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Long‐term efficacy and safety of topical tacrolimus in the management of ulcerative\erosive oral lichen planus

European Journal of Dermatology. Volume 13, Number 5, 466-70, September 2003, Therapy

Summary

Author(s) : Tim A. HODGSON, Neeraj SAHNI, Fotini KALIAKATSOU, John AG BUCHANAN, Stephen R PORTER , Oral Medicine, Eastman Dental Institute for Oral Health Care Sciences, UCL, University of London, 256 Gray‘s Inn Road, London, WC1X 8LD, United Kingdom .

Summary : The long‐term safety and clinical benefit of topical tacrolimus for the management of erosive or ulcerative oral lichen planus has not been evaluated. 50 adults (39 female 11 male\; group median age 59, range 29‐88 years) with symptomatic, erosive or ulcerative lichen planus recalcitrant to topical corticosteroids applied 0.1% topical tacrolimus ointment twice daily to symptomatic mucosal lesions. Topical tacrolimus was applied for a median time of 19.8 months (range 2‐39 months) in this patient group. Fourteen percent of the patients had complete resolution of ulcers or erosions, 80% partial resolution and 6% reported no clinical benefit. The most common adverse effects were a burning sensation (16%) at the site of application and transient taste disturbance (8%). No significant, long‐standing changes in hepatic or renal biochemistry were observed. The mean tacrolimus level decreased with duration of therapy from 2.7 µg\\l (week 1) to 0.5 µg\\l (week 32). 0.1% topical tacrolimus is an effective means of controlling the symptoms and signs of erosive or ulcerative oral lichen planus and has no notable adverse effects over a mean duration of application of 19.8 months.

Keywords : lichen planus, oral, tacrolimus, therapy

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ARTICLE

Auteur(s) : Tim A. HODGSON, Neeraj SAHNI, Fotini KALIAKATSOU, John AG BUCHANAN, Stephen R PORTER

Oral Medicine, Eastman Dental Institute for Oral Health Care Sciences, UCL, University of London, 256 Gray‘s Inn Road, London, WC1X 8LD, United Kingdom

Reprints: SR Porter Fax (+ 44) 20 7915 1105 E‐mail S.Portereastman.ucl.ac.uk

Article accepted on 15\7\03

Lichen planus is a common chronic mucocutaneous disease, of uncertain aetiology, affecting 0.5%‐2.2% of studied populations [1‐9]. Erosive\ulcerative oral lichen planus (OLP) is often painful and may interfere with eating, speech and swallowing [1]. Although symptomatic OLP may be refractory to all currently available therapies [10], recent reports suggest 0.1% topical tacrolimus ointment is efficacious in the management of erosive\ulcerative OLP [11‐17]. The aim of the current investigation was to test the efficacy, adverse effect profile and systemic absorption of topical tacrolimus prescribed for the management of erosive or ulcerative OLP in a larger cohort of patients, over a more extended period of time, than has been reported previously.

Methods

The study was undertaken as an extension of the open clinical phase II trial previously reported from the Oral Medicine Unit of the Eastman Dental Institute for Oral Health and Sciences and includes the 17 previously published patients who continued with tacrolimus therapy [13]. Tacrolimus ointment was manufactured at a concentration of 0.1% in a paraffin ointment base [13].

Entry criteria

Individuals with biopsy proven erosive or ulcerative oral lichen planus with the minimum entry criteria of disease refractory to topical corticosteroid therapy with either betamethasone sodium phosphate mouthwash (500 mcg in 15 ml of water) or fluticasone propionate spray (two 50 mcg puffs four times daily) were invited to commence topical tacrolimus therapy. A past history of renal, hepato‐biliary or malignant disease, uncontrolled hypertension or recurrent acute infection excluded an individual from the study.

Study design

Pre‐study assessment

Detailed information regarding the protocol and tacrolimus therapy was given by verbal explanation and written document and informed consent was obtained. A minimum data set (patient age, gender, past medical history, drug history and habits) was documented. All topical and systemic medications previously prescribed for ulcerative OLP were recorded and a subjective assessment of their benefits obtained.

Schedule

Prior to commencing tacrolimus therapy (Week 0) a baseline clinical assessment was recorded together with blood pressure, complete blood count, liver biochemistry, urea, electrolytes and blood glucose levels. Verbal and written instructions to apply 0.1% tacrolimus ointment sparingly to their painful OLP lesions, with clean fingers, twice daily for 8 weeks, were given. Patients were advised that they should refrain from eating or drinking for thirty minutes after application. Any lesion becoming asymptomatic ceased to receive tacrolimus therapy. After eight weeks continuous therapy, topical tacrolimus was applied on an as required‘ basis up to twice daily for the remainder of the study and no additional medication for lichen planus was prescribed. They were reviewed on weeks 1, 5, 8 and then every two months following initiation of therapy. At all subsequent review appointments clinical response was assessed, the blood pressure and adverse events monitored, and the full blood count, renal and liver biochemistry, and blood glucose reviewed.

Clinical response definitions

An erosion was clinically identified by mucosal erythema and ulceration as a inflammatory yellow\white necrotic slough both invariably associated with characteristic white striae.

Complete response at 8 weeks was defined as an asymptomatic patient and absence of mucosal erosion or ulceration following 8 weeks of continuous tacrolimus therapy.

Partial response was defined by a self‐reported decrease in symptoms, with incomplete resolution erosion or ulceration after 8 weeks of continuous topical tacrolimus therapy.

No response was defined by no change in symptoms or signs after 8 weeks of continuous 0.1% tacrolimus therapy.

Systemic absorption of tacrolimus

Tacrolimus absorption was monitored on weeks 1, 5, 8, 19 and 32 of the study by the Imx Tacrolimus II assay based on Microparticle Enzyme Immunoassay (MEIA) technology [18].

Statistical analysis

The variation of blood tacrolimus level with duration of therapy was analysed using ANOVA and the correlation coefficient used to determine an association between lesion surface area and blood tacrolimus level.

Results

Fifty subjects (11 male and 39 female; median age 59 years, range 29‐88 years) referred to Eastman Dental Institute for Oral Health Care Sciences between 1999 to 2002

comprised the study population. None disclosed a previous history of renal, hepatobiliary or malignant disease or recurrent infection, however 10 (20%) had well controlled hypertension. One patient underwent a right mastectomy for intra‐ductal carcinoma after one year of topical tacrolimus therapy, without adjuvant radiotherapy or oestrogen receptor antagonism.

Symptomatic oral lichen planus had been present for a mean time of 14.5 months (median 9 months, range 3 to 120 months) in the study group prior to commencing topical tacrolimus therapy and a range of topical and systemic medication had previously been prescribed (median number of medications 3, range 1‐10). Betamethasone sodium phosphate mouthwash (74% subjects) was the most common first line topical corticosteroid followed by fluticasone propionate spray (64% subjects) and fluticasone propionate cream (30% subjects) (Table I). Systemic corticosteroids and corticosteroid sparing agents had been used by 34% and 18% of subjects respectively. Two thirds of the patients had used benzydamine hydrochloride mouthwash for symptomatic relief (Table I).

Table I. Medication prescribed for oral lichen planus in 50 patients prior to topical tacrolimus therapy

Medication	Number of patients	Percentage
Topical
0.15% benzydamine hydrochloride	33	66
Betamethasone mouthrinse 500 µg in 15 ml of water bd	37	74
Topical ciclosporin mouthrinse 5 ml of 100 mg\ml suspension tds	14	28
1% prednisolone mouthrinse tds	1	2
0.05% Fluticasone propionate spray 100 µg qds	32	64
Beclometasone propionate spray 50 mcg tds	1	2
Hydrocortisone hemisuccinate lozenges 2.5 mg qds	4	8
0.05% Clobetasol propionate cream bd	9	18
0.05% Fluticasone propionate cream bd	15	30
Systemic
Deflazacort 1‐60 mg od	10	20
Prednisolone 1‐60 mg od	7	14
Systemic azathioprine 50‐200 mg od	7	14
Oxypentifylline 400 mg tds	1	2
Mycophenolate mofetil 500 mg, bd	2	4
Thalidomide 50 mg, od	1	2

od: once daily, bd: twice daily, tds: three times daily, qds: four times daily

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The mean duration of topical tacrolimus therapy was 19.8 months (range 2‐39). A complete response following 8 weeks of tacrolimus therapy occurred in 7 subjects (14%), who continued to use topical tacrolimus ointment on an as required‘, maximum twice daily basis, for a median duration of 22.3 months (range 14‐34 months) (Table II). A partial response occurred in 40 subjects (80%) at 8 weeks. The clinical response is documented in Figure 1. Despite the incomplete resolution of symptoms and signs, 38 of this group continued to use topical tacrolimus for a median duration of 21.6 months (range 12‐39 months) as it provided a more effective symptom control than any other topical agent. Only 3 subjects (6%) failed to respond to 0.1% topical tacrolimus therapy after 8 weeks (Table II).

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Table II. Clinical response of 50 patients with erosive\ulcerative lichen planus following topical tacrolimus therapy for 8 weeks.

Clinical response	Number of patients	Percentage of group	Median duration of tacrolimus therapy (months)	Range of tacrolimus therapy (months)
Complete response	7	14%	22.3	14‐34
Partial response	40	80%	21.6	12‐39
No response	3	6%	3	2‐5

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Few adverse effects were reported. 8 (16%) patients complained of local irritation at the site of application of tacrolimus, which decreased with the treatment duration in all but 2 subjects (who both stopped therapy after the initial 8 week period despite partially responding). Dysgeusia occurred initially in 5 subjects (10%) but resolved and 2 subjects (4%) had intermittent headaches.

There were no significant changes in the red cell indices. A transient neutrophilia developed in 3 patients (6%) during topical tacrolimus therapy related to acute respiratory tract infections, whereas 1 subject had transient neutropenia following the initiation of therapy. A transient lymphopenia occurred in 3 patients (6%) after the first week of therapy. One subject had a persistently low lymphocyte count which was noted prior to the initiation of therapy and did not significantly change. A transient lymphocytosis occurred in 3 subjects (6%). Insignificant changes were also observed in 4 subjects regarding eosinophil and monocyte counts. There were no changes in renal biochemistry and blood glucose levels, however 4 subjects (8%) had a transient and one subject had a persistent increase in alkaline phosphatase. Only one subject was found to have a persistently raised alanine transaminse.

The mean maximum blood tacrolimus level was observed in the first three weeks of therapy (2.7 µg\L) (Fig. 2). The mean value although below the lower therapeutic value used for renal transplantation maintenance (5‐10 µg\l), does indicate significant systemic absorption through the diseased oral mucosa or ingestion. The highest tacrolimus levels of 11 µg\L were recorded in weeks 1 and 5, subsequently decreased to zero by week 32 and were associated with no adverse systemic effects. The mean tacrolimus level decreased with duration of therapy from 2.7 µg\l (week 1) to 0.5 µg\l (week 32), however due to the wide 95% confidence intervals, analysis of variance (ANOVA) was insignificant at the 5% level (p ∓ 0.451) (Fig. 2). There was poor correlation between erosion or ulceration surface area and tacrolimus level (correlation coefficient 0.08) (Fig. 3). The mean volume of ointment used in weeks 1‐8 was 10ml in 21 days (range 7‐34) but was not correlated with the blood tacrolimus level. Although tacrolimus applied to the diseased oral mucosa is assumed to remain local since 54% of patients treated had measurable blood levels, a systemic effect cannot be excluded.

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Discussion

Topical tacrolimus is one of a new class of medications, the non‐corticosteroid topical immunomodulators. The present study significantly extends previous reported findings by this unit regarding the role of 0.1% topical tacrolimus ointment in the management of symptomatic erosive\ulcerative oral lichen planus [13] by both increasing treated patient numbers and duration of therapy. Following twice‐daily applications of 0.1% tacrolimus ointment to symptomatic oral lesions for 8 weeks 94% of patients reported symptomatic improvement. Lack of efficacy resulted in 3 patients terminating topical tacrolimus application whilst local irritation prevented 2 further patients continuing beyond the eighth week of therapy despite achieving partial symptom control.

Response to therapy was determined at 8 weeks as symptoms measured by the visual analogue scale and McGill Pain Questionnaire and erosion\ulceration surface area reduction plateaus following 5 weeks of therapy with the most significant changes occurring in the first week [13]. The results of the present study indicate that topical tacrolimus is effective for symptom control in erosive and ulcerative oral lichen planus, however for remission to be maintained continued intermittent therapy is required in all patients. On cessation of therapy symptom control may extend for up to 20 weeks, the median relapse time being 5 weeks (range 2‐20), however satisfactory disease control can be maintained by intermittent topical tacrolimus application. The frequency of application after the initial 8‐12 week period showed wide inter and intra‐patient variability from once every three days to twice daily. In the 90% of patients continuing therapy beyond 8 weeks the improvement in symptoms and signs was maintained and there appeared to be no loss of treatment efficacy.

The safety of topical tacrolimus was assessed based on the incidence of adverse events and changes from baseline in the haematological and biochemical laboratory profile. The most common application site events were tingling and or burning (16%) of short duration, mild or moderate in severity and of highest prevalence during treatment initiation, comparable to those reported during the treatment of atopic dermatitis [19‐21]. The only non‐site application adverse events were intermittent headaches (4%) but their incidence failed to increase with increasing cumulative topical tacrolimus administration and could not be attributed entirely to the medication.

Quantifiable whole‐blood tacrolimus concentration levels were detected in 27 (54%) patients, they were transient isolated occurrences, not associated with any adverse clinical event and not correlated with the surface area of erosion\ulceration being treated. Only 5 (10%) patients had tacrolimus blood levels greater than 5 µg\L (the minimal clinically effective concentration for transplantation use trough level), however it would appear that absorption associated with the lesions of oral lichen planus may be greater than skin affected by atopic dermatitis [22, 23]. In atopic dermatitis as the disease resolves cutaneous and systemic absorption is greatly reduced [24]. Our results suggest this trend but fail to reach significance. Though measurement of blood levels of tacrolimus remains an important surrogate marker for potential systemic adverse effects, it is of greater importance to determine whether clinically significant adverse effects are evident in clinical trials.

Long term consequences of systemic tacrolimus therapy are immunosuppression [25, 26] and an increased risk of malignancy, especially squamous cell carcinoma and lymphoid tumours [27]. Systemic tacrolimus is associated with a lower incidence of new malignancies compared to ciclosporin [28]. Most adverse effects associated with the systemic administration of tacrolimus are a result of long‐term exposure and it is anticipated the low blood levels associated with topical administration will minimise immunosupression [29]. No increased frequency or severity of local or systemic infection was reported while using topical tacrolimus ointment in this study. In view of the small inherent potential of oral lichen planus to undergo malignant transformation and prolonged use of the medication patients should be closely monitored.

The risk of toxicity with topical application of tacrolimus is much less than systemic administration. Although there are no generally accepted monitoring guidelines for the use of systemic tacrolimus in dermatological disease, a similar protocol to ciclosporin has been suggested [30]. This includes evaluation of blood pressure, full blood picture, renal and hepatic biochemistry. Since there were no clinically significant changes in this patient group or reported in the literature in blood pressure or creatinine, the importance of these investigations in monitoring topical application should be reviewed in the light of further clinical trials.

Tacrolimus, a new non‐steroidal topical immunomodulator, is finding increasing application in recalcitrant inflammatory skin and mucosal disease. We have demonstrated the efficacy and safety of topical tacrolimus for the treatment of 50 patients with erosive\ulcerative oral lichen planus treated over a mean duration of 19.8 months and suggest that following an unsuccessful response to treatment with moderate\potent topical corticosteroids topical tacrolimus be considered a management option before commencing systemic immunosuppresion.

This paper was first presented at the European Association of Oral Medicine 6^th Biennial Congress, 3‐5 October 2002, Centro Cultural de Belem, Lisbon. Abstract number O35.

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