|Year : 2019 | Volume
| Issue : 3 | Page : 222-227
Vitamin D in the treatment of oral lichen planus: A pilot clinical study
Juhi Gupta1, Anshul Aggarwal1, Md Asadullah1, Masood H Khan1, Neha Agrawal2, Kauser Jahan Khwaja1
1 Department of Oral Pathology/Oral Medicine and Radiology, Dr. Z.A. Dental College, AMU Aligarh, Uttar Pradesh, India
2 Department of Community Dentistry, Dr. Z.A. Dental College, AMU Aligarh, Uttar Pradesh, India
|Date of Submission||29-Apr-2019|
|Date of Acceptance||01-Aug-2019|
|Date of Web Publication||30-Sep-2019|
Dr. Masood H Khan
Department of Oral Pathology/Oral Medicine and Radiology, Dr. Z.A Dental College, AMU Aligarh - 202 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Lichen planus is an autoimmune disease with unknown etiology. Vitamin D not only affects the health of the bone but also has an impact on immunity. To understand the possible role of vitamin D in the pathophysiology of oral lichen planus (OLP), a clinical study was conducted on patients suffering from OLP who reported to the dental outpatient department of our dental college in Aligarh. Aims: To evaluate the possible co-relation between the OLP with vitamin D deficiency and the effect of vitamin D supplementation on the treatment of the OLP lesion. Settings and Design: A pilot clinical study was conducted in a dental college in Aligarh. Materials and Methods: Patients with clinical presentation of OLP were included in our study. Patients with drug-induced oral lesion or lesion associated with dental restoration (lichenoid reactions) were excluded from the study. Patients were divided into three different groups depending on factors such as stress, low vitamin D levels, or a combination of the above factors. Patients with severe vitamin D deficiency were supplemented with vitamin D. Statistical Analysis Used: Fisher's exact test. Results: There was a statistically significant improvement in both subjective and objective symptoms in patients who were supplemented with vitamin D with or without psychological counseling apart from topical steroid application for a short period. Conclusion: Marked improvement and long-term remission in the symptoms in vitamin D–deficient patients after restoration of normal vitamin D level suggests its role in pathogenesis of OLP like other autoimmune diseases. Therefore, further study and research work need to be carried out to understand the pathway through which vitamin D is related to the pathogenesis of OLP.
Keywords: Autoimmune disorder, immune modulator, lichen planus, steroids, vitamin D
|How to cite this article:|
Gupta J, Aggarwal A, Asadullah M d, Khan MH, Agrawal N, Khwaja KJ. Vitamin D in the treatment of oral lichen planus: A pilot clinical study. J Indian Acad Oral Med Radiol 2019;31:222-7
|How to cite this URL:|
Gupta J, Aggarwal A, Asadullah M d, Khan MH, Agrawal N, Khwaja KJ. Vitamin D in the treatment of oral lichen planus: A pilot clinical study. J Indian Acad Oral Med Radiol [serial online] 2019 [cited 2020 Feb 21];31:222-7. Available from: http://www.jiaomr.in/text.asp?2019/31/3/222/268283
| Introduction|| |
If we define immunity, then by definition it is a condition of being able to resist a particular disease especially through preventing the development of a pathogenic microorganism or by counteracting the effects of its products. Autoimmune disease is a condition in which the body immune system fails to recognize its own body cells or the antigen as “self” and the immune system starts targeting the own body cell leading to destruction and damage. In an autoimmune disease, the basic pathology is an interaction between autoreactive T lymphocytes and body antigen, or autoantibodies and antigen present on the targeted cells.
Lichen planus is also a type of autoimmune disease where the cells of the skin and mucosal surface are targeted by our own immune system. It is a chronic inflammatory disease which is characterized by cytotoxic T-cell-mediated damage of the basal cell of the epithelium and chronic inflammation. According to the reports, 1%–2% of oral lichen planus (OLP) cases may undergo malignant transformation, and the condition has categorized under “potentially malignant disorder” by the World Health Organization. As the etiology and exact pathogenesis of this condition are still obscure, it has drawn the attention of the researchers for the past many years.
The role of vitamin D on the immune system is now well-established. Vitamin D receptors (VDRs) are found to be present on immune cells such as B cells, T cells, and antigen-presenting cells. Active vitamin D metabolite is synthesized by these immune cells in the body, and further, this vitamin D acts upon the immune system and modulates it in various ways like down- or upregulation of immune cell differentiation. Vitamin D is also capable of modulating innate and adaptive immune responses. There are sufficient documented studies that relate deficiency of vitamin D to many autoimmune diseases such as insulin-dependent diabetes mellitus, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus (SLE), and rheumatoid arthritis. But its role in OLP is yet to be established.
With this background, a pilot clinical study was conducted on patients suffering from OLP reporting to the dental outpatient department of our dental college in Aligarh.
| Materials and Methods|| |
The study was conducted with 150 patients from various age groups suffering from OLP. The male-to-female ratio was 1:4. Informed consent was obtained from the patients. Ethical clearance from the ethical committee of the institution was obtained. The study sample was divided into three groups with even distribution of the number of subjects in each group. Out of 150 patients, there was a drop out of 44 patients. Hence, the effective sample size was 106.
- Clinical presentation or histopathological report compatible with OLP.
- Patients of all age groups and of both genders suffering from OLP.
Patients with history of aggravation of the lesion due to stressful episode
- Patients without any history of the treatment of OLP.
- Patients with oral lesion due to fixed dose reaction or amalgam restoration.
- Patients who were already on vitamin D supplementation or on systemic steroids.
- Pregnant patient/patients with bone pathology.
- Patients with any systemic disease or under medication.
A detailed history was documented in terms of symptoms associated with the condition. Aggravating factors such as stress were recorded. Detailed medical history and history of any medication were taken. Drug-induced lichenoid reaction was excluded by taking the history of the initiation of the lesion in relation to any drug intake. Complete oral examination was performed to look for amalgam-induced lichenoid reaction.
Diagnosis of the condition was based on the clinical presentation of the disease. The bilateral presentation, the typical reticular pattern (characteristic of OLP), burning sensation, and intolerance to spicy food were used as clinical diagnostic criteria for the disease. But in doubtful cases where the presentation was gingival desquamation and the reticular pattern was not clearly visible, biopsy was done to confirm the diagnosis.
Patients was asked about lower back pain, history of recent weight gain, fatigue, hair loss, and muscular pain that may indicate vitamin D deficiency. Most of the female patients were in the menopausal state, and none of the female patients was pregnant. Detailed history regarding any bone-related disease or disease affecting the vitamin D level was taken. None of the patients was on vitamin D supplementation at the onset of the study. Most of the patients gave a positive history of chronic lower back pain and recent weight gain (suggestive of vitamin D deficiency).
Serum vitamin D level estimation was advised for every patient. Usually, vitamin D deficiency is defined as 25(OH) D <20 ng/mL, insufficiency as 20–29 ng/mL, and sufficiency as ≥30 ng/mL. In our study, patients with serum vitamin D level ≤15 ng/mL were considered as severe vitamin deficiency. Serum level of vitamin D ≥15 but ≤20 ng/mL was considered as moderate vitamin D deficiency. Serum level of vitamin D ≥30 ng/mL was considered as normal.
Patients with severe vitamin D deficiency were asked to consult their endocrinologist regarding the initiation of vitamin D supplementation. Patients with vitamin D level ≥15 but ≤20 ng/mL were intentionally not advised for vitamin D supplementation to be used as a control group for the study. Most of the patients were kept on oral supplementation of vitamin D of 60,000 IU or more weekly, depending on the serum vitamin D level. For patients who were on vitamin D supplement, topical steroids were given only to control the initial acute condition and severe burning sensation. For these patients, topical steroid application was tapered and withdrawn over a period of 4 weeks of the treatment. Patients from all the three groups were followed for 12 weeks.
There are many scoring systems for the evaluation of OLP. In our study, we have followed the scoring system given by Kaliakatsou et al. for both clinical diagnosis and treatment outcome of the disease [Table 1].
Depending on the presence of OLP, vitamin D level, and the history of stress, patients were divided into three groups.
Group 1. History of stress alone with mild vitamin D deficiency (vitamin D level ≥ 15 ng/mL)
(Treatment given is topical steroids and psychological counseling)
Group 2. History of severe vitamin D deficiency alone (vitamin D level ≤15 ng/mL)
(Treatment given is topical steroids and vitamin D supplements)
Group 3. History of stress and severe vitamin D deficiency (vitamin D level ≤ 15 ng/mL and stress)
(Treatment given is topical steroids, vitamin D supplements, and psychological counseling)
| Results|| |
Data obtained were tabulated and subjected to statistical analysis. SPSS software version 16 was used for statistical analysis. Descriptive statistics and Fisher's exact test were applied. [Table 2] and [Table 4] show the pretreatment objective and subjective symptoms among various groups, respectively. Data analysis showed statistically significant improvement in symptoms (both subjective and objective) among patients who were kept on vitamin D supplement. It was observed that the improvement in burning sensation was more significant in patients who were on vitamin D supplements and psychological counseling [Table 3] and [Table 5]. [Table 3] shows the changes in the score of the objective signs and [Table 4] shows the changes in the score of the subjective signs. The effect of vitamin D supplement was better in patients who were able to control their stress [Table 5].
|Table 2: Pretreatment objective symptom among patients in various groups|
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|Table 4: Pretreatment subjective symptom among patients in various groups|
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|Table 3: Posttreatment objective symptom among patients in various groups|
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|Table 5: Posttreatment subjective symptom among patients in various groups|
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| Discussion|| |
The primary outcome of the study was marked improvement in burning sensation in patients with OLP who were supplemented with vitamin D. As the secondary outcome, it was noticed that in group 3 patients who were able to control their stress levels responded well to vitamin D which shows the possible negative/suppressive effect of stress in the treatment of patients suffering from OLP. It was also surprising to know that patients were unaware of their vitamin D deficiency state.
As sun rays play a vital role in the synthesis of the active metabolite of vitamin D in our skin, it is also known as the sunshine vitamin. The importance of vitamin D for our health is known since ancient age. The emphasis of adequate sun exposure by people in the past was actually to get an adequate amount of vitamin D in the body.
In general, we are aware of the importance of vitamin D in calcium homeostasis as it is important for the absorption of calcium, and thus improves the health of bone and teeth. But this is just one aspect of the effects of vitamin D the body homeostasis. Vitamin D is also found in the hormonal form in our body. The role of vitamin D as an immune modulator came into the light after 1980. An important finding of many studies related to the expression of VDRs on cells involved in immune system such as T and B cells, and the effect of the hormonal form of vitamin D on these cells indicates its crucial role in immunity.
The deficiency of vitamin D makes a person susceptible to autoimmune disease. 1,25-Dihydroxyvitamin D (1,25(OH) 2D3), the active form of vitamin D, is recognized as a pleiotropic hormone and possesses comprehensive physiological activities. Bhalla AK et al. found high-affinity binding sites for 1,25-(OH) 2D3 on monocytic cells. Further studies done by Veldman CM et al. found that CD8 lymphocytes may be a major site of action of (1,25(OH) 2D3). Anin vitro study done by Alroy I et al. showed suppression of T-lymphocyte proliferation by the active metabolite of vitamin D3, and thus decreases interleukin 2 (IL-2), gamma interferon (IFN-γ), and granulocyte-macrophage-colony-stimulating factor mRNA levels. There is a direct inhibition by a nuclear hormone receptor of transcriptional activators of the IL-2 gene. The suppressive effect of the active metabolite of vitamin D on IFN-γ promoters was further supported by a study done by Cippitelli M et al. on the effect of vitamin D on the immune system. Natural killer T (NKT) cells play an important role in the pathogenesis of autoimmune disease and also cancer. One important observation made by Yu and Cantornathat vitamin D not only promotes the proliferation of NKT cells but also increases IL-4 and IFN-γ production of NKT cells. Hence, the effects of vitamin D on multiple immune cells clearly indicate its role in immune-mediated disorders.
Lichen planus is a chronic inflammatory mucocutaneous disease. Cell-mediated cytotoxicity is regarded as a major mechanism of pathogenesis. Autocytotoxic CD8+ T cell triggers apoptosis of oral epithelial cells, and the subepithelial infiltration in OLP is composed of T cells and macrophages. Most T cells in the epithelium and adjacent to the damaged basal keratinocytes are activated CD8+ lymphocytes. Activated vitamin D inhibits the proliferation of T cells specifically CD8+ cells, and thus the production of IL-2.
The deficiency of vitamin D leads to dysregulation of T-cell proliferation and thus possibly leads to the development of OLP. Apart from that, a study done by Bin Zhao et al. indicates that lipopolysaccharide is responsible for VDR downregulation in oral keratinocytes, which is associated with OLP development.
Irrespective of developed or developing country, vitamin D insufficiency or deficiency among the general population has been noticed by many researchers. It may be due to a variety of reasons such as increased use of sunscreen, increased indoor activities, and greater skin coverage with clothing due to various cultural beliefs and religious practices or to protect against skin cancer. In our study, all the patients irrespective of whether or not there was any clinical sign or symptoms of vitamin D deficiency were advised to undergo vitamin D level estimation. In none of the patients, the vitamin D level was ≥20 ng/mL. The lowest vitamin D level in the study sample was 8.8 ng/mL and the maximum was 18 ng/mL. So there was low vitamin D level/vtamin D deficiency in all the patients. But none of the patients was aware of their low vitamin D level. In our study sample, it may be related to very less sun exposure due to greater skin coverage with clothing and minimal outdoor activity.
In a study conducted by Akanksha Gupta et al., it was found that vitamin D3 deficiency was more in OLP cases (70.6%) when compared with control group (34.3%). Thus indicating that deficiency of vitamin D might have a role in the pathogenesis of OLP.
In our study, patients with severe vitamin D deficiency alone or with history of stress had a higher Visual Analog Scale score for burning sensation when compared with patients with mild to moderate vitamin D deficiency [Table 3]. Apart from that, erosive lichen planus was a more common presentation in patients with vitamin D level less than 10 ng/mL [Figure 2]. The posttreatment improvement in burning sensation was highest in patients who were on a combination of topical steroids, vitamin D supplements, and psychological counseling, followed by topical steroid and vitamin D supplement, and was least in patients without any vitamin D supplement [Figure 3]. Improvement in the objective score for the lesion was also higher in study groups 2 and 3 when compared with group 1 [Table 3] and [Figure 4].
Low vitamin D level is also related to depression, and supplementation of vitamin D in such patients showed improvement in mental health. Moreover, although chronic stress does not decrease the vitamin D level, it increases the blood cortisol level. A study done by Godschalk M et al. found that glucocorticoids alter VDR number. It appears to decrease VDR mRNA by inhibiting VDR gene transcription or by affecting the processing of VDR mRNA. Hence, the stress indirectly suppresses the hormonal effect of vitamin D on many cells including the cells of the immune system thus affecting its immune-modulating effect.
Stress is one of the most common etiological factors associated with OLP. But how does it bring about its effect is still not clear. In our study, the second interesting observation was the effect of the treatment in patients of group 3 where severe vitamin D deficiency and stress were present. The overall treatment response was good in this group. But few patients who were unable to control their stress showed less response even after vitamin D supplementation. It may be due to the downregulation of the VDR, thus decreasing the hormonal effect of vitamin D. Apart from that, patients suffering from OLP are usually under constant stress due to the burning sensation and fear of having oral cancer. So it is a vicious cycle that further aggravates the condition and decreases the response to the treatment.
If we consider the effects of the stress on the activity of vitamin D and OLP, then the probable sequence could be hypothesized as explained in [Figure 5].
There are many studies done by researchers that had related vitamin D level and its effect on immune-mediated diseases such as SLE, rheumatoid arthritis, and multiple sclerosis.,, But literature regarding the use of vitamin D in the treatment of OLP is scanty. R Beena Varma et al. have reported an isolated case of a 40-year-old female suffering from erosive lichen planus in which marked improvement in the condition had been reported after intramuscular administration of 300,000 units of cholecalciferol. Jie Du et al. in their study concluded that 1,25(OH) 2 D3 has an anti-inflammatory role in OLP due to its effect on NF-kB signaling pathway.
Therefore, we hypothesized that low vitamin D level plays an important role in the etiopathogenesis of OLP. The outcomes of our study somewhat support the potential role of vitamin D in the treatment of OLP. As correction of vitamin D level improves sign and symptoms associated with OLP. The massive effect of hormonal form of vitamin D on the immune system opened up a new door to investigate the role of vitamin D in autoimmune disease. Autoimmune origin and infiltration of T cells into the subepithelial bands in lichen planus lesion indicates an abnormality in cell-mediated immune response. To our best knowledge, it is the first of such kind of study that indicates the role of vitamin D in the treatment with probable cure of OLP.
| Conclusion|| |
Small sample size and uneven distribution of subject due to the drop out of cases are the shortcomings of our study [Figure 6]. It was only a small clinical study which indicates the possible role of vitamin D in pathogenesis and thus treatment of OLP, and the findings of our study will definitely give a new direction to the research work in the field of management of OLP. It is important that the role of vitamin D in the treatment of OLP must be explored more extensively, and randomized control trial must be conducted on a large sample.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Georgakopoulou EA, Achtari MD, Achtaris M, Foukas PG, Kotsinas A. Oral lichen planus as a preneoplastic inflammatory model. J Biomed Biotechnol 2012;1-8.doi: 10.1155/2012/759626.
Aranow C. Vitamin D and the immune system. J Investig Med 2011;59:881-6.
Wang J, van der Waal I. Disease scoring systems for oral lichen planus; a critical appraisal. Med Oral Patol Oral Cir Bucal 2015;20:199-204.
Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, et al
. Vitamin D and human health. Lessons from vitamin D receptor null mice. Endocr Rev 2008;29:726-76.
Bhalla AK, Amento EP, Clemens TL, Holick MF, Krane SM. Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: Presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab 1983;57:1308-10.
Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D (3) receptor in the immune system. Arch Biochem Biophys 2000;374:334-8.
Alroy I, Towers TL, Freedman LP. Transcriptional repression of the interleukin-2 gene by vitamin D3: Direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol 1995;15:5789-99.
Cippitelli M, Santoni A. Vitamin D3: A transcriptional modulator of the interferon-gamma gene. Eur J Immunol 1998;28:3017-30.
Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development. Proc Natl Acad Sci 2008;105:5207-12.
Iijima W, Ohtani H, Nakayama T, Sugawara Y, Sato E, Nagura H, et al
. Infiltrating CD8 T cells in oral lichen planus predominantly express CCR5 and CXCR3 and carry respective chemokine ligands RANTES/CCL5 and IP-10/CXCL10 in their cytolytic granules. Am J Pathol 2003;163:261-8.
Cantorna MT, Snyder L, Lin Y-D, Yang L. Vitamin D and 1,25(OH) 2D regulation of T cells. Nutrients 2015;7:3011-21.
Zhao B, Li R, Yang F, Yu F, Xu N, Zhang F, et al
. LPS-induced vitamin D receptor decrease in oral keratinocytes is associated with oral lichen planus. Sci Rep 2018;8:1-9.
Gupta A, Prakash Sasankoti Mohan R, Kamarthi N, Malik S, Goel S, Gupta S. Serum vitamin D level in oral lichen planus patients of north India- A case-control study. JDRT 2017;1:19-35.
Godschalk M, Levy JR, Downs RW. Glucocorticoids decrease vitamin D receptor number and gene expression in human osteosarcoma cells. J Bone Miner Res 1992;7:21-7.
Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: Results from the Iowa Women's Health Study. Arthritis Rheum 2004;50:72-7.
Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296:2832-8.
Linker-Israeli M, Elstner E, Klinenberg JR, Wallace DJ, Koeffler HP. Vitamin D (3) and its synthetic analogs inhibit the spontaneous in vitro
immunoglobulin production by SLE-derived PBMC. Clin Immunol 2001;99:82-93.
Beena Varma R, Valappila NJ, Pai A, Channavir Saddu S, Mathew N. Oral lichen planus: Is vitamin D deficiency a predisposing factor? A case report. Int J Sci Stud 2014;2:230-2.
Du J, Li R, Yu F, Yang F, Wang J, Chen Q, et al.
Experimental study on 1,25(OH)2
D amelioration of oral lichen planus through regulating NF-κB signaling pathway. Oral Dis 2017;23:770-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]