SYMPTOMATIC ORAL LICHEN

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1 OBSERVATION Response of Oral Lichen Planus to Topical Tacrolimus in 37 Patients Julie A. Byrd, MD; Mark D. P. Davis, MD; Alison J. Bruce, MD; Lisa A. Drage, MD; Roy S. Rogers III, MD Background: Topical tacrolimus has been reported to be effective for the treatment of oral lichen planus. This article describes our experience with topical tacrolimus in patients treated for symptomatic oral lichen planus. Observations: A survey was mailed to 40 patients with symptomatic oral lichen planus treated with topical tacrolimus. Surveys were completed by 37 patients (93%) a mean of 1.3 years after initiation of treatment. Thirtythree (89%) of the 37 patients reported symptomatic improvement, and 31 (84%) reported partial to complete lesion clearance while using topical tacrolimus. On average, patients noted improvement in 1 month. Twelve patients (32%) reported adverse effects consistent with those reported previously (ie, burning, irritation, and tingling). Among the 28 patients still using the medication, 15 patients (54%) apply it at least once daily. Of the 9 patients who discontinued using the medication, 5 experienced recurrence. Conclusions: Topical tacrolimus is effective for the treatment of oral lichen planus. Most patients experienced symptomatic improvement in less than 1 month. However, the effect is temporary; when topical tacrolimus is discontinued, oral lichen planus may flare again. Arch Dermatol. 2004;140: Author Affiliations: Department of Dermatology, Mayo Clinic, Rochester, Minn. Financial Disclosure: None. SYMPTOMATIC ORAL LICHEN planus (OLP) may be recalcitrant to treatment and disabling. In addition to oral involvement, mucosal areas such as the genitalia, ear canal, and esophagus may be affected. When lichen planus involves other mucosal surfaces, it may be more resistant to treatment. 1-6 Multiple topical and systemic treatments for OLP have been reported to be effective, including topical and systemic corticosteroids, griseofulvin, hydroxychloroquine, dapsone, topical retinoids, and topical cyclosporine However, in some patients, OLP is resistant to these treatments, or patients are unable to tolerate a treatment because of its adverse effects. Topical tacrolimus has been reported to be effective for OLP, including those forms that had been recalcitrant to treatment (Table 1). Many of those reports are of few patients, however, and follow-up was relatively short. We report the experience of our patients with OLP, both erosive and reticulated, with topical tacrolimus and their response to treatment over a longer period. This is a larger group, which does not include the 13 patients on whom we reported in METHODS Forty patients who had been prescribed treatment with topical tacrolimus for OLP were identified; all had been seen in the Department of Dermatology at Mayo Clinic, Rochester, Minn, from February 2000 to August Demographic information was obtained from a retrospective review of the medical records. The institutional review board of Mayo Foundation approved the study. A follow-up survey was mailed to the patients by the Survey Research Center. The survey was used to obtain information regarding symptomatic and lesional response to topical tacrolimus treatment, time to improvement, current use, and adverse effects, if any. In addition, clinical findings after use of topical tacrolimus were retrospectively reviewed. Inclusion criteria consisted of the following: (1) clinical evidence of OLP, as shown by reticulated erythematous or erosive lesions involving the oral mucosa or histopathologic changes consistent with lichenoid mucositis, with or without supportive direct immunofluorescence testing (cytoid bodies with 1of the following: IgG, IgM, IgA, C3, or shaggy 1508

2 Table 1. Review of Studies of Symptomatic Oral Lichen Planus (OLP) Treated With Topical Tacrolimus No. of Patients Source Type at Follow-up (No. Enrolled) Sex Age, Mean, y Type of OLP, No. Location of Extraoral Lichen Planus Lesions, No. Vente et al 21 Retrospective 4 3 F, 1 M 62.5 Erosive Cutaneous, 2; genital, 1 Rozycki et al 23 Retrospective F, 2 M 63.3 Erosive, 9; plaque, 3; Cutaneous, 1; genital, 3 papular, 1 Kaliakatsou et al 24 Prospective 17 (19) 14 F, 5 M 62 Erosive or ulcerative Unknown Lener et al 22 Case report 1 F 69 Erosive Cutaneous Olivier et al 26 Prospective 8 (10) 6 F, 4 M 58.1 Erosive Unknown Morrison et al 25 Prospective 6 5 F, 1 M Unknown Erosive Scalp, 1; genital, 2 Source No. of Biopsy-proven OLP Cases Type of Tacrolimus Used Degree of Lesion Response, No. Vente et al % in petrolatum Complete resolution, 3; improved, 1 Rozycki et al %, 0.1%, and 0.3% in petrolatum Kaliakatsou et al % in paraffin ointment Responded, 11; did not respond, 2 Responded, 17 Time to Response Follow-up Time Time to Lesion Relapse After Stopping Treatment, No. 4 wk 7-16 wk Within 3-8 wk, 4 In 6 patients, 1 wk; in 5 patients, 1 mo Some response, 1 wk; complete response, 1mo Lip, 1 mo; intraoral, 3mo Lener et al % in petrolatum, white wax, paraffin Responded Olivier et al 26 8 Mouthwash Improved, 7; tacrolimus no response, 1 Morrison et al 25 Unknown 0.1% in petrolatum Improved, 6 Some response, 2 wk; complete response in all patients, 1 mo 1-12 mo Within 1-2 wk, 4 (mean, 6.5 mo) 22 wk Within 2-15 wk, 13 (mean, 4 wk) 12 mo No relapse at 1 y In 7 patients, 1 mo 12 mo Within 12 mo, 7 3 mo Within 2 wk, 2 deposition of fibrinogen along the basement membrane zone 27,28 ); (2) symptoms of pain, irritation, or both; and (3) prescription and use of topical tacrolimus. Patients who responded that their symptoms were somewhat better or much better were considered to have symptomatic improvement. Response was defined as reports that lesions were almost gone or completely gone. RESULTS Forty patients with symptomatic OLP who had been prescribed topical tacrolimus (twice-daily applications to the affected areas) were mailed a survey. Thirty-nine (98%) of the 40 patients responded that they were using the medication, and 1 patient responded that he did not fill the prescription. Two patients wrote a comment on the survey and did not complete the questionnaire. One responded that topical tacrolimus made her tongue feel as if it had been burned, and the other responded that he had difficulty getting the medication to stay on his cheeks. Our results are from the remaining 37 patients (93%) who used the medication and responded to the survey. Because the commercial form of topical tacrolimus was not yet available, some patients were initially prescribed a formulation of tacrolimus mixed with a petrolatum ointment (Aquaphor; Beiersdorf, South Norwalk, Conn) to make 0.03% and 0.1% concentrations. Fourteen patients (38%) initially received the 0.03% concentration and 1 patient (2%) the 0.1% concentration in petrolatum, but the commercial product was prescribed for all patients when it became available. Twenty-two patients were initially prescribed commercially prepared topical tacrolimus, 18 patients (49%) the 0.03% concentration, and 4 patients (11%) the 0.1% concentration. Patient demographics and clinical characteristics are summarized in Table 2. The mean age of the 32 women and 5 men was 64 years (range, years). Twentythree (62%) of the 37 patients had predominantly reticulated lichen planus, and 14 (38%) had predominantly erosive lichen planus. All patients had OLP, some at more than 1 site. Concomitant genital involvement was present in 11 patients (30%) and cutaneous involvement in 3 patients (8%). Two (5%) had otic involvement, and 1 (3%) had esophageal lichen planus. Twentyfive patients (68%) had histopathologic confirmation of lichen planus, and 11 (30%) had supportive results from direct immunofluorescence studies. The mean duration of OLP before starting topical tacrolimus treatment was 4.4 years. Prior treatment had been unsuccessful in nearly all patients (35 of 37). In the 2 remaining patients, topical tacrolimus was first-line therapy. One patient continues to take hydroxychloroquine, 1 patient continues to take oral corticosteroids, and 3 patients continue to use topical antifungals intermittently. The responses to the survey are summarized in Table 3. Surveys were completed a mean of 1.3 years after initiation of topical tacrolimus treatment (range, 49 days to 2.7 years). Thirty-one patients (84%) reported 1509

3 Table 2. Demographics of Patients With Oral Lichen Planus Using Topical Tacrolimus Characteristic Patients* Sex Female 32 (86) Male 5 (14) Age, mean (range), y 64 (38-82) Duration of disease before treatment initiation, y Mean (range) 4.4 (10 d-17.6 y) Median 3.4 Symptom Pain 35 (95) Irritation 15 (41) Type of disease Erosive 14 (38) Reticulated 23 (62) Location of lesions Tongue 6 (16) Gingiva 17 (46) Lips 7 (19) Buccal mucosa 24 (65) Extraoral disease Genital 11 (30) Cutaneous 3 (8) Otic 2 (5) Esophageal 1 (3) Laboratory evaluation consistent with disease Histopathologic 25 (68) Direct immunofluorescence 11 (30) Prior treatment Oral corticosteroid 10 (27) Griseofulvin 2 (5) Fluconazole 8 (22) Metronidazole 5 (14) Hydroxychloroquine 6 (16) Topical corticosteroids 27 (73) Topical cyclosporine 4 (11) Topical antifungals 11 (30) Topical retinoid 2 (5) Mycophenolate mofetil 2 (5) Intravenous immunoglobulin, dapsone, etretinate, colchicine, 1 (3) for each medication oral cyclosporine *Values are given as number (percentage) unless otherwise indicated. Table 3. Patient Response to Treatment of Oral Lichen Planus With Topical Tacrolimus Characteristic Response* Use of topical tacrolimus as instructed (n = 36) All the time 21 (57) Most of the time 13 (35) Rarely 2 (5) Symptoms (n = 37) Much better 22 (59) Somewhat better 11 (30) About the same 3 (8) Worse 1 (3) Lesion clearance (n = 37) Completely gone 5 (14) Almost gone 26 (70) The same 5 (14) Increased 1 (3) Time to improvement, mo Mean (range) 1.1 ( ) Median 0.75 Follow-up, d Patient still using topical tacrolimus Mean (range) 460 (49-968) Median 448 Patient no longer using topical tacrolimus Mean (range) 149 (27-466) Median 107 Satisfaction (n = 37) Very satisfied 20 (54) Somewhat satisfied 11 (30) Neither satisfied nor dissatisfied 2 (5) Somewhat dissatisfied 1 (3) Very dissatisfied 3 (8) *Values are given as number (percentage) unless otherwise indicated. that they were somewhat or very satisfied with topical tacrolimus treatment and that they would recommend the medication to others. On average, patients used topical tacrolimus for 1.1 years (range, 5 days to 2.7 years) and reported an improvement within 1 month (range, 3 days to 6 months). Thirtyfour patients (92%) reported that they used the medication as instructed all the time or most of the time. Symptomatic improvement was reported by 33 patients (89%). Thirty-one patients (84%) reported partial to complete lesion clearance with topical tacrolimus treatment (Figure). One patient reported that the lesions increased, and 1 reported that the symptoms were much worse. Clinical findings after topical tacrolimus use were available for 24 of the 37 patients. Of these 24 patients, 5 did not have a follow-up visit until 1 year or more after starting topical tacrolimus treatment because of traveling constraints; of these 5 patients, 2 had clinical improvement and 3 had resolution of their OLP lesions. The remaining 19 patients were seen a mean of 2 months after initiation of topical tacrolimus treatment; of these, 12 had clinical improvement and 7 had resolution of their OLP lesions. Twenty-five patients (68%) reported no difficulties, and 12 patients (32%) reported experiencing problems with using the medication. Of these 12 patients, 4 (11%) reported that the medicine caused irritation; 5 (14%), that it caused burning; and 3 (8%), that it caused tingling. Two patients (17%) also reported an objectionable taste. Four patients each reported other problems: bad breath, extra phlegm in the mouth, swelling of the mouth and lips, and teeth problems. Twenty-eight patients (76%) continue to use topical tacrolimus. The mean follow-up of the patients still using topical tacrolimus is 1.3 years (range, days). Fifteen (54%) of these 28 patients apply the medication more than once daily. The remaining 13 patients use topical tacrolimus twice weekly or less. Of the 9 patients (24%) not currently using topical tacrolimus, 5 reported that they discontinued the medicine because of adverse effects, 1 because she did not notice any change in the lichen planus, and 2 because the lichen planus was better. These patients applied the medi- 1510

4 A B Figure. Response of gingival lichen planus to tacrolimus treatment. A, Gingival lichen planus with characteristic erythema and Wickham striae; B, resolution of lichen planus after 7 weeks of treatment with tacrolimus ointment. cation for an average of 4.9 months (range, 5 days to 1.3 years). After stopping treatment with topical tacrolimus, 5 patients (56%) reported that the lichen planus returned, and 3 (33%) reported that it stayed the same. The remaining patient did not answer this question. COMMENT Topical tacrolimus treatment was safe and effective in most patients, 89% of whom experienced symptomatic response and 84% of whom reported lesion clearance. Lesions responded to treatment within 6 months (mean, 1 month). The demographic characteristics of our patients were similar to those of patients previously reported. Our patients had both erosive and reticulated OLP, whereas most prior reports focused on erosive OLP alone. Treatment with topical tacrolimus appears to be effective for both erosive and reticulated forms of OLP. Also, 30% of our patients had genital involvement associated with OLP, and 8% had either otic or esophageal involvement. It has been reported that patients with OLP associated with genital lichen planus (the vulvovaginal gingival syndrome) typically are more difficult to treat than those with other forms of lichen planus. 1-6 All 11 patients with both oral and genital lesions had symptomatic improvement in both areas. These data are discussed further in another article. 29 The 2 patients with otic involvement also had improvement in their otic lichen planus with a topical tacrolimus suspension. Topical tacrolimus treatment was effective as firstline therapy in 2 patients. Thirty-one patients whose OLP was recalcitrant to other therapies reported topical tacrolimus to be effective. Two patients who responded to the questionnaire continued systemic treatment, one with hydroxychloroquine and the other with corticosteroids; in both patients, OLP improved markedly with the addition of topical tacrolimus. Symptoms were unchanged in 3 patients, and 1 patient reported that symptoms and lesions worsened while using topical tacrolimus. Adverse effects were reported by one third of patients, and they were similar to those previously reported (irritation, burning, and/or tingling). Only 5 patients discontinued use of topical tacrolimus because of adverse effects; in the remaining patients, adverse effects resolved with continued use. Most of our patients continue to use topical tacrolimus. Although topical tacrolimus is effective at controlling disease, we found that it rarely seems to result in complete remission of OLP. This is consistent with observations from prior studies Long-term use ( 1 year) did not result in any serious adverse effects in our patients, most of whom were satisfied with topical tacrolimus treatment. This is a retrospective study with a patient survey and therefore is subject to patient recall bias. However, the mailed survey was the most effective way to follow up with our patients, who often live a great distance from our clinic. The survey offered a standardized, objective way to obtain our data, and the patients who were able to return for follow-up had clinical findings that correlated with the survey results. In summary, we followed up 37 patients with symptomatic OLP by means of a mailed questionnaire. Most of these patients responded to topical tacrolimus treatment with both clinical and symptomatic improvement. The effect of topical tacrolimus usually occurred within 1 month of treatment; however, most patients require maintenance therapy. No serious adverse effects of topical tacrolimus were noted after more than 1 year of followup, which supports the thesis that topical tacrolimus is a safe and effective treatment for OLP. Accepted for Publication: June 7, Correspondence: Mark D. P. Davis, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN REFERENCES 1. Pelisse M, Leibowitch M, Sedel D, Hewitt J. A new vulvovaginogingival syndrome: plurimucous erosive lichen planus [in French]. Ann Dermatol Venereol. 1982;109: Pelisse M. The vulvo-vaginal-gingival syndrome: a new form of erosive lichen planus. Int J Dermatol. 1989;28: Eisen D. The vulvovaginal-gingival syndrome of lichen planus: the clinical characteristics of 22 patients. Arch Dermatol. 1994;130:

5 4. Rogers RS III. Erosive orogenital lichen planus in women (vulvovaginal-gingival syndrome) [abstract]. J Oral Pathol Med. 1998;27: Eisen D. The evaluation of cutaneous, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88: Rogers RS III, Eisen D. Erosive oral lichen planus with genital lesions: the vulvovaginal-gingival syndrome and the peno-gingival syndrome. Dermatol Clin. 2003; 21: Edwards PC, Kelsch R. Oral lichen planus: clinical presentation and management. J Can Dent Assoc. 2002;68: Voute AB, Schulten EA, Langendijk PN, Kostense PJ, van der Waal I. Fluocinonide in an adhesive base for treatment of oral lichen planus: a double-blind, placebo-controlled clinical study. Oral Surg Oral Med Oral Pathol. 1993;75: Boisnic S, Branchet MC, Pascal F, Ben Slama L, Rostin M, Szpirglas H. Topical tretinoin in the treatment of lichen planus and leukoplakia of the mouth mucosa: a clinical evaluation [in French]. Ann Dermatol Venereol. 1994;121: Sieg P, Von Domarus H, Von Zitzewitz V, Iven H, Farber L. Topical cyclosporin in oral lichen planus: a controlled, randomized, prospective trial. Br J Dermatol. 1995; 132: Frances C, Boisnic S, Etienne S, Szpirglas H. Effect of the local application of ciclosporine A on chronic erosive lichen planus of the oral cavity. Dermatologica. 1988;177: 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: Becherel PA, Chosidow O, Boisnic S, et al. Topical cyclosporine in the treatment of oral and vulvar erosive lichen planus: a blood level monitoring study. Arch Dermatol. 1995;131: Eisen D, Griffiths CE, Ellis CN, Nickoloff BJ, Voorhees JJ. Cyclosporin wash for oral lichen planus [letter]. Lancet. 1990;335: Hersle K, Mobacken H, Sloberg K, Thilander H. Severe oral lichen planus: treatment with an aromatic retinoid (etretinate). Br J Dermatol. 1982;106: Sehgal VN, Abraham GJ, Malik GB. Griseofulvin therapy in lichen planus: a doubleblind controlled trial. Br J Dermatol. 1972;87: Eisen D. Hydroxychloroquine sulfate (Plaquenil) improves oral lichen planus: an open trial. J Am Acad Dermatol. 1993;28: Kumar B, Kaur I, Bhattacharya M. Dapsone in lichen planus [letter]. Acta Derm Venereol. 1994;74: Setterfield JF, Black MM, Challacombe SJ. The management of oral lichen planus. Clin Exp Dermatol. 2000;25: Cribier B, Frances C, Chosidow O. Treatment of lichen planus: an evidencebased medicine analysis of efficacy. Arch Dermatol. 1998;134: Vente C, Reich K, Rupprecht R, Neumann C. Erosive mucosal lichen planus: response to topical treatment with tacrolimus. Br J Dermatol. 1999;140: Lener EV, Brieva J, Schachter M, West LE, West DP, el-azhary RA. Successful treatment of erosive lichen planus with topical tacrolimus. Arch Dermatol. 2001; 137: Rozycki TW, Rogers RS III, Pittelkow MR, et al. Topical tacrolimus in the treatment of symptomatic oral lichen planus: a series of 13 patients. J Am Acad Dermatol. 2002;46: Kaliakatsou F, Hodgson TA, Lewsey JD, Hegarty AM, Murphy AG, Porter SR. Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus. J Am Acad Dermatol. 2002;46: Morrison L, Kratochvil FJ III, Gorman A. An open trial of topical tacrolimus for erosive oral lichen planus. J Am Acad Dermatol. 2002;47: Olivier V, Lacour JP, Mousnier A, Garraffo R, Monteil RA, Ortonne JP. Treatment of chronic erosive oral lichen planus with low concentrations of topical tacrolimus: an open prospective study. Arch Dermatol. 2002;138: Weedon D. Skin Pathology. London, England: Churchill Livingstone; 2002: Helander SD, Rogers RS III. The sensitivity and specificity of direct immunofluorescence testing in disorders of mucous membranes. J Am Acad Dermatol. 1994;30: Byrd JA, Davis MDP, Rogers RS III. Recalcitrant symptomatic vulvar lichen planus: response to topical tacrolimus. Arch Dermatol. 2004;140:

6 A variety of adverse cutaneous reactions have been described, ranging from self-limiting dermatitic rashes to erythroderma for which cessation of therapy was required. Also reported were reactions similar to graft-vshost disease, erythema nodosum, small-vessel vasculitis, exanthematous pustulosis, and Stevens-Johnson syndrome. 6,7 Sweet syndrome has been associated with chronic myeloid leukemia, 8 but the association is rare, and the only times our patient developed skin lesions were after the administration of imatinib. Accepted for Publication: November 4, Correspondence: Sanjay J. Ayirookuzhi, MD, Mail Box No. 161, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA (drsanjayjoseph@yahoo.com). Previous Presentation: This article was presented as a poster at the 41st Annual Meeting of the American Society of Dermatology; October 14-17, 2004; Boston, Mass. REFERENCES 1. Cooper PH, Frierson HF, Greer KE. Subcutaneous neutrophilic infiltrates in acute febrile neutrophilic dermatosis. Arch Dermatol. 1983;119: Deininger MW, Goldman JM, Lydon N, et al. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL positive cells. Blood. 1997;90: Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine-kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344: Kantarjian H, Sawyers S, Hochhaus A, et al; ; International STI571CML Study Group.. Hematologic and cytogenic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346: Drummond A, Micallef-Eynaud P, Douglas WS, et al. A spectrum of skin reactions caused by the tyrosine kinase inhibitor imatinib mesylate (STI 571, Glivec). Br J Haematol. 2003;120: Brouard M, Saurat JH. Cutaneous reactions to STI 571. N Engl J Med. 2001;345: Hsiao L, Chung H, Lin J, et al. Stevens-Johnson syndrome after treatment with STI571: a case report. Br J Haematol. 2002;117: Cohen PR, Kurzrock R. Chronic myeloid leukemia and Sweet syndrome. Am J Hematol. 1989;32: Correction Error in the Figure: In the article by Byrd et al titled Response of Oral Lichen Planus to Topical Tacrolimus in 37 Patients published in the December 2004 issue of the ARCHIVES (2004;140: ), parts A and B in the Figure were transposed. We regret the error. (REPRINTED) ARCH DERMATOL/ VOL 141, MAR American Medical Association. All rights reserved.