ARTICLE
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
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