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1 Recalcitrant Symptomatic Vulvar Lichen Planus Response to Topical Tacrolimus OBSERVATION Julie A. Byrd, MD; Mark D. P. Davis, MD; Roy S. Rogers III, MD Background: Topical tacrolimus has been reported to be an effective treatment for genital lichen planus in small case series. We retrospectively reviewed the medical records of 16 patients with symptomatic vulvar lichen planus who received treatment with tacrolimus ointment. Observations: All patients had symptomatic vulvar lichen planus recalcitrant to other treatments. Of 16 patients, 15 (94%) experienced a symptomatic response to tacrolimus treatment within 3 months (mean, 4.2 weeks) and had a partial or complete resolution of the lesions. Six patients (38%) reported mild adverse effects, irritation, burning, and tingling. With continued use of the medication, these adverse effects resolved. When patients stopped treatment, lichen planus returned in 10 (83%) of 12 patients within 6 months after discontinuation of therapy (median, 1 week; range, weeks), but in 6 patients the lesions were less severe than the lesions before treatment; all 10 patients resumed use of topical tacrolimus. Conclusions: In this retrospective series of 16 women with vulvar lichen planus, topical tacrolimus therapy effectively controlled symptoms and improved lesions in all but 1 patient. The effect may be temporary, requiring continued use of tacrolimus, which appears to be safe and effective in controlling disease activity. Arch Dermatol. 2004;140: From the Department of Dermatology, Mayo Clinic, Rochester, Minn. The authors have no relevant financial interest in this article. ORAL LICHEN PLANUS IS A relatively common condition affecting approximately 1% of the population. 1-4 Lichen planus is more common in women, and in 1 study it involved the genitalia in 25% of the women with oral lichen planus. 5 Genital lichen planus causes considerable discomfort, which may be debilitating. Typically, patients present in their fifth or sixth decade with pruritus, burning, pain, and dyspareunia. Physical examination findings range from erythema to erosions and frank ulcerations; in severe disease, vaginal adhesions and scarring develop, prohibiting sexual intercourse. 6-9 Besides the mouth and genitalia, other mucosal sites that may be involved with lichen planus include the esophagus, conjunctiva, and ear canals. Lichen planus in these sites may lead to scarring, resulting in disability and morbidity. 10 Scarring usually does not occur with oral lichen planus. Histopathologic examination reveals a lichenoid infiltrate, basal layer vacuolation, and scattered Civatte bodies. As expected, at mucosal sites many plasma cells may also be present. Direct immunofluorescence studies consistent with lichen planus and other lichenoid reactions reveal shaggy fibrinogen deposition at the dermalepidermal junction, with cytoid bodies staining with 1 or more of the following conjugates: IgG, IgM, IgA, or C3. 11,12 Therapeutic management is challenging. Genital lichen planus may be more severe and recalcitrant to treatment compared with oral lichen planus. 9,10 Variable benefit occurs with use of topical agents, such as antifungal agents, retinoids, estrogens, and cyclosporine, as well as systemic agents, such as retinoids, antifungal agents, hydroxychloroquine, and dapsone. 10,21-28 Frequently, systemic treatments have unproven benefit, expose the patient to adverse effects, and are expensive. Topical tacrolimus is an effective and safe therapy for oral lichen planus This therapy has been used for other mucosal forms of lichen planus, and there are reports of its efficacy for genital lichen planus. 29,35 We prescribed topical tacrolimus for 16 consecutive patients with symptomatic vulvar lichen planus; we report their responses to treatment in this study. 715

2 1. For how many weeks or months did you use tacrolimus ointment before you saw improvement? 2. When using tacrolimus ointment, how much better were the symptoms of lichen planus? Much Better 3. When using tacrolimus ointment, how much did the lesions change? Completely Gone Somewhat Better Weeks or Almost Gone If "Yes," what were the problems? 5. Are you currently using tacrolimus ointment? If "Yes," how often do you use tacrolimus ointment? Why did you stop using tacrolimus ointment? After you stopped using tacrolimus ointment, did your lichen planus stay the same or come back? When it came back, was it: Weeks or Months About the Same 6. Overall, how satisfied are you with tacrolimus ointment? METHODS The Same Somewhat Worse 4. Did you have any problems with tacrolimus ointment? No Yes Irritation Burning Tingling Other Months Much Worse Increased Twice Daily Once Daily 3 Times Weekly Weekly If "No," when did you stop using tacrolimus ointment? (month/day/year) Side Effects Stayed the Same Very Satisfied Worse Than Before Cost of the Medication Neither Satisfied nor Dissatisfied Somewhat Dissatisfied Came Back The Same as Before Somewhat Satisfied No Change in Lichen Planus If it came back, how long after stopping use of tacrolimus ointment did it come back? Very Dissatisfied Much Better Than Before Other Patient telephone questionnaire for follow-up of patients who were using tacrolimus ointment (Protopic; Fujisawa Healthcare, Inc, Deerfield, Ill). We retrospectively reviewed the medical records of 16 consecutive female patients with symptomatic vulvar lichen planus who were treated with topical tacrolimus. All patients were evaluated and treated in the Department of Dermatology at Mayo Clinic in Rochester, Minn, by the same clinician (R.S.R.) between April 2000 and November Patients fulfilled the following criteria: (1) vulvar lichen planus was diagnosed on the basis of history, physical examination, and, if available, histopathologic features of lichenoid mucositis with or without supportive direct immunofluorescence studies and (2) patients received treatment with topical tacrolimus for vulvar lichen planus. Topical tacrolimus 0.1% ointment (Protopic; Fujisawa Healthcare, Inc, Deerfield, Ill) was prescribed for all patients. They were instructed to apply the ointment to affected areas twice daily. Before this product was available, 8 patients initially used topical tacrolimus prepared by the Mayo Clinic pharmacy: tacrolimus capsules (Prograf; Fujisawa) were compounded in a bland ointment base (Aquaphor; Beiersdorf, South Norwalk, Conn) in 2 concentrations, 0.1% (3 patients) and 0.03% (5 patients), until the commercial form became available. Neither the physician nor the patient perceived a difference between the Protopic ointment and the compounded product. Follow-up data were obtained by means of a patient telephone questionnaire. The use of this questionnaire was approved by the Mayo Foundation Institutional Review Board. The topics of the questions included symptoms and lesions, use of the ointment, and patient satisfaction (Figure). Response to treatment was evaluated according to change in symptoms and clearance of lesions. Symptoms were graded on the following scale: much better, somewhat better, about the same, somewhat worse, or much worse. Patients who responded that their symptoms were much better or somewhat better were considered to have had a symptomatic response. Patients were asked whether the lesions were completely gone, almost gone, the same, or increased after treatment. Lesions were considered completely resolved if the patient believed that the lesions were completely gone; lesions were considered partially resolved if the patient believed that the lesions were almost gone. In addition to the patient questionnaire, a retrospective review of the patients medical charts was performed to obtain clinical examination findings after the use of topical tacrolimus. If use of the medication was discontinued, the patient was asked whether the disease relapsed, when the relapse occurred, and how the severity of the relapse compared with the episode before treatment (worse than before, the same as before, or much better than before). Patient satisfaction with the use of tacrolimus was determined (very satisfied, somewhat satisfied, neither satisfied nor dissatisfied, somewhat dissatisfied, or very dissatisfied). RESULTS Demographic and clinical data from the patients studied are summarized in Table 1. All 16 patients were white women. Age ranged from 47 to 75 years (mean, 63 years). All patients had painful, erosive lesions of vulvar lichen planus. Reported symptoms included pain in 16 patients, soreness in 4, burning in 3, and bleeding in 1. The diagnosis of lichen planus was confirmed with biopsy results in 12 (75%) of the 16 patients. Of these 12 patients, 5 had direct immunofluorescence findings that showed changes consistent with lichen planus. One patient had nondiagnostic findings on direct immunofluorescence testing. Clinical diagnosis in others was made on the basis of the presence of concomitant oral,, otic, or esophageal lichen planus. The was involved in 14 patients, and the vulva in 6. Labial involvement was present in 6 patients; in 2 of these patients the inflammation and destruction from lichen planus had obliterated the labia minora and majora. Lichen planus involved extragenital sites in most of these patients (Table 1): oral mucosa in 14 patients, skin in 5, ear in 3, esophagus in 2, and the perianal region in 2. The mean duration of disease before initiation of therapy with topical tacrolimus was 4.3 years (range, 1-12 years). All patients had recalcitrant disease, and all patients had tried at least 1 form of treatment before receiving tacrolimus therapy. Prior treatments included use of topical corticosteroids (13 patients), antifungal medications (7 patients), topical estrogen (5 patients), systemic corticosteroids (5 patients), and hydroxychloro- 716

3 Table 1. Data for Patients Using Topical Tacrolimus for Vulvar Lichen Planus Patient No./ Age, y/ Duration, y Site Symptoms in Genital Area Signs of Vulvar Lichen Planus Extragenital Involvement Biopsy Specimen DIF Results Prior Treatment 1/75/10 Introitus Pain, bleeding Erosions None Not done Topical corticosteroids 2/69/1 Vulva Pain Erosions, scarring Oral None Not done Topical oral corticosteroid 3/74/4 Vulva, Pain, soreness Erosions None Vulva Not done Topical antifungal 4/72/1 Introitus Pain, soreness Erosions Gingival, Nondiagnostic results Not done Topical topical estrogen 5/60/6 Vulva, labia Pain Erosions, scarring otic Gingiva and vulva Positive Topical hydroxychloroquine, oral corticosteroid 6/47/4 Introitus Pain Erosions Gingival Gingiva Positive Topical antifungal, hydroxychloroquine, topical estrogen 7/57/2 Vulva, Pain Erosions perianal Gingiva and labia Positive Topical antifungal 8/47/2 Introitus Pain Erosions Oral, gingival Vagina Not done Antifungal, hydroxychloroquine 9/53/6 Introitus, labia Pain Erosions, stenosis otic Vagina Not done Topical antifungal 10/74/6 Vulva, Pain, soreness Erosions Gingival, Gingiva Positive Topical corticosteroids perianal 11/66/5 Introitus, labia Pain, burning Erosions Gingival, Wrist Not done Oral corticosteroid 12/49/1 Introitus, labia Pain Erosions, scarring esophageal None Not done Topical antifungal, oral corticosteroid, hydroxychloroquine* 13/68/3 Introitus Pain, burning Erosions None Vulva Positive Topical antifungal, topical estrogen, oral corticosteroid* 14/65/12 Vulva, 15/67/4 Introitus, labia Pain, soreness, burning Pain Erosions Oral, gingival Labia majora Not done Topical retinoid Erosions, stenosis, labia destroyed 16/67/1 Introitus, labia Pain Erosions, stenosis, labia destroyed Abbreviation: DIF, direct immunofluorescence. *Patient used this medication concomitantly with topical tacrolimus., otic, esophageal Vulva Not done Topical topical estrogen Esophageal Nondiagnostic Topical estrogen quine (4 patients). Two patients continued to receive systemic therapy during topical tacrolimus therapy: 1 received oral corticosteroids and the other received hydroxychloroquine. Both patients were able to decrease the dose of systemic medication when topical tacrolimus therapy was initiated. A summary of the responses of the patients to initiation of therapy with topical tacrolimus is presented in Table 2. Of the 16 patients, 15 (94%) experienced a symptomatic response to treatment within 3 months (mean, 4.2 weeks; range, weeks). These 15 patients also noted partial or complete resolution of the vulvar lesions. One had no symptomatic improvement. Patients were followed up for at least 2 months (mean, 15.7 months; range, 2-28 months). Clinical examination findings are available in Table 2. Of the 16 patients, 13 returned for follow-up appointments. Of these 13, 10 had no clinical evidence of erosions and 3 had smaller erosions that were healing. Follow-up examination occurred in an average of 3 months (range, 1-12 months) after initiation of topical tacrolimus therapy. Twelve patients stopped applying topical tacrolimus for various reasons (Table 3): 7 stopped because the lichen planus resolved, 3 forgot to apply it, 1 stopped because of adverse effects (burning and irritation), and 717

4 Table 2. Response to Topical Tacrolimus Therapy* Patient No. Time Before Response, wk Change in Symptoms Change in Lesion Adverse Effects Objective Findings on Follow-up Examination (Months of Therapy) Frequency of Current Use Follow-up Duration, mo 1 3 Somewhat better Almost gone Itching No erosions; erythema present (12) Weekly Much better Completely gone None No erosions or erythema (4) Once daily 14 3 NA None None None NA None Much better Almost gone None No erosions; erythema present (3) 3 times/wk Somewhat better Almost gone Burning, irritation Erosions healing (1) Weekly Somewhat better Almost gone None Erosions healing (2) Twice daily Much better Almost gone Burning No erosions or erythema (3) Once daily Much better Completely gone None NA Once daily Much better Almost gone Burning No erosions or erythema (1) Once daily Much better Completely gone Burning NA Weekly Much better Almost gone None No erosions; erythema present (7) Weekly Much better Almost gone None No erosions or erythema (1) Twice daily Much better Almost gone None No erosions or erythema (1.5) Once daily Much better Almost gone Tingling Erosions healing (6) None Much better Almost gone None No erosions; erythema present (2) Once daily Much better Completely gone None No erosions or erythema (1) Once daily 9 Abbreviation: NA, not applicable. *Frequency of initial application was twice daily for all patients. Table 3. Recurrence of Lichen Planus in Patients Who Discontinued Use of Topical Tacrolimus* Patient No. Reason for Stopping Therapy Time Before Recurrence, wk Severity of Lesion at Recurrence Compared With Before Therapy 1 LP resolved 3 Worse 2 LP resolved 2 Much better 3 No change in LP NA NA 4 LP resolved 0.3 Much better 5 Adverse effects 3 Same 6 Forgot to apply 1 Same 7 Forgot to apply 0.3 Much better 8 NA NA NA 9 NA NA NA 10 LP resolved 1 Same 11 LP resolved 24 Much better 12 NA NA NA 13 LP resolved 1 Much better 14 LP resolved NA NA 15 Forgot to apply 1 Much better 16 NA NA NA Abbreviations: LP, lichen planus; NA, not applicable. *Lichen planus recurred in all these patients except patient believed that the medicine was not helping. In 10 patients the lesions recurred within 6 months after discontinuation of therapy with topical tacrolimus (median, 1 week; range, weeks). The recurrent lesions, compared with lesions before therapy, were less severe or of the same severity in 9 patients. One patient believed that her lesions recurred in a more severe form, and 1 patient believed that her lesions were unchanged during topical tacrolimus therapy (therefore, stopping the therapy did not result in any change in her lesions). Remission of lichen planus occurred in 1 patient (duration of followup, 25 months). Minor adverse effects occurred in 6 patients, irritation, burning, and tingling. One patient discontinued using topical tacrolimus because of adverse effects, but when the lesions recurred, she reapplied it and had no adverse effects. The patients who experienced adverse effects stated that they resolved with continued use of tacrolimus. At present, 14 patients continue to use topical tacrolimus: 2 apply it twice daily, 7 apply it once daily, 1 applies it 3 times weekly, and 4 apply it weekly. Fifteen patients reported satisfaction with the treatment. COMMENT Topical tacrolimus ointment was remarkably effective in controlling the symptoms of recalcitrant vulvar lichen planus in all but 1 of the patients studied. Of the 16 female patients, 15 (94%) reported that their symptoms and lesions had improved. However, in most patients the benefit was not sustained. Soon after the patients stopped the treatment, the lesions and symptoms returned; in most patients, however, the lesions were less severe than the lesions before treatment, and the lesions responded when topical therapy was resumed. The tacrolimus was well tolerated; symptoms of burning resolved with continued use of the ointment. Our results are consistent with results from previous reports of recalcitrant genital lichen planus that responded to topical tacrolimus (Table 4). However, we report a larger number of patients than that previously reported, and we describe a relatively long duration of follow-up (mean, 15.7 months). We believe that our results are valid: the diagnosis of lichen planus was made in a consistent manner (diagnosed by 1 physician; confirmed in more than two thirds of the cases with oral, vulvar, or esophageal biopsy); the treatment was consistently prescribed and advised; and follow-up data were obtained by 1 physician in a consistent, standardized manner. All but 2 of the patients with vulvar lichen planus had lichen planus at multiple sites. These patients had oral,, otic, esophageal, perianal, or perineal lichen planus in addition to genital in- 718

5 Table 4. Previously Reported Cases of Genital Lichen Planus Responding to Therapy With Topical Tacrolimus* Vente et al 29 Kirtschig et al 35 Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Age, y Duration of disease, y Genital site Vulva, Vulva, Vulva, Vulva, vagina Vulva, vagina Extragenital involvement Oral None None Oral Oral Prior treatment Topical topical retinoids Topical antimycotics, estrogen Topical topical retinoids, topical cyclosporine Topical and oral dapsone, griseofulvin, acitretin, hydroxychloroquine Topical and oral dapsone, griseofulvin, acitretin, hydroxychloroquine Frequency of application Twice daily Twice daily Twice daily 3 Times weekly 3 times weekly Time to response 4 wk to complete resolution 4 wk to good improvement; 8 wk to further improvement 4 wk to little improvement; 16 wk to almost complete resolution 4 wk to improvement; 8 wk to completely healed 4 wk to improvement; 12 wk to controlled Current use Unknown Unknown Unknown Once weekly 3 times weekly Occurrence of relapse after 3 wk No relapse 6 mo 3 wk Unknown Unknown cessation of therapy after cessation Adverse effects Slight burning None None Slight burning Slight burning Duration of follow-up, wk *All patients were women. Patients received 0.1% tacrolimus (Prograf; Fujisawa Healthcare, Inc, Deerfield, Ill) in a hydrophilic petrolatum ointment containing bleached beeswax, stearyl alcohol, cholesterol, and white petrolatum. Patients received 0.1% tacrolimus (Prograf; Fujisawa) in a paraffin ointment. volvement. Many of the patients had the vulvovaginalgingival variant of erosive lichen planus, which has been reported to be more recalcitrant to treatment. All patients had not had a response with other treatments. We recognize that a retrospective review of clinical material is not optimal; however, we benefited from the consistency of 1 expert physician making the diagnosis. Follow-up data were obtained by means of a telephone survey, which has its own shortcomings because the patients are subject to recall bias and memory lapses. However, we tried to avoid creating bias in our telephone survey. The survey was the only practical means of following up our patients because many of them lived too far from our institution to conveniently return for follow-up. Yet the patients who returned for follow-up had improvement on clinical examination that was consistent with the questionnaire responses. Genital lichen planus is well recognized as a debilitating condition for many patients. Symptoms of genital pruritus, burning, pain, and dyspareunia may have detrimental psychological effects. Erosions and ulcerations due to lichen planus may lead to scarring and adhesions that prohibit sexual intercourse. Treatment options are limited by the lack of consistently effective and safe drugs. Surgical procedures to reconstruct the stenotic, fibrosed vaginal vault have been performed; however, scarring frequently recurs after the procedure. 10 Tacrolimus is a macrolide immune modulator produced by Streptomyces tsukubaensis, which has been reported to be effective in treating oral lichen planus Tacrolimus has also been reported to be effective for treatment of erosive vulvovaginal lichen planus. 29,35 Although the exact mechanism of action in treating lichen planus is unknown, topical tacrolimus has been shown to inhibit T-lymphocyte activation by inhibiting the phosphatase activity of calcineurin. Without calcineurin to dephosphorylate the nuclear factor of activated T cells, gene transcription for lymphokines, interleukin 2, and -interferon is inhibited, leading to a decrease in numbers of these lymphocytes. 36,37 In this retrospective review of 16 consecutive female patients with vulvar lichen planus, therapy with topical tacrolimus was safe and effective in controlling the symptoms and improving lesions in most (94%) of the patients. Topical tacrolimus is a promising new treatment option for this often recalcitrant and problematic disease. Accepted for publication January 20, Corresponding author and reprints: Mark D. P. Davis, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN REFERENCES 1. Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25: Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus, and other oral keratoses in 23,616 white Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol. 1986;61: Axell T, Rundquist L. Oral lichen planus: a demographic study. Community Dent Oral Epidemiol. 1987;15: Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol. 2002;46: Eisen D. The evaluation of, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88: Pelisse M, Leibowitch M, Sedel D, Hewitt J. A new vulvovaginogingival syn- 719

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