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Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus
Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus F. Kaliakatsou, BDS, MSc,a T. A. Hodgson, FDS RCS, MRCP(UK),a J. D. Lewsey, PhD,b A. M. Hegarty, MSc, MFDS RCSI,a A. G. Murphy, MSc, B Pharm, MRPharmS,c and S. R. Porter, MD, PhD, FDS RCSEa London, United Kingdom Objective: Our purpose was to investigate the efficacy and safety of 0.1% topical tacrolimus in erosive or ulcerative oral lichen planus. Methods: This was an open-label, noncomparative study conducted in an outpatient oral medicine unit in London, United Kingdom. The study covered an 8-week period with a 22-week follow-up after cessation of therapy. Nineteen patients, aged 28 to 87 years with biopsy-proven oral lichen planus refractory to, or dependent on, systemic immunosuppressive agents, were enrolled. Seventeen patients (89%) completed the study. Application of 0.1% tacrolimus was administered to all symptomatic oral mucosal lesions. Clinical review took place 1, 3, 5, 7, and 8 weeks after commencing therapy. Alleviation of symptoms was evaluated by using a visual analogue scale as well as the McGill Pain and Oral Health Impact profile questionnaires. The extent of the oral mucosal erosion or ulceration was directly measured by the same clinician at all visits. Safety assessments included monitoring of adverse events, complete blood cell count, renal and hepatic clinical chemistry, and tacrolimus blood concentrations. Results: Tacrolimus caused a statistically significant improvement in symptoms within 1 week of commencement of therapy. A mean decrease of 73.3% occurred in the area of ulceration over the 8-week study period. Local irritation (in 6 subjects, 35%) was the most commonly reported adverse effect. Laboratory values showed no significant changes with time. Therapeutic levels of tacrolimus were demonstrated in 8 subjects but were unrelated to the extent of oral mucosal involvement. Thirteen of 17 patients suffered a relapse of oral lichen planus within 2 to 15 weeks of cessation of tacrolimus therapy. Conclusion: Topical tacrolimus is effective therapy for erosive or ulcerative oral lichen planus. (J Am Acad Dermatol 2002;46:35-41.)
L
ichen planus is a common chronic mucocutaneous disease, of uncertain origin, affecting 0.5% to 2.2% of studied populations.1-9 Oral lichen planus (OLP) may arise in more than 70% of persons with skin lesions, although it more commonly occurs as an isolated mucosal disorder.10,11 OLP is often asymptomatic; however, the erosive and ulcerative forms are often painful and interfere with eating, speech, and swallowing.1 A wide spectrum of theraFrom the Unit of Oral Medicinea and the Biostatistics Unit,b Eastman Dental Institute for Oral Health Care Sciences, University College London; and Pharmacy Technical Services, University College Hospital.c Funding: None. Conflicts of interest: None. Accepted for publication May 6, 2001. Reprints not available from authors. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 + 0 16/1/120535 doi:10.1067/mjd.2002.120535
pies has been proposed in the management of symptomatic OLP, but the majority have not been evaluated in randomized controlled clinical trials.12 Topical corticosteroids remain the mainstay of therapy.13 Systemic corticosteroids and other immunosuppressants are often used in the management of OLP, but their application is limited by the adverse effects associated with their long-term use. Symptomatic OLP may be refractory to all currently available therapies and new therapeutic agents require evaluation.13 Tacrolimus is a macrolide immunosuppressant that exerts an activity that is 10 to 100 times higher than that of cyclosporine in vitro.14 Its action occurs at a point in T-lymphocyte activation between T-cell receptor ligation and the transcription of early genes.14,15 Tacrolimus first found application in the prevention of allograft rejection.16 Significant therapeutic benefit has also been reported in the treatment of atopic and contact dermatitis,17-21 psoriasis,22 and pyoderma gangrenosum.23 35
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J AM ACAD DERMATOL JANUARY 2002
Table I. Previous medications used for the management of erosive/ulcerative lichen planus and scores before and after tacrolimus therapy for the Visual Analogue Scale (VAS) and the McGill Pain (McGill) and the Oral Health Impact Profile (OHIP) questionnaires for individual patients VAS
McGill
OHIP
Patient No.
Medications
Week 0
Week 8
Week 0
Week 8
Week 0
Week 8
1 2 3 4 5 6 7 8 9 11 13 14 15 16 17 18 19
1, 2, 5, 10, 12 1, 2,3, 4, 5, 11 1, 5, 11, 12 1, 2, 3, 5, 11, 12 1, 5, 7, 10, 12 1, 4, 5, 11 1, 5, 9, 11 1, 3, 5, 8, 11 1, 2, 3, 5, 10, 12 1, 2, 5, 7, 11, 12 1, 4, 7, 10, 12 1, 3, 5, 6, 7, 9, 10, 12, 13 1, 2, 3, 4, 5, 9, 10 1, 2, 4, 5, 11, 12 1, 5, 10, 12 1, 4, 5, 6, 11, 14 1, 2, 5, 9, 11
43 76 51 75 54 100 97 54 62 63 82 61 54 83 65 16 66
27 2 23 10 24 41 76 0 1 1 0 6 57 2 4 23 11
2 2 2 3 2 2 4 1 2 3 2 2 2 2 1 1 2
0 0 0 0 1 2 2 0 0 1 2 1 1 0 1 1 1
39 6 0 17 25 27 30 18 13 32 24 26 30 16 11 16 6
15 1 0 4 10 14 39 11 0 3 3 3 28 2 5 12 2
Key to medications: 1, Benzydamine hydrochloride 0.15% mouthrinse/spray two puffs as required; 2, triamcinolone acetonide 0.1% in Orabase applied 4 times daily to ulcerated/eroded areas; 3, hydrocortisone hemisuccinate lozenges 2.5 mg sucked 4 times daily; 4, fluticasone propionate 50 µg metered dose spray two puffs to oral lesions 4 times daily; 5, betamethasone sodium phosphate 0.5 mg tablet dissolved in 15 mL of water, used as a mouthrinse; held in mouth for 5 minutes 4 times daily and expectorated; 6, fluticasone propionate 0.05% cream applied sparingly to symptomatic lesions twice daily; 7, clobetasol propionate 0.05% ointment applied sparingly to symptomatic lesions twice daily; 8, cyclosporine in bioadhesive paste (concentration unknown as patient transferred from another center) applied sparingly to symptomatic lesions twice daily; 9, cyclosporine oral solution 100 mg/mL, 5 mL used as a mouth rinse 3 times daily; 10, deflazacort 1-60 mg daily; the dose varied depending on whether initiating therapy or maintenance regimen; 11, prednisolone 1-60 mg daily; the dose varied depending on whether initiating therapy or maintenance regimen; 12, azathioprine 50-200 mg daily; 13, pentoxifylline 400 mg 3 times daily; 14, mycophenolate mofetil 500 mg twice daily.
Recently topical tacrolimus was reported to be effective in the short-term management of 4 persons with severe recalcitrant OLP.24 The aims of the current investigation were to test the potential efficacy and safety of topical tacrolimus in the management of erosive or ulcerative OLP in a larger population.
MATERIAL AND METHODS The study was undertaken as an open clinical phase II trial in the Oral Medicine Unit of the Eastman Dental Institute for Oral Health and Sciences, London, United Kingdom. Ethical approval was obtained before commencement of the study. Tacrolimus ointment preparation Tacrolimus ointment was manufactured at a concentration of 0.1% in a paraffin ointment base.18 This formulation differs from that used for cutaneous application.19,20,25 The half-life of the preparation was unknown; therefore small quantities were produced every 3 to 4 weeks. All study patients
were asked to store the tacrolimus ointment in a cool dry place. Entry criteria Patients with biopsy-proven erosive or ulcerative OLP refractory to, or dependent on, systemic corticosteroid or immunosuppressive therapy were invited to join the study. Medications previously used to manage the patient’s oral mucosal disease are documented in Table I. None had a history of renal, hepatobiliary, or malignant disease; hypertension; or recurrent acute infection. Study design Prestudy assessment. Detailed information regarding the study protocol and tacrolimus therapy was given by verbal explanation and written document to each subject. Subsequently, informed consent was obtained. A minimum data set (patient age, gender, medical history, drug history, and habits) was documented. All topical and systemic medication previously prescribed for ulcerative OLP was
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J AM ACAD DERMATOL VOLUME 46, NUMBER 1
stopped a minimum of two weeks before the initiation of tacrolimus therapy. Benzydamine hydrochloride 0.15% mouthwash was prescribed for palliation of symptoms during this period.26 Subjective assessment. Each subject reported their response to therapy by completing a selfadministered assessment. This included the Visual Analogue Scale (VAS),27 which is a simple, reproducible instrument; it allows the severity of the pain experienced to be expressed as a numeric value. The VAS is represented as a plain horizontal 100-mm line. The patient is instructed to bisect the line at a point appropriate to their present discomfort. A zero value equates to being pain free, whereas the most severe pain they have experienced is rated at 100. The McGill Pain Questionnaire28 is an easily administered assessment of pain quality. The patient is presented with 5 descriptions of their present discomfort ranging from “no pain” to “excruciating”; the responses are rated from 0 to 5. The Oral Health Impact Profile (OHIP 14) Questionnaire29 is a measure of the negative impact of oral disease on a person’s general well-being and is reliable, valid, and precise. The impact, each rated from “never” to “very often,” of the oral problem on 14 distinct quality-of-life questions is assessed. The responses are summed, giving a minimum score of zero and maximum of 56. Clinician (objective) assessment. In this study an erosion was defined clinically as an area of mucosal erythema that was invariably associated with white striae. In contrast, an ulcerated area was represented as yellow/white sloughed inflammatory necrotic tissue secondary to a break in the continuity of the mucosal epithelium. The extent of eroded or ulcerated areas was recorded by using a scoring system based on a variation of criteria previously described30,31 (Table II). In addition, areas of erosion and ulceration were measured with a sterile flexible surgical ruler, recorded on a grid; the total surface area of the lesions was estimated in square millimeters. Clinical photographs were taken of all eroded or ulcerated regions. Schedule. Before the commencement of tacrolimus therapy (week 0), baseline subjective and objective assessments were recorded together with blood pressure, complete blood cell count (CBC), liver biochemistry, and levels of urea, electrolytes, and blood glucose. Each patient was instructed to sparingly apply 0.1% tacrolimus in hydrophilic petroleum ointment solely to their painful OLP lesions with clean fingers, twice daily for 8 weeks. It was recommended they should refrain from eating or drinking for 30 minutes after application. Tacrolimus therapy was discontinued for any lesion becoming
Table II. Clinical ranking system for erosive/ulcerative lichen planus Score
0 1 2 3 4 5
Clinical status
No lesion White striae only White striae and erosion <1 cm2 White striae and erosion >1 cm2 White striae and ulceration <1 cm2 White striae and ulceration >1 cm2
Modified from Thongaprassom K, Luangjarmekorn L, Severat T, Taweesap W (J Oral Pathol Med 1992;21:456-8) and Carbone M, Conrotto D, Carrozzo M, Broccoletti R, Gandolfo S, Scully C (Oral Dis 1999;5:44-9).
asymptomatic. The patients were reviewed by the same clinician at weeks 1, 3, 5, 7, and 8. At all subsequent review appointments subjective and objective assessments, blood pressure monitoring, phlebotomy, and any adverse effects were recorded. After completion of the 8-week study period, tacrolimus therapy was withdrawn. Benzydamine hydrochloride 0.15% mouthwash was prescribed for control of symptoms. All patients were reviewed 10, 14, 18, and 22 weeks after initial entry to the study. Systemic absorption of tacrolimus Tacrolimus absorption was monitored on weeks 5 and 8 of the study by the Imx Tacrolimus II assay based on microparticle enzyme immunoassay (MEIA) technology.32 Statistical analysis The VAS, OHIP, and lesion measurement scores were analyzed by paired t test. The differences in patients’ responses to the McGill Pain Questionnaire were analyzed by the Wilcoxon signed rank test.
RESULTS Study group Nineteen patients (14 women, 5 men; mean age, 62 years; range, 28-87 years) were enrolled in the study. Two patients withdrew after 3 weeks. One underwent surgical removal of a renal calculus; the other patient developed a recurrence of chronic maxillary sinusitis. These disorders were thought to be unrelated to tacrolimus therapy. Both patients had significant reduction of their OLP lesions during the 3-week period in which they received treatment, but they were not included in the final analysis. Relief of symptoms Tacrolimus significantly reduced painful symptoms as recorded on the VAS (Table I). All patients
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Fig 1. Mean VAS in 17 patients with OLP over 8-week period of topical tacrolimus therapy. Error bars represent 95% confidence interval.
Table III. The adverse effects of topical tacrolimus therapy used for oral lichen planus Adverse side effects
Tingling sensation in the mouth after application or when eating Burning sensation on the tongue when eating Altered taste sensation Slight nausea Mild headache Constipation
No. of patients
6 1 1 1 1 1
reported rapid relief from pain and had a significant reduction in VAS scores during the 8-week study period (Fig 1). The reduction in reported pain and discomfort experienced fell significantly even after 1 week of tacrolimus therapy (P < .001). All patients had a reduction in the McGill Pain Questionnaire scores and the group score had reduced significantly after 8 weeks of tacrolimus therapy (P < .001) (Table I). Finally, there was a 54.7% reduction in the OHIP group score, reflecting a significant improvement in the patient’s perception of the impact of their oral disease on their well-being (P < .001) (Table I). Change in clinical signs All 17 patients had a significant reduction in their ranking scale scores after 8 weeks of tacrolimus therapy (P < .002). There was a 73.3% reduction in the mean surface area of OLP lesions after 8 weeks of topical tacrolimus therapy (Fig 2). This reduction was highly statistically significant (P < .001). All
Fig 2. Mean total surface area of erosive and ulcerative lesions of 17 patients with OLP over 8-week period of tacrolimus therapy. Error bars represent 95% confidence interval.
patients had a reduction in lesion surface area (Fig 3); the reduction varied from 45% to 100%. The reduction in lesion surface area was found to be significant at the end of 1 week of therapy (P < .001). The greatest reduction in lesion area occurred in weeks 1 to 5, after which the clinical response plateaued. Examples of the clinical improvement in the ulcerative form of OLP are shown in Fig 4. Adverse side effects No serious adverse effects were observed during the 8-week study period. Seven of the 17 patients (41%) experienced no adverse side effects. Ten patients (59%) reported transient minor side effects (Table III). The paresthesia and burning-type sensation experienced by 7 subjects decreased within 72 hours of the cessation of tacrolimus therapy. The severity of local irritation decreased with a reduction in lesion size. The dysgeusia of one affected patient resolved within 48 hours of the cessation of tacrolimus treatment. Absorption of tacrolimus Eight of the 17 patients had systemic absorption within the therapeutic range (3-28.6 µg/L) (Table IV). None of these patients experienced any adverse side effects. The systemic absorption of tacrolimus after topical application was unrelated to the surface area of ulceration. Relapse after cessation of tacrolimus therapy After the cessation of topical treatment with tacrolimus ointment, 13 of the 17 patients (76.5%) suffered a relapse of OLP within 2 to 15 weeks; the mean time to relapse was 4 weeks. These 13 patients had an increase in both the total OLP sur-
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J AM ACAD DERMATOL VOLUME 46, NUMBER 1
Fig 3. Total surface area of lesions in 17 patients with OLP over 8-week period of topical tacrolimus therapy.
face area and VAS score. For the remaining 4 patients, their disease did not deteriorate after cessation of tacrolimus therapy. Two subjects continue to show improvement and two patients are still in remission.
DISCUSSION The results of this study indicate that topical tacrolimus is an effective and safe treatment for erosive or ulcerative OLP recalcitrant to topical and systemic corticosteroids or other immunosuppressants such as azathioprine. The mean duration of symptomatic OLP disease in the patient group was 6 years (range, 4 months-25 years); despite topical and systemic immunosuppressive pharmacotherapy, symptom control had been difficult if not impossible to achieve. Therefore, significantly extending the findings of Vente and colleagues,24 we have shown that topical tacrolimus treatment provides a safe and efficacious alternative to systemic immunosuppression in persons with recalcitrant OLP. This study was not placebo controlled; thus the positive outcomes may be exaggerated. Relief of symptoms may reflect the increased patient contact with an enthusiastic clinician. However, in patients with severe erosive or ulcerative OLP refractory to many previously documented medications, significant deterioration of symptoms over an 8-week period would occur in the absence of therapy. OLP characteristically follows an unpredictable course of exacerbation and remission.33 Therefore it could be argued that the clinical improvement in this cohort
Table IV. Maximum blood levels of tacrolimus in 17 patients with OLP over the 8-week study period (therapeutic range, 3-28.6 µg/L) Study No.
1 2 3 4 5 6 7 8 9 11 13 14 15 16 17 18 19
Maximum blood levels of tacrolimus (µg/L)
<2 4 11 <2 <2 4 11 <2 <3 3 7 4.2 3 2 9 <2 3
over the 8-week period is the result of the natural history of the disease. However, this is most unlikely in view of the highly significant changes in initial symptoms on the commencement of tacrolimus, the profound change in clinical signs after 8 weeks of therapy, and deterioration in 13 subjects after tacrolimus withdrawal.
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B
A
Fig 4. A, Mucosal ulceration on dorsum of tongue before topical tacrolimus therapy. B, Dorsum of tongue after 8 weeks of topical tacrolimus therapy.
The choice of carrier for the tacrolimus was principally white soft paraffin, as previously described in the successful treatment of 4 cases of erosive/ulcerative lichen planus.24 Because this agent does not adhere well to the oral mucosal surface, there may be some loss of the active agent. The formulation used in this study was based on a simple eye ointment. Wool fat in the formulation absorbs water, improves adherence to the oral mucosa, and aids wetting of the dispersed drug powder. There is a need to consider more effective methods of drug delivery. The use of polymers (eg, carmellose sodium that strongly adheres to the oral mucosa) might further enhance the formulation by prolonging drug-mucosa contact. However, it is not known whether this will reduce tacrolimus diffusion. The etiology of lichen planus is unknown, but an immune pathogenesis has been proposed.34 The effectiveness of tacrolimus in OLP may be the result of local inhibition of T-lymphocyte activation.14,35 Because 4 patients in the study group had detectable tacrolimus levels in blood, a systemic effect may also have occurred. One of these patients remained symptom free 22 weeks after cessation of tacrolimus therapy. This observation suggests that systemic administration may be an appropriate therapy in those patients who fail to respond to topical tacrolimus. This may be a potential method of disease modification. No patients had significant adverse effects with tacrolimus therapy in this 8-week study period. Local irritation appears to be the most commonly reported side effect of cutaneous topical tacrolimus therapy.25 This was also the most commonly reported adverse effect of oral mucosal application. The symptoms rapidly resolved after cessation of treatment and were regarded as a minor inconvenience by the patients. Adverse effects associated with systemic
absorption could not be confirmed. In the patients reporting nausea and constipation, systemic blood levels of tacrolimus were less than 21 µg/L during the treatment period. Unfortunately the therapeutic improvement associated with 8 weeks of topical tacrolimus treatment failed to be maintained after drug cessation in the majority of patients. It may be that once symptom control is achieved, a maintenance regimen may prevent relapse, but this requires further investigation. Reports of the benefits of topical cyclosporine, another calcineurin inhibitor, in the management of erosive/ulcerative lichen planus have been contradictory.36-39 The cost of topical tacrolimus treatment twice daily is one seventh the cost of topical cyclosporine elixir used as mouthwash 3 times daily. (assuming the average use of 0.1% tacrolimus ointment is 10 mL weekly and cyclosporine oral solution 100 mg/mL at 5 mL 3 times daily; $25 as opposed to $180). It is evident that topical tacrolimus may be an effective method of treating OLP that is recalcitrant to more established therapies in the short term. During an 8-week period, none of the patients in this study experienced any significant adverse effects. There is a need to undertake more detailed objective clinical studies to determine the exact benefits of tacrolimus when compared with conventional therapies including clobetasol30 and to examine the influence of different dose regimens and formulations. REFERENCES 1. Silverman S, Lozada-Nur F, Migliorati C. Clinical efficacy of prednisolone in the treatment of patients with oral inflammatory ulcerative diseases: a study of fifty-five patients. Oral Surg Oral Med Oral Pathol 1985;59:360-3. 2. Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus and other keratoses in 23,616 white Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol 1986;61:373-81.
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3. Axéll T. Occurrence of leukoplakia and some other white lesions among 20,333 adult Swedish people. Community Dent Oral Epidemiol 1987;15:46-51. 4. Axéll T, Rundquist G. Oral lichen planus: a demographic study. Community Dent Oral Epidemiol 1987;15:52-6. 5. Hogewind WFC, Van der Wall I. Prevalence study of leukoplakia in a selected population of 1000 patients from the Netherlands. Community Dent Oral Epidemiol 1988;16:302-5. 6. Salem G. Oral lichen planus among 4277 patients from Gizan, Saudi Arabia. Community Dent Oral Epidemiol 1989;17:322-4. 7. Axéll T, Zain RB, Siwamongstham P, Tantiniran D, Thampipit J. Prevalence of oral soft tissue lesions in out-patients at two Malaysian and Thai dental schools. Community Dent Oral Epidemiol 1990;18:95-9. 8. Borgelli RF, Pettiniari IL, Chuchurru JA, Stirparo MA. Oral lichen planus in patients with diabetes: an epidemiologic study. Oral Surg Qral Med Oral Pathol 1993;75:498-500. 9. Lozada-Nur F, Miranda C. Oral lichen planus: topical and systemic therapy. Semin Cutan Med Surg 1997;16:295-300. 10. Samman PD. Lichen planus: an analysis of 200 cases. Trans St Johns Hosp Derm Soc 1961;46:36. 11. Altman J, Perry HO. Variations and course of lichen planus. Arch Dermatol 1961;84:179. 12. Chan ES-Y, Thornhill M, Zakrzewska J. Interventions for treating oral lichen planus. In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software Ltd. 13. Scully C, Beyli M, Ferreiro MC, Ficarra G, Gill Y, Griffiths M, et al. Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med 1998;9:86-122. 14. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today 1992;13:136-42. 15. Glynne R, Akkaraju S, Healy JI, Rayner J, Goodnow CC, Mack DH. How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis. Nature 2000;403:672-7. 16. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989;2:1000-4. 17. Nakagawa H, Etoh T, Ishibashi Y, Higaki Y, Kawashima M, Torii H, et al. Tacrolimus ointment for atopic dermatitis. Lancet 1994; 24:883. 18. Ayoama H, Tabata N, Tanaka M, Uesugi Y, Tagami H. Successful treatment of resistant facial lesions of atopic dermatitis with 0.1% FK506 ointment. Br J Dermatol 1995;133:492-500. 19. Ruzicka T, Bieber T, Schopf E, Rubins A, Dobozy A, Bos JD, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997;337:816-21. 20. Alaiti S, Kang S, Fielder VC, Ellis CN, Spurlin DV, Fader D. Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol 1998;38:6976. 21. Ruzicka T, Assmann T, Homey B.Tacrolimus: the drug for the turn of the millennium? Arch Dermatol 1999;135:574-80. 22. Remitz A, Reitamo S, Erkko P, Granlund H, Lauerma AI. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol 1999;141:103-7.
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23. Schuppe HC, Homey B, Assmann T, Martens R, Ruzicka T. Topical tacrolimus for pyoderma gangrenosum. Lancet 1998;351:832. 24. Vente C, Reigh K, Rupprecht R, Neumann C. Erosive mucosal lichen planus: response to topical treatment with tacrolimus. Br J Dermatol 1999;140:338-42. 25. Reitamo S, Wollenberg A, Schopf E, Perrot JL, Marks R, Ruzicka T, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol 2000;136: 999-1006. 26. Mathews RW, Scully CM, Levers BG, Hislop WS. Clinical evaluation of benzydamine, chlorhexidine, and placebo mouthwashes in the management of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1987;63:189-91. 27. Scott J, Huskisson EC. Graphic presentation of pain. Pain 1976; 2:175-84. 28. Melzack R.The McGill Pain Questionnaire: major properties and scoring method. Pain 1975;1:277-99. 29. Slade GD. Derivation and validation of a short-form oral health impact profile. Community Dent Oral Epidemiol 1997;25:284-2. 30. Thongprassom K, Luangjarmekorn L, Severat T, Taweesap W. Relative efficacy of fluocinolone acetonide in treatment of oral lichen planus. J Oral Pathol Med 1992;21:456-8. 31. Carbone M, Conrotto D, Carrozzo M, Broccoletti R, Gandolfo S, Scully C. Topical corticosteroids in association with miconazole and chlorhexidine in the long-term management of atrophicerosive oral lichen planus: a placebo controlled and comparative study between clobetasol and fluocinonide. Oral Dis 1999; 5:44-9. 32. Alak AM, Moy S, Cook M, Lizak P, Niggebiugge A, Menard S, et al. An HPLC/MS/MS assay for tacrolimus in patient blood sample with results of an ELISA assay. J Pharm Biomed Anal 1997;16: 7-13. 33. Silverman S, Gorsky M, Lozada-Nur F, Giannotti K. A prospective study of findings and management in 214 patients with oral lichen planus. Oral Surg Oral Med Oral Pathol 1991;72:665-70. 34. Porter SR, Kirby A, Olsen I, Porter SR. Immunologic aspects of dermal and oral lichen planus: a review. Oral Surg Oral Med Oral Path Oral Radiol Endod 1997;83:358-66. 35. Sigal NH, Dumont FJ. Cyclosporine A, FK506 and rapamycin: pharmacological probes of lymphocyte signal transduction. Annu Rev Immunol 1992;10:519. 36. Jungell P, Malmstrom M. Cyclosporin A mouthwash in the treatment of oral lichen planus. Int J Oral Maxillofac Surg 1996;25: 60-2. 37. Eisen D, Ellis CN, Duell EA, Griffiths CE, Voorhees JJ. Effect of topical cyclosporine rinse on oral lichen planus: a double-blind analysis. N Engl J Med 1990;323:290-4. 38. Porter SR, Scully CS, Eveson JW. The efficacy of topical ciclosporin in the management of desquamative gingivitis due to lichen planus. Br J Dermatol 1993;129:753-4. 39. Voute AB, Schulten EA, Langendijk PN, Nieboer C, Van der Waal I. Cyclosporin A in an adhesive base for the treatment of recalcitrant oral lichen planus: an open trial. Oral Surg Oral Med Oral Pathol 1994;78:437-41.
L
ichen planus is a common chronic mucocutaneous disease, of uncertain origin, affecting 0.5% to 2.2% of studied populations.1-9 Oral lichen planus (OLP) may arise in more than 70% of persons with skin lesions, although it more commonly occurs as an isolated mucosal disorder.10,11 OLP is often asymptomatic; however, the erosive and ulcerative forms are often painful and interfere with eating, speech, and swallowing.1 A wide spectrum of theraFrom the Unit of Oral Medicinea and the Biostatistics Unit,b Eastman Dental Institute for Oral Health Care Sciences, University College London; and Pharmacy Technical Services, University College Hospital.c Funding: None. Conflicts of interest: None. Accepted for publication May 6, 2001. Reprints not available from authors. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 + 0 16/1/120535 doi:10.1067/mjd.2002.120535
pies has been proposed in the management of symptomatic OLP, but the majority have not been evaluated in randomized controlled clinical trials.12 Topical corticosteroids remain the mainstay of therapy.13 Systemic corticosteroids and other immunosuppressants are often used in the management of OLP, but their application is limited by the adverse effects associated with their long-term use. Symptomatic OLP may be refractory to all currently available therapies and new therapeutic agents require evaluation.13 Tacrolimus is a macrolide immunosuppressant that exerts an activity that is 10 to 100 times higher than that of cyclosporine in vitro.14 Its action occurs at a point in T-lymphocyte activation between T-cell receptor ligation and the transcription of early genes.14,15 Tacrolimus first found application in the prevention of allograft rejection.16 Significant therapeutic benefit has also been reported in the treatment of atopic and contact dermatitis,17-21 psoriasis,22 and pyoderma gangrenosum.23 35
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Table I. Previous medications used for the management of erosive/ulcerative lichen planus and scores before and after tacrolimus therapy for the Visual Analogue Scale (VAS) and the McGill Pain (McGill) and the Oral Health Impact Profile (OHIP) questionnaires for individual patients VAS
McGill
OHIP
Patient No.
Medications
Week 0
Week 8
Week 0
Week 8
Week 0
Week 8
1 2 3 4 5 6 7 8 9 11 13 14 15 16 17 18 19
1, 2, 5, 10, 12 1, 2,3, 4, 5, 11 1, 5, 11, 12 1, 2, 3, 5, 11, 12 1, 5, 7, 10, 12 1, 4, 5, 11 1, 5, 9, 11 1, 3, 5, 8, 11 1, 2, 3, 5, 10, 12 1, 2, 5, 7, 11, 12 1, 4, 7, 10, 12 1, 3, 5, 6, 7, 9, 10, 12, 13 1, 2, 3, 4, 5, 9, 10 1, 2, 4, 5, 11, 12 1, 5, 10, 12 1, 4, 5, 6, 11, 14 1, 2, 5, 9, 11
43 76 51 75 54 100 97 54 62 63 82 61 54 83 65 16 66
27 2 23 10 24 41 76 0 1 1 0 6 57 2 4 23 11
2 2 2 3 2 2 4 1 2 3 2 2 2 2 1 1 2
0 0 0 0 1 2 2 0 0 1 2 1 1 0 1 1 1
39 6 0 17 25 27 30 18 13 32 24 26 30 16 11 16 6
15 1 0 4 10 14 39 11 0 3 3 3 28 2 5 12 2
Key to medications: 1, Benzydamine hydrochloride 0.15% mouthrinse/spray two puffs as required; 2, triamcinolone acetonide 0.1% in Orabase applied 4 times daily to ulcerated/eroded areas; 3, hydrocortisone hemisuccinate lozenges 2.5 mg sucked 4 times daily; 4, fluticasone propionate 50 µg metered dose spray two puffs to oral lesions 4 times daily; 5, betamethasone sodium phosphate 0.5 mg tablet dissolved in 15 mL of water, used as a mouthrinse; held in mouth for 5 minutes 4 times daily and expectorated; 6, fluticasone propionate 0.05% cream applied sparingly to symptomatic lesions twice daily; 7, clobetasol propionate 0.05% ointment applied sparingly to symptomatic lesions twice daily; 8, cyclosporine in bioadhesive paste (concentration unknown as patient transferred from another center) applied sparingly to symptomatic lesions twice daily; 9, cyclosporine oral solution 100 mg/mL, 5 mL used as a mouth rinse 3 times daily; 10, deflazacort 1-60 mg daily; the dose varied depending on whether initiating therapy or maintenance regimen; 11, prednisolone 1-60 mg daily; the dose varied depending on whether initiating therapy or maintenance regimen; 12, azathioprine 50-200 mg daily; 13, pentoxifylline 400 mg 3 times daily; 14, mycophenolate mofetil 500 mg twice daily.
Recently topical tacrolimus was reported to be effective in the short-term management of 4 persons with severe recalcitrant OLP.24 The aims of the current investigation were to test the potential efficacy and safety of topical tacrolimus in the management of erosive or ulcerative OLP in a larger population.
MATERIAL AND METHODS The study was undertaken as an open clinical phase II trial in the Oral Medicine Unit of the Eastman Dental Institute for Oral Health and Sciences, London, United Kingdom. Ethical approval was obtained before commencement of the study. Tacrolimus ointment preparation Tacrolimus ointment was manufactured at a concentration of 0.1% in a paraffin ointment base.18 This formulation differs from that used for cutaneous application.19,20,25 The half-life of the preparation was unknown; therefore small quantities were produced every 3 to 4 weeks. All study patients
were asked to store the tacrolimus ointment in a cool dry place. Entry criteria Patients with biopsy-proven erosive or ulcerative OLP refractory to, or dependent on, systemic corticosteroid or immunosuppressive therapy were invited to join the study. Medications previously used to manage the patient’s oral mucosal disease are documented in Table I. None had a history of renal, hepatobiliary, or malignant disease; hypertension; or recurrent acute infection. Study design Prestudy assessment. Detailed information regarding the study protocol and tacrolimus therapy was given by verbal explanation and written document to each subject. Subsequently, informed consent was obtained. A minimum data set (patient age, gender, medical history, drug history, and habits) was documented. All topical and systemic medication previously prescribed for ulcerative OLP was
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stopped a minimum of two weeks before the initiation of tacrolimus therapy. Benzydamine hydrochloride 0.15% mouthwash was prescribed for palliation of symptoms during this period.26 Subjective assessment. Each subject reported their response to therapy by completing a selfadministered assessment. This included the Visual Analogue Scale (VAS),27 which is a simple, reproducible instrument; it allows the severity of the pain experienced to be expressed as a numeric value. The VAS is represented as a plain horizontal 100-mm line. The patient is instructed to bisect the line at a point appropriate to their present discomfort. A zero value equates to being pain free, whereas the most severe pain they have experienced is rated at 100. The McGill Pain Questionnaire28 is an easily administered assessment of pain quality. The patient is presented with 5 descriptions of their present discomfort ranging from “no pain” to “excruciating”; the responses are rated from 0 to 5. The Oral Health Impact Profile (OHIP 14) Questionnaire29 is a measure of the negative impact of oral disease on a person’s general well-being and is reliable, valid, and precise. The impact, each rated from “never” to “very often,” of the oral problem on 14 distinct quality-of-life questions is assessed. The responses are summed, giving a minimum score of zero and maximum of 56. Clinician (objective) assessment. In this study an erosion was defined clinically as an area of mucosal erythema that was invariably associated with white striae. In contrast, an ulcerated area was represented as yellow/white sloughed inflammatory necrotic tissue secondary to a break in the continuity of the mucosal epithelium. The extent of eroded or ulcerated areas was recorded by using a scoring system based on a variation of criteria previously described30,31 (Table II). In addition, areas of erosion and ulceration were measured with a sterile flexible surgical ruler, recorded on a grid; the total surface area of the lesions was estimated in square millimeters. Clinical photographs were taken of all eroded or ulcerated regions. Schedule. Before the commencement of tacrolimus therapy (week 0), baseline subjective and objective assessments were recorded together with blood pressure, complete blood cell count (CBC), liver biochemistry, and levels of urea, electrolytes, and blood glucose. Each patient was instructed to sparingly apply 0.1% tacrolimus in hydrophilic petroleum ointment solely to their painful OLP lesions with clean fingers, twice daily for 8 weeks. It was recommended they should refrain from eating or drinking for 30 minutes after application. Tacrolimus therapy was discontinued for any lesion becoming
Table II. Clinical ranking system for erosive/ulcerative lichen planus Score
0 1 2 3 4 5
Clinical status
No lesion White striae only White striae and erosion <1 cm2 White striae and erosion >1 cm2 White striae and ulceration <1 cm2 White striae and ulceration >1 cm2
Modified from Thongaprassom K, Luangjarmekorn L, Severat T, Taweesap W (J Oral Pathol Med 1992;21:456-8) and Carbone M, Conrotto D, Carrozzo M, Broccoletti R, Gandolfo S, Scully C (Oral Dis 1999;5:44-9).
asymptomatic. The patients were reviewed by the same clinician at weeks 1, 3, 5, 7, and 8. At all subsequent review appointments subjective and objective assessments, blood pressure monitoring, phlebotomy, and any adverse effects were recorded. After completion of the 8-week study period, tacrolimus therapy was withdrawn. Benzydamine hydrochloride 0.15% mouthwash was prescribed for control of symptoms. All patients were reviewed 10, 14, 18, and 22 weeks after initial entry to the study. Systemic absorption of tacrolimus Tacrolimus absorption was monitored on weeks 5 and 8 of the study by the Imx Tacrolimus II assay based on microparticle enzyme immunoassay (MEIA) technology.32 Statistical analysis The VAS, OHIP, and lesion measurement scores were analyzed by paired t test. The differences in patients’ responses to the McGill Pain Questionnaire were analyzed by the Wilcoxon signed rank test.
RESULTS Study group Nineteen patients (14 women, 5 men; mean age, 62 years; range, 28-87 years) were enrolled in the study. Two patients withdrew after 3 weeks. One underwent surgical removal of a renal calculus; the other patient developed a recurrence of chronic maxillary sinusitis. These disorders were thought to be unrelated to tacrolimus therapy. Both patients had significant reduction of their OLP lesions during the 3-week period in which they received treatment, but they were not included in the final analysis. Relief of symptoms Tacrolimus significantly reduced painful symptoms as recorded on the VAS (Table I). All patients
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Fig 1. Mean VAS in 17 patients with OLP over 8-week period of topical tacrolimus therapy. Error bars represent 95% confidence interval.
Table III. The adverse effects of topical tacrolimus therapy used for oral lichen planus Adverse side effects
Tingling sensation in the mouth after application or when eating Burning sensation on the tongue when eating Altered taste sensation Slight nausea Mild headache Constipation
No. of patients
6 1 1 1 1 1
reported rapid relief from pain and had a significant reduction in VAS scores during the 8-week study period (Fig 1). The reduction in reported pain and discomfort experienced fell significantly even after 1 week of tacrolimus therapy (P < .001). All patients had a reduction in the McGill Pain Questionnaire scores and the group score had reduced significantly after 8 weeks of tacrolimus therapy (P < .001) (Table I). Finally, there was a 54.7% reduction in the OHIP group score, reflecting a significant improvement in the patient’s perception of the impact of their oral disease on their well-being (P < .001) (Table I). Change in clinical signs All 17 patients had a significant reduction in their ranking scale scores after 8 weeks of tacrolimus therapy (P < .002). There was a 73.3% reduction in the mean surface area of OLP lesions after 8 weeks of topical tacrolimus therapy (Fig 2). This reduction was highly statistically significant (P < .001). All
Fig 2. Mean total surface area of erosive and ulcerative lesions of 17 patients with OLP over 8-week period of tacrolimus therapy. Error bars represent 95% confidence interval.
patients had a reduction in lesion surface area (Fig 3); the reduction varied from 45% to 100%. The reduction in lesion surface area was found to be significant at the end of 1 week of therapy (P < .001). The greatest reduction in lesion area occurred in weeks 1 to 5, after which the clinical response plateaued. Examples of the clinical improvement in the ulcerative form of OLP are shown in Fig 4. Adverse side effects No serious adverse effects were observed during the 8-week study period. Seven of the 17 patients (41%) experienced no adverse side effects. Ten patients (59%) reported transient minor side effects (Table III). The paresthesia and burning-type sensation experienced by 7 subjects decreased within 72 hours of the cessation of tacrolimus therapy. The severity of local irritation decreased with a reduction in lesion size. The dysgeusia of one affected patient resolved within 48 hours of the cessation of tacrolimus treatment. Absorption of tacrolimus Eight of the 17 patients had systemic absorption within the therapeutic range (3-28.6 µg/L) (Table IV). None of these patients experienced any adverse side effects. The systemic absorption of tacrolimus after topical application was unrelated to the surface area of ulceration. Relapse after cessation of tacrolimus therapy After the cessation of topical treatment with tacrolimus ointment, 13 of the 17 patients (76.5%) suffered a relapse of OLP within 2 to 15 weeks; the mean time to relapse was 4 weeks. These 13 patients had an increase in both the total OLP sur-
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Fig 3. Total surface area of lesions in 17 patients with OLP over 8-week period of topical tacrolimus therapy.
face area and VAS score. For the remaining 4 patients, their disease did not deteriorate after cessation of tacrolimus therapy. Two subjects continue to show improvement and two patients are still in remission.
DISCUSSION The results of this study indicate that topical tacrolimus is an effective and safe treatment for erosive or ulcerative OLP recalcitrant to topical and systemic corticosteroids or other immunosuppressants such as azathioprine. The mean duration of symptomatic OLP disease in the patient group was 6 years (range, 4 months-25 years); despite topical and systemic immunosuppressive pharmacotherapy, symptom control had been difficult if not impossible to achieve. Therefore, significantly extending the findings of Vente and colleagues,24 we have shown that topical tacrolimus treatment provides a safe and efficacious alternative to systemic immunosuppression in persons with recalcitrant OLP. This study was not placebo controlled; thus the positive outcomes may be exaggerated. Relief of symptoms may reflect the increased patient contact with an enthusiastic clinician. However, in patients with severe erosive or ulcerative OLP refractory to many previously documented medications, significant deterioration of symptoms over an 8-week period would occur in the absence of therapy. OLP characteristically follows an unpredictable course of exacerbation and remission.33 Therefore it could be argued that the clinical improvement in this cohort
Table IV. Maximum blood levels of tacrolimus in 17 patients with OLP over the 8-week study period (therapeutic range, 3-28.6 µg/L) Study No.
1 2 3 4 5 6 7 8 9 11 13 14 15 16 17 18 19
Maximum blood levels of tacrolimus (µg/L)
<2 4 11 <2 <2 4 11 <2 <3 3 7 4.2 3 2 9 <2 3
over the 8-week period is the result of the natural history of the disease. However, this is most unlikely in view of the highly significant changes in initial symptoms on the commencement of tacrolimus, the profound change in clinical signs after 8 weeks of therapy, and deterioration in 13 subjects after tacrolimus withdrawal.
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B
A
Fig 4. A, Mucosal ulceration on dorsum of tongue before topical tacrolimus therapy. B, Dorsum of tongue after 8 weeks of topical tacrolimus therapy.
The choice of carrier for the tacrolimus was principally white soft paraffin, as previously described in the successful treatment of 4 cases of erosive/ulcerative lichen planus.24 Because this agent does not adhere well to the oral mucosal surface, there may be some loss of the active agent. The formulation used in this study was based on a simple eye ointment. Wool fat in the formulation absorbs water, improves adherence to the oral mucosa, and aids wetting of the dispersed drug powder. There is a need to consider more effective methods of drug delivery. The use of polymers (eg, carmellose sodium that strongly adheres to the oral mucosa) might further enhance the formulation by prolonging drug-mucosa contact. However, it is not known whether this will reduce tacrolimus diffusion. The etiology of lichen planus is unknown, but an immune pathogenesis has been proposed.34 The effectiveness of tacrolimus in OLP may be the result of local inhibition of T-lymphocyte activation.14,35 Because 4 patients in the study group had detectable tacrolimus levels in blood, a systemic effect may also have occurred. One of these patients remained symptom free 22 weeks after cessation of tacrolimus therapy. This observation suggests that systemic administration may be an appropriate therapy in those patients who fail to respond to topical tacrolimus. This may be a potential method of disease modification. No patients had significant adverse effects with tacrolimus therapy in this 8-week study period. Local irritation appears to be the most commonly reported side effect of cutaneous topical tacrolimus therapy.25 This was also the most commonly reported adverse effect of oral mucosal application. The symptoms rapidly resolved after cessation of treatment and were regarded as a minor inconvenience by the patients. Adverse effects associated with systemic
absorption could not be confirmed. In the patients reporting nausea and constipation, systemic blood levels of tacrolimus were less than 21 µg/L during the treatment period. Unfortunately the therapeutic improvement associated with 8 weeks of topical tacrolimus treatment failed to be maintained after drug cessation in the majority of patients. It may be that once symptom control is achieved, a maintenance regimen may prevent relapse, but this requires further investigation. Reports of the benefits of topical cyclosporine, another calcineurin inhibitor, in the management of erosive/ulcerative lichen planus have been contradictory.36-39 The cost of topical tacrolimus treatment twice daily is one seventh the cost of topical cyclosporine elixir used as mouthwash 3 times daily. (assuming the average use of 0.1% tacrolimus ointment is 10 mL weekly and cyclosporine oral solution 100 mg/mL at 5 mL 3 times daily; $25 as opposed to $180). It is evident that topical tacrolimus may be an effective method of treating OLP that is recalcitrant to more established therapies in the short term. During an 8-week period, none of the patients in this study experienced any significant adverse effects. There is a need to undertake more detailed objective clinical studies to determine the exact benefits of tacrolimus when compared with conventional therapies including clobetasol30 and to examine the influence of different dose regimens and formulations. REFERENCES 1. Silverman S, Lozada-Nur F, Migliorati C. Clinical efficacy of prednisolone in the treatment of patients with oral inflammatory ulcerative diseases: a study of fifty-five patients. Oral Surg Oral Med Oral Pathol 1985;59:360-3. 2. Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus and other keratoses in 23,616 white Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol 1986;61:373-81.
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