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Home , Herpes simplex, Lichen planus

Universal Journal of Medical Science 2(3): 25-30, 2014 http://www.hrpub.org DOI: 10.13189/ujmsj.2014.020301

Relevance of to Oral Planus

Sang-Yeon Park, Eung Ho Choi*

Department of , Yonsei University Wonju College of Medicine *Corresponding Author : [email protected]

Copyright © 2014 Horizon Research Publishing All rights reserved.

Abstract Background: Oral (OLP) is a and occurs twice as often in females2. While lichen planus chronic inflammatory involving the that of hairless is generally cured spontaneously, OLP is induces pain and burning sensations, thus decreasing a chronic, has a tendency to recur, is mostly not cured patient’s quality of life. Although its etiology has not yet spontaneously, and has a possibility of malignant been clearly defined, infection has been suggested to be transformation3. Various clinical symptoms can arise with associated with OLP. We tried to clarify the relevance of OLP: Pain is the most common, and a burning sensation, (HSV) infection in OLP, since HSV itching, and may also occur. OLP also precludes infection is the most common infection in the oral mucosa of patients from consuming hot or spicy food, therefore, adults with characteristics of recurrence due to psychological further degrading their quality of life4-6. and physical stress. Methods: We enrolled thirty subjects The precise cause of OLP has not yet been elucidated, but diagnosed with OLP by clinical manifestation and an immune reaction of cytotoxic T cells in is pathologic findings. We tested serum IgG levels against thought to be a main cause7-9. There are various factors that HSV-1 and 2, and performed PCR testing of biopsy affect such an immune reaction, including allergens, drugs, specimens for HSV. Additionally, we assessed the treatment and viruses10, 11. Other hypotheses regarding its pathogenesis effect of an oral anti-viral agent for OLP. Results: Serum include consistent irritation due to dentures or amalgams, HSV-1, 2 IgG levels were markedly elevated in the OLP drug response, infection, an autoimmune condition, and subjects. HSV DNA was not found in the PCR biopsy genetic polymorphism12-15. One prominent hypothesis states specimens. Eight out of thirteen subjects(61.5%) who took that oral infection is involved in initiating OLP. Herpes oral acyclovir improved in subjective symptoms and simplex virus (HSV) infection is the most common objective manifestations. OLP patients treated with infectious disease in the oral mucosa of adults, and conventional treatments showed improvement in 58.8%. frequently recurs due to psychological or physical stress. We Conclusions: Although we did not observe decisive findings, performed this research to find out whether HSV infection is such as a positive HSV-PCR result, to establish a link relevant to the occurrence of OLP, and if antiviral treatment between HSV and OLP, we did observe an increase in HSV could be used as an alternative treatment option for OLP. IgG levels and a therapeutic response to oral acyclovir in subjects with OLP. Keywords Oral Lichen Planus, Herpes Simplex Virus, 2. Methods Acyclovir 2.1. Subjects

This study was conducted with 30 adult OLP patients over 1 . Background 30 years of age who visited the Department of Dermatology, Wonju Severance Christian Hospital over a seven-year Lichen planus, first reported by Erasmus Wilson in 1869, period (2005 to 2011). The subjects were diagnosed with is a mucocutaneous disease that involves skin, oral, and OLP through characteristic clinical features and genital mucosa, hair follicles of the scalp, and finger nails1. histopathological findings. Serum IgG to HSV-1 Among these, oral lichen planus (OLP) is a chronic and HSV-2 were tested. And the subjects who did not show inflammatory disease of unknown cause that occurs in the response to conventional treatment such as , oral mucous. It is a relatively common disease in oral intralesional steroid injection, topical calcineurin inhibitor mucosa that appears in approximately 1-2% of the were treated with oral acyclovir. Control group were treated population. OLP affects mostly adults in their 40s and 50s, with conventional treatments (Fig. 1). 26 Relevance of Herpes Simplex Virus Infection to Oral Lichen Planus

Figure 1. The clinical manifestations and histopathological findings of patient Reticulated white streaks () on reddish patches were observed in gingival mucosa of patient 3(a), and in buccal mucosa of patient 10(b). Histopathological findings showed acanthosis with saw-tooth rete ridges, basal degeneration, and band-like infiltration of in the upper in patient 3 (c: H&E x40, d: H&E x 100). 2.2. History Taking and Physical Examinations 2.4. Evaluation of response to treatment We obtained information on the subjects’ subjective and Oral acyclovir was prescribed to the OLP subjects (400mg objective symptoms, disease duration, medical history, and daily) who did not show improvement by conventional treatment history by reviewing medical records, and added treatments. All patients were periodically assessed the the clinical manifestations of OLP using photographs. improvements to the OLP and subjective symptoms.

2.3. Histopathology and HSV-PCR Study 3. Results Biopsies were done on the OLP subjects’ lesions. Based on characteristic clinical manifestations and typical 3.1. Epidemiological and Clinical Characteristics of histopathology, we confirmed OLP in the subjects. Using the Subjects biopsied specimens, polymerase chain reaction (PCR) testing was done to detect HSV DNA. The DNA of Among the OLP subjects, thirteen were female and HSV-infected cells was used as a positive control. The DNA seventeen were male, and their average age was 57.6 years. of normal tonsil tissue or distilled water was used as a The disease duration of OLP varied from several weeks to 10 5' 3' negative control. GCG CTT GTC ATT ACC ACC GC years, with 19.4 months on average. Among the 30 patients, 5' 3' and TAC CCG AGC CGA TGA CTT AC were used as thirteen had developed OLP in their 50s and six in their 60s, primers. We encased the extracted template DNA in a composing more than half the subjects. Most common microcentrifuge tube and added 1X PCR buffer. These clinical type was reticular type(61.5% in antiviral treated samples were denatured in a thermal cycler at 94 for 5 group, 58.8% in control group) and followed by erosive and minutes. We read the 118 base pair PCR band to confirm atrophic type. In antiviral treated group, erosive and atrophic HSV DNA. ℃ type was 23.1% and 15.4% respectively. In control group, they were 29.4% and 5.9% (Table 1). All the subjects complained of pain and burning sensations in the oral mucosa and could not eat either spicy or hot food. Universal Journal of Medical Science 2(3): 25-30, 2014 27

Table 1. Clinical types and previous treatment of enrolled patients with oral lichen planus Antiviral treatment Conventional treatment group(n=13) group(n=17) Age(mean±S.D : years) 55.4±12.0 59.3±12.8 Sex Male 5 (38.5%) 12 (70.6%) Female 8 (61.5%) 5 (29.4%) Duration(mean±S.D : months) 21.2±27.5 17.6±22.9 Clinical types Reticular 8 (61.5%) 10 (58.8%) Atrophic 2 (15.4%) 2 (11.8%) Erosive 3 (23.1%) 5 (29.4%) Previous treatments Topical steroid 10 5 Intralesional steroid injection 4 9 Topical calcineurin inhibitor 1 4 Cryotherapy 0 8

3.2. Serologic HSV IgG Test and HSV-PCR calcineurin inhibitor. We regarded as no response if there Using Biopsy Tissues was no improvement to more than 3 months of conventional treatments. The patients who did not respond to these We examined the HSV-1 and HSV-2 IgG titers in therapies were treated with antiviral agent. The intralesional seventeen patients, the average of HSV-1 and HSV-2 IgG steroid injection was most commonly used treatment remedy, titer was 4209.15 and 1071.61, respectively. These were followed by cryotherapy, treatment with topical steroids. In 10.5-fold higher and 3.5-fold higher than normal range. In thirteen subjects, daily acyclovir (400 mg) was prescribed, the PCR on HSV DNA performed with tissue specimens they took acyclovir for about 4.3months. In 61.5% of taken from the 11 OLP subjects, HSV DNA was not found in patients who underwent antiviral treatment, the symptoms all subjects. and lesions were improved and about 23.1% showed marked improvement. In patients who treated with only conventional 3.3. Response of OLP to Treatments therapies, the symptoms were improved in 58.8% and 5.9% of patients showed marked improved (Fig. 2) (Table 2). All patients underwent with conventional treatment such as topical steroid, intralesional steroid injection, topical

Table 2. Response of OLP patients to treatment Antiviral treatment Conventional treatment group (n=13) group (n=17) No 5 (38.5%) 7 (41.2%) Mild 5 (38.5%) 3 (17.6%) Moderate - 3 (17.6%) Much 3 (23.1%) 1 (5.9%) * No: no response, Mild: improvement < 30% Moderate: 30% < improvement < 60%, Much: 60% < improvement 28 Relevance of Herpes Simplex Virus Infection to Oral Lichen Planus

Figure 2. The OLP lesion after the treatment with oral acyclovir After five months of treatment with oral acyclovir (400mg daily), the OLP lesion on the lower was much improved in patient 11 (a: before the treatment, b: after the treatment). 4. Discussion reported that the mucosal LP is associated with autoimmune , such as thyroid disease, Sjogren syndrome, HSV infection is one of the most common oral infectious multiple sclerosis. A study reported that about 28% of diseases and recurs depending on a patient’s level of stress mucosal LP patients had at least one more autoimmune and body condition. We have observed that some OLP disease and thyroid antibody was significantly higher in OLP patients improved after oral antiviral therapy. Although we patients than healthy control14. There are also some studies did not experience the recurrence of typical examining infectious causes of OLP. Ebrahimi et al. reported symptoms of herpetic , we intended to that the antibodies against HSV were observed in higher rate study whether HSV infections could play a role in than control and patients with significantly higher titers had the occurrence of OLP. We evaluated HSV-1 and HSV-2 more oral symptoms and signs than the other patients14. IgG levels in the blood of 17 OLP subjects, and carried out There are some reports linking OLP with chronic hepatitis HSV-PCR testing with biopsy tissues in 11 OLP patients. C21, 22. According to one study, the frequency of CYP2D6*4 We also reviewed the response of OLP to antiviral therapy. allele polymorphism of cytochrome P450 was high, and The results of HSV-PCR testing came out negative for all molecular mimicry existed between CYP2D6*4 WT protein tissues. Brice conducted HSV-PCR in lesional tissue to and autoimmune hepatitis type 213. Since the relevance observe the relevance of HSV in multiforme between OLP and HCV has been reported previously, a patients. He reported that HSV DNA was found in erythema hypothesis that a sequence homology between CYP2D6*4 16, 17 multiforme tissue . Therefore, the fact that HSV DNA WT protein and HCV protein as a pathogenesis of OLP was was not detected in any of the biopsied specimens of OLP raised. They argued that CYP2D6*4 WT protein has a with HSV-PCR leads us to infer that HSV infection is not similar sequence to HSV type 1, and that HSV infection and directly related to OLP occurrence. CYP2D6*4 polymorphism may be a pathogenesis of OLP13. Serum HSV-1 and HSV-2 IgG antibody testing showed Based on this argument, they performed genotyping of that the HSV-1 IgG titer increased in all of tested OLP CYP2D6*4 with collected whole blood of a subject, but subjects and HSV-2 IgG increased in seven(41.2%) OLP polymorphism of the CYP2D6*4 allele was not found (data subjects. However, normal, healthy individuals also not shown). We infer that ethnic differences related to produced IgG antibodies against HSV-1 and HSV-2. In one CYP2D6*4 allele gene sequences might have affected the Korean study, every Korean adult subject above thirty years result. That is, polymorphism of the CYP2D6*4 allele that of age had IgG antibodies against HSV-1, and 12-13% of was found in Western OLP subjects could not be found in 18 them had IgG antibodies against HSV-2 . Malkin et al. Korean OLP subjects. But, these results could come from the reported that approximately 67% of French adults have IgG racial difference between Korean and Westerner. Thus, antibodies against HSV-1, and approximately 17.2% have further studies about specific SNP that involved in OLP 19 IgG antibodies against HSV-2 . We have noted that an pathogenesis are needed. increase in HSV IgG titer of more than 5- to 6-fold over the A standard treatment for OLP has not yet been established. normal range indicates recurrent infection. Per Juto et al. Because OLP treatment should primarily focus on reported that the IgG titers were higher in recurrent herpetic preventing symptom aggravation and improving erosive infections than in primary, in contrast to IgM of which much lesions, avoiding aggravating factors such as physical 20 higher titers were found in primary infections . Our OLP damage or chemical irritation would be a base of treatment. subjects had IgG antibody levels against HSV-1 more than Since smoking is known as one of the major factors that 10-fold the normal titer, and in the case of HSV-2 more than exacerbates OLP, it is crucial to quit smoking3-5. There are 3-fold. various treatments currently being used, and the most Exact pathogenesis of OLP is still not known. But, it is common method is to apply a topical that is Universal Journal of Medical Science 2(3): 25-30, 2014 29 above mid-potency, 3-4 times a day1, 3, 4. When the lesion is Conflict of Interests severe, it is possible to try systemic corticosteroid therapy for a short period of time. Topical calcineurin inhibitors This study was supported by a grant from Yonsei (, ) have also been used effectively University Wonju College of Medicine (2012-5-5061). in cases that do not respond to topical . The authors have no conflict of interest to disclose. Prior Topical could be used as a second choice23, 24. Since presentation: none we have observed that OLP improves after oral antiviral therapy, we prescribed oral acyclovir to OLP subjects with highly elevated HSV IgG levels. As a result, eight out of thirteen subjects showed improvements to subjective symptoms and clinical lesions. 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