|Year : 2017 | Volume
| Issue : 2 | Page : 69-75
Role of high-mobility group box-1 as a marker of disease severity and diagnosis of metabolic syndrome in psoriatic patients
Mahmoud N Kamel1, Eman M Hassan1, Mona M Sobhy2, Maryam M.I. El Sayes1
1 Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||05-Mar-2017|
|Date of Acceptance||21-May-2017|
|Date of Web Publication||4-Aug-2017|
Eman M Hassan
Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Alexandria University, Elazarita - 21521, Alexandria
Source of Support: None, Conflict of Interest: None
Psoriasis is a chronic inflammatory disease with systemic immunological disturbance. Suggested pathophysiology linking psoriasis and metabolic syndrome involves overlapping inflammatory and genetic pathways. High-mobility group box-1 (HMGB1) is a nuclear transcriptional protein, which is released extracellularly to function as a proinflammatory mediator. Elevated HMGB1 was reported in autoimmune and inflammatory disorders. However, its role in inflammatory dermatological conditions such as psoriasis is under investigation.
The goals of this study were to evaluate the serum level of HMGB1 in psoriasis patients and its relation to disease severity. In addition, the study aimed to compare its level between psoriatic patients with and without metabolic syndrome with assessment of its prognostic potential to diagnose metabolic syndrome in the psoriatic population.
Patients and methods
Fifty psoriatic patients and 20 healthy controls were included. Serum level of HMGB1 was measured using enzyme-linked immunosorbent assay and its relation to disease severity and duration using psoriasis area and severity index. Metabolic syndrome was identified among psoriatic patients, using International Diabetes Foundation. Receiver operating characteristic analysis was employed to calculate the area under the curve for HMGB1 to find the best cutoff value capable of diagnosis of metabolic syndrome in psoriasis.
Significantly higher HMGB1 level in psoriasis patients than in controls was detected (P=0.037) and was correlated with disease severity. A higher HMGB1 level among psoriatic patients with metabolic syndrome than that among patients without metabolic syndrome was reported (P=0.007). At receiver operating characteristic analysis, HMGB1 showed 80% sensitivity and 50.43% specificity in detecting metabolic syndrome in psoriasis.
HMGB1 may be considered as a useful marker of psoriasis severity in addition to its predicting potential for metabolic syndrome in psoriatic patients.
Keywords: high-mobility group box-1, metabolic syndrome, psoriasis
|How to cite this article:|
Kamel MN, Hassan EM, Sobhy MM, El Sayes MM. Role of high-mobility group box-1 as a marker of disease severity and diagnosis of metabolic syndrome in psoriatic patients. Egypt J Dermatol Venerol 2017;37:69-75
|How to cite this URL:|
Kamel MN, Hassan EM, Sobhy MM, El Sayes MM. Role of high-mobility group box-1 as a marker of disease severity and diagnosis of metabolic syndrome in psoriatic patients. Egypt J Dermatol Venerol [serial online] 2017 [cited 2018 Feb 23];37:69-75. Available from: http://www.ejdv.eg.net/text.asp?2017/37/2/69/212224
| Introduction|| |
Psoriasis is a multifactorial disease with a genetic background. Its autoimmune process and the action of autoreactive T cells are still of questionable role ,.
The proposed molecular nature of psoriasis assigns specific importance to an interaction between both innate and acquired immunity. First, special epidermal and dermal dendritic cells are activated and produce the messenger mediators, tumor necrosis factor α (TNF-α) and interleukin 23, which, in turn, stimulate T helper (Th) 1 and Th17 cells. T cell mediators can influence both the epidermal and vascular picture in psoriasis .
Of special concern, diseases that share a similarity in immune pathophysiology with psoriasis have been investigated. It was suggested that patients with psoriasis carry an increased risk of myocardial infarction and atherosclerotic conditions. Similarly, metabolic syndrome, which is a clustering of cardiovascular risk factors, like obesity, hypertension, dyslipidemia, and insulin resistance, is associated with chronic inflammation .
The suggested pathophysiology linking psoriasis and metabolic syndrome may indicate overlapping inflammatory pathways including chronic Th-1-mediated and Th-17-mediated inflammation with dysregulation of cytokines, and genetic susceptibility ,.
High-mobility group box-1 (HMGB1) was detected as a nuclear protein with rapid migration in electrophoretic gels, a character leading to its nomenclature. It is the first identified member of the HMGB family, containing HMGB1, 2, and 3 ,. Under physiological conditions, HMGB1 is located in the nucleus where it is associated as a structural part with chromatin and specific cotranscriptional factors to help the programming of nuclear proteins and assist in replication of DNA ,.Once cell activation or injury or death occurs, HMGB1 can translocate outside of the cell , and becomes a proinflammatory mediator by binding to some cell surface receptors of immune cells, acting as a damage-associated molecular pattern to activate innate immune mechanism ,.
HMGB1 stands at the crossroad between innate and acquired immunity. HMGB1 can be secreted by leukocytes which, in turn, stimulate dendritic cells, cause their maturation and lymph node chemokines response, and thus their capability to reach the related lymph nodes. It was noted that HMGB1 has direct action on T cells, can modulate the regulatory T cells’/Th17 balance and development of autoreactive B cells . HMGB1 has been suggested to influence the pathogenesis of some inflammatory and autoimmune disorders . A novel suggestion is of increased secretion of HMGB1 from the adipose tissue that engages Toll-like receptors contributing to the proinflammatory state and insulin resistance of metabolic syndrome .
The role of HMGB1 in psoriasis is under investigation. It is reported as a newly translocated extracellular mediator in the disease process with special relation to disease severity. However, the present study tried to assess the serum level of HMGB1 in psoriatic patients compared with that in healthy subjects and its role to assess disease severity as well as its relation to patient’s age, sex, and disease duration. In addition, the study aimed to compare the serum level of HMGB1 between psoriatic patients with and without metabolic syndrome with assessment of its prognostic potential to diagnose metabolic syndrome in the psoriatic population.
| Patients and methods|| |
The present study was carried out at Dermatology and Phototherapy Outpatient Clinics of Main University Hospital, Faculty of Medicine, Alexandria University. It included the following two groups:
Group A (cases group): Included 50 psoriatic patients who were recruited from Dermatology and Phototherapy Outpatient Clinics.
Group B (control group): Included 20 healthy volunteers.
Patients excluded from the study were those with systemic lupus erythematosus, atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and hepatic, renal, or cardiac disease. Patients using topical antipsoriatic treatment, apart from topical Vasline (Unilever Company, Trumbull, Connecticut, USA) within the past 2 weeks, and patients subjected to systemic treatment or phototherapy for psoriasis within the past month as well as those on medication that may alter carbohydrate or lipid metabolism, such as corticosteroids and lipid-lowering agents, at least 1 month before enrollment in the study were excluded. Pregnant and breast feeding females were similarly excluded.
A written informed consent was signed by both patients and control subjects before enrollment in the study. The present study protocol conforms to ethical guidelines of the Declaration of Helsinki and has also obtained the approval of the Medical Ethical Committee of Faculty of Medicine, Alexandria University.
All included patients were subjected to history taking and complete physical examination.
Patients were examined to determine the site, size, and distribution of lesions. The psoriasis area and severity index (PASI) score was measured, as both intensity and extent of the psoriatic plaques were calculated . Assessment of fasting blood glucose level and lipid profile was carried out. The patients were evaluated for metabolic syndrome criteria, according to the International Diabetes Foundation .
Metabolic syndrome was diagnosed if the psoriatic patient had three of the following criteria: fasting glucose 100 mg/dl or more (or receiving drug therapy for hyperglycemia), blood pressure 130/85 mmHg or higher (or on drug therapy for treatment of hypertension), triglycerides 150 mg/dl or more (or on drug treatment for hypertriglyceridemia), high-density lipoprotein cholesterol level less than 40 mg/dl in male patients or less than 50 mg/dl in female patients (or on drug therapy for decreased high-density lipoprotein cholesterol), and waist circumference 94 cm or greater in men or 80 cm or greater in women according to the ethnic background.
Blood samples (5 ml) were collected into sterile tubes. Sera were isolated by centrifugation at 2000–3000 rpm for 20 min, and thereafter were stored at −20°C until the time of assay.
High-mobility group box-1 level
Serum levels of HMGB1 were quantitated with commercially available enzyme-linked immunosorbent assay kit (E1635Hu; Bioassay Technology Laboratory, Shanghai, China), according to the manufacturer’s instructions. The minimum detection level for HMGB1 was 0.1 ng/ml. The assay was conducted in a blind fashion on coded samples by an investigator who was not informed of the subject’s clinical condition, after the collection of the whole samples had been finished.
Data were fed to the computer and analyzed using IBM SPSS software package IBM SPSS stastiticss for windows, version 20.0, IBM Corp., Armonk, NY). As regards categorical variables’ comparison between studied groups, χ2-test was used. Quantitative variables’ distribution were tested for normality using Shapiro–Wilk test and D’Agostino test, as well as histogram and QQ plot were used for vision test. When normal data distribution was revealed, parametric tests were used, and when data were distributed abnormally, nonparametric tests were applied. As regards abnormally distributed data, the Mann–Whitney test was used to analyze two independent populations. The Kruskal–Wallis test was used for comparison between more than two groups. The Spearman coefficient was used to assess correlations between two abnormally quantitative variables. Receiver operating characteristic curve (ROC) was generated by plotting sensitivity versus specificity at different cutoff values. The area under the ROC curve denotes the diagnostic performance of the test. An area more than 50% gives acceptable performance and an area of about 100% is the best performance for the test. Significance of the obtained results was judged at the 5% level.
| Results|| |
Subjects submitted to this study were divided into two groups: group A, which included 50 psoriasis patients and group B, which included 20 healthy controls. Group A included 28 (56%) male patients and 22 (44%) female patients. Their mean age was 46.88±15.72 years. Group B included 11 (55%) male individuals and nine (45%) female individuals with a mean age of 41.85±11.43 years. No statistically significant difference between the two groups regarding sex (P=0.939) and age was detected (P=0.182) ([Table 1]).
|Table 1 Comparison between the two studied groups according to demographic data|
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The duration of the disease was classified under three categories  (≤5 years, between 6 and 15 years, and ≥15 years) and it was less than or equal to 5 years in 62% of cases, between 6 and 15 years in 24% of cases, and more than 15 years in 14% of cases.
The mean PASI score in group A was 6.58±5.44 with a range between 1.5 and 27 with further subdivision of its severity  in which a PASI score less than 7 was considered as mild disease, between 7 and 12 as moderate disease, and greater than 12 as severe disease. The PASI score was mild in 72% of cases, moderate in 16% of cases, and severe in 12% of cases.
Evaluation of high-mobility group box-1 serum level
The mean HMGB1 serum level among psoriasis patients was 12.23±12.96 ng/ml and among control subjects was 6.47±2.89 ng/ml. A statistically significant higher level was observed in the psoriatic group than in the control group (P=0.037) ([Table 2]). There was no statistically significant difference between male and female patients (P=0.506), and this serum level of HMGB1 was not correlated with different ages of the patients (rs=0.088, P=0.543).
|Table 2 Comparison between the two studied groups according to serum high-mobility group box-1 level|
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As regards the disease duration, no statistically significant difference between different disease durations in the level of HMGB1 (P=0.289) was detected.
On assessing the disease severity, there was a statistically significant difference between the serum levels of HMGB1 among the three groups (P≤0.001), between the first group (PASI<7) and the third group (PASI>12) (P=<0.001) and between the second group (PASI=7–12) and the third group (PASI>12) (P=0.003), whereas there was no statistically significant difference between the serum levels of HMGB1 between the first group (PASI<7) and the second group (PASI=7–12) (P=0.703) ([Table 3]).
|Table 3 Relation between psoriasis area and severity index and high-mobility group box-1 level in patients group|
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In addition, a statistically significant positive correlation was observed between PASI score and serum level of HMGB1 (rs=0.368, P=0.009).
On assessing the metabolic syndrome, it was found that there was a higher percentage of metabolic syndrome in cases (30%) in relation to the control group (15%); yet, it does not reach the level of significance.
The HMGB1 level was significantly higher in psoriatic patients with metabolic syndrome (22.91±19.38 ng/ml) when compared with that in psoriatic patients without metabolic syndrome (7.65±3.92 ng/ml) (P=0.007) ([Table 4]).
|Table 4 Comparison between psoriatic patients with and without metabolic syndrome as regards high-mobility group box-1 serum level|
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In order to determine whether serum HMGB1 level has a prognostic potential for diagnosis of metabolic syndrome in psoriatic patients, ROC curve, sensitivity, and specificity were calculated. The area under the ROC curve was 0.743 (P=0.007) (95% confidence interval, 0.592–0.894). The cutoff value of serum HMGB1 level was 8.4 ng/ml with sensitivity of 80% and specificity of 51.43%.
| Discussion|| |
Psoriasis is a hyperproliferative skin disease with abnormally differentiated keratinocytes and associated with upregulated cytokines and growth factors in the skin and in the circulation of the affected patients .
The molecular pathogenesis of psoriasis indicates an interaction between acquired and innate immunity. The principal drivers of psoriatic lesion development and persistence are T lymphocytes, some cytokines release, in addition to the endothelial cells, natural killer T cells, and neutrophils .
HMGB1 can be translocated from the nucleus to the cytoplasm and thereafter released into the extracellular compartment . Two active and passive pathways are known to cause release of HMGB1 extracellularly. The active process occurs when cells are subjected to some inflammatory mediators like interferon-γ and TNF-α, whereas cellular necrosis leads to the passive process ,.
Extracellular HMGB1 has been implicated in the pathogenesis of different inflammatory as well as autoimmune diseases. Elevated serum levels of HMGB1 in systemic lupus erythematosus patients were reported ,. Similar results were detected in rheumatoid arthritis  and ankylosing spondylitis . Moreover, it was implicated in systemic sclerosis pathogenesis  and Sjogren’s syndrome .
Lee et al.  reported increased HMGB1 expression in skin samples and serum samples of patients with alopecia areata, in which high serum levels of HMGB1 showed more association with acute disease and poor response to treatment.
A previous study tried to explore its role in atopic dermatitis . They found that there was no significant elevation in serum levels of HMGB1 in atopic dermatitis patients compared with that in control subjects, and no correlation was detected between SCORAD scores and HMGB1 levels in atopic dermatitis patients. However, the expression of HMGB1 in the cytoplasmic part was detectable in atopic dermatitis patients, and the ratio of expression of HMGB1 in cytoplasmic protein to nuclear protein in atopic dermatitis patients was also significantly higher than in the control group.
The HMGB1 role in different inflammatory skin diseases such as psoriasis vulgaris is still under investigation. The aim of the present study was to answer whether HMGB1 has a role in the etiopathogenesis of psoriasis.
In the present study, a significantly higher serum level of HMGB1 was found in patients with severe form of the disease compared with that in patients with mild or moderate disease. In addition, a significant positive correlation between PASI and HMGB1 was also detected. Similar results as regards increased serum levels of HMGB1 in psoriatic patients than in healthy control subjects and their correlation with disease severity according to PASI score were reported by different studies ,,. However, in the present study the mean serum levels of HMGB1 in psoriatic patients (12.23±12.96 ng/ml) were lower than those reported by Chen et al.  (77.73±66.46 ng/ml); this could be attributed to lower values of PASI score in the present study that ranged from 1.50 to 27.0 with a median value of 5.05, whereas they reported a PASI score that ranged from 4.8 to 36.4 with a median value of 14.8.
Bergmann et al.  defined mild disease as PASI less than 5, moderate as PASI between 5 and 15, and severe as PASI greater than 15. The median level of HMGB1 in the mild group (42 patients) was10 ng/ml, in the moderate group (24 patients) it was 20 ng/ml, the same as the control group (20 ng/ml), and finally in the severe group (24 patients) it was 30 ng/ml. They noticed with every disease progression, an increase in HMGB1 serum concentrations in the psoriatic patients by around 10 ng/ml, whereas in the present study a noticeable significant rise in the value of HMGB1 levels in severe cases in comparison with lower values in mild and moderate cases (about four-fold more) was detected.
It should be noted that Bergmann et al.  observed that in moderate cases, HMGB1 values were equal to that of the control group. They explained that by the younger age of the control group than the intervention groups, because HMGB1 declines with progressing age . In contrast, there was no significant difference between both groups in the present study as regards their ages, and hence the age as a confounding factor did not affect our results.
In the current clinical study, there was no statistically significant difference between different groups in HMGB1 serum level as regards the disease duration and age or sex among psoriatic patients.
Chen et al.  supported nuclear extraction of HMGB1 under abnormal conditions, and thus a part of systemic mediators in various diseases, by demonstrating increased cytoplasmic fraction expression of HMGB1 in the lesional psoriatic epidermis. In addition, the protein level of HMGB1 in cytoplasmic fraction was detected in psoriatic patients in contrast to its nuclear fraction expression in control subjects. In the present study, serum level of HMGB1 was noticed to be higher in psoriatic patients than in control subjects, which may support its pathogenic role in psoriasis.
Methotrexate in low dose is used for the treatment of inflammatory diseases including psoriasis. Kuroiwa et al.  detected HMGB1 as a direct binding protein of methotrexate by using T7 phage display system, impeding HMGB1/RAGE interaction, and thus blocking the HMGB1-induced TNF-α release as well as mitogenic activity. Bergmann et al.  reported that HMGB1 concentration was reduced under treatment with TNF-α inhibitors, methotrexate, and fumaric acid esters, with lowest serum levels of HMGB1 in patients treated with methotrexate. This may reflect the idea of HMGB1 as a new target of therapy for psoriasis.
The increased prevalence of metabolic syndrome in patients with psoriasis has been reported in multiple studies, which suggested that the association of psoriasis with metabolic syndrome occurs early in the course of the disease , another point of view that increasing psoriasis severity was associated with higher odds of metabolic syndrome. In addition, it was suggested that metabolic disorders lead to worsening severity of psoriasis . Similar results were detected in the present study that showed a higher percentage of metabolic syndrome in cases in relation to the controls, although it did not reach the level of significance, may be owing to the small number of the sample. This obvious linking of psoriasis with metabolic syndrome is of clinical importance in applications relevant to daily practice on assessing psoriatic patients.
It is worth noting that psoriasis is considered as an immunometabolic disorder .
A recent suggestion is that HMGB1 might be an adipocytokine that acts as an innate proinflammatory mediator in obese patients, which correlates with other inflammatory markers of metabolic syndrome .
In a study conducted on 60 obese children, their data revealed a close correlation between HMGB1 and all parameters included in the diagnostic criteria of metabolic syndrome. They concluded that HMGB1 is an excellent diagnostic marker for this condition .
These results were reported in another study, in which HMGB level increased in cases with metabolic syndrome, and its level increased with increasing numbers of metabolic syndrome risk factors .
In the current study, the HMGB1 level was significantly higher in psoriatic patients with metabolic syndrome when compared with that in psoriatic patients without metabolic syndrome. At ROC analysis, serum HMGB1 level has a prognostic potential for diagnosis of metabolic syndrome in psoriatic patients with a cutoff value of serum HMGB1 level of 8.4 ng/ml with a sensitivity of 80% and a specificity of 51.43%.
Given the relation between psoriasis and metabolic syndrome, it was suggested that patients undergo appropriate screening of diagnostic criteria of metabolic syndrome as a part of routine medical care ,.
The current results reflected that serum HMGB1 level might be an important marker in the detection of metabolic syndrome in psoriatic patients, which provide improvement in patients’ health status.
| Conclusion|| |
The present study has shed light on the suggested role of HMGB1 in the pathogenic process of psoriasis and its related metabolic disorder. Extracellular HMGB1 has been detected as a proinflammatory cytokine that stands at the crossroad between innate and adaptive immunity. Its involvement in other inflammatory and autoimmune diseases may strengthen our concept of the HMGB1 role in psoriasis pathogenesis especially those with metabolic syndrome. Knowledge about early markers such as HMGB1 may facilitate diagnosis of psoriatic disease severity, monitoring the treatment, detection of metabolic syndrome in psoriatic patients, taking steps at decreasing cardiovascular risk in such patients, and recognizing the impact metabolic syndrome has on the efficacy of psoriasis treatments.
The limitation of the present study is the small number of patients. The prognostic power of HMGB1 in serum should be tested in other clinical trials and compared with other prognostic markers for psoriatic diathesis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]