113.5–133.3]*

Lp(a) (mg/dL) 28.30 [15.70–47.60] 41.50 [27.18–71.85]** 39.75 [26.48–67.20] 40.20 [24.85–66.63] 44.00 [21.70–74.00]*

TBA (mmol/L) 1.18 [1.00–1.41] 1.36 [1.20–1.56] 1.22 [1.05–1.52] 1.15 [0.97–1.45] 1.20 [0.97–1.39]---

oxLDL (U/L) 69.0 [60.0–76.5] 75.0 [66.8–88.0]* 70.0 [62.3–86.5] 77.0 [64.0–91.0] 70.0 [62.8–86.3]-

TAS (mmol/L) 1.30 [1.09–1.61] 1.30 [1.21–1.40] 1.25 [1.20–1.40] 1.30 [1.20–1.33] 1.30 [1.20–1.40]

TBA/TAS (·10-3) 0.90 [0.73–1.13] 1.03 [0.88–1. 24] 1.01 [0.80–1.25] 0.88 [0.78–1.18] 0.88 [0.74–1.11]---

oxLDL/LDL ratio 0.05 [0.04–0.06] 0.06 [0.05–0.08]*** 0.06 [0.05–0.07] 0.06 [0.05–0.07] 0.06 [0.05–0.07]**--

Adiponectin (ng/mL) 6122 [4116–7668] 4242 [3451–6212]** 4406 [3098–6040] 4315 [3257–6478] 4864 [3262–6686]*-

CRP (mg/L) 1.50 [0.60–2.58] 4.03 [1.20–8.05]*** 3.31 [1.38–7.23] 2.85 [1.17–8.30] 2.82 [1.15–5.93]**-

PASI 14.8 [9.4–26.1] 7.1 [3.6–16.5] 4.4 [2.8–11.9] 3.1 [1.7–5.6]---

a Loss of significance when adjusted for body mass index.

Apo-A = apolipoprotein A1; Apo-B = apolipoprotein B; CRP = C-reactive protein; HDL-C = high-density lipoprotein cholesterol; LDL = low-density lipoprotein;

LDL-C = LDL cholesterol; Lp(a) = lipoprotein (a); oxLDL = oxidized LDL; TAS = total antioxidant status; TBA = thiobarbituric acid reactivity; TG = triglycerides;* p < 0.05 vs control, ** p £ 0.01 vs control, *** p £ 0.001 vs control; - p £ 0.05 vs T0, -- p £ 0.01 vs T0, --- p £ 0.001 vs T0.

426 Coimbra et al.


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control subjects (table I). Patients presented with a significantly

higher body mass index (BMI) compared with control subjects

(median [interquartile range] of 27.49 [25.10–29.73] vs 24.06

[22.55–25.04] kg/m2; p< 0.001), and 76% of patients presented

with a BMI >25 kg/m2. However, after adjustment for BMI, the

only between-group differences that lost statistical significance

were for LDL-C and Apo-A.

At T12, the patients did not present with significant lipid

profile modifications (vs T0), maintaining the atherogenic lipid

profile. Concerning oxidative stress, a significant reduction

in TBA, TBA/TAS, oxLDL, and oxLDL/LDL was observed

(vs T0), returning to values similar to those of the control

subjects, except for oxLDL/LDL. Considering inflammation, a

significant increase in adiponectin levels and a significant

reduction in CRP were found compared with baseline. How-

ever, both values were still significantly different from those

observed in control subjects: adiponectin remained lower and

CRP remained higher.

When the psoriatic population was analyzed according to

the disease duration (table II), no significant differences were

observed between the groups considered.

Analyzing the results according to the therapies used

(table III), we found that topical therapy was not associated

with any significant change, except for TBA, which was sig-

nificantly reduced.We also observed that, for patients receiving

topical therapy, oxLDL/LDL was higher than the control

group at T0 and T12.

After NB-UVB treatment (table III), no lipid profile changes

were observed. However, this group, which had a higher PASI

score than the topical therapy group, presented at baseline with

several lipid risk factors (vs control), namely lower HDL-C,

and higher cholesterol/HDL-C and Lp(a) values; TG levels

were also higher, but this significance was lost after BMI ad-

justment. At T12, both cholesterol/HDL-C and Lp(a) main-

tained significantly higher values than the control group.

Concerning the other parameters, a significant reduction was

observed in TBA, TBA/TAS, and in CRP values. TBA,

oxLDL/LDL, and CRP values were significantly higher than

the control group at T0, and they remained significantly higher

than the control group, except for TBA, at T12.

Following PUVA therapy (table III), we found that at T12

there were no significant lipid profile changes, except for Lp(a),

which was significantly reduced compared with T0. However,

this group, with the highest PASI score, presented at T0 with

several lipid risk changes compared with the control group,

namely lower HDL-C, and Apo-A, and higher cholesterol/

Table II. Lipid profile, oxidative stress, and inflammatory markers according to the duration of psoriasis. Values are at baseline (T0), and expressed as median

[interquartile ranges]

Parameter Duration of psoriasis

<10 y (n = 11) 10–20 y (n = 11) >20 y (n = 12)

Cholesterol (mg/dL) 242.0 [184.0–283.0] 211.0 [177.0–239.0] 235.0 [185.3–281.0]

HDL-C (mg/dL) 52.0 [42.0–57.0] 46.0 [41.0–50.0] 54.5 [49.0–63.8]

Cholesterol/HDL-C ratio 4.52 [3.32–6.30] 5.14 [3.82–5.44] 4.40 [3.92–4.91]

LDL-C (mg/dL) 113.0 [93.0–153.0] 107.0 [81.0–141.0] 143.0 [95.0–153.8]

TG (mg/dL) 109.0 [97.0–190.0] 175.0 [108.0–222.0] 156.0 [100.3–225.5]

Apo-B (mg/dL) 90.0 [78.0–101.0] 79.0 [67.0–95.0] 92.5 [70.3–101.3]

Apo-A (mg/dL) 125.0 [113.0–133.0] 122.0 [117.0–126.0] 122.5 [114.5–127.8]

Lp(a) (mg/dL) 56.10 [28.80–70.60] 42.50 [27.20–77.90] 37.35 [20.10–67.53]

TBA (mmol/L) 1.28 [1.08–1.56] 1.36 [1.21–1.41] 1.42 [1.26–1.68]

oxLDL (U/L) 80.0 [66.0–93.0] 71.0 [64.0–86.0] 77.5 [67.3–95.5]

TAS (mmol/L) 1.30 [1.20–1.40] 1.30 [1.25–1.40] 1.28 [1.20–1.42]

TBA/TAS (·10-3) 0.98 [0.72–1.30] 1.01 [0.91–1.08] 1.37 [0.86–1.44]

oxLDL/LDL ratio 0.06 [0.05–0.07] 0.06 [0.06–0.08] 0.06 [0.05–0.08]

Adiponectin (ng/mL) 3993 [3480–5925] 4373 [3541–6442] 4242 [2899–7747]

CRP (mg/L) 6.20 [3.73–15.30] 1.79 [1.04–6.80] 3.61 [1.43–7.45]

PASI 16.3 [10.5–26.5] 12.8 [9.5–23.6] 14.8 [8.2–33.4]

Apo-A = apolipoprotein A1; Apo-B = apolipoprotein B; CRP = C-reactive protein; HDL-C = high-density lipoprotein cholesterol; LDL = low-density lipoprotein;

LDL-C = LDL cholesterol; Lp(a) = lipoprotein (a); oxLDL = oxidized LDL; PASI = Psoriasis Area and Severity Index; TAS = total antioxidant status;

TBA = thiobarbituric acid reactivity; TG = triglycerides.



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–283.5

]226.0

[185.5

–271.0

]0.3

00

227.0

[198.0

–260.0

]225.0

[210.0

–265.0

]0.8

29

239.0

[184.7

–252.7

]228.5

[192.0

–246.7

]0.2

94

HD

L-C

(mg/d

L)

46.0

[41.5

–58.5

]**48.0

[40.5

–54.0

]***

0.6

48

52.0

[43.0

–56.0

]*53.0

[44.0

–55.0

]0.4

69

53.5

[49.0

–61.7

]51.5

[46.5

–59.5

]0.0

71

Chole

ste

rol/H

DL-C

4.3

5[3

.76–5.4

4]*

4.7

1[4

.17–5.4

7]**

0.5

52

4.5

9[3

.74–5.5

3]*

4.7

7[4

.07–5.1

4]*

0.7

22

4.2

9[3

.18–5.2

8]

4.1

3[3

.55–5.6

1]

0.2

85

LD

L-C

(mg/d

L)

140.0

[100.0

–154.0

]142.0

[108.0

–173.5

]0.2

54

107.0

[89.0

–141.0

]121.0

[82.0

–161.0

]0.2

12

113.5

[84.7

–153.7

]111.5

[90.2

–149.2

]0.5

00

TG

(mg/d

L)

140.0

[101.5

–195.0

]*a148.0

[124.0

–193.5

]*a0.9

17

119.0

[104.0

–199.0

]*a115.0

[95.0

–177.0

]0.6

57

187.5

[90.2

–278.0

]*a165.0

[71.7

–244.5

]0.0

74

Apo-B

(mg/d

L)

90.0

[78.5

–96.5

]95.0

[80.0

–114.5

]0.0

54

90.0

[67.0

–105.0

]79.0

[74.0

–105.0

]0.6

10

88.5

[63.7

–101.7

]88.5

[71.2

–96.5

]0.5

75

Apo-A

(mg/d

L)

119.0

[104.5

–124.0

]**-

120.0

[108.5

–126.0

]**0.9

44

126.0

[115.0

–131.0

]120.0

[116.0

–133.0

]0.3

27

127.5

[117.7

–148.7

]129.5

[115.0

–147.2

]0.5

07

Lp(a

)(m

g/d

L)

38.6

0[2

0.9

0–70.1

0]

28.2

0[1

5.4

5–65.9

5]

0.0

16

67.1

0[2

8.8

0–78.7

0]**

52.3

0[4

3.7

0–78.4

0]**

0.8

59

40.6

0[2

8.6

7–58.5

0]

37.0

5[2

8.6

7–64.1

7]

0.9

59

TB

A(m

mol/L

)1.2

6[1

.10–1.4

2]

1.2

1[0

.83–1.2

8]

0.0

10

1.3

8[1

.26–1.5

6]*

1.1

8[1

.03–1.4

6]

0.0

16

1.3

4[1

.16–1.6

6]

1.1

3[0

.90–1.5

0]

0.0

46

oxLD

L(U

/L)

77.0

[69.5

–93.0

]**74.0

[67.5

–85.0

]0.0

54

75.0

[64.0

–86.0

]66.0

[55.0

–78.0

]0.3

76

71.5

[55.0

–104.0

]73.5

[58.7

–90.0

]0.2

23

TA

S(m

mol/L

)1.3

5[1

.21–1.4

6]

1.2

5[1

.18–1.4

5]

0.0

44

1.3

0[1

.20–1.3

4]

1.3

0[1

.29–1.3

0]

0.4

16

1.2

8[1

.20–1.4

0]

1.3

3[1

.17–1.4

2]

0.7

33

TB

A/T

AS

(·10

-3)

1.0

0[0

.76–1.1

9]

0.9

3[0

.67–1.1

1]

0.0

29

1.0

6[0

.93–1.1

7]

0.8

8[0

.79–1.0

8]

0.0

32

1.0

4[0

.79–1.4

6]

0.7

9[0

.68–1.3

6]

0.1

44

oxLD

L/L

DL

0.0

6[0

.05–0.0

8]*

0.0

5[0

.05–0.0

7]

0.0

67

0.0

6[0

.06–0.0

8]**

*0.0

6[0

.05–0.0

7]*

0.0

62

0.0

7[0

.06–0.0

8]**

*0.0

6[0

.05–0.0

8]**

0.0

97

Adip

onectin

(ng/m

L)

3578

[3021–4376]**

3969

[3020–5269]*

0.0

33

4563

[3999–6656]

5861

[3889–6741]

0.2

86

4808

[2497–6457]

4907

[2745–6877]

0.2

84

CR

P(m

g/L

)4.1

6[1

.93–14.5

5]**

*2.6

9[1

.35–6.6

0]*

0.0

09

4.2

0[1

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0]**

*4.0

5[1

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6]*

0.0

47

2.1

3[0

.91–5.7

2]

2.9

6[1

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7]

0.2

08

PA

SI

26.5

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19.2

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3.7

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428 Coimbra et al.


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is prohibited.

HDL-C values; at T12, the same parameters maintained an

even higher significance (as shown by p-values) when compared

with the control group. TG levels were higher at T0 and at T12,

but the difference versus controls lost significance after BMI

adjustment. For the other parameters, we observed a significant

reduction in TBA, TAS, TBA/TAS, and CRP values, a signi-

ficant increase in adiponectin levels, and a trend towards lower

oxLDL and oxLDL/LDL values.

Discussion

Studies about lipid values in patients with psoriasis are con-

troversial, and thismay be due to the fact that the patients studied

presented with different forms of psoriasis and underwent dif-

ferent therapies.[4,5,35-39] Moreover, most of these studies were

cross-sectional. Follow-up studies are known to provide more

powerful results than cross-sectional studies. All of our patients

presented with the same type of psoriasis – psoriasis vulgaris –

and were studied before and during the course of a precise ther-

apy; they were analyzed all together and as separate groups ac-

cording to disease duration and type of therapy.

At the University Hospital of Coimbra, PUVA and NB-

UVB treatment is previously scheduled by the patient’s derm-

atologist, and may start at any time during the morning. As a

central hospital, it receives patients from all over the region of

Coimbra, whomay live far from the hospital. Considering these

difficulties, and because there are no substantial differences

between fasting and non-fasting lipid and lipoprotein levels

(except for TG) in the short term,[40] we decided to collect blood

on a non-fasting basis.

In accordance with the literature, our data confirm psoriasis

as a pro-atherogenic condition, as it is associated with dyslipid-

emia, oxidative stress, inflammation, and overweight. This

association with different risk factorsmay underlie the reported

high rates of morbidity and mortality due to CVD events in

psoriasis.[41] It was recently reported[42] that several risk factors

for CVD are amplified by oxLDL (which was present in higher

levels in our psoriasis patients), triggering a chronic inflam-

matory reaction that could result in a more vulnerable plaque,

prone to rupture and thrombosis. Our patients also presented

with higher CRP levels; prospective cohort studies showed

CRP as a reliable measure of underlying systemic inflammation

and a strong predictor of future myocardial infarction and

stroke.[42]

After treatment of the patients, although no significant dif-

ferences were observed in the lipid profile compared with

baseline, some changes suggested that the treatment could

somehow alter lipid metabolism, as the reduction in HDL-C

and apolipoprotein A and the increase in the atherogenic index

cholesterol/HDL-C maintained an even higher significance (as

shown by p-values) when compared with the control group.

The analytical changes observed after treatment, which were

linked to a significant reduction in PASI, seem to reflect the

inhibition of cellular proliferation and of release of cell acti-

vation products, including proinflammatory mediators. As a

result, there was a significant improvement in adiponectin and

CRP levels after treatment. Considering the results, it seems

that inflammation and atherogenic changes still persist after

treatment, independent of the therapy used.

In considering the disease duration, we did not find signif-

icant differences between groups at T0 (or at T12, data not

shown), suggesting that the observed changes were not due to a

cumulative effect of the therapies, but related to psoriasis.

However, we note that the groups were very heterogeneous in

severity and treatment history (data not shown). To clarify the

influence of therapies, at least in the short term (12 weeks), we

analyzed our data in accordance with the therapy used.

We found no significant changes in lipid profiles or in in-

flammatory or oxidative stress markers with topical therapy

except for TBA, which was significantly reduced, suggesting

that the reduction in the hyperproliferative process within the

lesions is very important for lipid peroxidation. Actually, this

was a common finding in the course of all three therapies, which

also showed a trend towards a reduction in oxLDL/LDL. We

must emphasize that at T0 these patients receiving topical

therapy presented with milder psoriasis, as defined by PASI,

and did not have any significant differences in the measured

parameters from the control group, except for the oxLDL/LDL

ratio that, although reduced after treatment, was still sig-

nificantly higher than in controls, further strengthening the role

of oxidative stress in psoriasis. Patients treated with NB-UVB,

who presented with higher PASI scores than the topical therapy

group, already had significant changes in their lipid profiles at

baseline comparedwith controls; TBA, oxLDL/LDL, andCRP

were also higher than controls. After NB-UVB treatment,

cholesterol/HDL-C and Lp(a) levels were still higher than

controls (although Lp(a) levels decreased, this reduction was

not statistically significant); a significant reduction in TBA,

TBA/TAS, and CRP was observed.

The changes observed before starting treatment with NB-

UVB seem to be mostly related to the more severe disease

presentation. The therapy was successful as defined by PASI;

however, values for oxLDL/LDL, cholesterol/HDL-C, Lp(a),

and CRP remained higher than in control subjects, reflecting a

persistent increased inflammation and atherogenic risk.



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In the PUVA group, which had the highest baseline PASI

score, some lipid profile changes at T0 were similar to those

observed for the NB-UVB group, when compared with the

control group, except for a reduced value in Apo-A; higher

values than the control subjects were observed for oxLDL,

oxLDL/LDL, and CRP, and lower values for adiponectin.

PUVA treatment seems to be more effective than NB-UVB in

reducing oxidative stress and oxidative modifications, as shown

by the significant reduction in TBA, TAS, and TBA/TAS; the

reduction in oxLDLand oxLDL/LDLalmost achieved statistical

significance. The reduction in inflammation also seems to be

more effective with PUVA, as there was a significant improve-

ment in CRP and adiponectin levels, although values continued

to be different from the control group.

Lp(a) levels, largely determined genetically, are accepted

as an independent CVD risk factor. Lp(a) levels appear to be

a contributing factor to an increased cardiovascular risk

in psoriatic patients.[43] Lp(a) is composed of Apo-A, which

is covalently bound to LDL via a single disulfide bond on

Apo-B.[44] Recently, it was reported that a reduction in the

availability of Apo-B particles compromises Lp(a) synthesis.[45]

It is noteworthy that in our study, Lp(a) values before treat-

ment were similar to controls for PUVA patients but were

significantly higher than controls for NB-UVB patients; the

Apo-B values are similar for controls and these two groups of

patients. After PUVA treatment there was a significant Lp(a)

reduction, associated with an almost significant Apo-B increase

(p = 0.054); these changes were not observed after NB-UVB

treatment, suggesting that PUVA treatment may interfere in a

different way in Apo-B and/or Lp(a) metabolism. The pro-

posed mechanism of action for PUVA includes the intercala-

tion of psoralen into DNA, forming cross-links between DNA

strands that interact with DNA synthesis, inhibiting cell pro-

liferation. However, to reach the cell target, psoralen has to

penetrate the cell lipid membrane, which is achieved due to its

lipophilicity.When cell membranes are irradiatedwith psoralen

inside them, there is a high likelihood for photochemical cross-

links to be formed between psoralen and the lipid molecules.[46]

It seems reasonable, therefore, to hypothesize that psoralen

may also interact with plasma lipids, inducing modifications in

their molecules and/or in their metabolism that might explain

the observed Lp(a) reduction, which was not observed for NB-

UVB or topical treatment. Because Apo-B levels are not re-

duced by PUVA, and therefore their availability for Lp(a)

synthesis is not compromised, we should also consider the

hypothesis that Lp(a) could be altered in a way that favors

its removal or clearance. Actually, some Lp(a) is cleaved by

metalloproteinases and elastase, resulting in Apo-A fragments

that are then cleared by the kidney.[45,47] High elastase levels in

plasma and in psoriatic lesions, particularly in the severe forms

of psoriasis, have been reported.[48,49] Considering that our

PUVA-treated patients presented with the highest PASI scores,

the interaction with elastase and/or with psoralen should be

considered as an explanation for the Lp(a) reduction.

As mentioned previously, there are several cross-sectional

studies addressing the effect of therapies and the duration of

disease on the lipid profile, inflammation, and oxidative stress;

however, there are only a few follow-up studies, which are more

powerful than cross-sectional studies, concerning those issues.

Corbetta et al.[30] performed a follow-up study addressing the

effects of retinoid treatment on insulin sensitivity, lipid profile,

and circulating adipocytokines, and found that after treatment

patients presented with a decrease in HDL-C levels and no

alterations in adiponectin values. After treatment with topical,

NB-UVB, and PUVA therapies we did not find any changes in

the lipid profile, except that Lp(a) was decreased with PUVA

therapy (which was not evaluated by Corbetta et al.[30]). None

of the treatments that we studied induced a decrease in HDL-C

levels; nonetheless, PUVA therapy was associated with an en-

hancement in adiponectin levels.

CRP was substantially increased in the active stage of the

disease, and a significant decrease was observed for patients re-

ceiving topical and PUVA treatments, as found byChodorowska

et al.[28] in a follow-up study. Moreover, in accordance with our

findings, they reported that CRP levels remained significantly

elevated after treatment when compared with controls.

Conclusion

Our data show that psoriatic patients present with several

lipid profile changes that seem to be related to the severity of the

disease and/or to the treatment used. Mild psoriasis patients

receiving topical treatment presented before starting the ther-

apy with a lipid profile similar to controls, whereas patients

undergoingNB-UVB and PUVA, who had higher PASI scores,

presented with several risk factors. Moreover, PUVA therapy

seems to interact in a different way with lipids that might result

from an interaction of psoralen with plasma lipids, namely

Lp(a). Inflammation, a hallmark of psoriasis, also seems to be

related to psoriasis severity. Both NB-UVB and PUVA were

effective, as shown by the reduction in PASI score, as well as in

oxidative and in inflammatory stress markers. However, after

effective treatment with NB-UVB and PUVA, a low-grade

inflammatory process still persists that might be related to the

duration of remission of psoriasis.

430 Coimbra et al.


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Acknowledgments

This study was supported by FCT (POCI/SAU-OBS/58600/2004) andby FEDER. No sources of funding were used to assist in the preparation

of this study. The authors have no conflicts of interest that are directly

relevant to the content of this study.

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Correspondence: Dr Susana Coimbra and Alice Santos-Silva, PhD, Servico de

Bioquımica, Faculdade de Farmacia, Universidade do Porto, R Anıbal

Cunha 164, 4050-047 Porto, Portugal.

E-mail: [email protected]; [email protected]

432 Coimbra et al.


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Psoriasis Therapy and Cardiovascular Risk Factors