1. health and fitness
2. therapy

STUDY
Treatment of Lichen Planus
An Evidence-Based Medicine Analysis of Efficacy
Bernard Cribier, MD, PhD; Camille Frances, MD; Olivier Chosidow, MD, PhD
Objective: To critically appraise the body of literature
concerning treatment of lichen planus (LP).
Design: Review of MEDLINE and BIOSIS databases to
identify articles published with at least an English abstract before March 1998 that examined treatment of LP.
Main Outcome Measures: Forming a primary database on which most recommendations are based. We thus
selected 83 clinical trials or small series of patients in the
medical literature that referenced clinical data on patients treated for LP.
Results: There are no large randomized trials with definitive results in the medical literature examining the efficacy
of the various drugs or physical treatments of LP. There are
only 3 level B trials (small randomized trials with uncertain
results because of moderate to high a or b error) that address efficacy of treatment in LP, ie, 1 with acitretin in cu-
taneous LP and 2 with topical corticosteroids in mucosal LP.
The remainder of the published trials are observational and
are not always prospective. Many of the recommendations
of the experts are based on their personal experience.
Conclusions: Although LP may be associated with substantial morbidity and altered quality of life, especially
the erosive mucosal LP, definitive clinical trials have not
been performed. Acitretin is the first-line therapy in cutaneous LP. The efficacy of systemic corticosteroids and
psoralen plus UV-A therapy has not been established with
a high level of proof. Topical corticosteroids are the firstline therapy in mucosal erosive LP. Other treatments, such
as topical cyclosporine or extracorporeal photochemotherapy, remain to be evaluated. European-US cooperation is warranted to perform large randomized controlled trials in cutaneous and mucosal LP.
Arch Dermatol. 1998;134:1521-1530
L
From the Dermatology Clinic,
Hoˆpitaux Universitaires de
Strasbourg, Strasbourg, France
(Dr Cribier), and Department
of Internal Medicine , Groupe
Hospitalier Pitie´-Salpeˆtrie`re,
Paris, France (Drs Frances and
Chosidow).
ICHEN PLANUS (LP) is a
well-characterized dermatological condition affecting the skin, mucosa, hair,
and nails, but its treatment
is often disappointing and controversial.
Various drugs or physical treatments
have been proposed in the past 30 years,
but the majority of these reports consist
of small series of patients or anecdotes.
Controlled studies on large numbers of
patients are rare, probably because LP is
not a common disease; it has many different clinical forms that have different
natural courses and may require different
treatments. As a result, large and randomized studies are difficult to perform.
Furthermore, no standardized methods
exist for the evaluation of the severity of
the disease, there are no consensual criteria of improvement or cure, and the
course of the disease is variable from one
patient to another and varies according
to the clinical form. To correctly interpret the results, the natural course of the
disease must be kept in mind. According
to large series in the literature, spontaneous remissions of cutaneous LP after 1
year occur in 64% to 68% of the cases.1,2
On the other hand, spontaneous remissions of oral LP are much rarer and were
estimated to occur in less than 2.8% of
the cases in a series of 570 patients3 and
in 6.5% of 214 patients with a mean
follow-up of 7.5 years. 4 The reported
mean duration of oral LP is about 5
years, but the erosive form does not
spontaneously resolve.5 The reticular
form has the best prognosis, since spontaneous remission occurs in 40% of
cases. 6 Recurrences are occasionally
observed,7 but their prevalence has never
been studied in large prospective studies.
Malignant transformation of oral LP has
been described4 but remains controversial.8 Among all articles published on the
treatment of LP, we have found only a
minority of them to be controlled studies, the largest series comprising 65
patients.9
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METHODS
A review of the literature by means of MEDLINE and
BIOSIS databases was conducted to identify articles
published before March 1998 examining treatment
of LP. We used the key words “lichen and treatment
or therapy” and we combined each treatment modality with “lichen.” When possible, the criteria defined by Sackett10 were applied to establish the level
of proof. Level A indicates large randomized controlled trials that allow definitive conclusions. Clinical trials with rigorous methods in which small numbers of patients were included are classified in the level
B group (randomized trials with uncertain results because of moderate to high a or b error). Controlled
trials with less than 20 patients in each group were
classified into group C, as well as trials without randomized controls (either with contemporary controls, with historical controls, or without controls).
We selected 83 clinical trials (3 level B and 80
level C trials) in the medical literature that contained specific data on LP and its treatment. Case reports or anecdotal reports of drug efficacy were not
considered as clinical trials but were nevertheless analyzed, as were review articles containing therapeutic data. Articles without English abstracts were not
included. Together, these articles form the primary
database on which most recommendations are based.
To facilitate practical decisions, we decided to evaluate separately the cutaneous and oral forms of LP in
the present analysis.
RESULTS
CUTANEOUS LP
Retinoids
Acitretin. A double-blind vs placebo trial was carried out
on 65 patients with cutaneous LP.9 Treatment consisting
of 30 mg of acitretin per day for 8 weeks demonstrated the
drug’s efficacy, as 64% (18/28) of the treated patients experienced significant improvement or remission in contrast
to 13% (4/31) of the placebo group. The criteria for remission and marked improvement are not detailed. One figure clearly showed that papules persisted in the majority
of patients under acitretin. Nevertheless, the intensity of pruritus, papulosis, and erythema was significantly lower in
the acitretin group. After administration of acitretin to subjects who had been in the placebo group, 83% were considered to have responded favorably. Side effects were recorded in all patients, mainly cheilitis and dry mouth, but
the tolerability was considered to be good or very good in
73% of cases. Among the 65 patients, 23 also had associated mucosal LP lesions (of unknown type), and significant
improvement was recorded for 74% of them. Neither the
duration of the disease before inclusion nor the extent of
the lesions was detailed in this trial. Nevertheless, this is
theonlycontrolledtrialpublishedoncutaneousLPthatcould
be classified as level B according to Sackett.10
Acitretin allowed complete clearance or major improvement in 6 of 8 patients with cutaneous LP treated
with 30 mg/d for 8 weeks.11 Dramatic improvement was
noted after 12 weeks of acitretin treatment in a 9-yearold boy12 who suffered from exanthematous LP. Acitretin has also been used successfully in 1 case of palmoplantar lichen nitidus.13
Etretinate. An open study tested the efficacy of etretinate, 50 mg/d for 2 to 3 weeks, followed by 25 mg/d in
28 patients with cutaneous LP.14 No criteria for evaluation were provided in this study, which showed a “good
effect” in 23 cases, and the time of withdrawal of the drug
was chosen “more or less at random.” Two small groups
of patients with “chronic” cutaneous LP15 or eruptive LP16
had good or excellent responses, but patients with LP were
mixed with patients affected by various other skin diseases. The efficacy of etretinate was also noted in 4 anecdotal reports: 2 cases of cutaneous LP,17,18 1 case of ulcerative LP,19 and 1 case of LP affecting the nails.20
Oral Isotretinoin and Tretinoin. Oral isotretinoin, 0.5
mg/kg per day, was effective in 2 cases of severe LP with
both cutaneous and oral lesions,21 but we could not find
a controlled study using this drug. More recently, a small
series of 13 patients with cutaneous LP were treated with
oral tretinoin in an open study.22 The dosage was 10 to
30 mg/d for 1 to 10 months. Twelve of the 13 patients
experienced complete remission, without side effects other
than cheilitis in 3 cases. A complete failure was observed in 1 additional patient who had only nail involvement. The use of oral tretinoin in the treatment of LP was
introduced as early as 1971.23-25 It is difficult to evaluate
critically the efficacy of tretinoin in those studies, since
(1) patients were treated either locally or orally or both
for unknown reasons, (2) the dose and duration of treatment were not available in all patients, and (3) the criteria for response were not clearly stated. The results
seemed to be encouraging, although multiple systemic
side effects were recorded. Hypertrophic cutaneous lesions did not respond to oral tretinoin.25
Temarotene, a new member of the retinoid family,
has been tried in 13 patients,26 of whom 10 had complete or near-complete remission after 2 to 3 months of
treatment. Transient increases in transaminase levels, nausea, and vomiting were recorded in 6 cases. A placebocontrolled assay was in progress in 1989, but results have
not been published yet.
Before definitive conclusions can be drawn, the various oral retinoids should be compared,27 but of all systemic retinoids, only acitretin has shown a relatively good
level of evidence of its efficacy in the treatment of cutaneous LP. The association of retinoids with psoralen plus
UV-A (PUVA) therapy has not been evaluated.
Photochemotherapy
A cure rate of 75% after 8 weeks was reported in 2 open
studies conducted in 7 and 70 patients, but no criteria
for a cure were described.28,29 Only 1 small controlled trial
was published, in 198430; it used hemicorporeal UV-A
irradiation after ingestion of psoralen (dosage un-
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known). Eight of the 10 patients improved partially and
5 of them were completely cured, with a total dose ranging from 100 to 457 J/cm2. The absence of any observed
contralateral effect of the PUVA therapy supports its local efficacy, and half of the patients have been in complete remission for up to 4 years. The surface and type
of lesions were not detailed, except in 1 patient who had
involvement of the palm, soles, and nails of unknown evolution after PUVA.
An open study of 75 patients with cutaneous LP who
underwent bath PUVA therapy31 showed that 2 cycles of
therapy led to a cure rate of 65% and an improvement
rate of 15%. Fifty milligrams of trioxsalen was added to
150 L of water, and the patients were exposed to UV-A
after 10 minutes of bathing. After 2 to 5 years of followup, the relapse rate was 25%, occurring 3 weeks to 3 years
after the end of the second cycle. There were 5 other open
studies with small populations.31-36 In one,34 10 patients
received conventional PUVA and 13 had bath PUVA. Although the response rate was a little higher in the bath
PUVA group, the retrospective comparison of nonrandomized patients in an uncontrolled study did not allow any clear-cut conclusion. Moreover, at 1 year of follow-up, 74% of the treated patients had papules again,
while 55% of untreated control patients were cured, suggesting an exacerbation or a relapse of the disease after
withdrawal of therapy.34 In the most recent open study,32
11 of 12 patients with resistant LP were cured or had significant improvement with bath PUVA, with the use of
methoxsalen at 1 mg/L.
The level of evidence of PUVA efficacy in the treatment of cutaneous LP is therefore weak. In some cases,
PUVA is able to decrease pruritus during the first weeks
of treatment28 or to rapidly cure patients with resistant
long-standing LP. Bath PUVA could be more effective than
oral PUVA, but the possibility of exacerbation of the disease induced by PUVA29 or after the treatment34 has been
raised; thus, the results must be interpreted cautiously.
Corticosteroids
Examination of the literature, especially general reviews devoted to LP, shows numerous recommendations concerning the use of oral corticosteroids, but, surprisingly, no published study evaluated their efficacy until
1990.37 In contrast, many patients were treated with various drugs (oral cyclosporine, retinoids, immunosuppressors, dapsone) after the failure of systemic corticosteroid therapy or the inability to discontinue it without
relapse. Corticosteroids remain the most widely used treatment in LP.38-41 Prednisone dosages of 30 to 60 mg/d are
recommended,39 with an efficacy threshold of 15 to 20
mg/d.40-41 The mean duration of treatment is 6 weeks, but
it has been stated that corticosteroid therapy does not affect the total duration of the disease.42 Different dosage
regimens were also proposed: prednisone, 5 to 10 mg/d
for 3 to 5 weeks, was successful in 3 cases of LP of the
nails,43 and megadoses of methylprednisolone (1 g intravenously on 3 consecutive days) resulted in a favorable response in a patient with severe resistent LP of the
skin, genitalia, and scalp.44 The most recent study was
made in 38 patients who received either prednisolone,
30 mg/d (without gradual reduction), or placebo for 10
days and whose LP was evaluated by a linear scale of severity.37 After a follow-up of 2 years, data for 28 patients
(14 in each group) could be evaluated. The median time
for LP to clear was 18 weeks in the corticosteroid group
and 29 weeks in the placebo group (P = .02), and 3 of 14
patients in the placebo group vs none in the corticosteroid group failed to clear after 2 years. The changes at 6
weeks were significantly higher in the treated group
(P,.05). Two patients treated with prednisolone had severe relapse after discontinuation of the drug, so that a
more prolonged course of corticosteroid therapy was necessary. No other controlled study could be found in the
literature. It is not known whether the conventional 4to 6-week treatment is superior to the short-course prednisolone regimen.
Topical corticosteroids are also frequently applied
to reduce itching, but we could not find any clinical trial
addressing this issue. For some authors,39 clobetasol propionate has the ability to clear skin lesions when used
frequently, leading them to recommend triamcinolone
acetonide under occlusion for generalized disease. Intralesional injections of triamcinolone acetonide, 10 mg/
mL, are used in hypertrophic lesions.39 Topical corticosteroids are the most popular form of therapy in children.40
Others recommend topical corticosteroids only in case
of limited involvement, with occlusion overnight to increase efficiency.7 Surprisingly, none of these recommendations is based on clinical trials.
There are few studies published before 1970 dealing with topical corticosteroids in various cutaneous diseases in which patients with LP were included. Two of 7
patients treated with fluocinolone acetonide, 0.2%, 3 times
per day, cleared after an unkown delay.45 Fluocinonide
was administered to 29 patients with LP in a doubleblind trial vs betamethasone valerate and hydrocortisone topically, but the patients were mixed together with
811 other patients suffering from various dermatoses.46
The results in the patients with LP were not available.
Triamcinolone acetonide, 0.025%, in 70% dimethyl sulfoxide was tested in 224 patients, including 13 patients
with LP, but their specific results were not detailed.47 Triamcinolone acetonide, 0.5%, in flexible collodion was administered on 1 side to 7 patients with LP compared with
excipient on the opposite side.48 Only 3 of them had clear
benefit on the corticosteroid side.
Intradermal injections of triamcinolone acetonide,
5 mg/mL, in the posterior nail fold were given 3 times at
intervals of 2 to 4 weeks in 11 patients with LP of the
nails.49 Seven of them were “greatly improved,” but 2 relapsed after 8 and 12 months.
We could not find any clinical trial specifically
dedicated to the treatment of cutaneous LP with topical corticosteroids.
Although the level of evidence of corticosteroid efficacy is low, unpublished clinical experience has showed
that short-course systemic therapy can be effective in reducing the duration of the disease. The frequency and
level of relapse of LP after withdrawal have also never
been established. Topical corticosteroids are widely used,
but there is no convincing evidence of their efficacy in
the literature.
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Griseofulvin
Griseofulvin, 1000 mg/d, was administered for 1 to 10
months in 15 patients with cutaneous LP associated or
not with oral lesions50 and in 25 patients with cutaneous LP.51 In the first open study,50 12% of the patients
improved and 12% experienced exacerbation of the disease. In the second study,51 86% of the patients had complete disappearance of the lesions after a 3-month delay.
Two trials in which the methods were incompletely detailed have been published.52,53 The first study51 included 2 groups of 17 patients each who received either
placebo or griseofulvin for 4 to 6 weeks. “Complete regression” was observed in 71% of griseofulvin-treated patients vs 30% of placebo-treated patients, but the definition of a cure was based only on flattening of lesions and
reduction of itching. In the second study,53 44 patients
with cutaneous LP were treated with griseofulvin, 1 g/d,
or placebo for 8 weeks. Griseofulvin resulted in “complete improvement” in 82% of patients and partial remission in 18%, whereas partial remission occurred in
only 23% of placebo-treated patients. The extension and
type of lesions are unknown. The methods used in both
studies do not allow definitive conclusions.
in 7 of the 10 patients described.66-68 In 1 study of 30 patients with cutaneous LP associated or not with oral lesions,
phenytoin, 100 to 300 mg/d, was administered for 8 to 24
weeks.69 Inclusion and efficacy criteria are lacking, but the
authors described 14 patients with complete clearance and
11 with improvement. In 1 case of severe LP70 and in 1 case
of LP associated with pemphigoid,71 azathioprine plus systemic corticosteroids proved effective, and cyclophosphamide was effective in 3 cases of resistant cutaneous LP.72
In 2 isolated cases of LP pemphigoid, the lesions were cleared
by tetracycline and nicotinamide,73 and by dapsone in combination with prednisone.74 In both cases, the treatment was
effective in controlling the relapse observed after reduction
of dosage. There is 1 anecdotal report of thalidomide efficacy after 12 weeks in a patient with cutaneous LP associated with erosive penile lesions.75 Since a few cases of LP
occurring in patients infected by hepatitis C virus cleared
with interferon alfa 2b, 3 patients with generalized LP who
were negative for hepatitis C virus76 received this cytokine.
Clearance of all papules was achieved after 10 weeks, and
recurrences after dosage reduction were controlled by readministrationofinterferon.Finally,inanopenstudyenoxaparin sodium, a low-molecular-weight heparin, proved successful within 4 to 10 weeks in 8 of 10 patients.77 The itch
disappeared within 2 weeks in these patients.
Cyclosporine
MUCOUS LP
Oral cyclosporine has been used only in 4 small uncontrolled series54-57 and 1 isolated case.58 In every instance,
these patients had severe cutaneous LP resistant to retinoids or systemic corticosteroid therapy. In a total of 21
patients treated,54-58 a complete response was obtained
with doses ranging from 1 to 6 mg/kg per day, without
relapse during several months of follow-up in the majority of the patients. Pruritus diseappeared after 1 to 2
weeks of treatment, and clearance of the rash was noted
in a mean of 6 weeks, which could be interpreted as a
strong argument in favor of cyclosporine efficacy. It seems
that low doses (1-2.5 mg/kg) are sufficient to cure or control the disease,57 since relapses could be controlled by
topical corticosteroids only. We found only 1 study evaluating the effects of topical cyclosporine under occlusion
in 4 cases of chronic hypertrophic LP.59 Although the
plaque thickness was reduced, none of the treated areas
cleared completely, and the effect of occlusion alone was
not compared with that of cyclosporine.
Various Drugs
Dapsone, 200 mg/d for 16 weeks, was used in 92 patients
with various forms of LP, and this treatment was followed
by 65% complete clearance and 19% partial response.60 This
study was not a true open trial, but rather a summary of the
experience of these authors in the use of dapsone. No criteria for efficacy were available in this letter. Successful treatment of actinic LP was occasionally reported with the use
of hydroxychloroquine sulfate, 200 to 400 mg/d,61-64 but often in association with topical corticosteroids. In 1 patient,65
LP involving the nails was cleared with chloroquine hydrochlorideonly,buttherewerenocontrolledstudiesthatcould
assess the efficacy of antimalarials. Metronidazole was used
in 3 small groups of patients, producing complete clearance
Topical Corticosteroids
Fluocinonide and Fluocinolone. Fluocinonide in an adhesive base, applied 6 times per day for 9 weeks, was compared with its vehicle in 40 patients with oral LP.78 Thirteen of the 20 treated patients entered complete remission
or had a good response, compared with 4 good responses in the placebo group. The efficacy of the corticosteroid was better than that of the excipient on functional signs (15 of 20 complete responses vs 7 of 20). This
study included 12 patients with erosive LP, 13 with reticular LP, and 15 with a combination. Four of the patients with erosive LP or the combined form treated with
the corticosteroid had no response to treatment. No adverse effects were recorded. Although this controlled study
included relatively few patients, the clinical data and the
criteria of efficacy are well documented, demonstrating
the efficacy of this corticosteroid (level B trial).
Fluocinonide in an adhesive gel used for 6 months
resulted in improvement of erosive and atrophic LP in
18 of 20 patients who also received chlorhexidine gluconate mouthwashes and miconazole nitrate gel.79 The
clinical results remained stable in 61% of these patients
after a 6-month follow-up. In a review of 214 patients,
22 patients with oral LP received fluocinonide, and all
of them had a 50% to 75% reduction of their lesions, but
clinical details are not available in this study.4 The same
authors also studied 67 patients with oral LP who were
treated with fluocinonide in an adhesive base.80 Initially, 11 patients participated in a double-blind trial with
crossover. A partial response was observed in 5 of them
and a complete response in the other 6 treated with the
corticosteroid, compared with 1 partial response with placebo. Subsequently, 56 other patients were treated openly;
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29 obtained a complete response after 2 weeks of therapy;
and some of the patients had relapse but the exact number is impossible to calculate because various oral diseases were mixed in the follow-up study. The type of oral
LP was probably erosive, since these patients with LP were
mixed together with patients with other “vesiculoerosive” diseases, but clinical data are not available.
The efficacy of 0.1% fluocinolone acetonide was
tested against that of 0.1% triamcinolone acetonide (4
applications per day for 4 weeks) to treat oral LP in 40
patients with erosive (18 cases) and atrophic (22 cases)
LP.81 The efficacy was based on the reduction of the surface of lesions. Fluocinolone was found to be more effective, with 13 of 19 patients cured vs 8 of 19 with triamcinolone, but the rate of success in the 2 forms of LP
was not detailed. Oral candidiasis was observed in 13 patients, 9 of whom were in the fluocinolone group, which
was cured in all cases with topical antifungals. After a
1-year follow-up, only 2 patients in the fluocinolone group
remained completely cured. This is the second level B
study we found in the treatment of oral LP.
Fluocinolone acetonide 0.05% was also compared
with 0.05% clobetasol propionate (in orabase) in 60 patients with “oral vesiculoerosive lesions,” 35 of whom had
LP of unkown extent and duration.82 All patients were
mixed together, and specific results of patients with LP
are not available. Both medications significantly lessened pain and decreased the size and number of lesions,
but clobetasol seemed to reduce pain better. Because the
results are not reported in detail, the superiority of clobetasol in LP cannot be definitively concluded.
vulvovaginal LP90: 10 patients responded favorably after
3 weeks of prednisone (0.5 mg/kg per day), but they had
relapses as soon as the dose was lowered to 10 mg/d. In
a report on 55 patients with “inflammatory and erosive
lesions of the mouth,”91 prednisone dosages of 10 to 50
mg/d were successfully used; however, no clear conclusions can be drawn from this study because various diseases of unkown diagnosis were mixed. Systemic corticosteroids were associated with topical corticosteroids
in oral LP,92,93 but the superiority of this combination over
local or systemic corticosteroid therapy has not been demonstrated. Because oral LP in its erosive form can be highly
symptomatic, prednisone, 30 to 80 mg/d, is recommended by many authors.4,94,95 Prednisone, 0.75 mg/kg
per day, has also been used in LP of the esophagus.96 Secondary candidiasis is frequent and relapses are common
when the dosage is lowered, but it is believed that benefits outweigh side effects in severe cases.95 Mouthwashes with prednisolone are also currently used94,95 but
have not been evaluated by clinical trials.
As noted in cutaneous LP, the efficacy of systemic
corticosteroids in mucous LP has not been demonstrated by rigorous trials, and the level of evidence of their
efficacy is poor, despite widespread use based on clinical experience. The efficacy of fluocinonide and fluocinolone has been assessed by controlled assays in small
groups of patients. Triamcinolone seems to be less effective than fluocinolone. The alternative choices are clobetasol and betamethasone. Topical corticosteroids are
considered to be the most useful drugs in oral LP.94
RETINOIDS
Betamethasone Valerate. In an open study, 30 patients with
oral LP were treated topically 4 times daily, of whom 20 were
significantly improved after 1 to 12 months of treatment,83
but no objective criteria were used in this study. A doubleblind clinical study compared betamethasone valerate aerosol, 4 sprays per day for 2 months, with a placebo in 23 patients with oral LP, 18 of whom had erosive lesions.84 After
2 months of therapy, 8 of 11 patients had a “good or moderate” response (6 of them having erosive LP) vs 2 moderate responses in the placebo group, but these ratings were
obtained by means of a subjective, overall evaluation.
Injections of Corticosteroids or
Administration Under Occlusion
Anecdotal reports have described the administration of
corticosteroids topically by injections within the lesion85,86 or under occlusion by flexible soft tray, vaginal
prosthetic device, or cloth strips87-89 in severe erosive LP
of the buccal or vaginal mucosa. In a retrospective analysis, 24 patients were treated with topical corticosteroids
by means of cloth strips on the mucosal lesions and an
adhesive paste on gingival lesions.89 All but 1 were improved by repeated applications.
Systemic Corticosteroids
There are no controlled studies that evaluated the efficacy of oral corticosteroids in mucous LP. Systemic corticosteroid therapy seems to be effective against erosive
Five open studies have tested the efficacy of etretinate
in 58 cases of oral LP.97-101 The initial dosages ranged from
0.6 to 1 mg/kg per day for various durations. A good outcome, difficult to assess because of the lack of precise criteria, was reportedly obtained in 4 of the 5 studies. In a
series of 10 patients, the benefits were minimal and were
considered to be outweighed by side effects.99 Only 1 small
controlled trial has been published; it was conducted on
28 patients suffering from severe oral LP who were treated
with etretinate, 75 mg/d, vs placebo for 2 months,102 followed by crossover with etretinate in 9 cases. Six of 23
patients treated with etretinate stopped the treatment prematurely because of side effects. This therapy led to improvement (reduction of more than 50% of the erosions
and infiltration) in 93% of lesions as opposed to 5% of
the lesions in the control group. The majority of lesions
were “atrophic and erosive,” but it is unclear whether all
patients had erosive lesions. Percentages of patients who
had good improvement are not available, and complete
cure did not seem to occur. Moreover, 3 months after the
end of treatment, 66% of the patients had had relapses.
Oral tretinoin has been administered in 3 open studies at doses ranging from 10 to 60 mg/d.22,103,104 Although favorable results have been reported, the lack of
clinical data and detailed criteria of efficacy,103 the various dosages, and the association with topical tretinoin104 make it impossible to assess the efficacy of systemic tretinoin. Only anecdotal reports on the efficacy
of oral isotretinoin have been published,21,105,106 with good
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results in patients whose lesions were resistant to other
treatments. In a series of 6 patients, only minimal benefits were reported with isotretinoin.107
Topical retinoic acid has been used in a few open
studies lacking details on dosages or clinical evaluation.104,108 Two comparative studies have examined 0.1%
retinoic acid vs placebo to treat oral LP.109,110 The majority of erosive and atrophic lesions of 23 nonrandomized patients improved,109 but relapses were common after 3 months, as confirmed by an unpublished experience
mentioned in the study.95 The most recent study was randomized and double-blind, comparing 0.1% retinoic acid
in 10 patients and the excipient in 10 others,110 all patients with plaquelike LP lesions. After 4 months of
therapy, 9 patients in the tretinoin group had improved
or were cured as opposed to 4 in the placebo group. The
diminution of the lesions, evaluated in a test area, was
91% in the tretinoin group vs 21% in the placebo group.
Unfortunately, the sizes of the groups compared do not
allow any definitive conclusions to be drawn. Another
randomized double-blind study evaluated topical 0.05%
tretinoin vs fluocinonide in 33 patients with atrophic and
erosive LP.111 The reduction of severity score was significantly higher with fluocinonide than with topical tretinoin (P = .01). The results according to the clinical form
of LP are unclear. Among the 15 patients who received
tretinoin, there was only a small decrease in the severity
score. It could be hypothesized that the concentration
of 0.05% is too low, as previously suggested.94
Isotretinoin gel was administrered in 20 patients with
mucous LP, 4 of whom had lesions of the penis.112 After
8 weeks, “clinical and symptomatic” improvement was
noted in 80% of patients, mainly on nonerosive areas, but
a 45% recurrence rate was observed. In a double-blind
study, 20 patients with oral LP were randomized to receive either isotretinoin gel or the excipient alone for 2
months; the respective improvements obtained in their
severity scores were 90% and 10%.113 After administration of isotretinoin to patients who had initially received the placebo, their scores dropped significantly to
reach 90% improvement (P,.05).
The results of a limited trial using the new retinoid
fenretinide have been published but allow no conclusions to be drawn, since only 2 patients with oral LP were
studied.114 Complete disappearance of local pain and burning sensation was described.
In conclusion, etretinate seems to be effective in reducing the lesions of oral LP. Both 0.1% tretinoin and
0.1% isotretinoin seem to be effective when applied topically to oral LP. All of these findings need further confirmation, since very small groups of patients were examined in the available controlled studies. The efficacy
of 0.05% tretinoin is poor. After withdrawal of systemic
or topical retinoids, recurrences are common.
CYCLOSPORINE
Topical application of cyclosporine on mucous LP was
evaluated in multiple, small, uncontrolled trials115-129 that
are very difficult to compare because of the highly disparate forms of lichen treated, application modalities practiced (mouthwash, manual administration with local mas-
sage), various doses (ranging from 50-1500 mg/d), and
excipients. Indeed, no galenical formulation adapted to
topical application is currently available. The findings are
controversial. Most studies reported favorable results in
severe recalcitrant oral LP, mainly erosive LP responsible for severe pain. Nevertheless, poor efficacy was reported in 3 of these studies.119,122,125 A possible efficacy
in genital LP, with or without erosion, has been suggested,118,127-129 but 1 case of squamous cell carcinoma arising on the penis during cyclosporine treatment was reported.130 The dose administered probably plays a role
because, with the same modality of administration, the
favorable outcome obtained with 1500 mg/d was not observed with 600 mg/d. As a consequence, it was postulated that only systemic administration of cyclosporine
could generate a beneficial response; however, this hypothesis was refuted by the results of a study that showed
that the efficacy of topical applications was not correlated with cyclosporine blood levels.127
Four controlled trials evaluated topical cyclosporine.131-134 The first demonstrated the efficacy of 3 washes
per day (1500 mg/d) against symptomatic oral LP in 16
patients.131 Compared with the control group, which received a placebo, erythema (P = .003), reticulated lesions (P = .007), erosions (P = .02), and functional signs
(P = .002) were significantly attenuated after 8 weeks of
treatment. In a subsequent controlled trial132 that included 13 patients, the same modality of cyclosporine application was compared with triamcinolone paste; no difference between the efficacies of the 2 regimens was noted.
The application of an oil-based cyclosporine solution (50
mg 3 times daily) compared with an aqueous 1% triamcinolone acetonide solution in 20 patients133 did not show
any difference between the drug efficacies, but it must
be emphasized that no statistical analysis of the results
was provided. Fourteen patients with erosive oral LP were
treated either with 5 mL of cyclosporine (500 mg) or with
placebo in different sites.134 After 4 weeks of treatment,
there was a significant difference in the rate of healing
in favor of cyclosporine, with reduced pain.
In conclusion, topical cyclosporine washes seem to
be effective against oral LP, especially the severe erosive
forms, but they do not appear to be better than local corticosteroid therapy. The lack of statistical power in these
studies limits their contribution, especially in light of the
high cost of this drug, which is neither formulated for
topical mouth applications nor approved for treating LP.
ORAL PHOTOCHEMOTHERAPY
AND EXTRACORPOREAL
PHOTOCHEMOTHERAPY
Oral PUVA therapy with low-dose UV-A was effective in
treating oral LP of various forms (erosive, atrophic, or
reticular) in 4 open studies.135-138 A total of 65 patients
were treated in these studies, which showed improvement or clinical cure in the majority of cases. After a follow-up of 12 to 24 months, complete remission was observed in only 5 of 17 patients in 1 study.137 This treatment
remains experimental, since irradiation was provided by
an apparatus designed for light-cured dental fillings. A
controlled study of oral PUVA therapy using the same
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irradiation source was conducted on 18 patients with erosive or ulcerative oral LP after ingestion of psoralen (0.6
mg/kg) and randomized unilateral irradiation.139 The end
point of the trial was the comparison in the same patient of the unilateral treated side vs the nontreated other
side used as a control. After 12 sessions (total dose, 16.5
J/cm2), the treated side showed marked or slight improvement in 13 patients and the control side improved
in 6 patients. Side effects, mainly nausea, were related
to oral ingestion of psoralen.
A series of 7 patients with severe resistant erosive
oral LP were treated successfully with extracorporeal photochemotherapy, a method usually applied to patients with
cutaneous T-cell lymphomas.140 Complete remission of
erosive lesions was obtained in all patients.
VARIOUS DRUGS
Griseofulvin was of little benefit in 2 groups of 7 and 23
patients with various forms of oral LP treated openly,141,142
but 3 cases of severe erosive LP with dramatic response
to 1 g/d for 8 to 10 weeks were described.143 Dapsone
proved effective in 2 isolated cases of recalcitrant erosive oral LP.144,145 Among a small group of 10 patients with
erosive and reticular oral LP, 9 had an excellent response after 1 to 2 months of hydroxychloroquine, and
3 of the 6 who had erosions achieved healing.146 In 1 case,
LP of the lower lip was improved after treatment with
chloroquine phosphate for 3 months.147 Thalidomide was
administered in 2 patients with erosive oral LP and produced major reduction or complete healing, without recurrence after 15 and 36 months of follow-up.148 Six
patients with oral LP were treated with levamisole hydrochloride, but it is not known whether the patients improved.149 Levamisole hydrochloride, 150 mg/d, was also
given with prednisolone, 15 mg/d, for 3 days each week
in 23 patients with recalcitrant oral LP. Pain relief and
healing of erosions were noted in all patients after 4 to 6
weeks, and they remained lesion free 6 months after withdrawal of the drugs.150 This combination was not tested
against prednisolone alone, and the interest in levamisole therefore remains speculative.
COMMENT
The Table, which summarizes the main published results, shows that we did not find any level A trial in the
medical literature examining the efficacy of the various
drugs or physical treatments of LP. There are only 3 trials with satisfactory methods including more than 20 patients in each group. The remainder of the published trials are controlled trials with imprecise methods or
extremely small populations, uncontrolled studies, or observational series that are not always prospective. Therefore, critical analysis of the literature is disappointing.
Most reports include favorable responses to the studied
treatment, suggesting possible publication bias in the reports. Finally, it is extremely difficult to compare all the
studies, because different criteria were used to define a
cure or attenuation. Rigorous evaluation of efficacy is often lacking, since efficacy criteria were mainly based on
imprecise global evaluation. Many studies lack precise
Main Published Trials of Lichen Planus Therapy
No. of Studies by
Classification*
Treatment
Cutaneous lichen planus
Psoralen plus UV-A therapy
Conventional
Bath
Etretinate (cutaneous)
Acitretin (cutaneous)
Oral tretinoin
Corticosteroids
Griseofulvin
Oral cyclosporine
Dapsone
Phenytoin
Mucosal lichen planus
Topical corticosteroids
Systemic corticosteroids
Etretinate
Oral tretinoin
Topical tretinoin
Topical isotretinoin
Topical cyclosporine
Oral psoralen plus UV-A therapy
Extracorporeal photochemotherapy
Griseofulvin
Hydroxychloroquine
A
B
C
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
2
6
3
1
4
1
4
4
1
1
0
0
0
0
0
0
0
0
0
0
0
2
0
0
0
0
0
0
0
0
0
0
7
2
6
3
5
2
18
5
1
3
1
*Classification according to Sackett’s10 criteria. Anecdotal reports are not
included.
clinical data, especially the type and extent of lesions and
the duration of disease before inclusion. There are no studies using quality-of-life scales, despite the extremely
severe pain often present in oral LP. Meta-analysis is
therefore impossible in the field of LP therapy.
Taking into consideration only the controlled
studies, an attempt can be made to set forth therapeutic
indications, using evidence-based medicine analysis.
CUTANEOUS LP
The first-line therapy in cutaneous LP is acitretin. All other
methods or drugs are of uncertain efficacy. Based on clinical experience worldwide, systemic corticosteroid therapy
is recommended by many authors and could be classified as second-line treatment in cutaneous LP. All other
treatments, mainly PUVA therapy and griseofulvin, should
be evaluated by rigorous controlled trials before being
recommended in an evidence-based medicine review.
ORAL LP
The first-line therapy in oral LP is topical corticosteroid
therapy. No treatment has demonstrated convincingly its
superiority over topical corticosteroids. This first-line
choice is accepted in most reviews.94,95,151-153 The secondline therapy in plaquelike LP should be topical retinoids or etretinate, but strong evidence of efficacy is lacking. All others are unapproved treatments, of uncertain
or doubtful efficacy. The use of topical cyclosporine could
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be recommended as third-line therapy in severe multiply drug-resistant cases.
Finally, this review shows the lack of clear-cut results in the treatment of LP, even for those drugs considered to be classical standards. For future studies, oral
and cutaneous LP should clearly be separated, since the
modalities of clinical evaluation and treament are different. The duration of disease before inclusion, the type
of lesion, and the involved body surface should be detailed. The major criteria for efficacy should be based on
objective criteria, and global evaluation should be considered only as accessory criteria. Erosive and reticular
mucous membrane LP must be separated and research
concerning adapted topical treatments continued. The
new promising treatments, such as topical cyclosporine, extracorporeal photochemotherapy, or even retinoids plus PUVA therapy should be tested in large controlled trials. Quality-of-life studies could be helpful in
the evaluation of oral LP therapy. Finally, European-US
cooperation is warranted to perform large randomized
controlled trials in cutaneous and mucosal LP to improve treatment of these patients.
Accepted for publication June 5, 1998.
Corresponding author: Olivier Chosidow, MD, PhD,
47–83, boulevard de l’Hoˆpital, 75651 Paris Cedex 13, France
(e-mail: [email protected]).
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