EVIDENCE-BASED REVIEW
Treatments for Cutaneous Lichen Planus: A Systematic Reviewand Meta-Analysis
Lihi Atzmony1 • Ofer Reiter1 • Emmilia Hodak1,2 • Michael Gdalevich3 • Daniel Mimouni1,2
� Springer International Publishing Switzerland 2015
Abstract
Background Cutaneous lichen planus (CLP) is an
inflammatory dermatosis. Its chronic relapsing course and
frequently spontaneous regression hamper the assessment
of treatment effectiveness.
Objective To evaluate the efficacy of available treatment
modalities for CLP.
Data Sources PubMed, Cochrane Central Register of
Controlled Trials (CENTRAL), ClinicalTrials.gov registry.
Methods We performed a systematic review of the cur-
rent literature. All randomized controlled trials, nonran-
domized case–control studies, and cohort studies with more
than one treatment arm were included. The primary out-
comes were complete response and time to complete
response. The secondary outcomes were partial response,
relapse, time to relapse, reduction of itch, the adverse event
rate, and withdrawal due to adverse events.
Data Synthesis Sixteen studies met the inclusion criteria,
of which 11 were randomized controlled trials. Most trials
had a small sample size. In the rare studies in which
variants other than generalized or classic lichen planus
were included, they could not be analyzed separately.
Body-of-evidence quality ranged from very low to mod-
erate. Acitretin, sulfasalazine, and griseofulvin were
associated with increased overall response rates in com-
parison with placebo. Narrow-band ultraviolet B radiation
(NBUVB) was more effective than 6 weeks’ low-dose
prednisolone in achieving a complete response, and
prednisolone was more effective than enoxaparin.
Hydroxychloroquine was more effective than griseofulvin
in achieving an overall response. Betamethasone valerate
0.1 % ointment had comparable efficacy to calcipotriol
ointment. Methotrexate was effective, with a nonsignifi-
cant difference in the complete response rate in compar-
ison with oral betamethasone. In nonrandomized
controlled trials, oral psoralen plus ultraviolet A pho-
tochemotherapy (PUVA) had comparable efficacy to a
PUVA bath and NBUVB. Psoralen plus sunlight exposure
(PUVASOL) and betamethasone dipropionate 0.05 %
cream were effective relative to a short course of oral
metronidazole.
Conclusions Several effective treatment options are
available for CLP. Further well-designed studies are war-
ranted to investigate the efficacy of topical glucocorti-
coids—the current first-line therapy—as well as other
treatment modalities, and the treatment of different variants
of CLP.
L. Atzmony and O. Reiter contributed equally to this work.
Electronic supplementary material The online version of thisarticle (doi:10.1007/s40257-015-0160-6) contains supplementarymaterial, which is available to authorized users.
& Daniel Mimouni
1 Department of Dermatology, Rabin Medical Center,
Beilinson Hospital, 39 Jabotinski Street, 49100 Petach Tikva,
Israel
2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv,
Israel
3 Faculty of Health Sciences, Ben-Gurion University of the
Negev and South District Health Office, Ministry of Health,
Beer Sheva, Israel
Am J Clin Dermatol
DOI 10.1007/s40257-015-0160-6
Key Points
All treatments for cutaneous lichen planus that were
tested in comparative studies (randomized controlled
trials, nonrandomized controlled trials, and cohorts
with more than one treatment arm) were evaluated in
this systematic review.
Several treatment modalities were found to be
effective in randomized controlled trials, including
acitretin, sulfasalazine, narrow-band ultraviolet B
radiation, oral glucocorticoids, and griseofulvin. The
results are mainly applicable to classic or generalized
cutaneous lichen planus.
Further well-designed studies are warranted and
should focus on both classic cutaneous lichen planus
and other variants of this disease.
1 Introduction
Lichen planus is a common idiopathic inflammatory dis-
ease, affecting the skin, mucous membranes, hair, and
nails. Specifically, cutaneous lichen planus (CLP) affects
0.2–1 % of the adult population [1]. However, its treatment
is based mainly on the results of small studies and anec-
dotal reports, and remains controversial.
In the last 30 years, three systematic reviews on the
treatment of CLP have been reported. The first, which
appeared in 1996, included three randomized controlled
trials (RCTs) [2]; the second systematic review, from
2014, included eight RCTs and one additional study of
the same patient population, which was counted as a
separate trial [3]; and the third, also from 2014, included
only three RCTs [4]. None of the reviews was conducted
in accordance with the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA)
statement [5].
To assess the efficacy of various treatment modalities
for CLP, we performed a systematic review and meta-
analysis of all relevant RCTs, case–control studies, and
cohort studies with two or more treatment arms.
2 Methods
This systematic review was conducted in accordance with
the PRISMA statement [5].
2.1 Eligibility Criteria
Only studies that met the following criteria were included
in the analysis:
• Language: English
• Study design: RCTs, quasi-randomized and nonran-
domized controlled trials, and cohort studies with more
than one treatment arm
• Population: patients of any age with CLP, with or
without mucosal lichen planus, who were diagnosed at
least according to clinical features
2.2 Outcomes
2.2.1 Primary Outcomes
The primary outcomes of the analysis were as follows:
• Proportion of patients achieving a complete response:
complete response was defined as disappearance of at
least 80 % of active cutaneous lesions. Post-inflammatory
hyperpigmentation was considered inactive disease.
• Time to complete response.
2.2.2 Secondary Outcomes
The first secondary outcome was the proportion of patients
achieving a partial response. Partial response was defined
as disappearance of 50–79 % of active cutaneous lesions.
Accordingly, overall response was defined as complete
response plus partial response.
If the above primary and/or secondary outcomes were not
reported, other endpoints with different definition of response
were considered. Additional secondary outcomes were:
• Proportion of patients with a relapse: relapse was
defined as the recurrence of active cutaneous lesions
after initial improvement.
• Time to relapse.
• Reduction of itch: itch was rated by a visual analog
scale or another scale detailed in the study.
• Rate of adverse events.
• Rate of withdrawal due to adverse events.
2.3 Literature Search
One reviewer (O.R.) searched the Cochrane Central
Register of Controlled Trials (CENTRAL; from inception
until May 2014), using the term ‘‘lichen planus’’, and
searched PubMed, using the Medical Subject Heading
(MeSH) term ‘‘lichen planus’’ and free-text words. The
L. Atzmony et al.
PubMed search strategy is detailed in Electronic Supple-
mentary Material 1. In addition, the ongoing trials registry
of the US National Institutes of Health (http://www.
clinicaltrials.gov) was screened for additional trials that
published results. The reference lists of the included trials
were searched for relevant publications. Authors were
contacted for missing data and clarifications.
2.4 Study Selection and Data Extraction
One reviewer (O. R.) screened the titles and abstracts of all
retrieved articles. Subsequently, when the titles and/or
abstracts suggested potential eligibility for the review, the
same author screened the full texts and extracted the rel-
evant data into a predefined electronic form. A second
reviewer (L.A.) checked the extraction of the data from all
included studies. Disagreements were resolved by discus-
sion with a third reviewer (D. M.).
2.5 Risk-of-Bias Assessment
The risk of bias was assessed in both randomized and
nonrandomized studies, using the criteria generated by
Downs and Black [6]. The checklist included 27 items
divided into five subcategories. The maximum achievable
scores for each of the subcategories were as follows: 10 for
reporting; 3 for external validity; 7 for internal validity—
bias in the measurement of the intervention and outcomes;
6 for internal validity—confounding (selection bias); and
1 for power. The total achievable maximum score was 27.
For the present review, the power item was simplified to a
simple check of whether the study included a statistical
power calculation. Downs and Black score ranges were
grouped into the following four quality levels: excellent
(26–27); good (20–25); fair (14–19); and poor (B13).
2.6 Strength of Body of Evidence
The quality of the evidence was graded as high, moderate,
low, or very low, as defined by the Grading of Recom-
mendations Assessment, Development and Evaluation
(GRADE) system [7].
2.7 Data Analysis and Synthesis
We calculated the relative risks (RRs) and 95 % confidence
intervals (CIs). Intention-to-treat (ITT) analysis was
applied when the data were adequate, and available case
analysis was used when they were not. When possible,
qualitative analysis using Review Manager (RevMan)
version 5.3 was performed with the random-effects model.
Otherwise, a qualitative synthesis was done.
The heterogeneity of the trial results was assessed by
visual examination of the forest plot to detect non-over-
lapping CIs, using a chi-squared test of heterogeneity (with
P\ 0.1 indicating statistical significance) and an I2
statistic for inconsistency (with 30–60 % denoting mod-
erate levels of heterogeneity).
3 Results
Our search yielded 2040 studies (Fig. 1). Sixteen studies
fulfilled the eligibility criteria, including 11 RCTs [8–18],
one adverse event report of an already included trial com-
bined with the initial trial data [19], three nonrandomized
prospective case–control studies [20–22], and one nonran-
domized retrospective case–control study [23]. The char-
acteristics of the included trials are detailed in Table 1. The
available data were not adequate to clearly support one
treatment approach over another. Most of the RCTs that
were included were rated as fair, using the Downs and Black
checklist (Table 2). The detailed appraisal of risk of bias is
shown in Electronic Supplementary Material 2. Six trials
included patients with generalized CLP [9, 12, 14, 15, 19,
20]. None of the trials reported treatment for specific CLP
variants separately (such as lichen planopilaris or lichen
planus pigmentosus). Only two trials included a few patients
with hypertrophic CLP—a much more resistant subtype—
precluding analysis of this subgroup separately [20, 21].
The definitions of the outcome measures varied among
the studies, as did the timing of their appraisal, which
ranged from 4 to 12 weeks; in one trial [12], the timing was
not stated. Most studies reported dichotomous clinical
response data. Time-to-event outcomes either were not
reported or were reported using inappropriate statistical
methods in all included trials but one [23], and so they
were not included in this review.
3.1 Phototherapy
Four of the included studies investigated the efficacy of
phototherapy in CLP [13, 20, 21, 23]. In the only RCT,
52.17 % of patients (12/23) treated with narrow-band
ultraviolet B radiation (NBUVB) achieved a complete
response, compared with 13.04 % of patients (3/12) treated
with prednisolone 0.3 mg/kg/day for 6 weeks (RR 4
[95 % CI 1.3–12.33]) [13].
The second study—a retrospective cohort study—com-
pared NBUVB with oral psoralen plus ultraviolet A pho-
tochemotherapy (PUVA) [23]. The complete response rate
was higher for PUVA, but the difference did not reach
statistical significance (4/13 versus 10/15, RR 0.46
[95 % CI 0.19–1.12]). There were no between-group dif-
ferences in the partial response rate (6/13 versus 5/15,
Treatments for Cutaneous Lichen Planus
RR 1.38 [95 % CI 0.55–3.49]) and the overall response
rate (77 versus 100 %). It is of note that two patients with
hypertrophic lichen planus lesions (one in each interven-
tion group) did not respond to NBUVB and had a partial
response to PUVA. Another two patients who did not
respond to NBUVB were switched to PUVA and thereafter
achieved a complete response. Relapse rates for the two
treatments were comparable (3/10 versus 7/15, RR 0.64
[95 % CI 0.55–3.49]), as were the times to relapse (rates of
sustained response at 1 month follow-up: 72 % for PUVA
versus 54 % for NBUVB, P = 0.86) and the rates of
adverse events (RR 0.23 [95 % CI 0.01–4.37]).
The third study—a non-RCT—compared the efficacy of
oral PUVA with a PUVA bath [20]. The overall response
rate was nonsignificantly higher for the PUVA bath (11/13
versus 5/10, RR 1.69 [95 % CI 0.87–3.28]). The non-
significant difference was attributable mostly to the partial
response rate (9/13 versus 4/10), not the complete response
rate (2/13 versus 1/10).
The fourth study—a non-RCT—compared oral
8-methoxypsoralen plus sunlight exposure (PUVASOL)
with oral metronidazole 200 mg three times daily and with
cetirizine plus betamethasone dipropionate 0.05 % cream
[21]. The rate of overall ‘‘clinical improvement’’ (from a
mild decrease in symptoms and in lesion size and number
to complete disappearance of symptoms and lesions) was
significantly higher for PUVASOL (70.8 %) and for ceti-
rizine plus betamethasone dipropionate (69.6 %) than for
metronidazole (34.8 %, RR 1.92 [95 % CI 1.02–3.59] and
RR 2.04 [95 % CI 1.1–3.77], respectively). However,
metronidazole was administered for only 3 weeks, whereas
the other treatments were administered for 12 weeks. In
addition, the definition of ‘‘response’’ was very permissive.
There was no between-group difference in the rate of
adverse events.
3.2 Systemic Therapy
3.2.1 Oral Glucocorticoids
Three RCTs compared the efficacy of oral glucocorticoids
with other therapies including enoxaparin, NBUVB, and
Fig. 1 Study flow chart. CENTRAL Cochrane Central Register of Controlled Trials
L. Atzmony et al.
Table
1Characteristicsoftrials
included
inthereview
Trial
IDCountry
Studydesign
Drugarms
Regim
ens
Assessm
ent
time
NAge(years)
Fem
ale
sex(%
)
CLPtypes
Follow-up
Bhuiyan,
2010[12]
Bangladesh
RCT
PO hydroxychloroquine
400mg/day,6months
NS
80
Range:
20–60
33.75
‘‘Classic’’
1.5
years
PO
griseofulvin
500mg/day,6months
Bouloc,
2000[8]
France
RCT
KH
1060
BID
,8weeks
12weeks
92
Mean:50.2
NS
NS
12weeks
Vehicle
BID
,8weeks
Chopra,
1999[22]
India
Non-RCT
Topical
betam
ethasone
0.1
%BID
,3months
1–3months
75
60%
30–60years
old
48
LPvulgaris,
hypertrophic,
actinicus,linearis,
follicular,atrophicus,
annularis,
pigmentosus,mucous
mem
brane
3months
PO
dapsone
50mgTID
,3months
Hazra,
2013[9,19]
Bangladesh
RCT
PO
methotrexate
10mgonce
weekly,
12weeks
12weeks
44
Mean:33.9
63.6
Generalized
12weeks
PO
betam
ethasone
5mgtwiceweekly,12weeks
Helander,
1987[20]
Finland
Non-RCT
PO
methoxalen
0.6
mg/kg?
UVA
Range:
8–46exposures
EndofPUVA
treatm
ent
99
Mean:43
NS
Generalized
?localized
Range:
10–43months
50mgmethoxalen
bath?
UVA
Notreatm
ent
Iraji,
2011[13]
Iran
RCT
NBUVB
3times
weekly,70%
of
MED,6weeks
6weeks
46
Mean±
SD:
prednisone
42.04±
2.46;
NBUVB
36.13±
2.88
74
Generalized
6weeks
PO
prednisolone
0.3
mg/kg/day,6weeks
Iraji,
2013[14]
Iran
RCT
SCenoxaparin
5mgonce
weekly,
max
8weeks
8weeks
54
Mean:enoxaparin
38.8;
prednisone36.7
60.4
Generalized
6months
PO
prednisone
0.5
mg/kg/day,max
8weeks
Kellett,
1990[10]
UK
RCT
PO
prednisone
30mg/day
?hydrocortisone
17butyrate
cream
BID
,
10days
6weeks
30
NS
NS
NS
2years
PO
placebo
OD
?hydrocortisone
17butyrate
cream
BID
,
10days
Laurberg,
1991[11]
Denmark
RCT
PO
acitretin
30mg/day,8weeks
8weeks
65
Mean:acitretin
44.5;placebo
53
49.2
NS
16weeks
PO
placebo
OD,8weeks
Omidian,
2010[15]
Iran
RCT
PO
sulfasalazine
2.5
g/day,6weeks
6weeks
52
Mean:33.45
NS
Generalized
6weeks
PO
placebo
OD,6weeks
Treatments for Cutaneous Lichen Planus
Table
1continued
Trial
IDCountry
Studydesign
Drugarms
Regim
ens
Assessm
ent
time
NAge(years)
Fem
ale
sex(%
)
CLPtypes
Follow-up
Sehgal,
1972[17]
India
RCT
PO
griseofulvin
500mgOD,4weeks
4–6weeks
24
Range:
10–55
55.9
NS
4–6weeks
PO
placebo
OD,4weeks
Sehgal,
1980[18]
India
RCT
PO
griseofulvin
500mgOD,8weeks
8weeks
44
Range:
8–70
45.4
NS
8weeks
PO
placebo
OD,8weeks
Sharma,
2003[21]
India
Non-RCT
PO
metronidazole
200mgTID
,3weeks
12weeks
70
Mean:33.71
51.4
Classic,hypertrophic,
guttate,
atrophic
NS
PO
oxoralen
4mg/kg?
30min
sunlight
3times
weekly,12weeks
PO
cetirizine
10mg?
topical
betam
ethasonedipropionate
cream
0.05%
OD,
12weeks
Theng,
2004[16]
Singapore
RCT
Calcipotriolointm
ent
50mg/g
BID
,12weeks
12weeks
31
Range:
14–75
52
Allbut1patienthad
multiple-site
involvem
ent(lim
bs
andtrunk)
12weeks
Betam
ethasone
valerateointm
ent
0.1
%BID
,12weeks
Wackernagel,
2007[23]
Austria
Retrospective
cohort
PO
PUVA
PO
oxoralen0.6
mg/
kg?
UVA;mean:25.9
exposures(range:
9–34)
Mean:
10.5
weeks
(range:
4–18)
Mean:
8.2
weeks
(range:
5–12)
18
Mean:PUVA
47
(range:
16–65);
NBUVB51
(range:
19–69)
75
Generalized;1patientin
each
grouphad
hypertrophiclesionsin
addition
Mean:
20.5
months
(range:
2–49)
NBUVB
Mean:22.5
exposures(range:
15–31)
Mean:
35.7
months
(range:
3–60)
BID
twotimes
daily,CLPcutaneouslichen
planus,
LPlichen
planus,
maxmaxim
um,MED
minim
alerythem
atousdose,NBUVBnarrow-bandultravioletB
radiation,NSnotstated,OD
once
daily,
PO
per
os,PUVApsoralen?
ultravioletA
photochem
otherapy,RCTrandomized
controlled
trial,SCsubcutaneous,TID
threetimes
daily,UVAultravioletA
L. Atzmony et al.
methotrexate [9, 13, 14], and one RCT compared the
efficacy of oral prednisolone with placebo [10]. Overall,
the complete response rates ranged from 13.04 to 59.26 %.
Specifically, in the study of 10 days’ prednisolone
(30 mg/day) versus placebo, the complete response rates at
6 weeks were comparable in the two arms (4/14 versus
Table 2 Efficacy outcomes of trials included in the review
Trial ID Drug arms (N) Overall
response,
% (n)
Partial
response,
% (n)
Complete
response,
% (n)
Risk-of-bias
ratingdITTe/per-
protocol
analysis
Bhuiyan, 2010 [12] PO hydroxychloroquine (N = 40) 70 (28)* 52.5 (21) 17.5 (7) 18 NS
PO griseofulvin (N = 40) 42.5 (17)* 37.5 (15) 5 (2)
Bouloc, 2000 [8] KH 1060 (N = 49) NS 28.6 (14) NS 19 ITT
Vehicle (N = 43) 34.8 (15)
Chopra, 1999 [22]a Topical betamethasone 0.1 % (N = 25) 40 (10) NS NS 8 NS
PO dapsone (N = 59) 49.2 (29)
Hazra, 2013 [9] PO methotrexate (N = 23) NS NS 69.6 (16) 18 Per-protocol
PO betamethasone (N = 21) 47.6 (10)
Helander, 1987 [20] PO PUVA (N = 10) 50 (5) 40 (4) 10 (1) 9 Per-protocol
PUVA bath (N = 13) 84.6 (11) 69.2 (9) 15.4 (2)
Iraji, 2011 [13] NBUVB (N = 23) NS NS 52.2 (12)* 16 ITT
PO prednisolone (N = 12) 13 (3)*
Iraji, 2013 [14] SC enoxaparin (N = 27) 66.7 (18) 37 (10) 29.6 (8)* 20 ITT
PO prednisone (N = 27) 81.5 (22) 22.2 (6) 59.3 (16)*
Kellet, 1990 [10] PO prednisone (N = 14) NS NS 28.6 (4) 14 ITT
PO placebo (N = 14) 7.1 (1)
Laurberg, 1991 [11]a PO acitretin (N = 32) 56.3 (18)* 37.5 (12)* 18.75 (6) 22 ITT
PO placebo (N = 33) 12.1 (4)* 9 (3)* 3 (1)
Omidian, 2010 [15] PO sulfasalazine (N = 26) 73 (19)* 42.3 (11)* 30.8 (8) 21 ITT
PO placebo (N = 26) 7.7 (2)* 3.8 (1)* 3.8 (1)
Sehgal, 1972 [17] PO griseofulvin (N = 17) NS NS 70.6 (12) 14 Per-protocol
PO placebo (N = 17) 35.3 (6)
Sehgal, 1980 [18] PO griseofulvin (N = 22) 100 (22)* 18.2 (4)a 81.8 (18)* 16 Per-protocol
PO placebo (N = 22) 22.7 (5)* 22.7 (5)a 0*
Sharma, 2003 [21] PO metronidazole (N = 23) 34.8 (8)*,b NS NS 11 Per-protocol
PUVASOL (N = 23) 70.8 (16)*,b
PO cetirizine 10 mg ? betamethasone
dipropionate 0.05 % cream (N = 24)
69.6 (17)*,b
Theng, 2004 [16] Calcipotriol 0.05 % ointment (N = 15) 47.6 (7)c 6.6 (1) NS 19 ITT
Betamethasone valerate 0.1 % ointment
(N = 16)
50 (8)c 0 NS
Wackernagel, 2007 [23] PO PUVA (N = 15) 100 (15) 33.3 (5) 66.7 (10) 15 Per-protocol
NBUVB (N = 13) 77 (10) 46.2 (6) 30.8 (4)
ITT intention-to-treat, NBUVB narrow-band ultraviolet B radiation, NS not stated, PO per os, PUVA psoralen ? ultraviolet A pho-
tochemotherapy, PUVASOL psoralen ? sunlight exposure, SC subcutaneous
* A statistically significant difference was observed (P\ 0.05)a A detailed definition of ‘‘response’’ was not supplied in the original articleb Overall response = clinical improvement defined as a range of responses from a mild decrease in symptoms and in lesion size and number to
complete disappearance of symptoms and lesions; clinical improvement was significantly greater with PUVASOL or betamethasone than with
metronidazolec Overall response = lesion flatteningd The risk of bias was assessed using the Downs and Black checklist [6]; the total achievable maximum score was 27e ITT/modified-ITT
Treatments for Cutaneous Lichen Planus
1/14, RR 4 [95 % CI 0.51–31.46]), although improvement,
graded by a linear analog severity scale, was significantly
greater in the prednisolone group (the median score at entry
minus the score at 6 weeks: 2.5 versus 0.85, P\ 0.05).
On meta-analysis of the complete response rate with oral
glucocorticoids against other therapies, the pooled RR was
0.76 [95 % CI 0.27–2.09], with substantial heterogeneity
(Fig. 2). Because of the small number of included trials, the
heterogeneity could not be resolved with subgroup or
sensitivity analysis. However, when each trial was exam-
ined separately, the complete response rate was signifi-
cantly higher for oral prednisone than for enoxaparin [14],
and lower than for NBUVB [13]. There was no significant
difference in the complete response rate between oral
betamethasone 5 mg twice weekly and methotrexate
10 mg/week [9]. In the only RCT (prednisone versus
enoxaparin) reporting the partial response rate [14], no
between-group difference was shown. Two trials reported
the relapse rate [10, 14]: one reported a nonsignificantly
higher rate for prednisone than for placebo (6/16 versus
1/14, RR 4.38 [95 % CI 0.58–33.1]), and the other found
no difference between prednisone and enoxaparin (6/18
versus 9/22, RR 0.81 [95 % CI 0.36–1.86]). Three trials
reported adverse events [10, 14, 19], but their method of
reporting varied. A nonsignificantly higher proportion of
patients experienced adverse events with prednisone than
with enoxaparin or placebo (5/27 versus 1/27 and 2/16
versus 0/14, respectively). After 12 weeks of treatment,
prednisone was associated with more events of anemia,
edema, dyspepsia, acne, moon face, striae, and menstrual
abnormalities than methotrexate, but there were no
between-group differences in blood cell counts, liver
function tests, and plasma glucose levels (P\ 0.05).
3.2.2 Acitretin
One RCT compared the efficacy of 30 mg acitretin daily
for 8 weeks with placebo [11]. The overall response rate
was higher for acitretin (18/32 versus 4/33, RR 4.64
[95 % CI 1.76–12.22]), with no between-group difference
in the complete response rate (6/32 versus 1/32, RR 6.19
[95 % CI 0.79–48.57]). In addition, the acitretin group had
a significantly higher proportion of patients with pruritus at
baseline and a significantly lower proportion after 8 weeks
of treatment (50 versus 75.8 %, RR 0.66 [95 % CI
0.44–0.98]). It is worth noting that adverse events occurred
at a significantly higher rate in the acitretin group (88
versus 52 %, RR 1.7 [95 % CI 1.19–2.42]), but none of the
patients withdrew from the study for this reason.
3.2.3 Griseofulvin
Three trials assessed the efficacy of griseofulvin [12, 17,
18]—two against placebo [17, 18] and one against
hydroxychloroquine [12]. In comparison with placebo, 4 or
8 weeks’ treatment with griseofulvin 500 mg/day was
associated with a higher overall response rate (34/39 versus
11/39, RR 2.85 [95 % CI 1.4–5.79]), with moderate
heterogeneity (I2 = 48 %), and a nonsignificantly higher
complete response rate (30/39 versus 6/39, RR 7.28
[95 % CI 0.15–361.6]), with substantial heterogeneity
(I2 = 87 %). One trial that reported the relapse rate found
no cases of relapse during 9 months of follow-up [17]. In
comparison with hydroxychloroquine 400 mg/day, how-
ever, 6 months’ treatment with griseofulvin 500 mg/day
was associated with a significantly lower response rate
(42.5 versus 70 %, RR 0.6 [95 % CI 0.4–0.92]) [12]. There
were no between-group differences in the partial response
and complete response rates (RR 0.71 [95 % CI 0.43–1.17]
and RR 0.29 [95 % CI 0.06–1.29], respectively). Impor-
tantly, the timing of the outcome appraisal was not stated.
3.2.4 Sulfasalazine
Sulfasalazine 2.5 mg/day for 6 weeks was compared with
placebo in one trial [15]. There was no between-group differ-
ence in the complete response rate (8/26 versus 1/26, RR 8
[95 % CI 1.08–59.5]), although sulfasalazine was associated
with significantly higher partial response (11/26 versus 1/26,
RR 11 [95 % CI 1.53–79.16]) and overall response rates (19/
26 versus 2/26, RR 9.5 [95 % CI 2.46–36.71]). An improve-
ment in patient self-assessed pruritus was documented in 21/26
patients treated with sulfasalazine and in only 2/26 patients
treated with placebo (RR 10.5 [95 % CI 2.74–40.29]). Only
Fig. 2 Oral glucocorticoids (GC) versus other therapies: complete response rates. CI confidence interval, df degrees of freedom, M–H Mantel–
Haenszel
L. Atzmony et al.
patients treated with sulfasalazine experienced adverse events
(8/26 versus 0/26, RR 17 [95 % CI 1.03–280.07]). Neverthe-
less, although the sulfasalazine group had a higher rate of
withdrawal due to adverse events, the difference in comparison
with the placebo group was not significant (3/26 versus 0/26,
RR 7 [95 % CI 0.38–280.07]).
3.2.5 Enoxaparin
One trial assessed the efficacy of subcutaneous enoxaparin
5 mg/week against oral prednisone 0.5 mg/kg/day for up to
8 weeks [14]. The complete response rate was significantly
lower for enoxaparin (8/27 versus 16/27, RR 0.95
[95 % CI 0.26–0.97]). Accordingly, the enoxaparin group
had a lesser reduction in itch (rated by a visual analog
scale) after treatment (2.84 versus 0.83, P = 0.005).
However, there were no significant between-group differ-
ences in the partial and overall response rates (10/27 versus
6/27, RR 1.67 [95 % CI 0.71–3.94] and 18/27 versus
22/27, RR 0.5 [95 % CI 0.13–1.91], respectively) or the
relapse rates (6/18 versus 9/22, RR 0.81 [95 % CI
0.36–1.86]). The number of patients with adverse events
was nonsignificantly lower in the enoxaparin group (1/27
versus 5/27, RR 0.2 [95 % CI 0.02–1.6]).
3.2.6 Methotrexate
One trial tested the efficacy and safety of oral methotrexate
10 mg/week against oral betamethasone for 12 weeks [9,
19]. As mentioned above, there was no between-group
difference in the complete response rate. The rates of some
adverse events were higher with betamethasone.
3.2.7 Metronidazole
A lower proportion of patients achieved overall ‘‘clinical
improvement’’ after 3 weeks of treatment with metron-
idazole than with PUVASOL and topical glucocorticoids
[21]. However, the planned intervention was not compa-
rable in terms of treatment duration. These results are
discussed in the section on phototherapy.
3.2.8 Hydroxychloroquine
A comparison of hydrochloroquine 400 mg/day with
griseofulvin 500 mg/day for 6 months yielded overall
response rates of 70 and 42.5 %, respectively [12]. These
results are discussed in the section on griseofulvin.
3.2.9 Dapsone
A nonrandomized case–control study comparing dapsone
150 mg/day with topical betamethasone 0.1 % reported a
nonsignificant between-group difference in the ‘‘good
response’’ rate after 3 months’ treatment (29/59 versus
10/25, RR 1.28 [95 % CI 0.75–2.12]) [22]. The authors
did not mention the type of betamethasone used. Of note,
most of the patients had classic lichen planus, but the
cohort also included patients with lichen actinicus, linear
lichen planus, lichen planus pigmentosus, and mucosal
lichen planus. Their responses were not analyzed sepa-
rately, so the possible effect of the different variants on
treatment in terms of direction and size could not be
determined.
3.3 Topical Therapy
Although topical glucocorticoids are used as a first-line
therapy in CLP, their efficacy has not been tested in a well-
designed RCT. Only three of the trials that were eligible for
the present review included topical glucocorticoids as a
treatment arm [16, 21, 22]. One assessed the efficacy of
calcipotriol 0.05 % against betamethasone valerate 0.1 %
ointment and found no difference between the groups in
‘‘lesion flattening’’ after 12 weeks (7/15 versus 8/16, RR 0.93
[95 % CI 0.45–1.94]) [16]. It is worth noting that the rate of
adverse events (irritation and increased pruritus severity) was
higher for calcipotriol, but the difference in comparison with
betamethasone dipropionate did not reach statistical signifi-
cance (3/15 versus 0/16, RR 7.43 [95 % CI 0.42–132.96]).
The second study of topical glucocorticoids reported a high
‘‘clinical improvement’’ rate for betamethasone dipropionate
0.05 % cream in comparison with oral metronidazole [21] at
12 weeks. However, this trial was subject to a high risk of
bias (see the sections on phototherapy and metronidazole).
The third study compared dapsone with topical betametha-
sone and showed a comparable ‘‘good response’’ (see section
on dapsone) [22].
One group examined the efficacy of KH 1060 ointment
(lexacalcitol)—a vitamin D3 analog—which had been
found to be approximately as effective as calcipotriol
ointment in the treatment of psoriasis [24], in comparison
with placebo [8]. After 8 weeks of treatment, there was no
between-group difference in the partial response rate (14/
49 versus 15/43, RR 0.95 [95 % CI 0.72–1.26]).
3.4 Strength of Body of Evidence
Table 3 details the results of the body-of-evidence analysis.
4 Discussion
In this systematic review, we aimed to evaluate the efficacy
of different treatment modalities for CLP. In contrast to
previous reviews, which included only small numbers of
Treatments for Cutaneous Lichen Planus
RCTs [2–4], our review included 16 trials, of which 11
were RCTs. The overall quality of evidence was very low
to moderate in terms of treatment efficacy. Acitretin, sul-
fasalazine, and griseofulvin were associated with higher
overall response rates than placebo. Acitretin and sul-
fasalazine caused significantly more adverse events than
placebo, but griseofulvin did not. NBUVB was more
effective than prednisolone in achieving a complete
Table 3 Quality of evidence for reviewed treatments
Intervention No. of
trials
Quality of
evidence
Effects
Oral prednisone 3 Moderate 10-day course did not significantly increase response and relapse rates versus placebo;
small sample size [10]
Medium dose for 8 weeks was more effective in achieving CR than enoxaparin [14]
Low dose for 6 weeks was less effective in achieving CR than NBUVB [13]
Topical GC 1 Moderate Flattening of lesions with betamethasone valerate 0.1 % ointment comparable to
calcipotriol ointment at 12 weeks (50 %); low PR rate; lichen planus type not
mentioned [16]
1 Low High and comparable ‘‘clinical improvement’’ rates with PUVASOL or betamethasone
dipropionate cream ? oral cetirizine for 12 weeks; permissive definition of
‘‘response’’ [21]
1 Very low Comparable ‘‘clinical improvement’’ rates with betamethasone 0.1 % (type not
mentioned) and dapsone [22]
Acitretin 30 mg/day for
8 weeks
1 Moderate More effective than placebo in achieving OR and reducing pruritus [11]
PO griseofulvin 500 mg/day
for 8 weeks
3 Moderate High response rate; more effective than placebo in achieving OR (not CR) [17, 18]
No relapses during 9 months’ follow-up [17]
In one low-quality RCT, response rate significantly lower than with hydroxychloroquine
[12]
Metronidazole 200 mg TID
for 3 weeks
1 Low Lower proportion of patients achieved overall ‘‘clinical improvement’’ after 3 weeks of
treatment with metronidazole than with PUVASOL or betamethasone dipropionate
0.1 % cream ? oral cetirizine [21]; short treatment duration compared with other
treatment arms
Sulfasalazine 2.5 mg/day for
6 weeks
1 Moderate More effective than placebo in achieving OR (not CR) and reducing pruritus [15]
Hydroxychloroquine
400 mg/day for 6 months
1 Low More effective than griseofulvin in achieving OR (not CR) [12]
SC enoxaparin 5 mg/week
for 8 weeks
1 Moderate Less effective than medium-dose prednisolone in achieving CR; comparable OR [14]
Dapsone 150 mg/day for
3 months
1 Very low ‘‘Clinical improvement’’ rates comparable to betamethasone 0.1 % (type not mentioned)
[22]
Methotrexate 10 mg/week
for 12 weeks
1 Low Nonsignificant difference in response rates and better safety profile compared with oral
betamethasone; quality downgraded to low because of inconclusiveness of results and
small sample size [9]
NBUVB 1 Moderate More effective than low-dose prednisone for 6 weeks in achieving CR [13]
1 Low OR rates comparable to PUVA; small sample size [23]
Topical PUVA 1 Low OR rate nonsignificantly higher with PUVA bath than with oral PUVA; small sample
size [20]
Oral PUVA 2 Low Effectiveness comparable to NBUVB; see above [23]
PUVASOL for 12 weeks 1 Low High and comparable ‘‘clinical improvement’’ rates with PUVASOL or betamethasone
dipropionate cream ? oral cetirizine for 12 weeks [21]
Topical vitamin D
derivatives
2 Moderate Comparable efficacy of calcipotriol 0.05 % and betamethasone valerate 0.1 % ointment
for 12 weeks [16]
Similar efficacy of KH 1060 and placebo for 8 weeks [8]
Quality assessment refers to OR/PR/CR/other reported response outcomes
CR complete response, GC glucocorticoid, NBUVB narrow-band ultraviolet B radiation, OR overall response, PO per os, PR partial response,
PUVA psoralen ? ultraviolet A photochemotherapy, PUVASOL psoralen ? sunlight exposure, RCT randomized controlled trial, SC subcuta-
neous, TID three times daily
L. Atzmony et al.
response, and prednisolone was more effective than
enoxaparin in achieving a complete response but not an
overall response. Hydroxychloroquine was more effective
than griseofulvin in achieving an overall response. Treat-
ment with low-dose methotrexate was effective, with a
good safety profile, but the difference in comparison with
oral betamethasone was not significant. Betamethasone
valerate 0.1 % ointment had comparable efficacy to cal-
cipotriol. Treatment with KH 1060 was not effective. In
nonrandomized controlled trials, oral PUVA had compa-
rable efficacy to a PUVA bath and NBUVB. PUVASOL
and betamethasone dipropionate 0.05 % cream were
effective in comparison with a short course of oral
metronidazole.
Because CLP may resolve spontaneously, the goals of
therapy are to shorten the time between onset and lesion
resolution and to reduce itching. Thus, the effectiveness of
therapy can be appraised by outcome measures of the
short-term response, time to response, and itch scores. In a
long-term follow-up study of patients with CLP, Irvine
et al. [25] found that the duration of the inflammatory
eruption was 1 year or less in 68 % of patients and
6 months or less in 42 %. In an older cohort, when potent
topical steroids were not available, 61 % of patients
showed lesion clearance within 12 months [26]. All but
one of the trials [12] included in this review reported the
short-term response. However, almost none reported the
time to response, and—with one exception [23]—those that
did used inappropriate statistical methods. In addition,
most of the trials did not use an itch score to evaluate
reduction of itch.
The decision on which CLP treatment to use for a
specific patient should be based on disease severity as well
as the patient’s medical background, the safety profile of
the treatment, and patient preferences. Although some
treatments were found to be less successful than others in
achieving a specific efficacy outcome, they may be con-
sidered first-line options in specific circumstances. For
example, subcutaneous enoxaparin was reported to be less
effective than oral prednisone in achieving a complete
response after 8 weeks of treatment. However, the overall
response rates in the two arms were comparable [14]. The
high overall response rate for enoxaparin was supported in
previous trials of lower methodological quality [27, 28].
Furthermore, its rate of adverse events was nonsignificantly
lower than that of prednisone [14]. The wide range of side
effects of systemic glucocorticoids is well known. There-
fore, a clinician may prefer enoxaparin for a patient with a
background of diabetes or osteoporosis.
Several limitations of this systematic review and the
current evidence should be noted. First, although there are
many variants of CLP with different clinical behaviors, this
review focused on classic (including generalized) CLP, and
the applicability of the results is restricted to these types.
Few patients with hypertrophic CLP and other variants
were included in a few trials [20–22], and we could not
analyze their responses to treatment separately. Given the
restricted number of published comparative trials, we
compromised our analysis by including those with unclear
definitions of ‘‘response’’. As this reporting bias can impact
the outcome effect size and even direction, in such cases,
we downgraded the quality of evidence. Second, we pre-
sented primarily analyses for modified-ITT and clinically
evaluable populations. In noninferiority studies, the ITT
results might bias the overall results toward no difference
[29]. Nevertheless, we opted for ITT analysis because in
clinical practice, we are interested in the results for all
patients treated (the ITT population), and derivation of the
per-protocol population in the included trials could have
led to other biases. Third, since most of the included trials
had a short follow-up and a small sample size, we could not
appropriately assess adverse drug effects. The small sample
size also led to inconclusive results in some noninferiority
trials [9, 14].
5 Conclusions
Taking the limited quality of the evidence into consider-
ation, several treatment modalities were found to be
effective for CLP—specifically, for classic or generalized
CLP. Systemic treatments with acitretin, sulfasalazine,
and griseofulvin were associated with increased overall
response rates compared with placebo. Hydroxychloro-
quine was more effective than griseofulvin in achieving
an overall response. NBUVB was more effective than
6 weeks’ low-dose prednisolone in achieving a complete
response, and prednisolone was more effective than
enoxaparin. Methotrexate was effective, with a non-
significant difference in the complete response rate in
comparison with oral betamethasone. Topical treatment
with betamethasone valerate 0.1 % ointment had compa-
rable efficacy to calcipotriol ointment. Oral PUVA had
comparable efficacy to a PUVA bath and NBUVB.
PUVASOL and betamethasone dipropionate 0.05 %
cream were effective relative to a short course of oral
metronidazole. Further large-scale RCTs are warranted to
investigate the efficacy of topical glucocorticoids—the
current first-line therapy—as well as other treatment
modalities. Future studies should focus on both classic
CLP and different variants of CLP, with separate end-
points for each variant. Uniform definitions of ‘‘response’’
should be used, including evaluation of pruritus and time
to response.
Treatments for Cutaneous Lichen Planus
Compliance with Ethical Standards
Conflict of interest The authors—Lihi Atzmony, Ofer Reiter,
Emmilia Hodak, Michael Gdalevich, and Daniel Mimouni—have no
conflicts of interest that are directly relevant to this work.
Funding No funding was received for this work.
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