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Elizabeth V. Lener, MD; Joaquin Brieva, MD; Marianne Schachter, MD; Lee E. West, BS, RPh; Dennis P. West, PhD
Northwestern University Medical School, Chicago, Ill

Rokea A. el-Azhary, MD
Mayo Clinic and Mayo Clinic Foundation, Rochester, Minn

Arch Dermatol. 2001;137:419-422.

REPORT OF A CASE
A 69-year-old woman with a history of colon carcinoma, cirrhosis of the liver secondary to hepatitis C, and erosive oral lichen planus presented to the dermatology clinic for therapeutic options regarding a growing ulceration on her lower lip. In the past year, the ulceration had enlarged and she had begun to develop new, painful, shallow ulcerations in the oral mucosa. In addition, she complained of intermittently pruritic papules involving the distal volar surfaces of her forearms. Biopsies and direct immunofluorescence were performed to evaluate histopathological features. The patient was diagnosed with erosive oral and cutaneous lichen planus. The cutaneous lesions resolved on treatment with fluocinonide cream. However, the lip and oral ulcerations persisted despite topical application of fluocinonide and clobetasol propionate gel once or twice daily for 1 year.

Physical examination showed a 2.0 x 1.0-cm shallow ulceration involving the central lower lip (Figure 1). The oral mucosa revealed extensive superficial ulcerations involving the buccal, gingival, and lingual mucosal surfaces. In addition, there were ulcerations on the dorsum of the tongue and a superficial ulceration on the hard palate, with a fine, reticulated grayish-white plaque surrounding the area (Figure 2). The volar aspect of the forearms revealed violaceous, lichenoid papules. There were no nail changes detected.

View larger version (70K): [in this window] [in a new window] Figure 1. Enlarging ulceration with hemorrhagic crusting on the lower lip prior to topical tacrolimus therapy.

View larger version (43K): [in this window] [in a new window] Figure 2. Shallow ulceration of the hard palate with a fine, reticulated gray-white border.

Histopathological examination revealed an interface dermatitis with a dense bandlike infiltrate along the dermoepidermal junction. An occasional civette body was noted. Direct immunofluorescence showed a continuous, strong, shaggy deposition of fibrinogen along the basement membrane, with many scattered and clumped cystoids that tested positive for IgM and C3.

THERAPEUTIC CHALLENGE

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Treatment options for erosive lichen planus are numerous, including both topical and systemic agents; however, therapeutic results are often disappointing. Systemic immunosuppressive, immunomodulatory, and retinoid compounds were contraindicated because of the patient's recently diagnosed colon carcinoma and her history of liver cirrhosis. Our challenge was to find a safe and effective therapeutic modality with long-term benefits.

SOLUTION

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Therapy was initiated with 0.1% topical tacrolimus ointment (compounded by the Dermatology Pharmacy, Northwestern Medical Faculty Foundation, Chicago, Ill) to the lip ulceration twice daily. Follow-up at 1 month revealed complete resolution of the lower-lip ulceration (Figure 3). This proprietary formulation base (white petrolatum [US Pharmacopoeia (USP)], mineral oil [USP], propylene carbonate [National Formulary (NF)], white wax [NF], and paraffin [NF]) is designed to quickly deliver the drug to mucocutaneous tissue while minimizing systemic absorption. A solution or gel formulation would not have been optimal because it might have contained irritating solvents; in addition, it would not have targeted the drug to the lesions as well as an ointment. A paste base was not used to minimize the risk of inadequate diffusion of the drug from the vehicle into the target tissue.

View larger version (61K): [in this window] [in a new window] Figure 3. Complete resolution of the lip ulceration after 1 month of 0.1% topical tacrolimus ointment applied twice daily.

With the resolution of the lip ulceration, the patient was instructed to apply the tacrolimus ointment to the persistent oral mucosal ulcerations. The challenge was the application of the medication to the oral mucosa. The patient found it easy to apply the ointment as long as she dried the area with a gauze pad prior to application. She reported no difficulty with the dosage form. The intraoral ulcerations resolved after 3 months of daily application. The intraoral and lip ulcerations remained in remission after 1 year without maintenance therapy.

At the time of this report, the patient continued to have recurrences of the tongue ulceration 1 or 2 times per month. However, after a single application of tacrolimus, the tongue lesions resolve, and she returns to her normal eating habits.

COMMENT

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Lichen planus, a relatively common mucocutaneous disease, is estimated to occur in 0.5% to 1% of the adult population.^1-2 Fifty percent of patients with cutaneous lesions have oral involvement, whereas only 25% of patients with oral lesions have skin involvement.³ It is proposed that both endogenous and exogenous factors play a role in the development of the disease.

Clinical presentations of oral lichen planus are variously reported as reticulated, plaque-like, erosive, papular, atrophic, and bullous.⁴ The reticular form is the most common; however, the erosive, atrophic, and bullous forms are typically the most symptomatic, debilitating, and difficult to treat.³ Frequent complaints include severe burning and pain, particularly after eating foods that are either spicy or acidic. Most commonly, lesions are found on the posterior buccal mucosa and, in order of decreasing frequency, the gingiva, tongue, palate, lip, and floor of the mouth.⁵

Cell-mediated immunity seems to play a critical role in the development of lichen planus. Presently, the specific antigen(s) responsible for the activation of T cells has not been identified.⁵ HLA-Bw35⁶ and HLA-B8⁷; contact sensitizers such as dental amalgam³ and other metals⁴; medications; and infectious causes such as hepatitis C,⁸ herpes simplex virus, human immunodeficiency virus, syphilis, and amebiasis have all been reported to be associated with oral lichen planus eruptions.⁷

Treatment options exist for oral lichen planus, but all are less than optimal. These include topical and intralesional high-potency corticosteroids, retinoids, cyclosporine, psoralen–U-VA, and extracorporeal photochemotherapy. Other, anecdotal modalities include griseofulvin, hydroxychloroquine, dapsone, and thalidomide.

In a recent evidence-based review, topical corticosteroids were found to be the most helpful treatment for oral lichen planus.⁹ The efficacy of fluocinonide and fluocinolone has been assessed in small trials, with some improvement noted compared with placebo.⁹ In a comparison trial, 0.1% triamcinolone acetonide was shown to be less effective than 0.1% fluocinolone acetonide.¹⁰ In one study, 23 (96%) of 24 patients improved with the use of topical corticosteroids under occlusion.¹¹ Systemic corticosteroids are often used based on clinical experience, despite a lack of rigorous controlled studies to evaluate efficacy.

There have been controlled studies to evaluate the use of topical and systemic retinoids in the treatment of oral lichen planus. Topically, both 0.1% tretinoin and 0.1% isotretinoin seem to be effective in reducing the number of lesions and providing symptomatic relief. A comparison between 0.05% tretinoin and fluocinonide showed better results in the fluocinonide-treated groups.¹² It is hypothesized that this poor response to tretinoin may be due to the low concentration of tretinoin studied.¹³ Systemic treatment with etretinate was shown to reduce the number of lesions. However, systemic retinoids may produce significant adverse effects that patients may not tolerate.¹⁴

Topical cyclosporine has been evaluated for the treatment of erosive lichen planus in controlled trials.^15-17 Although topical cyclosporine was shown to be effective, there does not seem to be any benefit compared with using topical corticosteroids alone.

Psoralen–UV-A has been shown to be of some benefit in controlled trials.^18-19 Adverse effects include nausea and the potential for carcinogenicity. In addition, directing the light source to the target tissue may pose a significant obstacle to effective therapy.

Tacrolimus is one of the members of the immunosuppressive macrolide family, which includes cyclosporine, rapamycin, and ascomycin. It suppresses T-cell activation by initially binding to cytosolic FK-binding proteins, which, in turn, interferes with the Ca²⁺/calmodulin–dependent phosphatase calcineurin.²⁰ This ultimately results in the inhibition of cytokine (mainly interleukin 2 [IL-2], IL-4, and IL-5) gene transcription.²¹

Tacrolimus was introduced for the prevention of allograft rejection, with successful use in kidney, liver, and heart transplantation. Recently, topical tacrolimus was shown to be efficacious in atopic and contact dermatitis.^{20, 22-24} Systemic administration has been beneficial in psoriasis, Behçet disease, pyoderma gangrenosum, and Crohn disease.^25-29 It is presumed that some of the most promising targets for topical tacrolimus therapy are cyclosporine-responsive dermatoses, including lichen planus.²⁰

In a recent case report of 6 patients with recalcitrant erosive oral lichen planus, complete resolution was noted in 3 patients and substantial improvement in the other 3 patients after 4 weeks of therapy. Prolonged treatment resulted in continued improvement to complete resolution.³⁰

Percutaneous penetration of topical tacrolimus in various ointment concentrations (0.03%-3%) has been evaluated. In vitro studies have shown relatively low percutaneous absorption through intact skin.²⁰ Percutaneous absorption through damaged skin was approximately 7-fold higher than through intact skin. Occlusion did not significantly alter percutaneous penetration in one study.²⁰ Transmucosal penetration studies have not been reported.

Based on the safety demonstrated in atopic dermatitis trials that included children as young as age 2 years,³¹ topical tacrolimus ointment is apparently a safe, effective, and well-tolerated therapeutic modality. In order to fully evaluate its efficacy, randomized, controlled, double-blinded trials using topical tacrolimus are needed. In addition, comparison trials with high-potency topical corticosteroids are necessary to demonstrate any differences in treatment outcomes.

AUTHOR INFORMATION

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Accepted for publication December 7, 2000.

Corresponding author: Joaquin Brieva, MD, Department of Dermatology, Northwestern University, 675 N St Clair St, Suite 19-150, Chicago, IL 60611 (e-mail: j-brieva{at}nwu.com).

REFERENCES

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1. Axell T, Rundquist L. Oral lichen planus—a demographic study. Community Dent Oral Epidemiol. 1987;15:52-56. FULL TEXT | ISI | PUBMED 2. 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;61:373-381. FULL TEXT | ISI | PUBMED 3. Bricker SL. Oral lichen planus: a review [review]. Semin Dermatol. 1994;13:87-90. ISI | PUBMED 4. Scully C, Beyli M, Ferreiro M, et al. Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med. 1998;9:86-122. FREE FULL TEXT 5. Lozada-Nur F, Miranda C. Oral lichen planus: epidemiology, clinical characteristics, and associated diseases [review]. Semin Cutan Med Surg. 1997;16:273-277. FULL TEXT | ISI | PUBMED 6. Boyd AS, Neldner KH. Lichen planus [review]. J Am Acad Dermatol. 1991;25:593-615. ISI | PUBMED 7. Daoud MS, Pittelkow MR. Lichen planus. In: Freedburg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick's Dermatology in General Medicine. 5th ed. New York, NY: McGraw-Hill; 1999:561-577. 8. Sanchez-Perez J, De Castro M, Buezo GF, Fernandez-Herrera J, Borque MJ, Garcia-Diez A. Lichen planus and hepatitis C virus: prevalence and clinical presentation of patients with lichen planus and hepatitis C virus infection. Br J Dermatol. 1996;134:715-719. ISI | PUBMED 9. Cribier B, Frances C, Chosidow O. Treatment of lichen planus: an evidence-based medicine analysis of efficacy [review]. Arch Dermatol. 1998;134:1521-1530. FREE FULL TEXT 10. Thongprasom K, Luangjamekorn L, Sererat T, Taweesap W. Relative efficacy of fluocinolone acetonide compared with triamcinolone acetonide in treatment of oral lichen planus. J Oral Pathol Med. 1992;21:456-458. FULL TEXT | ISI | PUBMED 11. Aleinikov A, Jordan RC, Main JH. Topical steroid therapy in oral lichen planus: review of a novel delivery method in 24 patients. J Can Dent Assoc. 1996;62:324-327. 12. Buajeeb W, Kraivaphan P, Pobrurska C. Efficacy of topical retinoic acid compared with topical fluocinonide acetonide in the treatment of oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:21-25. FULL TEXT | ISI | PUBMED 13. Eisen D. The therapy of oral lichen planus [review]. Crit Rev Oral Biol Med. 1993;4:141-158. FREE FULL TEXT 14. Hersle K, Mobacken H, Sloberg K, Thilander H. Severe oral lichen planus: treatment with an aromatic retinoid (etretinate). Br J Dermatol. 1982;106:77-80. FULL TEXT | ISI | PUBMED 15. Eisen D, Ellis CN, Duell EA, Griffiths CEM, Voorhees JJ. Effect of topical cyclosporine rinse on oral lichen planus: a double-blind analysis. N Engl J Med. 1990;323:290-294. ABSTRACT 16. Sieg P, Von Domarus H, von Zitzewitz V, Iven H, Farber L. Topical cyclosporin in oral lichen planus: a controlled, randomized, prospective trial [review]. Br J Dermatol. 1995;132:790-794. ISI | PUBMED 17. Lopez Lopez J, Rosello Llabres XR. Cyclosporine A, an alternative to oral lichen planus erosive treatment. Bull Group Int Rech Sci Stomatol Odontol. 1995;38:33-38. PUBMED 18. Lehtinen R, Happonen RP, Kuusilehto A, Jansen C. A clinical trial of PUVA treatment in oral lichen planus. Proc Finn Dent Soc. 1989;85:29-33. PUBMED 19. Lundquist G, Forsgren H, Gajecki M, Emstetam L. Photochemotherapy of oral lichen planus: a controlled study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;79:554-558. FULL TEXT | ISI | PUBMED 20. Ruzicka T, Assmann T, Homey B. Tacrolimus: the drug for the turn of the millennium [review]? Arch Dermatol. 1999;135:574-580. FREE FULL TEXT 21. Bieber T. Topical tacrolimus (FK 506): a new milestone in the management of atopic dermatitis [editorial]. J Allergy Clin Immunol. 1998;102:555-557. FULL TEXT | ISI | PUBMED 22. Cooper KD. Atopic dermatitis: recent trends in pathogenesis and therapy [review]. J lnvest Dermatol. 1994;102:128-137. FULL TEXT | ISI | PUBMED 23. Aoyama 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;133:494-496. FULL TEXT | ISI | PUBMED 24. Nakagawa H, Etoh T, Ishibashi Y, et al. Tacrolimus ointment for atopic dermatitis [letter]. Lancet. 1994;344:883. ISI | PUBMED 25. Jegasothy BV, Ackerman CD, Todo S, Fung JJ, Abu-Elmagd K, Starzl TE. Tacrolimus (FK 506): a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol. 1992;128:781-785. FREE FULL TEXT 26. The European FK 506 Multicenter Psoriasis Study Group. Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a double-blind, placebo-controlled study. Arch Dermatol. 1996;132:419-423. FREE FULL TEXT 27. Koga T, Yano T, Ichikawa Y, Oizumi K, Mochizuki M. Pulmonary infiltrates recovered by FKS06 in a patient with Behçet's disease. Chest. 1993;104:309-311. FREE FULL TEXT 28. Abu-Elmagd K, Jegasothy BV, Ackerman CD, et al. Efficacy of FK 506 in the treatment of recalcitrant pyoderma gangrenosum. Transplant Proc. 1991;23:3328-3329. ISI | PUBMED 29. Sandborn WJ. Preliminary report on the use of oral tacrolimus (FK506) in the treatment of complicated proximal small bowel and fistulizing Crohn's disease. Am J Gastroenterol. 1997;92:876-879. ISI | PUBMED 30. Vente C, Reich K, Rupprecht R, Neumann C. Erosive mucosal lichen planus: response to topical treatment with tacrolimus. Br J Dermatol. 1999;140:338-342. FULL TEXT | ISI | PUBMED 31. Kang S, Lucky A, Pariser D, Lawrence I, Hanifin J for the Tacrolimus Ointment Study Group. A long-term, noncomparative trial to evaluate the safety of topically applied tacrolimus as treatment of atopic dermatitis in pediatric patients. Poster presented at: the 58th Annual Meeting of the American Academy of Dermatology; March 10-15, 2000; San Francisco, Calif.

SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE ANNA GLASER, MD; ELAINE SIEGFRIED, MD

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