Topical tacrolimus: a novel therapeutic

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题名	Topical tacrolimus: a novel therapeutic intervention for recalcitrant labial pemphigus vulgaris.
链接	http://www.jle.com/fr/revues/ejd/e-docs/topical_tacrolimus_a_novel_therapeutic_intervention_for_recalcitrant_labial_pemphigus_vulgaris_100574/article.phtml

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REFERENCES

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2 - Korman NJ. New immunomodulating drugs in autoimmune blistering diseases. Dermatol Clin 2001; 19: 637-48, viii.


3 - Nasr IS. Topical tacrolimus in dermatology. Clin Exp Derm 2000; 25: 250-4.


4 - Gupta AK, Adamiak A, Chow M. Tacrolimus: a review of its use for the management of dermatoses. JEADV 2002; 16: 100-14.


5 - Ayoama H, Tabata N, Tanaka M, Uesugi Y, Tagami H. Successful treatment of resistant facial lesions of atopic dermatitis with 0.1 % FK506 ointment. British Journal of Dermatology 1995; 133: 492-500.


6 - 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: 69-76.


7 - 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.


8 - 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.


9 - Nishifuji K, Amagai M, Kuwana M, Iwasaki T, Nishikawa T. Detection of antigen-specific B cells in patients with pemphigus vulgaris by enzyme-linked immunospot assay: requirement of T cell collaboration for autoantibody production. J Invest Dermatol 2000; 114: 88-94.


10 - Almawi WY, Assi JW, Chudzik DM, Chudzik DM, Jaoude MM, Rieder MJ. Inhibition of cytokine production and cytokine-stimulated T-cell activation by FK505 (tacrolimus). Cell Transplant 2001; 10: 615-23.


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16 - Rozycki TW, Rogers RS 3rd, Pittelkow MR, McEvoy MT, El-Azhary RA, Bruce AJ et al. Topical tacrolimus in the treatment of symptomatic oral lichen planus: a series of 13 patients. J Am Acad Dermatol 2002; 46: 27-34.


17 - Nazzaro G, Cestari R. Topical tacrolimus ointment in ulcerative lichen planus: an alternative therapeutic approach. Eur J Dermatol 2002; 12: 321.
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hile systemic corticosteroids remain the most established initial therapy for oral mucosal pemphigus vulgaris, the need for prolonged administration to achieve remission with attendant high morbidity, requires the use of corticosteroid-sparing immunosuppressive regimens (recently reviewed elsewhere) [1, 2]. Tacrolimus (FK506), a non-steroidal, potent macrolide lactone immunosuppressant has found increasing application in the management of dermatological disease [3, 4]. However, as yet its use in the management of mucosal pemphigus vulgaris has not been formally assessed.


We detail the rapid response of a persistent labial ulcer, in a female with known pemphigus vulgaris, to topical tacrolimus therapy which had previously failed to heal with topical and systemic corticosteroid and immunosuppressive therapy.


Case report


A 37 year old Asian female human resources manager presented in 1995 to the Oral Medicine Department of the Eastman Dental Institute, UCL, London with a three year history of recurrent ulceration of the buccal mucosae and crusted lips. Her medical history included irritable bowel syndrome and a hiatus hernia. On presentation she was taking no medication but was allergic to penicillin. She did not smoke tobacco, drank 5-10 units of alcohol weekly and gave no history of recreational drug use. Clinical examination, on presentation, revealed no cutaneous disease, however intraorally widespread superficial ragged ulceration of the buccal and labial mucosa and a desquamative gingivitis suggested a clinical diagnosis of pemphigus vulgaris, which was confirmed by direct immunofluorescence of perilesional tissue. Indirect immunofluorescence showed inter-cellular zone deposition of IgG antibodies on monkey oesophageal mucosa, with a titre of 1:160.


Initial disease control was achieved with prednisolone (1 mg kg-1 bodyweight daily) and symptomatic relief with benzydamine hydrochloride 0.15 % spray as required. Over the following three years recurrent exacerbations of oral mucosal and cutaneous disease were managed sequentially with dapsone (up to 100 mg daily), azathioprine (up to 3 mg kg-1 bodyweight daily) and ciclosporin (up to 3 mg kg-1 bodyweight daily). Therapy was changed due to the recurrence of oral lesions despite maximum tolerated dose (dapsone and ciclosporin) or adverse effects (azathioprine). Topical corticosteroids, including beclomethasone dipropionate spray (50 mcg metered dose aerosol inhalation two puffs four times daily) and fluticasone propionate 0.05 % cream applied directly to the oral mucosa twice daily were intermittently used as adjuvants to systemic therapy.


In October 1998 despite ciclosporin therapy the extensive mucosal disease recurred with an associated increase in IgG antibody titre to 1:5120. In addition, fluid-filled vesicles developed bilaterally in the submammary regions. Despite deflazacort 1.5 mg kg-1 bodyweight daily for 3 months and an additional 16 weeks of mycophenolate mofetil up to 1 gram twice daily an ulcer persisted on her right lower lip (Fig. 1). There was no significant clinical improvement of the lip lesion despite resolution of the cutaneous and all other mucosal disease and a fall in the IgG titre to 1:80. Corticosteroid therapy resulted in a marked increase in body weight, development of Cushingoid features and unpredictable mood swings and, in view of a lack of lip ulceration response, was reduced and withdrawn and the mycophenolate mofetil continued (without adverse effect other than a mild lymphopenia of 1.2 <=> 109 L-1). Topical application of triamcinolone acetonide 0.1 % in an adhesive base three times daily for one month followed by clobetasol propionate 0.05 % cream twice daily for one month resulted in a modest reduction in the ulcer size. Subsequent intralesional injections of triamcinolone acetonide 25 mg into the lip beneath the ulcer on 3 occasions 1 month apart failed to produce any clinical response.


The failure of the ulcer to heal with corticosteroid therapy in a patient with known pemphigus vulgaris and the risk regarding the development of cutaneous malignancy in subjects on prolonged immunosuppressive therapy suggested the lesion should be biopsied, however this was declined because of concerns regarding scarring. After being present for 15 months, the lesion resolved following the application of tacrolimus 0.1 % ointment to the lip twice daily for four weeks and the continuation of mycophenolate mofetil 1 gram twice daily (Fig. 2). Tacrolimus ointment was manufactured at a concentration of 0.1 % in a paraffin ointment base [5]. This formulation differs from that used for cutaneous application [6, 7]. Tacrolimus therapy was not associated with any adverse effects and there was no detectable evidence of systemic absorption with levels less than the lower limit of quantitation (2 mug L-1, Imx Tacrolimus II assay based on Microparticle Enzyme Immunoassay (MEIA) technology [8]) 6 hours post application to the lip on day 1 and then weekly for the duration of the therapy.

Mycophenolate mofetil (1 gram twice daily) successfully maintained disease remission for a further 9 months, however a marked clinical deterioration and rising IgG antibody titre to monkey oesophagus readily controlled by corticosteroids could not be maintained with mycophenolate mofetil alone. Currently a 15 month remission has been achieved with systemic tacrolimus (0.5-4.0 miligrams daily, tacrolimus levels 4.5-7.0 micrograms/litre).


Discussion


Although pemphigus is characterized by the production of pathogenic antibodies, the role of the cellular immune response is probably crucial in the production of autoantibodies by B-cells [9]. Tacrolimus inhibits T-cell activation by at least two methods; by inhibiting cytokine availability and by suppressing cytokine effect on target cells [10]. After exhausting all other therapeutic options and concluding the lip ulceration was most likely to be the result of localized disease, a trial of topical tacrolimus was considered, in close liaison with the patient, an appropriate treatment.


Severe mucosal vesiculobullous disease often remains refractory to treatment and remission is difficult to maintain [11, 12]. Topical tacrolimus is an important new therapy for the treatment of mucosal disease and has proven applications for oral erosive/ulcerative lichen planus [13-19], the oral manifestations of Crohn's disease and orofacial granulomatosis [20, 21]. Refractory benign familial pemphigus (Hailey-Hailey disease) is the only vesiculobullous disease previously reported to have responded to topical tacrolimus (0.1 % twice daily) [22]. We conclude topical tacrolimus may be a useful adjuvant therapy for mucosal pemphigus vulgaris and its role in the management of this and other vesiculobullous mucosal disease requires further investigation.


Article accepted on 6/1/2003