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Dramatic response to levamisole and low-dose prednisolone in 23 patients with oral lichen planus
Dramatic response to levamisole and low-dose prednisolone in 23 patients with oral lichen planus A 6-year prospective follow-up study Shin-Yu Lu, DDS, a Wei-Jen Chen, MD, b and Hock-Liew Eng, MD, c Taiwan, Republic of China GHANG GUNG MEMORIAL HOSPITAL, KAOHSIUNG MEDICAL CENTER
The purpose of this prospective study was to evaluate the short-term and long-term clinical efficacy of levamisole used with low-dose prednisolone in patients with refractory oral lichen planus. Twenty-three patients with OLP who had been treated unsuccessfully with other modalities were given 150 mg/day levamisole and 15 mg/day prednisolone for 3 consecutive days each week. Twelve patients showed dramatic remission of signs and symptoms within 2 weeks, whereas 11 had partial remission. All 23 reported significant pain relief and showed no evidence of erosive oral lichen planus after 4 to 6 weeks of treatment. All 23 also remained free from symptoms for 6 to 9 months after the treatment ended. There were few side effects from this treatment besides minor skin rash, headache, and insomnia from the levamisole in three cases. We conclude that the addition of levamisole to prednisolone may produce improved results in the management of erosive oral lichen planus. (ORALSURCORALMt:D ORAL PATHOLORALRAOIOLENDOD
1995;80:705-9)
Levamisole, the levisomer of tetramisole, was developed in 1966 and put to extensive use worldwide in both humans and domestic animals as an antihelmintic drug. It attracted interest as an effective agent in diseases in which cellular immune deficiency was suspected such as chronic and recurrent infections, primary and secondary immune deficiencies, rheumatoid arthritis, and in stabilization of tumor remission in cancer. 1-9 Studies have indicated that levamisole (1) restores normal phagocytic activity of macrophages and neutrophils, (2) immunomodulates or immunopotentiates host defenses (T cell-mediated immunity), (3) potentiates the activity of human interferon and interleukin-2, (4) inhibits fumarate reductase, (5) potently inhibits mammalian alkaline phosphatase, (6) inhibits aerobic tumor glycolysis, and (7) alters the natural course of chronic, recurrent, inflammatory diseases. 8-14 Oral lichen planus (OLP), a relatively common, chronic, inflammatory mucocutaneous disease of unknown cause, is often recalcitrant to therapeutic meaaClinical director, Department of Oral Medicine and Oral Diagnosis, Chang Gung Memorial Hospital, Kaohsiung Medical Center. bprofessor and Director of Pathology Department, Chang Gung Memorial Hospital, Kaohsiung Medical Center. CLecturer and pathologist, Chang Gung Memorial Hospital, Kaohsiung Medical Center. Received for publication July 27, 1994; returned for revision Aug. 19, 1994; accepted for publication Nov. 2, 1994. Copyright 9 1995 by Mosby-Year Book, Inc. 1079-2104/95/$5.00 + 0 7/14/62635
sures. 2 A 28-year-old female patient with biopsyproven severe erosive lichen planus who had been unsuccessfully treated with a daily high dose of prednisolone (120 to 60 mg) in an attempt to control her nephrotic syndrome was given levamisole at 150 rag/ day for 3 days each week. Unexpectedly, she showed dramatic improvement as seen by complete remission of the signs and symptoms of OLP within 2 weeks of the initiation of the two-drug regimen. The prednisolone was then tapered to the minimum effective dose (40 mg) necessary to control her nephrotic syndrome (Fig. 1). These findings suggested that use of levamisole in conjunction with prednisolone might both enhance disease control and facilitate a reduction of the prednisolone treatment dose. We therefore undertook a clinical trial to assess the benefits and clinical efficacy of the combination of prednisolone and levamisole in the treatment of OLP.
MATERIALAND METHODS Patients Twenty-three patients with OLP seen at the oral medicine clinic at Chang Gung Memorial Hospital, Kaohsiung Medical Center, composed the study group. Diagnosis was confirmed by clinical signs and biopsy findings. The clinical characteristics of this patient population are described in Table I. Patients participating in this study were those who for years had reported pain or discomfort associated with the diagnosis of OLP and who used no systemic medications, because some medications have been implicated in lichenoid reactions. 705
706
Lu, Chen, and Eng
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY December 1995
Fig. 1. Twenty-eight-year-old Chinese woman with 2-year history of nephrotic syndrome and 1-year history of persistent oral lichen planus. Notice severe gingival atrophic lichen planus (A), erosions and ulcers with peripheral striae on vermilion border of lower lip (B), and erosions and papular and plaque-type lesions on buccal mucosa (C). Dramatic resolution of oral lesions was seen by second week of therapy (D-F).
Treatment protocol Levamisole administered 50 mg three times a day and prednisolone administered 5 mg three times a day for 3 consecutive days per week were used as long as evidence of symptomatic OLP was seen. Patients were monitored once a week for the first 2 months and once a month thereafter for recording of clinical responses and side effects. Patients were given a special sheet to record days when pills were taken and to record the progression of disease and onset of new
outbreaks. With regard to clinical efficacy, 80% to 100% remission of signs and symptoms (Fig. 2) and a reduction in pain was defined as a dramatic response (DR). Partial response (PR) ranged from mild (50%) to marked (75%) remission of signs and symptoms with a reduction in the pain. No response or worsening of the disease was noted as NR. After a patient showed a dramatic response, we prescribed maintenance therapy for 2 weeks and then stopped all medication. The disease-free period was
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 80, Number 6 Table I. Age and sex distribution of 23 patients with OLP
Age (Yrs) 25-35 36-45 46-55 56-65 66-75 Total Percent
I
] Women
Men
Total
1 3 5 7 3 19 82
0 1 2 0 1 4 18
1 4 7 7 4 23
Lu, Chen, and Eng
Table II. Disease activity during the treatment of levamisole plus prednisolone
Disease (yrs) 2 2.5 3.5 3 4.5
707
[ Response within 2 weeks Response within 4 weeks Remission period (mo)
DR 12 22 9.5
J
PR 11 1' 6.3
I
NR 0 0 0
DR, Dramatic response (80% to 100% remission of symptoms and signs); PR, partial response (50% to 75% remission of symptoms and signs); NR, no response (unchanged or worsening of symptoms and signs). *Levamisole was discontinued after 3 weeks because of skin rash.
Average age 53 years.
recorded to assess the long-term effect of this regimen. RESUtTS As shown in Table II, 12 patients showed a dramatic response and 11 showed a partial response o f signs and symptoms within 2 weeks. Almost all exhibited a dramatic response after the whole treatment course of 4 to 6 weeks was complete and remained completely free from symptoms of disease from 6 to 9 months without any additional medication. Although the drug regimen did not cure OLP, all patients who initially responded to the combination therapy continued to do so whenever the drugs were reinstated. The time of response after initiation of therapy ranged from 1 to 4 weeks before effective clinical control was achieved. All patients showed marked improvement with resolution of erosions and ulcers. Response to treatment did not appear to be associated with site involvement (Table III). Side effects related to the levamisole included mild facial skin rash (one patient), headache (one patient), and insomnia (one patient). The reaction to levamisole was typically mild, and our study revealed very few contraindications to continuation of the regimen. No one showed complications related to prednisolone. DISCUSSION The purpose of our study was not to develop an optimal protocol for the treatment of OLP. Instead, our aim was to determine the effectiveness of levamisole as an aid in control of OLP. This open trial of systemic levamisole plus low-dose prednisolone in refractory erosive OLP showed both excellent objective and subjective therapeutic effects. The dosage schedule was simple enough for good patient compliance. The built-in resting time of 4 days a week helped avoid undesirable complications from longterm use of prednisolone. The patients indeed re-
Table Ill. Response within 2 weeks to levamisole plus prednisolone in 23 patients with OLP
Buccal mucosa BM + DG BM + lip BM + tongue
DR
PR
NR
Total
9 1 0 2
5 2 2 2
0 0 0 0
14 3 2 4
DR, Dramatic response (80% to 100% remission of symptoms and signs); PR, partial response (50% to 75% remission of symptoms and signs); NR, no response (unchanged or worsening of symptoms and signs); DG, desquamative gingivitis (gingival atrophic lichen planus); BM, buccal mucosa.
sponded within 1 to 4 weeks of initiation of the twodrug regimen, after which another 2-week maintenance therapy made for good disease control. Although minor side effects were caused by levamisole (skin rash, headache, insomnia), no one showed any complications from prednisolone. The study of patients with OLP reflects the problems encountered in conditions with no known curative treatment. 16-17 Many agents such as corticosteroids, vitamin A acid, griseofulvin, and cyclosporine have been helpful in managing OLP, 18-21 but in recalcitrant cases, when long-term systemic corticosteroids or retinoids are prescribed, the occurrence of side effects often limits their use. The high cost of effective doses of cyclosporine m a y limit its use as a monotherapeutic agent. 19-21 The systemic use of griseofulvin in the treatment of OLP yields inconsistent benefits, produces a delayed response, and has many adverse drug effects such as headache, nausea, vomiting, liver toxicity, possible carcinogenicity, and
teratogenicity.22-24
The literature has yet to recommend the use of levamisole in the treatment of OLP. In this open trial the combined use of levamisole with prednisolone appeared to be a beneficial modality in the control of severe oral lichen planus. The 3-day-a-week regimen seemed to reduce pain and resolve most of the ulcerations of erosive lichen planus. Before therapy, sig-
708
Lu, Chen, and Eng
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY December 1995
Fig. 2. Fifty-two-year-old Chinese woman with 4-year history of oral lichen planus. Notice diffuse erosions and ulcers with peripheral striae on buccal mucosa (A). Dramatic response with resolution of ulcerations was seen by second week of therapy (B). nificant discomfort and pain had been a problem for all 23 patients when they ate spicy foods, but this problem was greatly diminished after treatment, Twelve of 23 patients had dramatic relief of pain and disappearance of erosions, and 11 of 23 had a partial response within 2 weeks. After the 4- to 6-week course of treatment, all the patients had a 6- to 9-month remission period in which they had no symptoms. O f additional interest is that after partial control of oral lesions by systemic medication was achieved, further control with the topical use of triamcinolone was effective in maintaining or even augmenting the improvement. Analysis of these data showed that adjuvant therapy with levamisole plus low-dose prednisolone appears to reduce pain and facilitate the resolution of erosive OLP within a short period of time. This regimen provided more than 6 months of remission with no symptoms in this group of patients after a 4- to 6-week course of treatment. Although this regimen does not prevent recurrence, we found that booster doses could also achieve as rapid control as the initial treatment.
The interrupted schedule (3 days a week) provided a reduction of prednisolone side effects. The complications from levamisole were mild and tolerable in our study group. The side effects seemed to be doserelated and tended to disappear rapidly on withdrawal of the drug or with change in the medication schedule. Induced leukopenia is a possible severe adverse effect from levamisole, and periodic complete blood counts should be performed for patients on long-term treatment with this medication. The exact mechanism of action by which this combination works is not clear. Studies have shown significantly decreased serum levels of interferon-J3, reduced cytokine production of lymphocytes by interleukin-2 stimulation, weak lymphocyte blastogenesis, and cellular immunosuppression in patients with OLp.26, 27 However, levamisole has been shown to have immunoregulating properties that may influence host defenses (cell-mediated immune mechanisms) by restoring to normal the function of phagocytes and T lymphocytes in compromised hosts. The drug may also potentiate the activity of human interferon and
Lu, Chen, and Eng
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
709
Volume 80, Number 6
interleukin-2, both thought to be critical in the pathogenesis of lichen planus. 8-14,28-34 The information may explain why the combination of levamisole and prednisolone can produce the improved results in the management of erosive OLP. Prednisolone is a wellknown, anti-inflammatory, immunosuppressive drug that acts on lymphocytes, interfering with the inflammatory response. It is quite clear that the target cells acted upon by these two drugs are probably different. A tentative conclusion of this pilot study is that levamisole appears to alter the course of OLP treated with systemic prednisolone. We found that this corticosteroid-sparing, combination drug approach for patients with OLP seems to produce clinical control with diminution of the side effects related to longterm, high-dosage prednisolone. Although this treatment regimen appears promising, we realize that immunologically mediated disorders such as erosive lichen planus frequently undergo spontaneous remissions and exacerbations. For this reason this treatment protocol needs to be examined in a doubleblind, placebo-controlled fashion. REFERENCES 1. Moertel C, Fleming T, MacDonald J. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-8. 2. Lewinski U, Mavligib G, Hersh E. Cellular immune modulation after a single high dose of levamisole in patients with carcinoma. Cancer 1980;46:2185-94. 3. Lozoda F, Spitler L, Silverman S Jr. Clinical and immunologic responses to levamisole in 13 patients with erythema multiforme. Int J Immunopharmacol 1980;2:63-8. 4. Lozoda F. Levamisole in the treatment of erythema multiforme: a double-blind trial in 14 patients. ORAL SURG ORAL MED ORAL PATHOL 1982;53:28-31. 5. Lozoda F, Silverman S Jr, Cram D. Pemphigus vulgaris: a study of six cases treated with levamisole and prednisone. ORAL SURG ORAL MED ORAL PATHOL 1982;54:161-5. 6. Olson J, Silverman S Jr. Double-blind study of levamisole therapy in recurrent aphthous stomatitis. J Oral Pathol 1978; 7:393-9. 7. Schuemans Y. Levamisole in rheumatoid arthritis. Lancet 1975;1:111. 8. Redondo JM, Lopez-Guerrero JA, Fresno M. Potentiation of interleukin-2 activity by levamisole and imidazole. Immunol Lett 1978;4:31-41. 9. Veys E, Mielants H. Experience and recommendations for treatment schedule of levamisole to rheumatoid arthritis. J Rheumatol 1978;4(Suppl):S31-$41. 10. Scully C, E1 Kom M. Lichen planus: review and update on pathogenesis. J Oral Pathol 1985;14:431-58. 11. Treatment of oral lichen planus [Editorial Review]. Lancet 1990;336:913-4. 12. Munoz A, Garcia RA, Perez-Aranda A. Potentiation by levamisole, methisoprinol, and adenine or adenosine of the inhibitory activity of human interferon against encephalomyocarditis virus. Antimicrob Agents Chemother 1986;30:192-5. 13. Janssen PA. The levamisole story. Prog Drug Res 1976;20: 347-83.
14. Guminska, Kedryna T, Marchut E. Effect of levamisole on energy metabolism in Erlich ascities tumor cells in vitro. Biochem Pharmacol 1986;35:4369-74. 15. Tyldesley WR. Oral lichen planus. Br J Ora! Surg 1974;11: 187-206. 16. Silverman S Jr, Lozoda F, Gorsky M; A prospective follow-up study of 570 patients with oral lichen planus: persistence, remission, and malignant association. ORAL SURG ORAL MED ORAL PATHOL 1985;60:30-4. 17. Holmstrup P, Pindborg JJ. Course of various clinical forms of lichen planus: a prospective follow-up study of 611 patients. J Oral Pathol 1988;17:213-8. 18. Lozoda F, Silverman S Jr, Miglierati C. Adverse side effects associated with prednisone in the treatment of patients with oral inflammatory ulcerative diseases. J Am Dent Assoc 1984; 109:269-70. 19. Eisen D, Griffiths CEM, Ellis CN. Cyclosporin wash for oral lichen planus [Letter]. Lancet 1990;335:535-6. 20. Eisen D, Ellis CN, Duell EA. Cyclosporin swish and spit improves oral lichen planus: a double-blind analysis. N Engl J Med 1990;323:290-4. 21. Ellis CN, Eisen D. Topical cyclosporine for oral mucosal disorders. J Am Acad Dermatol 1990;23:1259-64. 22. Aufdemorte TB, De Viella RL, Gieseker BS. Griseofulvin in the treatment of three cases of oral erosive lichen planus. ORAL SURG ORAL MED ORAL PATHOL 1983;55:459-62. 23. Massa MC, Rogers RS. Griseofulvin therapy of lichen planus. Acta Derm Venereol (Stockh) 1981;61:547-50. 24. Sehgal V, Abraham G. Griseofulvin therapy in lichen planus: a double blind controlled trial. Br J Dermatol 1972;87:3 83-5. 25. Rosenthal M, Breysse Y, Dixon A. Levamisole and agranulocytosis. Lancet 1977; 1:904-5. 26. Yamamoto T, Yoneda K, Ueta E, Osaki T. Cellular immunosuppression in oral lichen planus. J Oral Pathol Med 1990; 19:464-70. 27. Urata M, Yoshida H, Yanagawa T. Interferon activity and its characterization in the sera of patients with premalignant lesions arising in oral mucosa. Int J Oral Maxillofac Surg 1986;15:134-47. 28. Miller MF. Use of levamisole in recurrent aphthous stomatitis. Drugs 1980;20:131-6. 29. Veys E, Mielants H, De Bussere A. Levamisole and rheumatoid arthritis. Lancet 1976;1:808-9. 30. Abb F, Abb H. Effect of cyclosporin on human leukocyte interferon production: selection inhibition of IFN-gamma synthesis. Transplant Proc 1983;7:2380-2. 31. Nickoloff BJ. Role of interferon-gamma in cutaneous trafticking of lymphocytes with emphasis on molecular and cellular adhesion events. Arch Dermatol 1988;124:1835-43. 32. Walsh LJ, Savage NW. Immunopathogenesis of oral lichen planus. J Oral Pathol Med 1990;19:389-96. 33. Sugerman PB, Volty MJ. Phenotypic and functional analysis of peripheral blood lymphocytes in oral lichen planus. J Oral Pathol Med 1992;21:445-50. 34. Lin SC, Hahn LJ, Kwan HW. Subsets of T lymphocytes in peripheral blood of patients with oral lichen planus. Int J Oral Maxillofac Surg 1988;17:84-6.
Reprint requests: Shin-Yu Lu, DDS Chairperson Department of Dentistry Chang Gang Memorial Hospital Kaohsiung 123, Ta-Pei Rd., Niao-Sung Hsiang Kaohsiung Hsien, Taiwan Republic of China
The purpose of this prospective study was to evaluate the short-term and long-term clinical efficacy of levamisole used with low-dose prednisolone in patients with refractory oral lichen planus. Twenty-three patients with OLP who had been treated unsuccessfully with other modalities were given 150 mg/day levamisole and 15 mg/day prednisolone for 3 consecutive days each week. Twelve patients showed dramatic remission of signs and symptoms within 2 weeks, whereas 11 had partial remission. All 23 reported significant pain relief and showed no evidence of erosive oral lichen planus after 4 to 6 weeks of treatment. All 23 also remained free from symptoms for 6 to 9 months after the treatment ended. There were few side effects from this treatment besides minor skin rash, headache, and insomnia from the levamisole in three cases. We conclude that the addition of levamisole to prednisolone may produce improved results in the management of erosive oral lichen planus. (ORALSURCORALMt:D ORAL PATHOLORALRAOIOLENDOD
1995;80:705-9)
Levamisole, the levisomer of tetramisole, was developed in 1966 and put to extensive use worldwide in both humans and domestic animals as an antihelmintic drug. It attracted interest as an effective agent in diseases in which cellular immune deficiency was suspected such as chronic and recurrent infections, primary and secondary immune deficiencies, rheumatoid arthritis, and in stabilization of tumor remission in cancer. 1-9 Studies have indicated that levamisole (1) restores normal phagocytic activity of macrophages and neutrophils, (2) immunomodulates or immunopotentiates host defenses (T cell-mediated immunity), (3) potentiates the activity of human interferon and interleukin-2, (4) inhibits fumarate reductase, (5) potently inhibits mammalian alkaline phosphatase, (6) inhibits aerobic tumor glycolysis, and (7) alters the natural course of chronic, recurrent, inflammatory diseases. 8-14 Oral lichen planus (OLP), a relatively common, chronic, inflammatory mucocutaneous disease of unknown cause, is often recalcitrant to therapeutic meaaClinical director, Department of Oral Medicine and Oral Diagnosis, Chang Gung Memorial Hospital, Kaohsiung Medical Center. bprofessor and Director of Pathology Department, Chang Gung Memorial Hospital, Kaohsiung Medical Center. CLecturer and pathologist, Chang Gung Memorial Hospital, Kaohsiung Medical Center. Received for publication July 27, 1994; returned for revision Aug. 19, 1994; accepted for publication Nov. 2, 1994. Copyright 9 1995 by Mosby-Year Book, Inc. 1079-2104/95/$5.00 + 0 7/14/62635
sures. 2 A 28-year-old female patient with biopsyproven severe erosive lichen planus who had been unsuccessfully treated with a daily high dose of prednisolone (120 to 60 mg) in an attempt to control her nephrotic syndrome was given levamisole at 150 rag/ day for 3 days each week. Unexpectedly, she showed dramatic improvement as seen by complete remission of the signs and symptoms of OLP within 2 weeks of the initiation of the two-drug regimen. The prednisolone was then tapered to the minimum effective dose (40 mg) necessary to control her nephrotic syndrome (Fig. 1). These findings suggested that use of levamisole in conjunction with prednisolone might both enhance disease control and facilitate a reduction of the prednisolone treatment dose. We therefore undertook a clinical trial to assess the benefits and clinical efficacy of the combination of prednisolone and levamisole in the treatment of OLP.
MATERIALAND METHODS Patients Twenty-three patients with OLP seen at the oral medicine clinic at Chang Gung Memorial Hospital, Kaohsiung Medical Center, composed the study group. Diagnosis was confirmed by clinical signs and biopsy findings. The clinical characteristics of this patient population are described in Table I. Patients participating in this study were those who for years had reported pain or discomfort associated with the diagnosis of OLP and who used no systemic medications, because some medications have been implicated in lichenoid reactions. 705
706
Lu, Chen, and Eng
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY December 1995
Fig. 1. Twenty-eight-year-old Chinese woman with 2-year history of nephrotic syndrome and 1-year history of persistent oral lichen planus. Notice severe gingival atrophic lichen planus (A), erosions and ulcers with peripheral striae on vermilion border of lower lip (B), and erosions and papular and plaque-type lesions on buccal mucosa (C). Dramatic resolution of oral lesions was seen by second week of therapy (D-F).
Treatment protocol Levamisole administered 50 mg three times a day and prednisolone administered 5 mg three times a day for 3 consecutive days per week were used as long as evidence of symptomatic OLP was seen. Patients were monitored once a week for the first 2 months and once a month thereafter for recording of clinical responses and side effects. Patients were given a special sheet to record days when pills were taken and to record the progression of disease and onset of new
outbreaks. With regard to clinical efficacy, 80% to 100% remission of signs and symptoms (Fig. 2) and a reduction in pain was defined as a dramatic response (DR). Partial response (PR) ranged from mild (50%) to marked (75%) remission of signs and symptoms with a reduction in the pain. No response or worsening of the disease was noted as NR. After a patient showed a dramatic response, we prescribed maintenance therapy for 2 weeks and then stopped all medication. The disease-free period was
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 80, Number 6 Table I. Age and sex distribution of 23 patients with OLP
Age (Yrs) 25-35 36-45 46-55 56-65 66-75 Total Percent
I
] Women
Men
Total
1 3 5 7 3 19 82
0 1 2 0 1 4 18
1 4 7 7 4 23
Lu, Chen, and Eng
Table II. Disease activity during the treatment of levamisole plus prednisolone
Disease (yrs) 2 2.5 3.5 3 4.5
707
[ Response within 2 weeks Response within 4 weeks Remission period (mo)
DR 12 22 9.5
J
PR 11 1' 6.3
I
NR 0 0 0
DR, Dramatic response (80% to 100% remission of symptoms and signs); PR, partial response (50% to 75% remission of symptoms and signs); NR, no response (unchanged or worsening of symptoms and signs). *Levamisole was discontinued after 3 weeks because of skin rash.
Average age 53 years.
recorded to assess the long-term effect of this regimen. RESUtTS As shown in Table II, 12 patients showed a dramatic response and 11 showed a partial response o f signs and symptoms within 2 weeks. Almost all exhibited a dramatic response after the whole treatment course of 4 to 6 weeks was complete and remained completely free from symptoms of disease from 6 to 9 months without any additional medication. Although the drug regimen did not cure OLP, all patients who initially responded to the combination therapy continued to do so whenever the drugs were reinstated. The time of response after initiation of therapy ranged from 1 to 4 weeks before effective clinical control was achieved. All patients showed marked improvement with resolution of erosions and ulcers. Response to treatment did not appear to be associated with site involvement (Table III). Side effects related to the levamisole included mild facial skin rash (one patient), headache (one patient), and insomnia (one patient). The reaction to levamisole was typically mild, and our study revealed very few contraindications to continuation of the regimen. No one showed complications related to prednisolone. DISCUSSION The purpose of our study was not to develop an optimal protocol for the treatment of OLP. Instead, our aim was to determine the effectiveness of levamisole as an aid in control of OLP. This open trial of systemic levamisole plus low-dose prednisolone in refractory erosive OLP showed both excellent objective and subjective therapeutic effects. The dosage schedule was simple enough for good patient compliance. The built-in resting time of 4 days a week helped avoid undesirable complications from longterm use of prednisolone. The patients indeed re-
Table Ill. Response within 2 weeks to levamisole plus prednisolone in 23 patients with OLP
Buccal mucosa BM + DG BM + lip BM + tongue
DR
PR
NR
Total
9 1 0 2
5 2 2 2
0 0 0 0
14 3 2 4
DR, Dramatic response (80% to 100% remission of symptoms and signs); PR, partial response (50% to 75% remission of symptoms and signs); NR, no response (unchanged or worsening of symptoms and signs); DG, desquamative gingivitis (gingival atrophic lichen planus); BM, buccal mucosa.
sponded within 1 to 4 weeks of initiation of the twodrug regimen, after which another 2-week maintenance therapy made for good disease control. Although minor side effects were caused by levamisole (skin rash, headache, insomnia), no one showed any complications from prednisolone. The study of patients with OLP reflects the problems encountered in conditions with no known curative treatment. 16-17 Many agents such as corticosteroids, vitamin A acid, griseofulvin, and cyclosporine have been helpful in managing OLP, 18-21 but in recalcitrant cases, when long-term systemic corticosteroids or retinoids are prescribed, the occurrence of side effects often limits their use. The high cost of effective doses of cyclosporine m a y limit its use as a monotherapeutic agent. 19-21 The systemic use of griseofulvin in the treatment of OLP yields inconsistent benefits, produces a delayed response, and has many adverse drug effects such as headache, nausea, vomiting, liver toxicity, possible carcinogenicity, and
teratogenicity.22-24
The literature has yet to recommend the use of levamisole in the treatment of OLP. In this open trial the combined use of levamisole with prednisolone appeared to be a beneficial modality in the control of severe oral lichen planus. The 3-day-a-week regimen seemed to reduce pain and resolve most of the ulcerations of erosive lichen planus. Before therapy, sig-
708
Lu, Chen, and Eng
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY December 1995
Fig. 2. Fifty-two-year-old Chinese woman with 4-year history of oral lichen planus. Notice diffuse erosions and ulcers with peripheral striae on buccal mucosa (A). Dramatic response with resolution of ulcerations was seen by second week of therapy (B). nificant discomfort and pain had been a problem for all 23 patients when they ate spicy foods, but this problem was greatly diminished after treatment, Twelve of 23 patients had dramatic relief of pain and disappearance of erosions, and 11 of 23 had a partial response within 2 weeks. After the 4- to 6-week course of treatment, all the patients had a 6- to 9-month remission period in which they had no symptoms. O f additional interest is that after partial control of oral lesions by systemic medication was achieved, further control with the topical use of triamcinolone was effective in maintaining or even augmenting the improvement. Analysis of these data showed that adjuvant therapy with levamisole plus low-dose prednisolone appears to reduce pain and facilitate the resolution of erosive OLP within a short period of time. This regimen provided more than 6 months of remission with no symptoms in this group of patients after a 4- to 6-week course of treatment. Although this regimen does not prevent recurrence, we found that booster doses could also achieve as rapid control as the initial treatment.
The interrupted schedule (3 days a week) provided a reduction of prednisolone side effects. The complications from levamisole were mild and tolerable in our study group. The side effects seemed to be doserelated and tended to disappear rapidly on withdrawal of the drug or with change in the medication schedule. Induced leukopenia is a possible severe adverse effect from levamisole, and periodic complete blood counts should be performed for patients on long-term treatment with this medication. The exact mechanism of action by which this combination works is not clear. Studies have shown significantly decreased serum levels of interferon-J3, reduced cytokine production of lymphocytes by interleukin-2 stimulation, weak lymphocyte blastogenesis, and cellular immunosuppression in patients with OLp.26, 27 However, levamisole has been shown to have immunoregulating properties that may influence host defenses (cell-mediated immune mechanisms) by restoring to normal the function of phagocytes and T lymphocytes in compromised hosts. The drug may also potentiate the activity of human interferon and
Lu, Chen, and Eng
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
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Volume 80, Number 6
interleukin-2, both thought to be critical in the pathogenesis of lichen planus. 8-14,28-34 The information may explain why the combination of levamisole and prednisolone can produce the improved results in the management of erosive OLP. Prednisolone is a wellknown, anti-inflammatory, immunosuppressive drug that acts on lymphocytes, interfering with the inflammatory response. It is quite clear that the target cells acted upon by these two drugs are probably different. A tentative conclusion of this pilot study is that levamisole appears to alter the course of OLP treated with systemic prednisolone. We found that this corticosteroid-sparing, combination drug approach for patients with OLP seems to produce clinical control with diminution of the side effects related to longterm, high-dosage prednisolone. Although this treatment regimen appears promising, we realize that immunologically mediated disorders such as erosive lichen planus frequently undergo spontaneous remissions and exacerbations. For this reason this treatment protocol needs to be examined in a doubleblind, placebo-controlled fashion. REFERENCES 1. Moertel C, Fleming T, MacDonald J. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-8. 2. Lewinski U, Mavligib G, Hersh E. Cellular immune modulation after a single high dose of levamisole in patients with carcinoma. Cancer 1980;46:2185-94. 3. Lozoda F, Spitler L, Silverman S Jr. Clinical and immunologic responses to levamisole in 13 patients with erythema multiforme. Int J Immunopharmacol 1980;2:63-8. 4. Lozoda F. Levamisole in the treatment of erythema multiforme: a double-blind trial in 14 patients. ORAL SURG ORAL MED ORAL PATHOL 1982;53:28-31. 5. Lozoda F, Silverman S Jr, Cram D. Pemphigus vulgaris: a study of six cases treated with levamisole and prednisone. ORAL SURG ORAL MED ORAL PATHOL 1982;54:161-5. 6. Olson J, Silverman S Jr. Double-blind study of levamisole therapy in recurrent aphthous stomatitis. J Oral Pathol 1978; 7:393-9. 7. Schuemans Y. Levamisole in rheumatoid arthritis. Lancet 1975;1:111. 8. Redondo JM, Lopez-Guerrero JA, Fresno M. Potentiation of interleukin-2 activity by levamisole and imidazole. Immunol Lett 1978;4:31-41. 9. Veys E, Mielants H. Experience and recommendations for treatment schedule of levamisole to rheumatoid arthritis. J Rheumatol 1978;4(Suppl):S31-$41. 10. Scully C, E1 Kom M. Lichen planus: review and update on pathogenesis. J Oral Pathol 1985;14:431-58. 11. Treatment of oral lichen planus [Editorial Review]. Lancet 1990;336:913-4. 12. Munoz A, Garcia RA, Perez-Aranda A. Potentiation by levamisole, methisoprinol, and adenine or adenosine of the inhibitory activity of human interferon against encephalomyocarditis virus. Antimicrob Agents Chemother 1986;30:192-5. 13. Janssen PA. The levamisole story. Prog Drug Res 1976;20: 347-83.
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Reprint requests: Shin-Yu Lu, DDS Chairperson Department of Dentistry Chang Gang Memorial Hospital Kaohsiung 123, Ta-Pei Rd., Niao-Sung Hsiang Kaohsiung Hsien, Taiwan Republic of China