Psoriasis is fundamentally a disease of the immune system in which keratinocyte proliferation and differentiation are a consequence of abnormal immune activity with persistent T-lymphocyte activation 1. Activated T cells release proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukins (ILs), granulocyte-macrophage colony-stimulating factor, and others 2. This chronic T-cell activation results in a persistant cycle of inflammation and formation of psoriatic plaques 3.
Obesity has a profound impact on clinical dermatology and has been implicated in a wide spectrum of dermatologic diseases including psoriasis. It has been reported that a substantial proportion of hospitalized psoriatic patients are either overweight or obese 4. A significant association between obesity and increased morbidity of psoriasis was observed. Obesity leads to a higher risk of developing psoriasis with a poorer long-term clinical outcome of the disease 5. Overweight patients also tend to have worse psoriasis in terms of the proportion of involved skin and the extent of their psoriatic lesions 6. Moreover, it has been reported that both a low-energy diet and gastric bypass surgery result in a favorable outcome for psoriasis 7,8. In adults, subcutaneous fat is almost entirely made up of white adipose tissue, which provides insulation and serves as an energy depot. White adipose tissue is composed of mature triglyceride-filled adipocytes, endothelial cells, fibroblasts, and leukocytes 9. The increase in adipose tissue during weight gain leads to the recruitment of macrophages into the adipose tissue, which is probably mediated by adipocyte-derived chemokines 10. Macrophages are the chief source of adipose tissue-derived TNF-α and are an important component of the nonadipocyte fraction of this tissue, which is also the main source of IL-6 11. These cytokines are abundant in the psoriatic skin, correlate with disease severity, and have established roles in psoriasis pathogenesis 12,13.
Leptin, a polypeptide hormone, is the product of the obese (ob) gene and is synthesized and secreted in the adipose tissue mainly by adipocytes 14. It acts primarily through specific receptors in the hypothalamus. Moreover, leptin receptors (Ob-R) have been located on tissues, including keratinocytes, fibroblasts, endothelial cells, and adipose tissue 15. Leptin decreases appetite and increases energy expenditure. Serum levels of leptin are known to reflect the body fat mass 16. In addition, leptin has been recognized as a cytokine-like hormone that modulates the adaptive immunity by enhancing T-cell survival and stimulating their production of proinflammatory cytokines such as IFN-γ and IL-2 17. It also activates monocytes and macrophages, potentiates the production of TNF-α, IL-6, and IL-9, and directs T-cell differentiation to T-helper 1 (Th1) phenotype 18. Moreover, a study has shown that leptin stimulates keratinocyte proliferation, expresses adhesion molecules, and promotes angiogenesis 19. A relationship between the immunopathogenesis of psoriasis and the proliferative and immunological effects of leptin has also been suggested 20. Recent studies suggested the relationship between elevated serum and tissue leptin levels and psoriasis vulgaris severity in nonobese patients 21,22. More studies are probably needed to further elucidate such a possible relationship.
This study aims at investigating the relationship between psoriasis vulgaris severity and BMI by focusing on the role of leptin, TNF-α, and IL-6 among overweight and obese individuals in patients with psoriasis with variable disease severity.
Patients and methods
This study included 30 patients with chronic psoriasis vulgaris recruited from the Dermatology Outpatient Clinic of Cairo University Hospital. Seventeen patients were either obese or overweight (BMI≥25), whereas the remaining 13 had normal average weight (BMI<25) and served as controls. They were diagnosed clinically on the basis of the presence of characteristic plaque-type psoriatic lesions. Patients with a history of acute or chronic infections, diabetes mellitus, hypertension, or chronic renal, hepatic, or neurological disease were excluded. Patients were excluded if they were known smokers or on a special diet. Patients who had received any topical or systemic immunomodulator therapy for less than 4 weeks before drawing blood samples were excluded to avoid any possible influence on cytokine production. Verbal consent of the patients was obtained and the nature and purpose of the study were clearly explained to the enrolled patients.
All patients were subjected to thorough history taking and clinical examination of the skin. Weight and height of each patient were recorded. BMI was calculated according to the following formula: BMI=weight in kilograms (kg) divided by the square of the height in meters (kg/m2) 23. According to BMI, the study group comprised 10 obese patients (>29 kg/m2) and seven overweight patients (≥25–29 kg/m2), whereas 13 normal weight patients (<25 kg/m2) constituted the control group. The degree of severity of psoriasis was clinically assessed by the psoriasis area and severity index (PASI) score for each patient. Accordingly, mild to moderate psoriasis and severe psoriasis were defined as PASI less than 15 and PASI of at least 15, respectively 24.
Venous blood samples of 10 ml were obtained from all patients following a 12 h fast. Blood was collected in serum separator vacutainers (BD Vacutainer Systems, Plymouth, UK) and left for 20 min at room temperature to clot and then centrifuged for 10 min at 3000 rpm to separate the serum. Serum samples were stored at −70°C until subsequent analysis.
Measurements of leptin, tumor necrosis factor-α, and interleukin-6
Assessment of serum leptin: The quantitative determination of leptin was conducted in serum by an immunometric sandwich enzyme-linked immunosorbant assay (ELISA) technique using a commercially available kit (DRG International Inc., Marburg, Germany) 25.
Assessment of serum TNF-α: Analysis was performed using a TNF-α ELISA Kit (Diaclone Research (URS), Besançon, France, Catalog Number 850.090.096) 26.
Assessment of serum IL-6: Analysis was performed using a commercially available kit (IL-6 ELISA Kit; Diaclone Research (URS), Catalog Number 850.030.096) 27.
Every sample was run in duplicate; measurements differed by less than 10%, and the mean value was calculated and used for statistical analysis.
All data were coded and entered using the program statistical package for social sciences version 15 (SPSS Inc., Chicago, Illinois, USA) under Windows XP. Descriptive data were summarized using mean, SD, and range for quantitative variables and using numbers and percentage for qualitative variables. Intergroup comparisons were made using the Pearson’s χ2-test for qualitative variables and the independent sample t-test for normally quantitative variables. Nonparametrical tests (the Mann–Whitney and Kruskal–Wallis tests) were used for quantitative variables. Pearson’s correlation co-efficient (r) test was used to test for linear correlation between quantitative variables. A P value of less than or equal to 0.05 was considered significant.
The study included 30 patients with chronic psoriasis vulgaris with variable BMI and variable severity. Of these patients, 18 were females (60%) and 12 were males (40%). The statistically descriptive data including age, height, weight, BMI, and PASI score are shown in Tables 1 and 2. According to BMI, the study group consisted of 10 obese patients (33.3%) and seven overweight patients (23.3%), with BMI ranging between 25.7 and 42.5 kg/m2 with a mean of 33.4±5.71 kg/m2, and 13 normal weight patients (43.3%), which were considered as the control group, with BMI ranging between 19 and 24 kg/m2 with a mean of 21.3±2.00 kg/m2. Seventeen patients (56.7%) had mild to moderate psoriasis, whereas 13 patients (43.3%) had severe psoriasis. Among the overweight and obese patients, 76.5% (13/17) had severe psoriasis vulgaris, whereas 23.5% (4/17) had mild to moderate psoriasis vulgaris. All 13 normal weight patients (100%) had mild to moderate psoriasis vulgaris.
Estimation of serum leptin level by enzyme-linked immunosorbant assay techniques
The estimated serum leptin level in overweight and obese psoriatic patients ranged between 18.7 and 104.6 ng/ml, with a mean of 65.29±33.37 ng/ml, whereas in normal weight patients it ranged between 12.8 and 39.8 ng/ml, with a mean of 20.62±7.51 ng/ml; the difference was statistically significant (P<0.001) (Table 3). A statistically significant correlation was found between serum leptin level and each of BMI (Fig. 1), PASI score (Fig. 2), TNF-α (Fig. 3), and IL-6 (Fig. 4) in all patients (r=0.759, P<0.001; r=0.722, P<0.001; r=0.737, P<0.001; r=0.554, P=0.002, respectively).
Estimation of tumor necrosis factor-α and interleukin-6 by enzyme-linked immunosorbant assay technique
The estimated serum TNF-α levels in overweight and obese patients ranged between78.60 and 211.30 pg/ml with a mean of 153.78 ± 43.39 pg/ml, whereas in normal weight patients it ranged between 76.30 and 133.40 pg/ml with a mean of 99.32 ± 15.85 pg/ml. The estimated serum IL-6 levels in overweight and obese patients ranged between 10.60 and 65.15 pg/ml with a mean of 31.10±17.16 pg/ml, whereas in normal weight patients it ranged between 10.60 and 45.20 pg/ml with a mean of 19.54±10.07 pg/ml. Both serum TNF-α and IL-6 were found to be significantly elevated in overweight and obese patients than in normal weight patients, and the difference was statistically significant (P=0.002 and 0.04, respectively) (Table 3). A statistically significant correlation was found between serum TNF-α and both BMI and PASI score (r=0.757, P<0.001 and r=0.718, P<0.001, respectively). Moreover, a statistically significant correlation was found between serum IL-6 and both BMI and PASI score (r=0.374, P=0.042 and r=0.482, P=0.007, respectively).
Recently, a strong association was suggested between psoriasis and BMI 4. In the present study, serum levels of leptin, secreted by adipocytes in adipose tissue 14, TNF-α, and IL-6, produced mainly by macrophages in adipose tissue 11, were investigated by the ELISA technique aiming at further elucidating the relationship between psoriasis vulgaris severity and BMI.
In this study, psoriatic patients were noted to be often overweight or obese. A majority (56.7%) of the studied patients had BMI greater than 25 kg/m2. This finding was in accordance with those of previous studies that found a positive association between obesity and psoriasis 4,6. However, controversy still exists as to whether obesity is a consequence of psoriasis or is a risk factor for its onset. The chronic, low-grade inflammatory state associated with adiposity may explain the increased risk of psoriasis among the obese population. Further, obesity may lead to increased friction and trauma in the waistline and intertriginous areas and worsen psoriasis by the Koebner phenomenon 28. In a case–control study, Naldi et al.29 demonstrated that a moderately increased BMI 26–29 was associated with slightly increased risk for psoriasis, whereas clinical obesity (BMI>29) was associated with at least double the risk for psoriasis as compared with average weight patients. In contrast, a case–control study 30 found that the BMI of psoriatic patients at disease onset less than 1 year did not differ from that of the control group, which supports the theory that obesity is possibly a consequence of psoriasis rather than a cause for it. Similarly, Neimann et al.31 found that the risk of obesity was significantly increased in patients with psoriasis when compared with healthy controls, and this risk was strongly associated with disease severity. Moreover, Herron et al.4 found that obesity was more prevalent in psoriatic patients than in the general population (34 vs. 18%, respectively). Therefore, they suggested that obesity may be a consequence of psoriasis. In this study we could clearly demonstrate the strong association between the degree of obesity and psoriasis severity. However, from our results, the etiological sequence is still open to question.
Results of the present study showed that the mean serum leptin level in overweight and obese patients was higher than in normal weight patients and that the difference was statistically significant (P<0.001). This result could be explained in view of previous studies that demonstrated that leptin plays an important role in chronic immune-mediated inflammatory diseases including psoriasis and obesity 17,29. Leptin, which is known to control food intake, bodyweight, and fat stores, has been shown to have an immunoregulatory effect as well 16. Leptin has been reported to modulate T-helper cell activity, activate monocytes and macrophages, potentiate the production of proinflammatory cytokines, and direct T-cell differentiation to Th1 phenotype 17. This suggested its important role in the majority of T cells involved in psoriasis belonging to the Th1 subset, which have the ability to produce the inflammatory cytokines upon activation.
When the serum leptin level was studied according to the severity of the disease, it was found to be significantly higher in overweight and obese patients with severe psoriasis than in normal weight patients with mild to moderate psoriasis (P<0.001). This appears to be in agreement with a previous study 32 that demonstrated that overweight and obese patients with severe psoriasis were associated with raised leptin levels, which suggested enhancement of Th1 immune responses and increased macrophage activity, with subsequent production of various cytokines. It has been proposed that hyperleptinemia in psoriatic patients is associated with an increased risk for developing metabolic syndrome, which may link chronic inflammation of psoriasis with metabolic disturbances 33.
The present study demonstrates that the mean serum TNF-α and IL-6 levels in overweight and obese patients were higher than those of normal weight patients, and the differences were statistically significant (P=0.002 and 0.04, respectively). Moreover, when serum TNF-α and IL-6 levels were considered according to the disease severity, they were found to be significantly higher in overweight and obese patients with severe psoriasis than in normal weight patients with mild to moderate psoriasis (P<0.001, P=0.007). Adipose tissue had been recognized as a metabolically active endocrine organ secreting numerous cytokines that are referred to as adipokines considered to be important in the inflammatory process 12. Obesity induces overproduction of the inflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α) in adipose tissue 13. The serum levels of TNF-α, IL-6, and IL-8 were reported to be increased in psoriasis and to be associated with disease severity 5.
These findings may be explained by the well-known fact that the expansion of adipose tissue during weight gain leads to the recruitment of macrophages into the adipose tissue, and this is probably mediated by adipocyte-derived chemokines 10. Macrophages are the chief source of adipose tissue-derived TNF-α and are an important component of the nonadipocyte fraction of this tissue, which is also the main source of IL-6 and CXCL8 34. These cytokines are abundant in psoriasis skin, their levels in suction blister fluids of involved psoriasis skin correlate with disease severity, and both have established roles in psoriasis pathogenesis 12,13.
It may be of interest that TNF-α blocking agents that target the proinflammatory pathways involved in both psoriasis and obesity have proven their benefit in the treatment of these entities 35.
In conclusion, the results of this study strongly support the positive relationship between BMI and severity of psoriasis vulgaris as evidenced by the clearly demonstrated correlation between both serum leptin and TNF-α with the BMI and PASI score. It can also be concluded that leptin may contribute to the pathogenesis of psoriasis, possibly by increasing the production of TNF-α and IL-6, the inflammatory infiltrates in overweight and obese psoriatic patients.
Conflicts of interest
There are no conflicts of interest.
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