|Year : 2014 | Volume
| Issue : 2 | Page : 102-106
Serum levels of tumor necrosis factor-α in patients with lichen planus
Abdullah Mahfouz Kato1, Doaa Salah Hegab1, Mohamed Abd El Rahman Sweilam2, Eman Samy Abd El Gaffar3
1 Dermatology and Venereology Faculty of Medicine, Tanta University, Tanta, Egypt
2 Clinical Pathology Faculty of Medicine, Tanta University, Tanta, Egypt
3 Dermatology and Venereology in the Ministry of Health, Egypt
|Date of Submission||10-Apr-2014|
|Date of Acceptance||04-Nov-2014|
|Date of Web Publication||29-Jan-2015|
Doaa Salah Hegab
17, Masjid El-Daawa St., Tanta 2nd, Gharbia
Source of Support: None, Conflict of Interest: None
Lichen planus (LP) is an inflammatory skin disorder of unknown etiology. Tumor necrosis factor-a (TNF-α) is a multifunctional proinflamatory cytokine, which plays an important role not only in immunity and inflammation but also in the control of cell proliferation, differentiation, and apoptosis.
The present study was designed to investigate the serum level of TNF-α in patients with LP of different clinical presentations in comparison with healthy participants to study its possible role in the pathogenesis of LP.
Patients and methods
A total of 30 patients with different clinical variants of LP (16 male and 14 female patients) and 30 controls matched for age and sex were enrolled in this prospective case-control study after exclusion of those who had received treatment for LP or immunological treatment within the preceding 6 weeks, or those whose serum levels of TNF-α were suspected to be elevated because of other causes or diseases. The serum level of TNF-α was measured by means of the ELISA method in both patients and controls.
The serum TNF-α level was significantly higher (P < 0.05) in patients than in controls, and it was also significantly higher in patients with oral LP than in those with cutaneous types of LP who do not have oral lesions (P < 0.05). The sensitivity and specificity of serum TNF-α was 62.5 and 81.8%, respectively, (cutoff value of 151 pg/ml) for the diagnosis of oral lesions in LP.
The findings in our study support the role of TNF-α in the pathogenetical process of LP and suggest that markedly elevated serum TNF-α level might be an important indicator of the risk for developing oral lesions in patients with LP.
Keywords: Lichen planus, tumor necrosis factor-a
|How to cite this article:|
Kato AM, Hegab DS, Sweilam MA, Abd El Gaffar ES. Serum levels of tumor necrosis factor-α in patients with lichen planus. Egypt J Dermatol Venerol 2014;34:102-6
|How to cite this URL:|
Kato AM, Hegab DS, Sweilam MA, Abd El Gaffar ES. Serum levels of tumor necrosis factor-α in patients with lichen planus. Egypt J Dermatol Venerol [serial online] 2014 [cited 2020 May 28];34:102-6. Available from: http://www.ejdv.eg.net/text.asp?2014/34/2/102/150261
| Introduction|| |
Lichen planus (LP) is a common, inflammatory, papulosquamous disorder affecting 0.1-4.0% of the general population, and it may affect the skin, mucous membranes, hair and nails ,. The exact pathogenesis is unknown, but cell-mediated immunity and humoral immunity have been implicated. Activation of the cell-mediated immune response destined towards keratinocyte apoptosis is the prime event in the pathogenesis of LP. The process involves three sequential stages: LP-specific antigen recognition, cytotoxic lymphocyte activation, and keratinocyte apoptosis ,. The predominance and close vicinity of activated T lymphocytes and macrophages/Langerhans cells in the dermoepidermal inflammatory infiltrate, combined with local and systemic release of various cytokines in both the skin and the serum, and liquefying degeneration of basal keratinocytes with damage to the basement membrane support this hypothesis ,.
Tumor necrosis factor-a (TNF-α) (cachexin or cachectin) is a potent multifunctional proinflammatory cytokine, which is a member of a group of cytokines that stimulate the acute phase reaction. It plays an important role not only in immunity and inflammation but also in the control of cell proliferation, differentiation, and apoptosis. It also has a role in the growth and differentiation of different cell types and has antitumoral activity both in vivo and on many tumor cell lines .
TNF-α plays a pivotal role in innate inflammatory responses , and it has been implicated in the pathogenesis of several chronic inflammatory disorders with an autoimmune component, such as psoriasis , and systemic lupus erythematosus . In some of these diseases, serum TNF-α concentration correlated with the activity and intensity of the disease and may be used as a prognostic factor. The main sources of TNF-α are macrophages, activated T lymphocytes, keratinocytes and Langerhans cells ,.
Although the importance of TNF-α in psoriasis is well established, its participation in LP is less clear .
The present study was designed to investigate the serum level of TNF-α in patients with LP of different clinical presentations in comparison with healthy participants.
| Patients and methods|| |
The present hospital-based case-control study included 30 patients with LP attending the outpatient clinic of Dermatology and Venereology Department in Tanta University Hospitals. Patients who had received any systemic steroids or other immunosuppressive drugs during the preceding 6 weeks were excluded from the study. Other exclusion criteria were patients with a history of trauma, surgery or recent infection 1 month before sampling, those suffering from any autoimmune disease, malignancy or hepatitis C virus (HCV] infection and patients who were smokers.
Thirty healthy individuals matched for age and sex served as controls. Written informed consent was obtained from all patients and controls.
LP was diagnosed clinically, and in cases with oral lichen planus (OLP) the clinical diagnosis was confirmed by means of a biopsy with a histologic appearance that included a band-like, mainly lymphocytic, infiltrate in the connective tissue adjacent to the epithelial basement membrane, liquefaction degeneration of the basement membrane, and destruction of basal keratinocytes.
Venous blood samples (5 ml) were taken from each patient and control and left to clot at 4°C in a sterile, clean, dry tube and kept inside the refrigerator. After clotting, the sample was centrifuged for 10 min at 5000 rpm and serum was separated and stored immediately at −20°C. Serum TNF-α was measured by means of ACCUCYTE (RareCyte Inc., Seattle, Washington, USA), which is a competitive enzyme immunosorbent assay designed to measure the 'Total' (bound+free) amount of TNF-α in serum. The assay was performed according to the manufacturer's instructions, and the results were expressed in pg/ml.
Statistical analysis of the data was performed using statistical package for social sciences (Version 17). Student's t-test was used to determine the statistical significance of serum TNF-α level within both patient and control groups. A P value less than 0.05 was considered to be statistically significant. Receiver operating characteristic curves were plotted to determine the best cutoff range for OLP screening for each value, and the relevant sensitivities and specificities were calculated.
| Results|| |
The LP patients group included 14 women (46.7%) and 16 men (53.3%). The age of LP patients ranged from 28 to 65 years, with a mean ± SD of 45.60 ± 10.82 years. The control group included six men and four women, and their ages ranged from 28 to 58 years with a mean ± SD of 42.50 ± 9.55 years. The patients and controls were age and sex matched (P < 0.05).
The serum TNF-α level in patients with LP ranged from 0.3 to 232 pg/ml, with a mean ± SD of 128.20 ± 19.63 pg/ml, and in the control group it ranged from 0 to 0.8 pg/ml, with a mean ± SD of 0.135 ± 0.08 pg/ml. The mean TNF-α level of patients with LP was significantly higher than that of the control group, and the difference was statistically significant (P < 0.001) [Table 1].
|Table 1: The mean serum level of tumor necrosis factor- a in patients of lichen planus and controls|
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The clinical varieties of LP noted in patients are delineated in [Table 2]. In the study group of 30 patients, eight patients had either sole or coexistent oral mucosal involvement. Among them, six had a reticular type and two had an erosive type of OLP.
|Table 2: The mean serum level of tumor necrosis factor-a in patients of lichen planus based on type|
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The serum level of TNF-α had a mean ± SD of 117.87 ± 12.29 pg/ml in patients with classic type of LP, 161.28 ± 22.14 pg/ml in oral type, 166.70 ± 19.63 pg/ml in patients having classic type with oral lesions, 115.80 ± 15.47 pg/ml in actinic type and 107.92 ± 13.36 pg/ml in hypertrophic type. The difference in serum levels of TNF-α among different clinical types of LP was statistically nonsignificant [Table 2].
The serum level of TNF-α had a mean ± SD of 163.25 ± 12.29 pg/ml in patients with OLP, whereas in the other patients with cutaneous types of LP who did not have oral lesions the mean serum level of TNF-α was 118.63 ± 10.36 pg/ml. This difference in serum levels of TNF-α among the two groups was statistically significant (P < 0.001) [Figure 1].
|Figure 1: The mean serum level of tumor necrosis factor-a (TNF-a) in patients with oral lichen planus (LP) in comparison with patients with cutaneous LP who do not have oral lesions.|
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The sensitivity and specificity of serum TNF-α for the diagnosis of oral lesions in LP was 62.5 and 81.8% (cutoff value of 151 pg/ml). The positive predictive value was 55.6% and the negative predictive value was 85.7%, with 0.739 accuracy [Figure 2].
|Figure 2: (a, b) Receiver operating characteristic curve analysis of the optimum cutoff value that could differentiate between lichen planus (LP) patients with and those without oral lesions. TNF-a, tumor necrosis factor-a.|
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There was no statistically significant difference between male and female patients of LP as regards the mean serum level of TNF-α. In addition, a statistically insignificant positive correlation was detected between the serum level of TNF-α and both the age of patients with LP and duration of the disease.
| Discussion|| |
LP is an inflammatory keratotic dermatosis of unknown etiology. Clinical and immunohistochemical studies strongly support an immunologic basis for the disease . Immunological reactions, mediated by T cells, against unknown foreign or self-modified antigen may initiate the lichenoid response resulting in a basal cell damage . The keratinocytes may become the target of damage because they express foreign or altered self-antigen on their surface .
Despite the simultaneous generation of both Th1 and Th2 cytokine profiles in LP lesions, local TNF-α has been implicated to have a key role in the initiation and progression of the disease .
Several previous reports have studied serum levels of TNF-α in patients with OLP ,,, but much fewer reports are available on cutaneous LP.
The results of the current study showed a significant elevation of TNF-α level in the sera of LP patients of different clinical types in comparison with the control group, and these data come in agreement with some previous reports ,.
The significant increase in serum TNF-α levels in patients with LP may be due to the local and systemic production of TNF-α by various cell types. TNF-α can be secreted by monocytes, macrophages, T and B lymphocytes, NK cells, endothelial cells, mast cells, fibroblasts, Langerhans' cells, and keratinocytes . It could be stated that TNF-α plays a role in the immunopathogenesis of LP (which is an immune-mediated disease) not only locally but also on systemic basis.
A previous research had found that LP patients had significantly increased serum levels of soluble TNF receptor 1 (sTNF-R1) as well as sTNF-R2. These enhanced serum titers were correlated with a prominent expression of TNF-R1 on lesional keratinocytes (basal>suprabasal) and of both receptors on skin-infiltrating lymphocytes. Its data suggest an important role of the TNF ligand/receptor interactions in the induction and/or perpetuation of the pathogenetical and apoptotic events in LP .
In the present study, the mean serum level of TNF-α was significantly increased in all types of LP in comparison with the control group. The difference in serum levels of TNF-α among different clinical types of LP was statistically insignificant. The mean serum level of TNF-α was significantly higher in patients with OLP compared with those with cutaneous types of LP who do not have oral lesions. A similar elevation of serum levels of TNF-α in patients with OLP had been reported in the literature by various authors ,,,.
One previous study showed that reticular OLP exhibited slightly elevated TNF-α serum levels compared with erosive OLP , whereas another study reported that serum levels of TNF-α in patients with erosive OLP was higher compared with those with nonerosive OLP . In contrast, some other investigators observed no statistical differences in the serum levels of TNF-α between OLP patients and controls when they studied their serum cytokine profiles .
Femiano and Scully  reported that serum levels of TNF-α were increased in patients who had oral reticular LP and HCV infection compared with those who had oral reticular LP but were negative for HCV infection and with those who had oral erosive LP but were negative for HCV, and compared with negative controls as well. In our study, we excluded patients with hepatitis C to avoid the possible impact of viral hepatitis on serum TNF-α levels.
Cutaneous LP lesions are typically self-limited and, regardless of therapy, show lower cytotoxic molecule expression and epithelial cell apoptosis. In contrast, oral lesions usually are more aggressive, rarely undergo spontaneous remission with significant morbidity and resistance to treatment, and are characterized by higher numbers of cytotoxic cells and associated epithelial cell apoptosis ,. The profound elevation in serum levels of TNF-α in patients with OLP detected in the present study might augment existing information in explaining these findings, and our work also has declared a cutoff value of serum TNF-α that is greater than 151 pg/ml as a predictive sign for OLP with 62.5% sensitivity and 81.8% specificity.
The observation of significantly higher TNF-α serum levels in OLP patients assessed in the present study is in line with the reported significantly high levels of nuclear factor-κB-dependent cytokines (TNF-α, IL-1-a, IL-6, and IL-8) that were found in tissue transudate of OLP patients in a previous report . Pezelj-Ribaric et al.  also showed increased salivary levels of TNF-α in OLP. Other studies have demonstrated that the levels of TNF-α in OLP decrease after steroid treatment ,.
In the present study, the mean serum level of TNF-α in female patients with LP was higher than that in male patients with LP, and the difference was statistically insignificant. This could be attributed to the fact that all our patients with OLP were female. It has been previously claimed that female-to-male ratio in OLP is about 2 : 1 .
Our findings are in agreement with a previous study that reported that the mean serum level of TNF-α in female patients with LP was higher than that in male patients with LP .
Rhodus et al.  reported that salivary levels of TNF-α in patients with oral squamous cell carcinoma were higher than its level in patients with OLP and in the control group. They concluded that the analysis of TNF-α level in saliva may provide a useful, noninvasive tool for monitoring malignant transformation as well as the therapeutic response of OLP.
Our findings raise the intriguing prospect that anti-TNF-α may offer a future therapeutic tool for LP, particularly for resistant cases of OLP who have an increased risk of developing cancer. However, it should be noted that in addition to the previous reports of successful treatment of LP with the TNF-α inhibitor etanercept , there have also been several reports of development of lichenoid reactions and even classic LP with oral affection in patients taking TNF-α inhibitors for other indications ,,,,, which is very unexpected. Investigators have suggested that in genetically prone patients, TNF-α inhibition might disrupt a delicate immune balance and a complex relationship between intertwined, or even opposing inflammatory cytokines, pushing the immune system towards IFN-a production, and triggering pathological activation of latent T cells and dendritic cells, which then induce inflammatory response .
| Conclusion|| |
This study shows that the serum TNF-α level is significantly higher in patients with LP than in healthy individuals, and in patients with OLP than in patients with other types of LP. These findings support the role of TNF-α in the pathogenetical process of LP and in expecting the development of oral lesions in patients of LP who have high elevation of serum levels of TNF-α.
| Acknowledgements|| |
Conflicts of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2]