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INTRODUCTION
Oral lichen planus (OLP) is defined as a T-cell mediated inflammatory disease of the oral mucosa1. OLP is a chronic disease and it rarely undergo spontaneous remission, and it has the potential to become malignant2. The conventional treatments for OLP are topical and systemic corticosteroids, mycophenolate mofetil, cyclosporine, methotrexate, dapsone, griseofulvin, retinoids, pimecrolimus, tacrolimus, PUVA, 308 nm-excimer laser, hydroxychloroquine and low molecular weight heparin (enoxaparin)3-13. Most patients have been treated with steroids, yet many patients who have underlying diseases such as diabetes, hypertension and malignancy have limitations for using immunosuppressants.
During the last decade, there have been several reports demonstrating the success with using levamisole and low dose prednisolone therapy for oral lichen planus14-16. Indeed, the patients with OLP showed a dramatic response to this therapy14,15. Levamisole is an effective immunomodulating agent that can restore the normal phagocytic activity of macrophages and neutrophils, it modulates T-cell mediated immunity and it potentiates the activity of human interferon17-21. It is used to treat several malignancies and autoimmune diseases (for example, rheumatoid arthritis and systemic lupus erythematosus), vitiligo and viral warts22-29.
In this article, we present a case series for evaluating levamisole monotherapy without steroids for treating OLP.
MATERIALS AND METHODS
Retrospective chart review
We performed a retrospective medical chart review of 11 patients who were diagnosed with OLP and we subsequently treated these patients with levamisole monotherapy at the Dermatology Department of Wonkwang University Hospital from 2005 to 2007. This study was approved by the Institutional Review Board at Wonkwang University Hospital, Iksan, Korea. The diagnosis of OLP was made by the clinical history, the physical examination and the histopathologic findings. Any patients who had an OLP-like lesion induced by drugs or dental prosthetics were excluded from the study. All the patients had drug washout periods of 3 months. On the retrospective chart review, we obtained the following information: the disease site, the disease duration, the previous treatment, the subjective and objective clinical responses to levamisole monotherapy, the adverse effects during levamisole monotherapy and the skin biopsy findings. Before the initiation of levamisole monotherapy, we performed a baseline complete blood cell count, liver and kidney function tests and chest x-ray. A blood test was performed once a month and a skin biopsy was performed in the event of a reticulated or ulcerated lesion.
The levamisole was administered at a dose of 50 mg thrice daily for three consecutive days, and then it was not administered on the following four days. This treatment cycle was repeated until the OLP oral lesion was cleaned out. Every patient was evaluated every 2 weeks, and they were evaluated again at least 3 months.
Based on objective clinical improvement, which was retrospectively analyzed by the patients' charts and the clinical photos, the patients were categorized as having achieved complete clearance, a partial response or no changes. One hundred percent remission of the patch and erosion was defined as complete clearance. A partial response was defined when some lesions of the patch or the erosion were remitted on physician's gross examination. No improvement or worsening of the disease was defined as no change. Treatment failure was classified as those patients who had no clinical improvement at least once during treatment over a 3 month period. The lesions that recurred after complete or partial improvement were counted as a complete or partial response, and we recorded the disease free-duration and the number of recurrences.
RESULTS
Eleven patients were diagnosed as having OLP and they were treated with levamisole monotherapy. Eight patients (72.7%) were female and the mean age of all the patients was 42.6 years (range: 20~61 years). The mean duration of OLP was 20.8 months (range: 3 months~5 years). All the patients had OLP on the buccal mucosa, except patient #1 who had OLP on the tongue base. All the patients had a whitish reticulated patch, except 1 patient who had an ulcerated patch. Three patients had dental prosthetics, but these dental prosthetics were not the cause of the OLP because of the distance between the oral lesion and the dental prosthetics (Table 1).
After 2 weeks of treatment, 8 patients (55%) showed a partial response (Fig. 1) and 3 patients had no response. No patient had complete clearance of lesion. Patient #4 had mild itching after receiving the medication, but the itching was controlled with antihistamine medication (Table 2).
After 4 weeks of treatment, 6 patients (72.7%) showed a partial response, 2 patients (18.2%) had complete clearance and 3 patients again showed no response (Table 2). After 3 months of treatment, 3 patients (72.7%) showed a partial response and 5 patients (45.5%) showed complete clearance. However, 3 patients showed no response, so they were defined as treatment failures. Interestingly, the disease duration of the patients who showed no response was shorter than that of the patients who had a response (Table 2).
Eight patients, except 3 patients who had no response, showed clinical improvement at the next visit (after 2 weeks). Complete clearance occurred in 5 patients and their treatment duration was 3 weeks to 3 months (mean: 6.2 weeks). However, patient #1 had several recurrences. During the 2 year follow up period, patient #1 had a total of 6 recurrences, but the lengths of disease free periods were increased.
No patient had any significant side effects or laboratory changes. Patient #4 had mild itching after receiving medication at week 2, but this resolved quickly with the use of an antihistamine (Table 3).
DISCUSSION
Oral lichen planus is a chronic and troublesome inflammatory oral disease. Even though there are many treatment options available for OLP, it is very hard to effectively treat this malady.
Levamisole is a levisomer of tetramisole ((-)-2,3,5,6-tetrahydro-6-phenylimidazole [2,1-6] thiazole monohydrochloride), and has been used as a broad spectrum anti-helminthic drug since 1966.
In 1978, Renoux et al.30 reported that levamisole increased cellular immunity. In 1990, the FDA approved levamisole for many autoimmune and inflammatory diseases. Levamisole is currently used for the treatment of vitiligo, viral warts, systemic lupus erythematosus, rheumatoid arthritis and colon cancer22-29.
The first treatment trial of levamisole for OLP was conducted by Lu et al.14 in 1995. In that trial, 23 patients were treated with levamisole (150 mg/d, 3 times per week) and low dose prednisolone. After 2 weeks of treatment, 12 patients showed over 80% improvement, whereas 11 patients showed no response. After 4 weeks of treatment, 23 patients had over 80% improvement and the remission duration was 9.5 months. Because most of the OLP patients in our trial had many underlying diseases, they were restricted from taking steroids, so we tried to treat the OLP without steroids. In our study, after 2 weeks of levamisole monotherapy, 6/11 patients (55%) showed clinical improvement. After 4 weeks of treatment, 2 patients (18.2%) showed complete clearance and 8 patients (73%) showed clinical improvement. After 3 months of treatment, 5 patients (45.4%) showed complete clearance of lesion. However, 3 patients showed no response from the initiation of this therapy.
The treatment effect of levamisole monotherapy might be lower and slower than that of levamisole combined with low dose prednisone. Nevertheless, levamisole monotherapy was shown to be effective for the treatment of OLP. Therefore, levamisole monotherapy can be recommended for those OLP patients who are unable to take steroids.
The number of patients who showed no response was 3. Interestingly, they had a short duration of disease (3, 6 and 6 months, respectively). The mean disease duration of the responders was 26.8 months and they had undergone many treatment trials with no response. At this point, we thought that levamisole monotherapy was a first line drug for treating these chronic OLP patients.
Only 1 patient had an adverse effect, which was itching after receiving medication. This was resolved by using an antihistamine (hydroxyzine Hcl). Levamisole has been reported to have many adverse effects such as nausea, vomiting, fever, dizziness, headache, tiredness, skin rash, anaphylaxis and most severely, agranulocytosis20,21,30-33. Agranulocytosis is commonly seen in those patients with HLA-B27 positivity and in those patients who have undergone long term levamisole therapy32,33. For this reason, levamisole is usually recommended for intermittent use. In rheumatoid arthritis patients, the number of agranulocytosis cases decreased after receiving levamisole 1~2 times a week, and the levamisole showed equivalent efficacy with levamisole continuous therapy34. Therefore, we recommend using levamisole (150 mg/d) 3 times a week with regular blood test monitoring.
In conclusion, we report that levamisole monotherapy is effective for treating OLP patients who are unable to use steroids and who had no response to conventional treatment.
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