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
.
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).
.
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 |
.
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.
.
.
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 6th Biennial Congress, 3‐5 October
2002, Centro Cultural de Belem, Lisbon. Abstract number O35.
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