Psoriasis is one of the most prevalent chronic inflammatory skin diseases, affecting 1-3% of the White population and causes significant impairment of quality of life 1. Although the precise patho-mechanism of psoriasis remains unknown, various cytokines and growth factors are involved 2. Tumor necrosis factor α (TNF-α) is an inflammatory cytokine, and studies indicate that it plays a critical role in the development of psoriasis 3.
Psoriasis is associated with increased risks of cardiovascular disease, metabolic syndrome (MS), diabetes and obesity. Several population-based studies have suggested that patients having psoriasis have an increased risk of MS 4.
It is estimated that ∼20–25% of the world’s adult population has MS 5. The most widely accepted criteria for MS definition have been issued by the Adult Treatment Panel III, which defines it as the presence of at least three of the following conditions: abdominal obesity [waist circumference (WC) >102 cm (40 in men) and >88 cm (35 in women)]; elevated serum triglycerides (TG) [>150 mg/dl (1.7 mmol/l) or under treatment]; low high-density lipoproteins (HDL) cholesterol [men <40 mg/dl (1 mmol/l) and women <50 mg/dl (1.3 mmol/l) or under treatment]; elevated blood pressure (>130/85 mmHg or under treatment); and elevated fasting glucose (>110 mg/dl or under treatment) 6.
Obesity provides a chronic level of low-grade inflammation by overproduction of inflammatory cytokines such as TNF-α, interleukin (IL)-1, IL-6 and IL-8 in adipose tissue and this may contribute to the pathogenesis of psoriasis and account for its severity 7. On the contrary, chronic and systemic T helper (Th)-1 and Th-17 mediated inflammation of psoriasis is characterized by increased levels of proinflammatory cytokines, such as TNF-α and IL-6. This inflammation promotes epidermal hyperplasia in psoriasis, antagonizes insulin signalling, alters adipokine expression, and mediates insulin resistance and obesity 8.
TNF-α promotes the development of Th-1 and Th-17 cells. These T cells secrete mediators that contribute to the vascular and epidermal changes of psoriasis 9. It acts by (a) increasing cytokines and chemokines release and by (b) increasing the expression of intercellular adhesion molecule-1 in the keratinocytes and vascular cell adhesion protein-1 in the endothelial cells, with consequent activation of the inflammatory process 10.
Adiponectin, also known as adipocyte complement-related protein-30 kDa, is secreted majorly by adipose tissue and has important metabolic effects 11. Considering the fact that adiponectin is related to MS, which can coexist with psoriasis, it may play a role in pathophysiological processes in psoriasis 12.
Adiponectin decreases with increasing obesity. This is in contrast to most other adipocytokines, whose levels increase in obesity in proportion to an increased total body fat mass. It is possible that although adiponectin expression is activated during adipogenesis, a feedback inhibition on its production may occur during the development of obesity 13,14.
Adiponectin inhibits both TNF-α-induced monocyte activation and adhesion molecule vascular cell adhesion protein-1, E-selectin and intercellular adhesion molecule-1 surface expression on endothelial cells and inhibits toll-like receptor-mediated NF-κB activation in macrophages 15. Adiponectin also inhibits the production of reactive oxygen species in human neutrophils and stimulates macrophage production of the anti-inflammatory cytokine IL-10 12.
Although previous reports indicated that adiponectin suppresses the inflammatory responses induced by TNF-α, others reported that adiponectin itself activates NF-κB and promotes inflammatory cytokines production. Jung et al.16 emphasized the role of adiponectin in the immune system and revealed that it has immune-regulatory ability by activating dendritic cells through enhancement of the costimulatory molecules, as well as by release of proinflammatory cytokines, resulting in Th-1 and Th-17 responses.
It has been shown that adiponectin plays a role in promoting the differentiation of naive T-cells into Th-17 cells in vitro. IL-17, the major cytokine of Th-17, induces the production of IL-1 and TNF-α in macrophages and fibroblasts. IL-17 also blocks the function of T regulatory cells and Th-2 cells 17.
The aim of this work was to compare the levels of TNF-α and adiponectin in patients with psoriasis versus controls, with and without MS, and to assess the changes of these markers after treatment of psoriasis.
Patients and methods
This case–control study included 100 participants; 50 patients with plaque psoriasis and 50 age-matched and sex-matched nonpsoriatic volunteers as controls. They were recruited from the dermatology clinic in Ain Shams University Hospital. Half of the patients and controls showed MS criteria, as agreed in our protocol.
We included patients with variable severities of chronic plaque psoriasis; none of them received systemic or topical treatment of psoriasis for at least 2 months before the start of this study. The patients were divided into mild group with PASI less than 10 and moderate to severe group with PASI of at least 10 18. These patients were treated till their initial PASI scores decreased to 50% (PASI 50). The modalities of treatment were variable like emollients, betamethasone valerate 1 mg/g cream and ointment, phototherapy and systemic agents like methotrexate, cyclosporine and acitretin. Treatment choice was according to the disease severity, the general condition and the history of previous medications in each patient.
Exclusion criteria involved other variants of psoriasis, pregnancy, lactation, known autoimmune diseases, malignancy, local and systemic infection or inflammation, and those taking drugs affecting serum TNF-α and adiponectin levels such as systemic corticosteroids, anti-inflammatory drugs, lipid-lowering agents, antipsychotics and antidepressants.
The Research Ethics Committee of Ain Shams Faculty of Medicine approved the study protocol, and informed written consents were signed by all the participants before the onset of the study. The diagnosis of psoriasis vulgaris was based on clinical examination. All the patients and controls in the study were subjected to full history taking, general and dermatological examination, and measurement of body height, weight, WC/hip circumference ratios, blood pressure and BMI.
Venous blood samples (5 ml) were collected from the controls and patients (before and after treatment). The samples were withdrawn between 07.00 and 08.00 a.m. after 20 min of supine rest, following overnight fasting period of 12 h, and allowed to clot for 30 min. Samples were then centrifuged, and sera were stored in aliquots at −20°C until assayed. Total plasma cholesterol, TG and HDL cholesterol were measured using an enzymatic calorimetric method with the Olympus AU 600 autoanalyser and reagents from Olympus Diagnostics GmbH (Hamburg, Germany). Low-density lipoprotein cholesterol levels were calculated using the Friedewald formula. Fasting blood sugar (FBS) was measured with the glucose oxidase method.
Serum TNF-α and adiponectin values were measured using sandwich enzyme-linked immunosorbent assay (ELISA) technique. The procedure was done according to the manufacturer instruction as supplied with kit from Assaypro LLC Human TNF-α ELISA Kit (Assaypro Biotechnology Company, Saint Charles, Missouri, USA) and Assaypro LLC Human Adiponectin ELISA Kit (Assaypro Biotechnology Company, Saint Charles, Missouri, USA).
The collected data were revised, coded, tabulated and introduced to a PC using the statistical package for the social sciences (SPSS 15.0.1 for Windows; SPSS Inc., Chicago, Illinois, USA). Qualitative data were presented as number and percentages whereas quantitative data with parametric distribution were presented as mean, SD and ranges and in case of nonparametric quantitative data as median and interquartile range. The comparison between two groups with qualitative data were done by using χ2 and/or Fisher exact test. Fisher exact test was used instead of χ2-test when the expected count in any cell was found to be less than 5. The comparison between two groups regarding quantitative data with parametric distribution was done by using independent t-test, whereas nonparametric data were compared using Mann–Whitney U-test. Spearman correlation coefficients (r) were used to assess the relation between two quantitative parameters in the same group. The confidence interval was set to 95% and the margin of error accepted was set to 5%. So P-value less than 0.05 was considered statistically significant.
This study included 50 patients with plaque psoriasis (24 males and 26 females) and 50 age-matched and sex-matched volunteers (23 males and 27 females) as controls. Patients’ ages ranged between 25 and 65 year with mean±SD of 41.24±14.41 year, whereas the age of controls ranged between 26 and 60 year with mean±SD of 39.50±9.18 years. Patients and controls were randomly recruited to include 50% with MS and 50% without MS, as agreed in our protocol. Cases and controls were statistically matching regarding age, sex, WC, FBS, TG, and systolic and diastolic blood pressures; however, cases showed statistically significant increase in BMI in comparison with controls. BMI of patients ranged between 19.8 and 42.9 kg/m2, with mean of 32.58±6.17 kg/m2 and the controls ranged between 20.8 and 40 kg/m2 with mean of 29.84±5.38 kg/m2.
Duration of psoriasis in the patients ranged between 0.5 and 40 year with a mean of 10.51±10.25. PASI scores ranged between 2.2 and 53.5, with a mean of 13.11±10.80. A total of 30 (60%) patients showed mild psoriasis with their PASI score less than 10, and 20 (40%) patients experienced moderate to severe disease with their PASI score of at least 10.
In this study, the median and interquartile serum levels of TNF-α and adiponectin showed statistically significant higher values in patients with psoriasis vulgaris before treatment [0.15 (0.1–0.40) ng/ml and 19 (10–25) ng/ml, respectively] in comparison with the controls [0.02 (0.01–0.15) ng/ml and 2.2 (1.7–2.5) ng/ml, respectively] as shown in Table 1.
Comparison between MS positive controls and MS negative controls regarding serum TNF-α and adiponectin levels showed statistically highly significant increased levels of serum TNF-α and decreased levels of serum adiponectin in MS positive controls (0.11±0.10 and 1.48±0.52 ng/ml, respectively) in comparison with MS negative controls (0.02±0.03 and 2.43±0.39 ng/ml, respectively). We also got the same results in the patients, and there was a statistically significant increased TNF-α and decreased adiponectin levels in MS positive patients (0.34±0.27 and 15.35±8.13 ng/ml, respectively) in comparison with MS negative patients (0.19 ±0.16 and 20.15±7.97 ng/ml, respectively). These values are shown in Figs. 1 and 2.
No significant statistical correlation was found between severity of psoriasis, represented with PASI score, and TNF-α (r=0.028 and P=0.848) on one side, or between PASI score and adiponectin on the other side (r=0.247 and P=0.083).
There were statistically significant positive correlations between patients’ serum TNF-α on one side, and each of the following variables: age (r=0.399 and P=0.004), FBS (r=0.412 and P=0.011), WC (r=0.349 and P=0.013) and BMI (r=0.358 and P=0.011), on the other side. On the contrary, there was a negative correlation between TNF-α and HDL, but it was not statistically significant (r=−0.195 and P=0.254). There was a statistically nonsignificant difference in the mean readings of serum TNF-α between male (0.32±0.29) and female (0.21±0.16) patients (P=0.099).
Regarding the mean values of the patients’ serum adiponectin, it showed, statistically significant, positive correlations with disease duration (P<0.01) and FBS (P<0.01), and negative correlation with BMI (P<0.01). There was a statistically significant increase in male (21.98±7.75 ng/ml) versus female (14.32±7.01 ng/ml) patients (P=0.001).
After receiving different modalities of treatment of psoriasis till their PASI scores decreased to half their initial values (PASI 50), the patients in this study showed statistically significant decrease in the mean readings of TNF-α and adiponectin , as shown in Table 2.
There was no statistical significant difference in the percent of decrease of mean values of serum TNF-α and adiponectin among the patients, after treatment, whatever the used treatment modality and whether or not they had MS.
An association between insulin resistance and psoriasis has been detected, suggesting that MS is closely related to the pathogenesis of psoriasis 3. Psoriasis and obesity share similar mediators of inflammation, called adipokines, which are TNF-α, adiponectin and IL-6 19,20.
This case–control study showed statistically significant higher BMI in patients when compared with controls. There was also a statistically significant higher serum level of TNF-α and adiponectin in patients versus controls. The results of higher levels of TNF-α in patients with psoriasis agree with Coimbra et al.21 who measured TNF-α levels in Portuguese patients with psoriasis vulgaris and Nakajima et al.22 who compared the TNF-α levels in psoriasis patients versus weight- and sex-matched controls. In the current study, there was nonsignificant positive correlation between TNF-α and PASI score, and this agrees with Abdel-Hamid et al.23 who assessed the level of TNF-α in 60 Egyptian patients with psoriasis in whom there were higher TNF-α levels in comparison with the healthy controls, with a statistically nonsignificant positive correlation between the levels of TNF-α and PASI score.
Our results regarding TNF-α values in controls with and without MS are in agreement with Litvinova et al.24 and Thomas et al.25 who compared TNF-α in MS positive persons with MS negative ones and found elevated TNF-α levels in the former group rather than the latter.
In this study, patients with psoriasis showed statistically highly significant increase in TNF-α levels in MS positive rather than MS negative ones. Patients’ mean value of TNF-α showed a statistically significant positive correlation with FBS, BMI, and their age. Abdel-hamid et al.23 pointed also to the positive correlation between TNF-α and psoriasis patients’ age, although the correlation was not statistically significant.
The current study showed statistically highly significant increase in serum adiponectin in patients when compared with controls; this agrees with Gerdes et al.26 who found higher levels of serum adiponectin in patients with plaque psoriasis in comparison with age- and sex-matched controls. Kaur et al.27 demonstrated that plasma concentration of adiponectin in normal weight patients with chronic plaque psoriasis was more than twice the levels in healthy normal weight controls.
However, our results are not in agreement with Takahashi et al.28 who assessed the plasma levels of adiponectin in Japanese patients with psoriasis in comparison with healthy individuals, and Shibata et al.29 who detected significantly lower adiponectin levels in patients with psoriasis compared with controls. Nakajima et al.22 measured the level of adiponectin in patients with psoriasis versus controls and found no significant differences in serum adiponectin levels, although the levels were higher in patients with psoriasis.
We do not have an exact explanation to the wide range of difference between the studies that measured adiponectin in patients with psoriasis versus controls. However, it could be owing to several causes; some studies did not mention if they involved patients with psoriasis and controls with MS or not in their studies, whereas we included patients and controls with and without MS to assess the role of MS in addition to the effect of psoriasis, or there may be a wide range of variation among different ethnic groups. Duration of the disease also may play a role, as we found in this study that there is a significant positive correlation between the serum adiponectin levels and the disease duration, which indicates that with chronicity of psoriasis, the level of adiponectin increases. This may suppose that maintained inflammation is associated with a loss of the protective anti-inflammatory mechanism of adiponectin.
This suggestion agrees with Baran et al.30 who measured adiponectin levels in patients with chronic plaque psoriasis with a range of disease duration from 7 months to 55 years and stated that there was a positive correlation between adiponectin levels and the duration of psoriasis, although this correlation was not statistically significant.
Our study showed lower levels of serum adiponectin in MS positive controls in comparison with the MS negative controls, and this result is in line with Shafiee et al.31 who compared adiponectin levels in (nonpsoriatic) MS positive Iranian persons versus age-matched and sex-matched MS negative healthy individuals and showed lower levels of adiponectin in the MS positive versus the MS negative persons.
This study shows that there is a statistically significant negative correlation between adiponectin and BMI of the patients with psoriasis, and this also agrees with the results of Baran et al.30 who showed a negative correlation between adiponectin and BMI, although their results were statistically nonsignificant. Coimbra et al.21 achieved similar results. They found that the concentration of circulating adiponectin was significantly lower in patients with psoriasis with BMI more than 30 compared with patients with psoriasis with BMI less than 25, which indicates the role of obesity effect on serum adiponectin.
The current study shows a post-treatment statistically significant decrease of serum TNF-α and adiponectin levels irrespective of the used treatment modality. These results agree with Kondelkova et al.32 who showed that the levels of adiponectin decreased after (Goeckerman) therapy for 10–19 days and the difference was highly significant.
TNF-α and adiponectin play a major role in the link between psoriasis and MS. Serum levels of TNF-α and adiponectin are higher in patients with psoriasis in comparison with controls, and their levels decrease with treatment of psoriasis, whatever the used treatment modality. The serum levels of adiponectin are lower in MS positive than MS negative patients with psoriasis, whereas TNF-α levels are higher in MS positive versus MS negative patients with psoriasis.
No financial support.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2018 Egyptian Women's Dermatologic Society
adiponectin; metabolic syndrome; psoriasis; tumor necrosis factor α