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Treatment of Chronic Erosive Oral Lichen Planus With Low Concentrations of Topical Tacrolimus
An Open Prospective Study
Valérie Olivier, MD;
Jean-Philippe Lacour, MD;
Aline Mousnier, PharmD;
Rodolphe Garraffo, PharmD, PhD;
Roger A. Monteil, DDS;
Jean-Paul Ortonne, MD
Arch Dermatol. 2002;138:1335-1338.
ABSTRACT
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Background Chronic erosive oral lichen planus (EOLP) is a severe form of lichen
of the buccal mucosa that is often resistant to systemic or topical therapies.
Objective To evaluate the efficacy and safety of topical tacrolimus, 0.1 mg per
100 mL of water, in treating EOLP.
Design Open-label, prospective, noncomparative study, with 6 months of treatment
and 6 months of follow-up.
Setting Dermatology department at a university hospital in Nice, France.
Patients Ten patients with histologically proved EOLP that was refractory to
treatment. Two patients were withdrawn because of noncompliance; findings
in 8 were available for evaluation.
Interventions Mouthwashes with tacrolimus, 0.1 mg per 100 mL of distilled water, 4
times daily for 6 months.
Main Outcome Measures Efficacy was assessed using a calculated score that combined the intensity
of spontaneous and meal-triggered pain and the surface area of erosions. Safety
assessment included the monitoring of adverse effects, clinical laboratory
values, and blood concentrations of tacrolimus.
Results Among the 8 patients evaluated, 1 had no improvement and 7 were improved.
The mean score decreased from 7.00 at baseline to 5.43 (a 22.43% decrease)
at 1 month, 4.14 (a 40.86% decrease) at 2 months, 3.00 (a 57.14% decrease)
at 3 months, 2.43 (a 65.29% decrease) at 4 months, 2.57 (a 63.29% decrease)
at 5 months, and 3.43 (a 51.00% decrease) at 6 months. A decrease of symptoms
was reported by the 7 responding patients as soon as the first month of treatment.
No severe adverse effects were observed. All patients had whole-blood concentrations
of tacrolimus below the detection limit of the assay (1.5 ng/mL) at all intervals.
At 9 months, 6 patients had had a relapse within a mean of 38.6 days. At 12
months, all patients had had a relapse and required treatment with topical
corticosteroids or systemic hydroxychloroquine sulfate.
Conclusion Results of our study suggest a rapid and important palliating effect
of low concentration of topical tacrolimus in distilled water in patients
with EOLP.
INTRODUCTION
CHRONIC EROSIVE oral lichen planus (EOLP) is a severe and painful form
of lichen of the buccal mucosa and is often resistant to systemic or topical
therapies. Topical corticosteroids are considered first-line therapy.1 Short courses of systemic corticosteroids are also
frequently used. However, many patients respond poorly to or will develop
adverse effects from prolonged administration of corticosteroids. Other agents,
such as topical or systemic retinoids,2-4 griseofulvin,5 antimalarial agents,6 and
thalidomide,7-8 have been used
for the treatment of EOLP, but their efficacy is debatable. Furthermore, all
of these medications are palliative, and relapses occur when they are stopped.
Because of the lack of a "gold standard" therapy and because of the significant
impact on quality of life, more invasive treatments such as extracorporeal
photochemotherapy have been proposed.9
Because of the T-cell–mediated pathogenesis of EOLP,10 several
studies have been conducted to test the efficacy of topical cyclosporine,
which targets the helper T cell. Some studies have shown a beneficial effect,11-12 whereas others have not.13 Tacrolimus is a macrolide immunosuppressant administered
systemically for the prevention of solid organ transplant rejection. It has
similar effects to those of cyclosporine, inhibiting the activation and proliferation
of T lymphocytes. It has been shown to be effective and well tolerated when
used topically in atopic dermatitis.14 For
these reasons, we sought to evaluate the efficacy and tolerability of topical
tacrolimus, 0.1 mg per 100 mL of distilled water, in the treatment of EOLP.
PATIENTS AND METHODS
We conducted an open prospective study from January 1, 2000, to December
31, 2000. All patients gave written informed consent, and the study was approved
by the local ethics committee. Enrolled patients had histologically proved
EOLP that was refractory to treatment for more than 6 months. The symptoms
were quantified using a calculated score based on the intensity of spontaneous
and meal-triggered pain and the surface area of the erosions. Spontaneous
and meal-triggered pain were scored from 0 to 4 using a visual analog scale.
The surface area of the erosions was evaluated using a drawing in which the
areas of various zones of the mouth were indicated as a percentage of the
whole surface area of the oral mucosa. Involvement of less than 5% was scored
as 1; 5% to 15%, 2; more than 15% to 25%, 3; and more than 25%, 4. The sum
of the 3 items gave a maximal possible score of 12. A minimal score of 3 was
necessary for inclusion. Neither topical nor systemic therapy with agents
such as corticosteroids, retinoids, cyclosporine, griseofulvin, dapsone, or
hydroxychloroquine sulfate was allowed during the study. All previous treatments
for EOLP were stopped at least 4 weeks before the study. Patients were allowed
to take acetaminophen in case of pain and topical amphotericin B in case of
oral candidiasis. Because of the increased permeability of oral mucosa compared
with skin and because of epithelial erosions, we chose a tacrolimus concentration
of 0.1 mg per 100 mL of water, a lower concentration than that used for the
treatment of atopic dermatitis. The topical medication was prepared by diluting
one 0.5-mg capsule of tacrolimus (Prograf; Fujisawa Pharmaceutical Company,
Ltd, Osaka, Japan) in 500 mL of distilled water. The medication was renewed
every 4 weeks by a hospital pharmacist. We previously verified that this suspension
would be stable for more than 1 month.
Four oral washes per day of 2 minutes each were performed during the
first phase of the study, using 15 mL of the preparation. The daily frequency
of oral rinses was subsequently modified on the basis of a clinical severity
score. If the score was decreased by at least 25% from the first visit, the
number of daily mouthwashes was decreased by 1 in the subsequent period. On
further decrease to less than 50% of the initial severity score, the number
of daily mouthwashes was additionally decreased by 1. If there was no improvement
at 2 consecutive visits, the number of daily mouthwashes was left unchanged.
In cases of worsening, the number of daily mouthwashes was increased to the
previous frequency.
The major criterion for efficacy was the clinical score, which was evaluated
by the same investigator (V.O.) at baseline, after 2 weeks, and then monthly
from the first (M1) to the sixth (M6) month of treatment. Investigators' and
patients' global assessments were considered secondary outcomes. The duration
of treatment was 6 months. Follow-up assessments were performed at 3 and 6
months (M9 and M12, respectively) after completion of treatment. The relationship
between the score and the treatment duration was analyzed using the Spearman
rank correlation coefficient.
Laboratory values (hematology, serum electrolytes, renal and hepatic
function, and serum glucose level) were tested at baseline and repeated after
15 days and 1 month, and then monthly for the duration of the study. Clinical
adverse effects were evaluated at all study intervals. To evaluate permucosal
absorption of tacrolimus, monthly whole-blood concentrations were measured
using a fluorescence polarization immunoassay (Abbott Laboratories; Abbott
Park, Ill).
RESULTS
Ten patients with EOLP (6 women and 4 men) were included between January
1, 2000, and June 30, 2000. Two were withdrawn because of noncompliance; 8
patients were evaluated (mean age, 58.1 years [range, 34-74 years]). All patients
had histologically proved, treatment-resistant EOLP, with a mean duration
of 3.6 years (range, 6 months to 7 years). The mean baseline score was 7.00
(range, 3-10). One patient, who had leukoplastic lesions, showed no improvement
after 2 months of treatment and was withdrawn from the study. Seven patients
showed improvement. A decrease in symptoms was reported by the 7 responding
patients as soon as the first month of treatment. Three of them were able
to eat normally again at that time. The mean score decreased in parallel to
5.43 (a 22.43% decrease) at M1 (range, 5-8), 4.14 (a 40.86% decrease) at M2
(range, 3-5), 3.00 (a 57.14% decrease) at M3 (range, 1-5), 2.43 (a 65.29%
decrease) at M4 (range, 1-5), 2.57 (a 63.29% decrease) at M5 (range, 0-6),
and 3.43 (a 51.00% decrease) at M6 (range, 0-6) (Figure 1 and Figure 2).
This improvement allowed a progressive subsequent decrease in the number of
daily mouthwashes. Three patients were able to stop treatment completely at
M5. However, relapse occurred after cessation of the mouthwashes. Although
the scores of treated patients continued to improve from M5 to M6, the scores
of the 3 who had discontinued treatment increased (from 1 to 3, 0 to 6, and
1 to 6), which led to a higher mean score at M6. Complete healing of the erosions
was observed in 3 patients at M3. The decrease of the mean score was closely
correlated with the duration of treatment (Spearman rank correlation coefficient,
-0.75; P = .052) (Table 1). No adverse effects were observed. Three patients complained
of tingling immediately after treatment, lasting less than 1 hour. Two also
reported oral dryness. One patient had a recurrence of labial herpes during
the treatment that was similar to his previous episodes and not suggestive
of a drug-related effect. No patient experienced oral candidiasis. No biological
adverse effects were recorded. All patients had whole-blood concentrations
of tacrolimus below the detection limit of the assay (1.5 ng/mL) at all intervals.
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Figure 1. Evolution of the mean scores of
7 patients with erosive oral lichen planus who responded to tacrolimus, from
the baseline visit to the 12th month of the trial (M12). Error bars indicate
SDs.
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Figure 2. Evolution of the surface area
of erosions and spontaneous and meal-triggered pain in 7 patients with erosive
oral lichen planus who responded to tacrolimus, from the baseline visit to
the 12th month of the trial (M12). Error bars indicate SDs.
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Correlation Between Score and Treatment Duration
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The 7 patients were examined 3 and 6 months (at M9 and M12, respectively)
after the end of treatment. At M9, 6 patients had relapsed within a mean of
38.6 days (range, 7 to 90 days); their mean score was 4.00 (range, 1-8). At
M12, all patients had had a relapse of EOLP and required treatment with topical
corticosteroids or systemic hydroxychloroquine. Whereas the patients were
resistant to usual treatments for EOLP before starting tacrolimus therapy,
they responded well when treated again with topical or systemic therapy. At
M12, their mean score was 2.71 (range, 0-6).
COMMENT
The results of our study demonstrate that topical tacrolimus at a concentration
of 0.1 mg per 100 mL of distilled water has a rapid and significant effect
in patients with EOLP that is refractory to other therapies. Among 8 patients,
a single failure of treatment was observed in a patient who had a particularly
leukoplastic form of oral lichen planus, perhaps due to decreased absorption
of tacrolimus over the hyperplastic mucosa. The efficacy of tacrolimus in
EOLP, which is considered to have a T-cell–mediated pathogenesis,10 may be due to its inhibitory effect on the activation
and proliferation of T lymphocytes. To our knowledge, few studies have assessed
the therapeutic effect of topical tacrolimus in EOLP. In the first observational
series, the possible efficacy of 0.1% tacrolimus was shown in 4 patients.15 In the same study, 2 additional patients were treated
for vulvar erosive lichen planus. In that study, tacrolimus was used twice
daily in a hydrophilic petrolatum ointment. In another case report,16 0.1% tacrolimus in a formulation base (white petrolatum,
mineral oil, propylene carbonate, white wax, and paraffin) was used; the results
in this patient also suggested that topical tacrolimus ointment could be a
safe, effective, and well-tolerated therapeutic modality. Subsequently, 2
open studies17-18 were published,
one of which was a retrospective study of 13 patients with EOLP.17 Those
patients were treated with various concentrations (0.03%, 0.1%, or 0.3%) of
tacrolimus in a bland ointment base, 2, 3, or 4 times daily. Eleven patients
had a symptomatic response to treatment that was partial in 8 cases and complete
in 3. Flares occurred soon after stopping the treatment. The other study18 was an open-label, noncomparative study of 0.1% tacrolimus
in a paraffin ointment base, administered twice daily. Tacrolimus therapy
caused a statistically significant improvement of symptoms within 1 week of
commencement of therapy. In that study, 13 of 17 patients had a relapse within
2 to 15 weeks of cessation of tacrolimus therapy. We chose to use a tacrolimus
suspension in distilled water because of its simple formulation and because
patients find mouthwashes to be more convenient and less uncomfortable than
applying ointment in the mouth.
In our study, no severe drug-related adverse effects were observed.
The sensation of mouth burning or dryness was observed in less than half of
the patients and was transient, resolving as EOLP improved. Blood concentrations
of tacrolimus were monitored in only 1 previous study,18 in
which tacrolimus levels were within the therapeutic range in 8 of 17 patients
who were observed after systemic administration. Despite mucosal erosions
and subsequent compromised barrier function, no systemic exposure to tacrolimus
could be detected in our study. This finding was likely due to the low concentration
of tacrolimus we used. The efficacy of such a low dose is an important finding,
since the long-term effects of topical immunosuppressants, particularly the
risks of skin cancer facilitation, are still unknown. Chronic EOLP carries
a risk of oral cancer independently,19 which
suggests that minimizing immunosuppressive effects should be considered.
A relapse of erosive lesions was observed in all of our patients a few
days to months after discontinuation of treatment, suggesting that tacrolimus
has a purely palliative and not a curative effect. However, an alternate-day
or intermittent treatment could probably be used on a long-term basis, with
minimal discomfort and adverse effects for the patients. Furthermore, whereas
EOLP in our patients was refractory to usual treatments before starting tacrolimus
therapy, their EOLP responded well to topical corticosteroids (6 patients)
or to hydroxychloroquine therapy (1 patient) when these patients relapsed
at the end of the study. This finding suggests that short-pulse treatment
with topical tacrolimus could be sufficient in some cases to improve symptoms
in case of resistance to conventional drugs.
There could be some bias in our trial, which was an uncontrolled study
and included a small number of patients. However, our study was prospective,
with stringent inclusion criteria and objective, scored evaluation of the
results, in contrast to studies that use imprecise trial methods and to observational
series of patients with EOLP that are not prospective.1 Furthermore,
spontaneous remission of oral lichen planus is rare, particularly when it
is in the erosive form. A large randomized, controlled, double-blinded trial
that compares topical tacrolimus with a reference treatment such as topical
corticosteroids and includes a quality-of-life study is needed to confirm
our results.
AUTHOR INFORMATION
Accepted for publication April 15, 2002.
This study was supported by a grant (Contrat d'Incitation à la
Recherche 1999) from the Centre Hospitalier et Universitaire de Nice, Nice,
France.
This study was presented in part at the annual meeting of the French
Society of Dermatology (Journées Dermatologiques de Paris 2000), Paris,
France, December 8, 2000.
We thank Dominique Ghio, MD, and José Santini, MD, for assistance
with patient recruitment; Shlomit Halachmi, MD, PhD, and Sasha Mann for editing
assistance; and Frédéric Berthier, MD, for statistical analysis.
Corresponding author: Jean-Philippe Lacour, MD, Department of Dermatology,
Hôpital Archet-2, BP 3079, 06202 Nice CEDEX, France (e-mail: lacour{at}unice.fr).
From the Departments of Dermatology (Drs Olivier, Lacour, and Ortonne)
and Pharmacy (Dr Mousnier), Hôpital Archet, and the Laboratories of
Pharmacology (Dr Garraffo) and Oral Pathobiology (Dr Monteil), Hôpital
Pasteur, Nice, France.
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