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 Review

Update on oral lichen planus

Expert Rev. Dermatol. 4(5), 483–494 (2009)

Marco Carrozzo† and
Rebecca J Thorpe
†
Author for correspondence
Department of Oral Medicine,
School of Dental Sciences,
University of Newcastle upon
Tyne, Framlington Place,
Newcastle upon Tyne,
NE2 4BW, UK
Tel.: +44 191 222 6797
Fax: +44 191 222 6137
marco.carrozzo@ncl.ac.uk
Oral lichen planus (OLP) is a relatively common chronic inflammatory disorder with a low risk
of associated malignancy. A genetic predisposition linked to Th1 cytokine polymorphisms may
predispose to the T-cell-mediated immunological response to an induced antigenic change that
is supposed to cause OLP lesions. Amalgam restorations, hepatitis C virus and systemic
medications may be etiologic factors. Topical immunomodulators such as powerful corticosteroids
and calcineurin inhibitors may control OLP lesions, but their long-term effects need to be better
explored and understood. Current therapeutic data are probably still insufficient to make
recommendations with regard to the specific dosage, formulation mode of delivery or length
of the therapy.
Keywords : amalgam • calcineurin inhibitor • hepatitis C virus • oral cancer • oral lichen planus • pathogenesis
• topical corticosteroid

Oral lichen planus (OLP) is an inflammatory
disorder affecting stratified squamous epithelia.
Despite the lack of exact epidemiological data,
OLP is thought to be relatively common, affect-
ing approximately 1–2% of the population [1] , an
incidence equal to the well-known dermato­logical
disease psoriasis [2] . Whereas in the majority of
instances cutaneous lesions of lichen planus (LP)
are self-limiting and cause itching, lesions in OLP
are chronic, rarely undergo spontaneous remis-
sion, are potentially premalignant and frequently a
source of morbidity. OLP most commonly affects
middle-aged adults of both sexes, with a slight
predominance in women, and the condition does
not appear to exhibit a racial predilection [3,4] .
Clinical features
Usually, OLP has distinctive clinical features and
distribution, characterized by multiple, bilateral
but not always symmetrical, mucosal lesions.
There are four clinical manifestations of OLP:
papular, reticular, erythematous (atrophic) and
erosive (ulcerated, bullous) [3] . Classification is
determined by the worst presenting form; thereby,
a patient presenting with reticular and erosive
changes would be best classified as having erosive
OLP [3] . However, some authors consider erosive
OLP to consist predominantly of erosive lesions.
Papular/reticular lesions, often the only clinical
manifestation of the disease, occur in isolation and
commonly take the form of minute white papules
that enlarge and coalesce to form either a reticular,
annular or plaque-like pattern. These reticular
lesions appear as an inter­connecting, overlapping
network of white lines (so-called ‘Wickham’s
striae’). Although patients may display an impres-
sive array of diffuse and widespread reticulated
lesions, these are rarely symptomatic and patients
are often unaware of their presence [3] .
Lesions of erythematous and erosive OLP result
in a varying degree of discomfort. The size, loca-
tion and number of ulcerated regions is variable,
spontaneous remission is rare and confusion
with the autoimmune diseases pemphigus vul-
garis (PV) and mucous membrane pemphigoid
(MMP), which share similar clinical features, is
common. However, concominant reticular lesions
aid clinical differentiation of OLP from PV and
MMP, which are characterized only by areas of
erythema and/or erosion [2] . The post­erior buccal
mucosa followed by the tongue, gingival, labial
mucosa and vermillion of the lower lip are the
most frequently involved sites, while lesions of the
palate, floor of mouth and upper lip are rare [2–4] .
Approximately 15% of patients with OLP
develop cutaneous lesions [5], with 20% of women
with OLP developing lesions of the genital mucosa,
the most frequent extra-oral site in females [6] .
The association of LP of the vulva, vagina and
gingiva is recognized as the vulvovaginal–gingival
syndrome [6] . Symptoms include burning, pain,
vaginal discharge and dyspareunia and are fre-
quently noted in patients with erythematous and
erosive genital disease.

www.expert-reviews.com 10.1586/EDM.09.44 © 2009 Expert Reviews Ltd ISSN 1746-9872 483

 Review Carrozzo & Thorpe
On occasion, patients with mild oral involvement display severe
erosive vulvovaginal disease, and patients afflicted with severe oral
involvement develop only mild asymptomatic genital disease.
Esophageal and conjunctival involvement in OLP patients has
recently been reported, and in both cases cicatricial lesions are
not uncommon [7–9] .
OLP & oral lichenoid lesions
Oral lichenoid reactions or lesions (OLL) are terms used to describe
lesions that clinically and histologically resemble OLP but have an
identifiable etiology [10] . However, some authors suggest the use
of these terms in the case of an inconclusive diagnosis of OLP in
the presence of clinical or histological features of the condition.
In addition, the term OLL is frequently used as negative terminol-
ogy to refute some hypotheses detailing the premalignant nature
of OLP or its etiologic associations [10] . Very few epidemiological
studies on the frequency of OLL exist and possible precipitants
include chronic graft-versus-host disease (cGVHD), some dental
materials, a range of drugs and some viruses. A recent inter­national
consensus proposed the classification of OLL into lichenoid contact
lesions (OLCL) (essentially amalgam induced), lichenoid drug
reactions (OLDR) and lichenoid lesions of GVHD [11] . Whilst
cGVHD is a clearly defined entity, showing substantial clinical and
pathogenetic differences in comparison with OLP [12,13] , OLCL
and OLDR are less understood and a matter of debate.
Lichenoid lesions have a tendency to be unilateral [14] and
erosive [15] with histological examination showing a more dif-
fuse lympho­c ytic infiltrate with eosinophils, plasma cells and
an increase in colloid bodies in comparison with classic OLP.
However, frequently OLL are indistinguishable from idiopathic
OLP. Stringent clinical and histological criteria have been
advocated but are still to be validated [16] .
In addition, it must be noted that further to OLP, OLCL,
OLDR and GVHD, the presence of a pattern of common histo­
pathological elements that have traditionally been referred to as
‘lichenoid tissue reaction/interface dermatitis’ can also be seen in
disorders associated with systemic illnesses (lupus erythemato-
sus [LE] and dermatomyositis), and in potentially fatal disorders
(Stevens–Johnson syndrome and toxic epidermal necrolysis) [17] .
While dermatomyositis, Stevens–Johnson syndrome and toxic
epidermal necrolysis are unlikely to exclusively affect the oral
cavity, oral lesions can be the sole manifestation of LE [18] . Mainly
discoid LE is readily misdiagnosed as OLP, despite rarely being
considered in the differential diagnosis of OLP/OLL [18,19] .
Etiology
Oral LP is possibly a T-cell-mediated immunological response to
an induced antigenic change in the skin or mucosa in predisposed
patients [20] . A key, early event in LP is the genetically induced
increased production of Th1 cytokines [20] . Cytokine poly­
morphisms appear to govern whether lesions develop in the mouth
in isolation (IFN-g associated) or in conjunction with skin lesions
(TNF-a associated) [20,21] . Another key event in OLP pathogenesis
is the recruitment of different subsets of denditric cells (DCs), such
as Langerhans cells, stromal DC-SIGN+ DCs and plasmacytoid,
484
possibly through the expression of the chemo­tacting agonist
chemerin by endothelial cells lining blood vessels [23] . Plasmacytoid
dendritic cells represent the main IFN-a producers among leuco-
cytes, and this cytokine may induce cytotoxicity, activating natural
killer/T cytotoxic cells or FasL-mediated apoptosis, all of which are
phenomena known to occur in OLP. MxA, an IFN-a-inducible
protein [24] , has been shown to be expressed within the inflamma-
tory infiltrate, indicating the active production of IFN-a in OLP
biopsy specimens, and moreover, IFI27, another IFN-a-inducible
protein, has been demonstrated to be upregulated in LP [25] .
Attraction and migration of the activated T cells to the oral
epithelium is further enhanced by intercellular adhesion mol-
ecules (ICAM-1 and VCAM), upregulation of epithelial base-
ment membrane extracellular matrix proteins (collagen types IV
and VII, laminin and integrins), and potentially CXCR3 and
CCR5 signaling pathways [26] . Binding of T cells to keratinocytes
and IFN-g, and subsequent upregulation of p53, matrix metallo­
proteinase (MMP)1 and MMP38 leads to apoptosis, culminating
in destruction of the epithelial basal cells [27] .
The chronic course of OLP may be due to the activation of the
inflammatory mediator NF-kB, and the inhibition of the TGF
control pathway (TGF-b/SMAD), which may cause keratinocyte
hyperproliferation, leading to development of the white lesions [28,29] .
Oral LP is unlikely to be caused by a single antigen. Studies of
T‑cell receptor variable region genes from lesional OLP T cells have
not revealed the use of a restricted number of different variable
region genes [30] . OLP is likely to be the common outcome of the
influence of a limited combination of extrinsic antigens, altered self
antigens or super antigens. In a minority of patients, precipitat-
ing factors have been identified, including dental materials (mainly
restorative materials such as amalgam), drugs (non­steroidal anti-
inflammatory drugs [NSAIDs] and angiotensin-converting enzyme
inhibitors), stress, trauma and infectious agents (herpes simplex virus
1, herpes virus 7, cytomegalovirus, human papillomavirus [HPV],
Epstein–Barr virus, Helicobacter pylori and hepatitis viruses) [31] .
Dental restorative materials
Dental restorative materials thought to cause OLP/OLL include
amalgam, composite resin, cobalt and gold [32] . When OLP lesions
are confined to the mucosa in close contact with, or in proximity
to, the restoration these reactions should be suspected [33] . They
are generally, but not invariably, unilateral. Some authors have sug-
gested that sensitization to mercury (the main component of amal-
gam alloy) is an important cause and that these lesions might rep-
resent a delayed hypersensitivity reaction to mercury [33] . However,
others have identified few who are sensitized to mercury and amal-
gam removal appears to have no beneficial effect [32] , which suggests
the involvement of other factors [34] . Moreover, in an animal model,
mercury appeared to be irrelevant in the development of OLL [35] .
Histological features cannot distinguish amalgam-associated OLL
from OLP [36] , and skin-patch testing cannot reliably predict the
response to amalgam removal [32] . However, a reaction to a patch
test for more than one mercurial allergen can increase the likelihood
of an accurate diagnosis [33] . In addition, there have been reports of
malignant transformation of restoration-related OLL [37] .
Expert Rev. Dermatol. 4(5), (2009)

Another possible explanation for oral lesions related to dental
restorations may be an immunological or toxic reaction to plaque
accumulation on the surface of the restoration, and such lesions
may disappear after improvements in oral hygiene [38] .
Drugs
Drugs inducing OLP/OLL are classically NSAIDs and angioten-
sin-converting enzyme inhibitors [39] . Withdrawal and reintro­
duction of the drug is the most reliable method of diagnosing a
drug reaction based on resolution or reactivation of the lesion.
However, this is often not practical and can be potentially danger-
ous. A systematic review stated that there is sufficient evidence that
b-blockers, methyldopa, penicillamine, quinidine and quinine play
a role in LP while NSAIDs should also be considered causative [40] .
Empirical withdrawal of the drug in question, and its substitu-
tion with another, may be warranted as it may take months for
resolution of the lichenoid reaction.
A large number of other drugs have also been linked to OLP/
OLL (see [41] for a comprehensive list), but many of these reports
have been based on sporadic cases only.
Stress
Stress has been widely acknowledged to be an important etio­logical
factor in OLP, but remarkably few studies have been carried out.
Most studies have not objectively examined stress levels, despite the
fact that signs of depression and raised anxiety levels are commonly
found in patients with OLP [42–47] . It is still un­determined whether
observed psychologic alterations constitute a direct etiologic factor
or just a consequence of OLP. Indeed, the chronic discomfort that
can afflict patients with OLP can itself be a stressing factor and
may partially explain any documented association.
Alternatively, some researchers have largely refuted the asso-
ciation between OLP and depression [48,49] , as notably, OLCL
patients have a tendency to be depressive [50] .
Infectious agents
Several infectious agents, including H. pylori and a number of
viruses, have been implicated in the precipitation of the cell-
mediated reaction that results in OLP but frequently on the basis
equivocal data [51,52] .
The role of human herpes viruses (herpes simplex virus  1,
Epstein–Barr virus, cytomegalovirus, human herpesvirus
[HHV]-6 and HHV-7) in the pathogenesis of OLP and LP, in
the case of HHV-7, is unclear and may be secondary to oral ero-
sive LP lesions [51,53] . Studies to detect HPV types in OLP have
revealed positive detection rates varying from 0 to 100%, and
a recent case report of HPV reactivation following treatment of
penile erosive LP suggested that detection of HPV DNA does not
confirm a causal relationship since its presence in lesional tissue
may be due to immunosuppressive therapy [51,54,55] .
The best available evidence of the involvement of a virus in
the pathogenesis of OLP pathogenesis concerns the hepato-
tropic hepatitis C virus (HCV) [56] . HCV is one of the major
causes of chronic liver disease worldwide, but its morbidity is
also due to a variety of extrahepatic manifestations including
www.expert-reviews.com
Update on oral lichen planus Review
mixed cryoglubulinemia, non-Hodgkin lymphoma, diabetes,
porphyria cutanea tarda and LP [56] . Epidemiological evidence
from more than 90 controlled studies worldwide in both LP and
chronic HCV infected patients strongly suggests that in OLP
HCV may be an etiologic factor [56] . The association is prevalent
in Southern Europe, Japan and the USA, however in studies
from countries with the highest HCV prevalence (Egypt and
Nigeria) negative or nonsignificant associations were identified,
suggesting that any LP–HCV association cannot be explained on
the basis of high prevalence in the general population alone [56] .
Geographic heterogenecity may be influenced by the prevalence
of HCV and HLA-DR6 [57,58] . The putative pathogenetic link
between LP and HCV is still under investigation but molecular
mimicry between the virus and host epitopes is unlikely, as well
as viral factors such as genotype or viral load [56] . Clinically
and histologically, HCV-related OLP is the same as ‘idiopathic’
OLP [59] ; however, the Th1 cytokine environment sustaining
the oral lesions may be due to the HCV immunologic pressure
and not genetically driven, as in idiopathic OLP [60] . Notably,
HCV may replicate in the oral mucosa [61,62] and may attract
specific T cells [63] . Indeed, a recent study showed that HCV
specific CD4 + and/or CD8 + T lymphocytes can be found in the
oral mucosa of patients with chronic hepatitis C and OLP [63] .
In addition, CD4 + polyclonal T‑cell lines were generated more
efficiently from lichen-infiltrating lympho-mononuclear cells
than from peripheral blood mononuclear cells from the same
patients, suggesting a higher frequency of HCV-specific T cells
in the oral compartment [63] .
Malignant transformation of OLP
The malignant potential of OLP remains controversial, and dif-
ferent research groups have proposed distinct approaches and
interpretations [64] . Ideally, the best way to establish the putative
premalignant nature of OLP is through a prospective follow-up
study of affected and unaffected individuals (including smok-
ers and nonsmokers) [65] . However, unfortunately such a study
is not in existence. The best evidence currently available on
the potentially malignant nature of OLP is from follow-up and
retrospective incidence studies [64,65] .
Three large independent retrospective controlled studies, using
strict diagnostic criteria, have shown a significant risk of malignant
transformation of OLP to squamous cell carcinoma (SCC) [66–68] .
On the basis of the available data, the transformation rate of OLP
appears to be approximately 1% over 5 years. However, an OLP
prevalence of 1% and a transformation rate of 0.2% per year would
mean that nearly every oral SCC should develop from OLP lesions,
and this is unlikely according to the published data [69] .
Similar uncertainty exists with regards to factors predisposing
or influencing the malignant evolution of OLP. Indeed, the risk
of malignant transformation seems to be independent of tobacco
and/or alcohol consumption, the clinical type of OLP or the
topical and systemic steroid therapy utilized [67] . However, other
treatments such as psoralen plus UVA or calcineurin inhibitors
could theoretically increase the risk of oral cancer and require
thorough investigation [70] .
485
 Review Carrozzo & Thorpe

Box 1. Empirical treatments for oral lichen Box 1. Empirical treatments for oral lichen
planus. planus.
Corticosteroids Other treatment modalities (cont.)
Topical • Doxycycline
• Betamethasone phosphate • Enoxaparin
• Betamethasone valerate* • Glycyrrhizin*
• Clobetasol propionate* • Griseofulvin‡
• Fluocinolone acetonide • Hydroxychloroquine sulfate‡
• Fluocinonide* • Mesalazine‡
• Fluticasone propionate • Interferon‡
• Hydrocortisone hemisuccinate • Magnetism
• Triamcinolone acetonide • Mesalazine‡
Systemic • Interferon laser‡
• Prednisone/prednisolone • Levamisole‡
• Betamethasone • Phenytoin‡
• Methylprednisolone • Photopheresis
Retinoids • Psychotherapy‡
• Psoralen plus UVA*
Topical
• Reflexotherapy
• Fenretinide
• Sirolimus
• Isotretinoin*
• Surgery‡
• Tazarotene*
• Thalidomide‡
• Tretinoin*
Systemic *Placebo-controlled studies confirm their efficacy in oral lichen planus.
‡
Treatment modalities suspected to induce lichenoid lesions.
• Acitretin* Modified from [74].
• Etretinate
• Isotretinoin It has also been suggested that malignant transformation of
• Temarotene
OLP may be associated with modifications in diet imposed by
• Tretinoin
symptoms [67] . Patients may have a reduced intake of fresh veg-
etables and fruit, especially citrus fruit, which may itself increase
Immunosuppresive agents cancer risk. However, severe symptoms are mainly associated with
Systemic the atrophic-erosive forms that do not appear to have an increased
• Azathioprine risk when compared with usually asymptomatic varieties [67] .
• Methotrexate Several infectious agents (including Candida, HPV and HCV)
Calcineurin inhibitors have also been advocated in promoting malignant transformation
of OLP, but conclusive and strong evidence is still lacking [64] .
Topical
The potential benefits of screening OLP patients for oral can-
• Ciclosporin*
cer are unclear. One study concluded that there is no evidence
• Tacrolimus to support a purposely designed screening program [71] , while
• Pimecrolimus* another worked from the assumption that screening would iden-
Biologic agents tify all oral cancers in OLP patients at stage I [72] . The study
• Alefacept concluded that such intervention would cost US$1,265,229 and
• Basiliximab would save 23.68 lives (US$53,430 per life). However, the cal-
• Efalizumab
culation was based on OLP prevalence and annual malignant
• Etanercept
transformation rate figures that have been deemed questionable
by the same research group [69,72] .
Other treatment modalities
• Aloe vera gel Diagnosis
• Amphotericin A The clinical features alone, particularly when presenting in the
• Diethyldithiocarbamate ‘classic’ reticular form, may be sufficiently diagnostic [2] . However,
• Dapsone given the chronic nature of OLP and the requirement for long-
*Placebo-controlled studies confirm their efficacy in oral lichen planus. term treatment and monitoring, biopsy would be prudent clinical
‡
Treatment modalities suspected to induce lichenoid lesions. practice, particularly prior to initiating an active treatment, as a
Modified from [74].
common cause of treatment failure is inappropriate diagnosis [11] .

486 Expert Rev. Dermatol. 4(5), (2009)


Despite the fact that the histopathological assessment of OLP can
be subjective [73] , an oral biopsy with histopathological exam­ination
is recommended to confirm the clinical diagnosis when the disease
does not present with its typical manifestations, mainly to exclude
dysplasia and malignancy [74] . Direct immunofluorescence testing
may be useful when there are exclusive gingival and/or predomi-
nantly erosive/ulcerative lesions to exclude an auto­immune bullous
disease. It may show shaggy fibrinogen deposits at the epithelial
basement membrane or cytoid bodies (Russell bodies) [75] .
Management of OLP
The elimination of precipitating or provoking factors is an
important initial step in the management of symptomatic OLP.
Precipitating factors and irritants (maloccluded or fractured teeth,
poorly fitting dentures, alcohol and tobacco consumption) should
be identified and avoided or eliminated where possible [74] . Good
oral hygiene along with the use of chlorhexidine mouth rinse, as
plaque reduction may have beneficial effects on the lesions, should
be advocated [76] .
As OLP is a chronic disease, the patient’s medical history,
psycho­logical state and treatment compliance, as well as pos-
sible drug interaction must be considered when evaluating the
cost–effectiveness of any treatment modality [74] .
Various treatment regimens (Box 1) have been designed to improve
management of symptomatic OLP, but a permanent cure is not yet
available, with treatments permitting clearance of lesions rather
than providing a definite cure for the disease. Curiously, several
suggested treatment modalities are also suspected to induce lichen-
oid lesions (Box 1) . Drug treatment with topical agents is generally
preferred as it has fewer adverse effects. However, systemic agents
may be required if lesions are widespread, mainly when they involve
the skin or other mucosa, or there is recalcitrant disease. Drugs for
OLP are fundamentally immunosuppressive and few were devel-
oped or intended for oral diseases; consequently, there is a lack of
adequate studies determining their efficacy [4] . Moreover, factors
such as optimal dose, duration of treatment, safety and true efficacy
remain largely unknown [31] . Patients should be warned about the
off-label use of most of the medications used to treat OLP and
the accompanying package inserts that state for external use only.
Topical corticosteroids
According to the majority of the published reviews, including two
systematic reviews [11,77] , topical corticosteroids are the most com-
monly employed and useful agents for the treatment of OLP. A
response to treatment with midpotency corticosteroids, such as tri-
amcinolone acetonide 0.1%, potent fluorinated corticosteroids such
as fluocinolone acetonide 0.1% and fluocinonide 0.05%, and super-
potent halogenated corticosteroids, such as clobetasol propionate
0.05%, has been reported in 30–100% of treated patients [78–84] .
Notably, clobetasol propionate appears to be the most effec-
tive topical steroid, with 56–75% of the patients undergoing a
complete remission of signs and symptoms [74] .
The greatest problem in using topical corticosteroids in the
mouth is adherance to the mucosa for a sufficient length of
time. The use of adhesive pastes, such as sodium carboxymethyl
www.expert-reviews.com
Update on oral lichen planus Review
A
B
Figure 1. (A) Atrophic-erosive gingival OLP. (B) Almost complete
remission with topical treatment with clobetasol propionate
0.05% ointment delivered with a soft splint.
cellulose (Orabase®) and hydroxyethyl cellulose, and special
drug delivery systems, such as lipid-loaded microspheres, has
been advocated for this purpose  [79,81,85] . At present, however,
there is no definitive data that topical steroids in special bases are
more effective than as base preparations [82,86] . Although there
are some reports of systemic absorption and adrenal suppression
from super-potent topical steroids in the treatment of chronic
skin disorders [87,88] , adrenal suppression has not been found even
in long-term oral application of topical corticosteroids such as
fluocinonide fluocinolone acetonide and clobetasol [81,89] if the
patients are correctly and carefully instructed about topical steroid
use in the mouth. Patients should be instructed to apply a small
quantity (corresponding to apparoximately a teaspoon) of the
agent several times daily, maintain­ing prolonged contact of the
medication with the mucosa by refraining from speaking, eating
and drinking for 0.5–1 h afterwards. Acute pseudomembranous
candidiasis is the only common side effect from topical corticoste-
roid therapy. Oral candidosis can be prevented with the addition
of an antifungal built into the regime (nistatin 100000 UI/CC
[90,91] , miconazole gel) alone or with chlorhexidine mouthwashes
[81,92] . When exclusive gingival lesions are present, topical steroids
may be best delivered using custom-made trays (Figure 1) [93] .
Prolonged use of these drugs may occasionally result in dimin-
ished biological effectiveness, which can be avoided by using
alternate day therapy or by using a very potent steroid (e.g., clo-
betasol) initially, followed by a moderately potent corticosteroid
(e.g., triamcinolone) for maintenance therapy [2] .
High-potency steroid mouthwashes, such as disodium
b-amethasone phosphate (500 mg dissolved in 20 ml of water)
or clobetasol propionate 0.05% in aqueous solution, can be used
in widespread OLP, but these may result in a significant systemic
absorption leading to a pituitary–adrenal axis suppression [94,95] .
487
 Review Carrozzo & Thorpe
A tacrolimus therapy are common [106] .
B
Figure 2. (A) Long-lasting lingual ulceration recalcitrant to high
powerful topical corticosteroid (B); significant improvement after
2 months of application of topical tacrolimus ointment 0.1%.
Other topical agents
Other immunosuppressants or immunomodulatory agents such
as calcineurin inhibitors (ciclosporin, tacrolimus, or pimecro-
limus) or retinoids can be beneficial, mainly if the lesions are
recalcitrant to the most powerful steroids.
Ciclosporin has been used as a mouth rinse (50–1500 mg/day)
[96] or in adhesive medium (48 mg/day) [97] but is expensive, not
always effective [98,99] and less effective than topical clobetasol
[100,101] in inducing clinical improvement in OLP, although
the two drugs do have comparable effects on symptoms [101] .
Tacrolimus, a topical immunosuppressive agent approved for
the treatment of atopic dermatitis, is 10–100-times as potent
as ciclosporin and has greater percutaneous absorption than
ciclosporin. Several uncontrolled, nonrandomized studies have
documented the efficacy and safety of this agent (at concen-
trantions ranging from 0.03 to 0.1%) (F igur e  2) in the man-
agement of recalcitrant erosive OLP [102–107] ; however, burn-
ing is a common side effect and is observed in approximately
20% of patients  [107] . Therapeutic levels of tacrolimus can be
488
demonstrated in OLP patients [103] and oral absorption after
topical application leading to systemic side effects has been
reported  [108] . In addition, relapses of OLP after cessation of
Pimecrolimus is the newest calcineurin inhibitor to be used in
OLP treatment. It has a similar mode of action to that of tacro-
limus but is more selective, having no effect on Langerhans cells.
The immunosuppressant capacity of pimecrolimus is weaker than
ciclosporin or tacrolimus, and it has lower permeation through
the skin than topical steroids or topical tacrolimus. Of note, three
small placebo-controlled, randomized, controlled trials found
1% pimecrolimus cream to be an effective and well-tolerated
treatment for erosive OLP [109–111] . Low levels of pimecrolimus
in the blood are sometimes detactable after oral topical applica-
tion. Pimecrolimus adhesive ointment (Elidel® 1% cream mixed
1:1 with a hydrophilic adhesive gel base) [112] has also been suc-
cessfully used in two cases, and pimecrolimus 1% seems to have
efficacy similar to a midpotency steroid, such as triamcinolone
acetonide 0.1%, in treating OLP [113] .
Recently, the US FDA issued a ‘black box’ warning attached to
the use of tacolimus and pimecrolimus because of a theoretical
increased risk of malignancy (SCC and lymphoma) in patients
using topical tacrolimus/pimecrolimus for cutaneous psoriasis.
Moreover, a recent case report suggested that the topical use of
tacrolimus 0.1% in a patient with OLP promoted the development
of a SCC of the tongue [114] .
Notably, topical rapamycin (Sirolimus), which has immuno­
suppressive and tumour inhibitor properties, inhibiting the
response to IL‑2 and thereby blocking activation of T and
B cells, has been very recently proposed in refractory erosive
OLP [115] .
Topical retinoids, such as tretinoin, isotretinoin, fenretinide
and tezarotene, have also been used to treat OLP [116,117] , but
often cause adverse effects and are generally less effective than
topical corticosteroids [118] .
Systemic drug treatment
The efficacy of systemic corticosteroids is undisputed and some
authors consider systemic corticosteroids to be the most effective
treatment for OLP. However, a recent comparative study could
not identify differences in response between systemic predni-
sone (1 mg/kg/day) with topical clobetasol in an adhesive base
and topical clobetasol alone [119] . Systemic corticosteroids are,
therefore, usually reserved for cases where topical approaches
have failed, where there is recalcitrant, erosive or erythematous
OLP, or for widespread OLP when the skin, genitals, esophagus
or scalp are also involved [2,11,74] . Prednisolone 40–80 mg daily
is usually sufficient to achieve a response when taken either for
brief periods of time (5–7 days), and then withdrawn abruptly,
or the dose is reduced by 5–10 mg/day gradually over 2–4  weeks
(Figure 3) . However, lesion recurrence has been observed in cases
where doses have been tapered to a level that is deemed too
high for long-term use without severe side effects. Therefore,
systemic corticosteroids are useful in acute erosive OLP but not
in chronic erosive OLP.
Expert Rev. Dermatol. 4(5), (2009)
 Update on oral lichen planus Review

Several other systemic immuno­suppressive

agents (including biologic agents, see Box 1)
have been used in the treatment of OLP A B
[120–126] , but there has been little evaluation
of their efficacy.
Nonpharmacological modalities, such
as aloe vera gel [127] , phototherapy [128] ,
surgery [129] and laser treatment (with
carbon dioxide and low-dose excimer
308‑nm laser) [130–132] , have been sug-
gested mainly in patients recalcitrant to
more conventional modalities, but their
effectiveness is yet to be proven and sur- C
D
gical intervention has been reported to
provoke OLP [133] .

Expert commentary
In the last 20  years, many significant
advances have been published on OLP.
The pathogenic mechanism is now partially
understood, with the recognition that OLP
shares clinical and histological features with
cGVHD. A putative genetic predisposition
linked to cytokine polymorphisms has been
revealed and some possible etiologic factors
(namely amalgam and HCV) have been Figure 3. Extensive erosive OLP of the bilateral buccal mucosae: almost
studied in detail. Moreover, it has been con- complete remission after treatment with prednisolone (1 mg/kg/day) for
sistently suggested that OLP has a potential 3 weeks. Left (A) and right (C) buccal mucosa before treatment; left (B) and right
malignant nature, although the pathway is (D) buccal mucosa after treatment.
still intensely debated and poorly explained.
On the other hand, we have a paucity of good epidemiologic standardized methods and diagnostic criteria. The molecular
studies on OLP, mainly, but not solely, due to the difficulty in pathway of malignant progression of OLP may be revealed,
distinguishing OLP from a range of OLP-like lesions including leading to more effective and focused follow-up programs.
the strangely underrated lupus erythematosus. The rapid development of new biologic therapeutic agents,
The most outstanding advance in OLP has probably been the such as alefacept, basiliximab, efalizumab and etanercept, has
management of the disease. OLP may have a significant morbid- attracted the interest of researchers on chronic intractable dis-
ity associated with persistent oral ulceration, and the patients’ eases including OLP. However, because of the general poor cost/
quality of life can be severely affected, however the risk of treat- benefit ratio in OLP, it is likely that their use will be confined to
ment should be weighed against the risks and complications of patients with severe manifestations of disease or those who have
the disease itself. Therefore, topical immunomodulators may be failed traditional first- and second-line therapies, such as topical
considerably safer than systemic immunosuppressives. The avail- corticosteroids/topical cancineurin inhibitors.
ability of extremely powerful topical medication, such as haloge- On the contrary, pharmakokinetic studies on topical medi-
nate corticosteroids and calcineruin inhibitors, have permitted cations in the mouth are clearly warranted, as well as multi-
an improved, and in most cases, safe and satisfactory control of center and multinational trials employing the most used topical
OLP lesions, even though current data is still insufficient to make medicaments.
a recommendations with regard to the specific dosage, formula-
tion, or mode of delivery or length of the therapy. Moreover, it Financial & competing interests disclosure
is still unknown whether improved control of the inflammatory The authors have no relevant affiliations or financial involvement with
disease lessens the risk of malignancy. any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript. This
Five-year view includes employment, consultancies, honoraria, stock ownership or
An increasing understanding of the pathogenic mechanisms options, expert testimony, grants or patents received or pending, or
underlining OLP may help to better identify and distinguish royalties.
this disorder from a number of OLP-like lesions. That could in No writing assistance was utilized in the production of this
turn permit more well designed epidemiological studies with manuscript.

www.expert-reviews.com 489
 Review Carrozzo & Thorpe

Key issues
• Oral lichen planus (OLP) is a chronic inflammatory disorder, probably occurring more frequently than its skin counterpart.
• OLP has a low, but probably real, risk of associated malignancy, for which the mechanism is poorly understood.
• A genetic predisposition linked to Th1 cytokine polymorphisms may have a role in oral lichen planus pathogenesis.
• Oral lichen planus is a T-cell-mediated immunological response to an induced antigenic change in the mucosa in predisposed patients,
unlikely to be caused by a single antigen.
• Amalgam restorations, hepatitis C virus and systemic medications may be etiologic factors.
• Biopsy and histological confirmation is recommended in cases of OLP where there is uncertainty about the diagnosis, where the lesions
are clinically atypical (to exclude the presence of dysplasia or malignancy) and prior to initiating active treatment.
• Topical immunomodulators, such as powerful corticosteroids and calcineurin inhibitors, may control OLP lesions, but their therapeutic
effects are usually transient and their long-term effects mainly regarding risk of malignancy to be better explored and understood.
• Current therapeutic data are still insufficient to make recommendations with regard to specific dosage, formulation, mode of delivery or
length of therapy.

References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1 Carrozzo M. How common is oral lichen
planus? Evid. Based. Dent. 9(4), 112–113
(2008).
2 Eisen D, Carrozzo M, Bagan Sebastian JV,
Thongprasom K. Number V Oral lichen
planus: clinical features and management.
Oral Dis. 11(6), 338–349 (2005).
3 Carbone M, Arduino PG, Carrozzo M
et al. Course of oral lichen planus: a
retrospective study of 808 northern
Italian patients. Oral Dis. 15(3), 235–243
(2009).
4 Bidarra M, Buchanan JA, Scully C,
Moles DR, Porter SR. Oral lichen planus:
a condition with more persistence and
extra-oral involvement than suspected?
J. Oral Pathol. Med. 37(10), 582–586
(2008).
5 Eisen D. The evaluation of cutaneous,
genital, scalp, nail, esophageal, and ocular
involvement in patients with oral lichen
planus. Oral Surg. Oral Med. Oral Pathol.
Oral Radiol. Endod. 88(4), 431–436 (1999).
6 Rogers RS 3rd, Eisen D. Erosive oral lichen
planus with genital lesions: the
vulvovaginal–gingival syndrome and the
peno–gingival syndrome. Dermatol. Clin.
21(1), 91–98 (2003).
7 Quispel R, van Boxel OS, Schipper ME
et al. High prevalence of esophageal
involvement in lichen planus: a study using
magnification chromoendoscopy. Endoscopy
41(3), 187–193 (2009).
8 Wedgeworth EK, Vlavianos P, Groves CJ,
Neill S, Westaby D. Management of
symptomatic esophageal involvement with
lichen planus. J. Clin. Gastroenterol. DOI:
10.1097/MCG.0b013e31819db2df (2009)
(Epub ahead of print).
9 Thorne JE, Jabs DA, Nikolskaia OV,
Mimouni D, Anhalt GJ, Nousari HC.
Lichen planus and cicatrizing
conjunctivitis: characterization of five
cases. Am. J. Ophthalmol. 136(2), 239–243
(2003).
10 Gandolfo S, Carrozzo M, Pagano M. Oral
lichenoid lesions: what are they? Oral
Oncol. 40(10), 1057–1058 (2004).
11 Al-Hashimi I, Schifter M, Lockhart PB
et al. Oral lichen planus and oral lichenoid
esions: diagnostic and therapeutic
considerations. Oral Surg. Oral Med. Oral
Pathol. Oral Radiol. Endod. 103(Suppl. 25),
E1–E12 (2007).
12 Sugerman PB, Faber SB, Willis LM et al.
Kinetics of gene expression in murine
cutaneous graft-versus-host disease.
Am. J. Pathol. 164(6), 2189–2202 (2004).
13 Hasséus B, Jontell M, Brune M,
Johansson P, Dahlgren UI. Langerhans
cells and T cells in oral graft versus host
disease and oral lichen planus. Scand.
J. Immunol. 54(5), 516–524 (2001).
14 Lamey PJ, McCartan BE, MacDonald DG,
MacKie RM. Basal cell cytoplasmic
autoantibodies in oral lichenoid
reactions. Oral Surg. Oral Med. Oral
Pathol. Oral Radiol. Endod. 79(1), 44–49
(1995).
15 McCartan BE, McCreary CE. Oral
lichenoid drug eruptions. Oral Dis. 3(2),
58–63 (1997).
16 van der Meij EH, van der Waal I. Lack of
clinicopathologic correlation in the
diagnosis of oral lichen planus based on the
presently available diagnostic criteria and
suggestions for modifications. J. Oral
Pathol. Med. 32(9), 507–512 (2003).
17 Sontheimer RD. Lichenoid tissue reaction/
interface dermatitis: clinical and
histological perspectives. J. Invest.
Dermatol. 129(5), 1088–1099 (2009).
18 Orteu CH, Buchanan JA, Hutchison I,
Leigh IM, Bull RH. Systemic lupus
erythematosus presenting with oral
mucosal lesions: easily missed?
Br. J. Dermatol. 144(6), 1219–1223 (2001).
19 Lourenço SV, de Carvalho FR, Boggio P
et al. Lupus erythematosus: clinical and
histopathological study of oral
manifestations and immunohistochemical
profile of the inflammatory infiltrate.
J. Cutan. Pathol. 34(7), 558–564 (2007).
20 Carrozzo M, Uboldi de Capei M, Dametto
E et al. Tumor necrosis factor-a and
interferon-g polymorphisms contribute to
susceptibility to oral lichen planus.
J. Invest. Dermatol. 122(1), 87–94 (2004).
•• First research suggesting cytokine
polymorphisms involvement in oral lichen
planus (OLP) pathogenesis.
21 Bai J, Lin M, Zeng X et al. Association of
polymorphisms in the human IFN-g and
IL-4 gene with oral lichen planus: a study
in an ethnic Chinese cohort. J. Interferon
Cytokine Res. 28(6), 351–358 (2008).
22 Santoro A, Majorana A, Roversi L et al.
Recruitment of dendritic cells in oral lichen
planus. J. Pathol. 205(4), 426–434 (2005).
23 Parolini S, Santoro A, Marcenaro E et al.
The role of chemerin in the colocalization of
NK and dendritic cell subsets into inflamed
tissues. Blood 109(9), 3625–3632 (2007).
•• Explains dendritic cell recruitment
in OLP.
24 Shaker OG, Hantar N, El-Tahlawi S et al.
Detection of myxovirus resistance
protein A in lichen planus lesions and its
relationship to hepatitis C virus.
Br. J. Dermatol. 160(5), 980–983 (2009).
25 Suomela S, Cao L, Bowcock A, Saarialho-
Kere U. Interferon a-inducible protein 27
(IFI27) is upregulated in psoriatic skin and
certain epithelial cancers. J. Invest.
Dermatol. 122(3), 717–721 (2004).

490 Expert Rev. Dermatol. 4(5), (2009)


26 Ichimura M, Hiratsuka K, Ogura N et al.
Expression profile of chemokines and
chemokine receptors in epithelial cell layers
of oral lichen planus. J. Oral Pathol. Med.
35(3), 167–174 (2006).
27 Kim SG, Chae CH, Cho BO et al.
Apoptosis of oral epithelial cells in oral
lichen planus caused by upregulation of
BMP-4. J. Oral. Pathol. Med. 35(1), 37–45
(2006).
28 Santoro A, Majorana A, Bardellini E,
Festa S, Sapelli P, Facchetti F. NF-kB
expression in oral and cutaneous lichen
planus. J. Pathol. 201(3), 466–472
(2003).
29 Karatsaidis A, Schreurs O, Axell T,
Helgeland K, Schenck K. Inhibition of the
transforming growth factor-b/Smad
signaling pathway in the epithelium of oral
lichen. J. Invest. Dermatol. 121(6),
1283–1290 (2003).
30 Thomas DW, Stephens P, Stephens M,
Patten DW, Lim SH. T-cell receptor Vb
usage by lesional lymphocytes in oral lichen
planus. J. Oral Pathol. Med. 26(3),
105–109 (1997).
31 Scully C, Eisen D, Carrozzo M.
Management of oral lichen planus. Am
J. Clin. Dermatol. 1(5), 287–306 (2000).
32 Issa Y, Brunton PA, Glenny AM,
Duxbury AJ. Healing of oral lichenoid
lesions after replacing amalgam
restorations: a systematic review. Oral Surg.
Oral Med. Oral Pathol. Oral Radiol. Endod.
98(5), 553–565 (2004).
• In-depth systematic review on amalgam
and OLP.
33 Thornhill MH, Pemberton MN,
Simmons RK, Theaker ED. Amalgam-
contact hypersensitivity lesions and oral
lichen planus. Oral Surg. Oral Med. Oral
Pathol. Oral Radiol. Endod. 95(3), 291–299
(2003).
34 Pigatto PD, Guzzi G. Oral lichenoid
lesions: more than mercury. Oral Surg.
Oral Med. Oral Pathol. Oral Radiol. Endod.
100(4), 398–400 (2005).
35 Dunsche A, Frank MP, Lüttges J et al.
Lichenoid reactions of murine mucosa
associated with amalgam. Br. J. Dermatol.
148(4), 741–748 (2003).
•• Animal model of amalgam
lichenoid lesions.
36 Thornhill MH, Sankar V, Xu XJ et al. The
role of histopathological characteristics in
distinguishing amalgam-associated oral
lichenoid reactions and oral lichen planus.
J. Oral Pathol Med. 35(4), 233–240
(2006).
www.expert-reviews.com
Update on oral lichen planus
37 Hougeir FG, Yiannias JA, Hinni ML,
Hentz JG, el-Azhary RA. Oral metal contact
allergy: a pilot study on the cause of oral
squamous cell carcinoma. Int. J. Dermatol
45(3), 265–271 (2006).
38 Bäckman K, Jontell M. Microbial-associated
oral lichenoid reactions. Oral Dis. 13(4),
402–406 (2007).
39 Robertson WD, Wray D. Ingestion of
medication among patients with oral
keratoses including lichen planus. Oral Surg.
Oral Med. Oral Pathol. 74(2), 183–185
(1992).
40 Thompson DF, Skaehill PA.Drug-induced
lichen planus. Pharmacotherapy 14, 561–571
(1994).
41 McCartan BE, McCreary CE. Oral
lichenoid drug eruptions. Oral Dis. 3(2),
58–63 (1997).
42 Burkhart NW, Burker EJ, Burkes EJ,
Wolfe L. Assessing the characteristics of
patients with oral lichen planus. J. Am. Dent.
Assoc. 127(5), 648–662 (1996).
43 Rojo-Moreno JL, Bagán JV, Rojo-Moreno J,
Donat JS, Milián MA, Jiménez Y.
Psychologic factors and oral lichen planus. A
psychometric evaluation of 100 cases. Oral
Surg. Oral Med. Oral Pathol. Oral Radiol.
Endod. 86(6), 687–691 (1998).
44 Vallejo MJ, Huerta G, Cerero R, Seoane JM.
Anxiety and depression as risk factors for oral
lichen planus. Dermatology. 203(4), 303–307
(2001).
45 Chaudhary S. Psychosocial stressors in oral
lichen planus. Aust. Dent. J. 49(4), 192–195
(2004).
46 Koray M, Dülger O, Ak G et al. The
evaluation of anxiety and salivary cortisol
levels in patients with oral lichen planus.
Oral Dis. 9(6), 298–301 (2003).
47 Ivanovski K, Nakova M, Warburton G et al.
Psychological profile in oral lichen planus.
J. Clin. Periodontol. 32(10), 1034–1040
(2005).
48 Allen CM, Beck FM, Rossie KM, Kaul TJ.
Relation of stress and anxiety to oral lichen
planus. Oral Surg. Oral Med. Oral Pathol.
61(1), 44–46 (1986).
49 McCartan BE. Psychological factors
associated with oral lichen planus. J. Oral
Pathol. Med. 24(6), 273–275 (1995).
50 Bergdahl J, Ostman PO, Anneroth G,
Perris H, Skoglund A. Psychologic aspects of
patients with oral lichenoid reactions. Acta
Odontol. Scand. 53(4), 236–241 (1995).
51 Lodi G, Scully C, Carrozzo M, Griffiths M,
Sugerman PB, Thongprasom K. Current
controversies in oral lichen planus: report of
Review
an international consensus meeting. Part 1.
Viral infections and etiopathogenesis. Oral
Surg. Oral Med. Oral Pathol. Oral Radiol.
Endod. 100(1), 40–51 (2005).
52 Shimoyama T, Horie N, Kato T, Kaneko T,
Komiyama K. Helicobacter pylori in oral
ulcerations. J. Oral. Sci. 42(4), 225–229
(2000).
53 De Vries HJ, van Marle J, Teunissen MB
et al. Lichen planus is associated with
human herpesvirus type 7 replication and
infiltration of plasmacytoid dendritic cells.
Br. J. Dermatol. 154(2), 361–364 (2006).
54 Giovannelli L, Campisi G, Lama A et al.
Human papillomavirus DNA in oral
mucosal lesions. J. Infect. Dis. 185(6),
833–836 (2002).
55 von Krogh G, Dahlman-Ghozlan K,
Syrjanen S. Potential human
papillomavirus reactivation following
topical corticosteroid therapy of genital
lichen sclerosus and erosive lichen planus.
J. Eur. Acad. Dermatol. Venereol. 16(2),
130–133 (2002).
56 Carrozzo M. Oral diseases associated with
hepatitis C virus infection. Part 2: lichen
planus and other diseases. Oral Dis. 14(3),
217–228 (2008).
57 Carrozzo M, Francia Di Celle P et al.
Increased frequency of HLA-DR6 allele in
Italian patients with hepatitis C virus-
associated oral lichen planus.
Br. J. Dermatol. 144(4), 803–808 (2001).
58 Carrozzo M, Brancatello F, Dametto E
et al. Hepatitis C virus-associated oral
lichen planus: is the geographical
heterogeneity related to HLA-DR6? J. Oral
Pathol. Med. 34(4), 204–208 (2005).
59 Romero MA, Seoane J, Varela-Centelles P,
Diz-Dios P, Otero XL. Clinical and
pathological characteristics of oral lichen
planus in hepatitis C-positive and -negative
patients. Clin. Otolaryngol. Allied Sci.
27(1), 22–26 (2002).
60 Carrozzo M, Dametto E, Fasano ME
et al. Cytokine gene polymorphisms in
hepatitis C virus-related oral lichen
planus. Exp. Dermatol. 16(9), 730–736
(2007).
61 Arrieta JJ, Rodriguez-Inigo E, Casqueiro
M, et al. Detection of hepatitis C virus
replication by in situ hybridization in
epithelial cells of antihepatitis C virus-
positive patients with and without oral
lichenplanus. Hepatology 32(1), 97–103
(2000).
•• First study demonstrating the possible
replication of hepatitis C virus within the
oral mucosa.
491
 Review Carrozzo & Thorpe
62 Carrozzo M, Quadri R, Latorre P et al.
Molecular evidence that the hepatitis C virus
replicates in the oral mucosa. J. Hepatol.
37(3), 364–369 (2002).
63 Pilli M, Penna A, Zerbini A et al. Oral lichen
planus pathogenesis: a role for the
HCV‑specific cellular immune response.
Hepatology 36(6), 1446–1452 (2002).
•• Hepatitis C virus-specific CD4 cells may be
recruited in OLP lesions.
64 Gonzalez-Moles MA, Scully C,
Gil‑Montoya A. Oral lichen planus:
controversies surrounding malignant
transformation. Oral Dis. 14(3), 229–243
(2008).
• In-depth review on malignant
transformation of OLP.
65 Lodi G, Scully C, Carrozzo M, Griffiths M,
Sugerman PB, Thongprasom K. Current
controversies in oral lichen planus: report of
an international consensus meeting. Part 2.
Clinical management and malignant
transformation. Oral Surg. Oral Med. Oral
Pathol. Oral Radiol. Endod. 100(2), 164–178
(2005).
66 Holmstrup P, Thorn JJ, Rindum J,
Pindborg JJ. Malignant development of
lichen planus-affected oral mucosa. J. Oral
Pathol. 17(5), 219–225 (1988).
67 Gandolfo S, Richiardi L, Carrozzo M et al.
Risk of oral squamous cell carcinoma in 402
patients with oral lichen planus: a follow-up
study in an Italian population. Oral Oncol.
40(1), 77–83 (2004).
68 Rodstrom PO, Jontell M, Mattsson U,
Holmberg E. Cancer and oral lichen planus
in a Swedish population. Oral Oncol. 40(2),
131–138 (2004).
69 van der Meij EH, Schepman KP, van der
Waal I. The possible premalignant character
of oral lichen planus and oral lichenoid
lesions: a prospective study. Oral Surg. Oral
Med. Oral Pathol. Oral Radiol. Endod.
96(2), 164–171 (2003).
70 Patel RV, Clark LN, Lebwohl M, Weinberg
JM. Treatments for psoriasis and the risk of
malignancy. J. Am. Acad Dermatol. 60(6),
1001–1017 (2009).
71 Mattsson U, Jontell M, Holmstrup P. Oral
lichen planus and malignant
transformation: is a recall of patients
justified? Crit. Rev. Oral Biol. Med. 13(5),
390–396 (2002).
72 van der Meij EH, Bezemer PD, van der
Waal I. Cost-effectiveness of screening for
the possible development of cancer in
patients with oral lichen planus. Community
Dent. Oral Epidemiol. 30(5), 342–351
(2002).
492
73 van der Meij EH, Reibel J, Slootweg PJ, van
der Wal JE, de Jong WF, van der Waal I.
Interobserver and intraobserver variability in
the histologic assessment of oral lichen
planus. J. Oral Pathol. Med. 28(6), 274–277
(1999).
74 Carrozzo M, Gandolfo S. The management
of oral lichen planus. Oral Dis. 5(3),
196–205 (1999).
75 Helander SD, Rogers RS 3rd. The sensitivity
and specificity of direct immunofluorescence
testing in disorders of mucous membranes.
J. Am. Acad. Dermatol. 30(1), 65–75 (1994).
76 Holmstrup P, Schiøtz AW, Westergaard J.
Effect of dental plaque control on gingival
lichen planus. Oral Surg. Oral Med. Oral
Pathol. 69(5), 585–590 (1990).
77 Cribier B, Frances C, Chosidow O.
Treatment of lichen planus. An evidence-
based medicine analysis of efficacy. Arch.
Dermatol. 134(12), 1521–1530 (1998).
78 Voute AB, Schulten EA, Langendijk PN,
Kostense PJ, van derWaal I. Fluocinonide in
an adhesive base for treatment of orallichen
planus. A double-blind, placebo-controlled
clinical study. Oral Surg. Oral Med. Oral
Pathol. Oral Radiol. Endod. 75(2), 181–185
(1993).
79 Lozada-Nur F, Miranda C, Maliksi R.
Double-blind clinical trial of 0.05%
clobetasol propionate ointment in orabase
and 0.05% fluocinonide ointment in orabase
in the treatment of patients with oral
vesiculoerosive diseases. Oral Surg. Oral
Med. Oral Pathol. 77(6), 598–604 (1994).
80 Rodstrom P, Hakeberg M, Jontel M et al.
Erosive oral lichen planus treated with
clobetasol propionate and triamcinolone
acetonide in Orabase: a double-blind clinical
trial. J. Dermatol. Treat. 5(1), 7–10 (1994).
81 Carbone M, Conrotto D, Carrozzo M,
Broccoletti R, Gandolfo S, Scully C.
Topical corticosteroids in association with
miconazole and chlorhexidine in the
long-term management of atrophic-erosive
oral lichen planus: a placebo-controlled
and comparative study between clobetasol
and fluocinonide. Oral Dis. 5(1), 44–49
(1999).
82 Buajeeb W, Pobrurksa C, Kraivaphan P.
Efficacy of fluocinolone acetonide gel in the
treatment of oral lichen planus. Oral Surg.
Oral Med. Oral Pathol. Oral Radiol. Endod.
89(1), 42–45 (2000).
83 Thongprasom K, Luengvisut P,
Wongwatanakij A, Boonjatturus C. Clinical
evaluation in treatment of oral lichen planus
with topical fluocinolone acetonide: a 2-year
follow-up. J. Oral Pathol. Med. 32(6),
315–322 (2003).
84 Carbone M, Arduino PG, Carrozzo M et al.
Topical clobetasol in the treatment of
atrophic-erosive oral lichen planus: a
randomized controlled trial to compare two
preparations with different concentrations.
J. Oral Pathol. Med. 38(2), 227–233 (2009).
85 Campisi G, Giandalia G, De Caro V,
Di Liberto C, Aricò P, Giannola LI. A new
delivery system of clobetasol-17-propionate
(lipid-loaded microspheres 0.025%)
compared with a conventional formulation
(lipophilic ointment in a hydrophilic phase
0.025%) in topical treatment of atrophic/
erosive oral lichen planus. A Phase IV,
randomized, observer-blinded, parallel group
clinical trial. Br J. Dermatol. 150(5),
984–990 (2004).
86 Lo Muzio L, della Valle A, Mignogna MD
et al. The treatment of oral aphthous
ulceration or erosive lichen planus with
topical clobetasol propionate in three
preparations: a clinical and pilot study on
54 patients. J. Oral Pathol. Med. 30(10),
611–617 (2001).
87 Gilbertson EO, Spellman MC,
Piacquadio DJ, Mulford MI. Super potent
topical corticosteroid use associated with
adrenal suppression: clinical considerations.
J. Am. Acad. Dermatol. 38(2 Pt 2), 318–321
(1998).
88 Pramick M, Whitmore SE. Cushing’s
syndrome caused by mucosal corticosteroid
therapy. Int. J. Dermatol. 48(1), 100–101
(2009).
89 Plemons JM, Rees TD, Zachariah NY.
Absorption of a topical steroid and evaluation
of adrenal suppression in patients with
erosive lichen planus. Oral Surg. Oral Med.
Oral Pathol. Oral Radiol. Endod. 69(6),
688–693 (1990).
90 Gonzalez-Moles MA, Scully C. Vesiculo-
erosive oral mucosal disease – management
with topical corticosteroids: (1) fundamental
principles and specific agents available.
J. Dental Res. 84(4), 294–301 (2005).
91 Gonzalez-Moles MA, Scully C. Vesiculo-
erosive oral mucosal disease – management
with topical corticosteroids: (2) protocols,
monitoring of effects and adverse reactions,
and the future. J. Dental Res. 84(4), 302–308
(2005).
92 Lodi G, Tarozzi M, Sardella A et al.
Miconazole as adjuvant therapy for oral
lichen planus: a double-blind randomized
controlled trial. Br. J. Dermatol. 156(6),
1336–1341 (2007).
93 Gonzalez-Moles MA, Ruiz-Avila I,
Rodriguez-Archilla A et al. Treatment of
severe erosive gingival lesions by topical
application of clobetasol propionate in
Expert Rev. Dermatol. 4(5), (2009)

custom trays. Oral Surg. Oral Med. Oral
Pathol. Oral Radiol. Endod. 95(6), 688–692
(2003).
94 Hegarty AM, Hodgson TA, Lewsey JD,
Porter SR. Fluticasone propionate spray and
betamethasone sodium phosphate
mouthrinse: a randomized crossover study
for the treatment of symptomatic oral lichen
planus. J. Am. Acad. Dermatol. 47(2),
271–279 (2002).
95 Gonzalez-Moles MA, Morales P,
Rodriguez-Archilla A, Isabel IR, Gonzalez-
Moles S. Treatment of severe chronic
oralerosive lesions with clobetasol
propionate in aqueous solution. Oral Surg.
Oral Med. Oral Pathol. Oral Radiol. Endod.
93(3), 264–270 (2002).
96 Eisen D, Ellis CN, Duell EA, Griffiths CE,
Voorhees JJ. Effect of topical Ciclosporine
rinse on oral lichen planus. A doubleblind
analysis. N. Engl. J. Med. 23(6 Pt 2),
290–294 (1990).
•• First double-blind randomized, placebo-
controlled study showing the efficacy of
ciclosporin in OLP treatment.
97 Voute AB, Schulten EA, Langendijk PN,
Nieboer C, van der Walle I . Ciclosporin A
in an adhesive base for treatment of
recalcitrant oral lichen planus. An open
trial. Oral Surg. Oral Med. Oral Pathol.
Oral Radiol. Endod 78(4), 437–441 (1994).
98 Levell NJ, Macleod RI, Marks JM. Lack of
effect of Ciclosporin mouthwash in oral
lichen planus. Lancet 337(8744), 796–797
(1991).
99 Itin P, Surber C, Buchner S. Lack of effect
after local treatment with a new ciclosporin
formulation in recalcitrant erosive oral
lichen planus. Dermatology 185(4),
262–265 (1992).
100 Sieg P, von Domarus H, von Zitzewitz V,
Iven H, Farber L. Topical Ciclosporin in
oral lichen planus: a controlled,
randomized, prospective trial.
Br. J. Dermatol. 132 (5), 790–794 (1995).
101 Conrotto D, Carbone M, Carrozzo M et al.
Ciclosporin vs. clobetasol in the topical
management of atrophic and erosive oral
lichen planus: a double-blind, randomized
controlled trial. Br. J. Dermatol. 154(1),
139–145 (2006).
• Double-blind, randomized, controlled trial
showing that clobetasol propionate is more
effective than ciclosporin in OLP.
102 Lener EV, Brieva J, Schachter M, West LE,
West DP, el Azhary RA. Successful
treatment of erosive lichen planus with
topical tacrolimus. Arch. Dermatol. 137(4),
419–422 (2001).
www.expert-reviews.com
Update on oral lichen planus
103 Kaliakatsou F, Hodgson TA, Lewsey JD,
Hegarty AM, Murphy AG, Porter SR.
Management of recalcitrant ulcerativeoral
lichen planus with topical tacrolimus.
J. Am. Acad. Dermatol. 46(1), 35–41
(2002).
104 Morrison L, Kratochvil FJ III, Gorman A.
An open trial of topical tacrolimus for
erosive oral lichen planus. J. Am. Acad.
Dermatol. 47(4), 617–620 (2002).
105 Rozycki TW, Rogers RS 3rd, Pittelkow
MR et al. Topical tacrolimus in the
treatment of symptomatic oral lichen
planus: a series of 13 patients. J. Am. Acad.
Dermatol. 46(1), 27–34 (2002).
106 Olivier V, Lacour JP, Mousnier A,
Garraffo R, Monteil RA, Ortonne JP.
Treatment of chronic erosive oral lichen
planus with low concentrations of topical
tacrolimus: an open prospective study.
Arch. Dermatol. 138(10), 1335–1338
(2002).
107 Hodgson TA, Sahni N, Kaliakatsou F,
Buchanan JA, Porter SR. Long-term
efficacy and safety of topical tacrolimus in
the management of ulcerative/erosive oral
lichen planus. Eur. J. Dermatol. 13(5),
466–470 (2003).
108 Conrotto D, Carrozzo M, Ubertalli AV
et al. Dramatic increase of tacrolimus
plasma concentration during topical
treatment for oral graft-versus-host disease.
Transplantation. 82(8), 1113–1115
(2006).
109 Swift JC, Rees TD, Plemons JM,
Hallmon WW, Wright JC. The
effectiveness of 1% pimecrolimus cream
in the treatment of oral erosive lichen
planus. J. Periodontol. 76(4), 627–635
(2005).
•• First double-blind, randomized, placebo-
controlled study on pimecrolimus in OLP.
Passeron T, Lacour JP, Fontas E, Ortonne
110
JP. Treatment of oral erosive lichen planus
with 1% pimecrolimus cream: a double-
blind, randomized, prospective trial with
measurement of pimecrolimus levels in the
blood. Arch. Dermatol. 143(4), 472–476
(2007).
111 Volz T, Caroli U, Lüdtke H et al.
Pimecrolimus cream 1% in erosive oral
lichen planus – a prospective randomized
double-blind vehicle-controlled study.
Br. J. Dermatol. 159(4), 936–941 (2008).
112 Dissemond J, Schröter S, Franckson T,
Herbig S, Goos M. Pimecrolimus in an
adhesive ointment as a new treatment
option for oral lichen planus.
Br. J. Dermatol. 150(4), 782–784 (2004).
Review
113 Gorouhi F, Solhpour A, Beitollahi JM et al.
Randomized trial of pimecrolimus cream
versus triamcinolone acetonide paste in the
treatment of oral lichen planus. J. Am. Acad.
Dermatol. 57(5), 806–813 (2007).
114 Becker JC, Houben R, Vetter CS,
Bröcker E. The carcinogenic potential of
tacrolimus ointment beyond immune
suppression: a hypothesis creating case
report. BMC Cancer 6, 7–13 (2006).
115 Soria A, Agbo-Godeau S, Taïeb A,
Francès C. Treatment of refractory oral
erosive lichen planus with topical
rapamycin: 7 cases. Dermatology 218(1),
22–25 (2009).
116 Boisnic S, Branchet MC, Pascal F,
Ben Slama L, Rostin M, Szpirglas H.
Topical tretinoin in the treatment of lichen
planus and leukoplakia of the mouth
mucosa. A clinical evaluation. Ann.
Dermatol. Venereol. 121(6–7), 459–463
(1994).
117 Tradati N, Chiesa F, Rossi N et al.
Successful topical treatment of oral lichen
planus and leukoplakias with fenretinide
(4-HPR). Cancer Lett. 76(2–3), 109–111
(1994).
118 Buajeeb W, Kraivaphan P, Pobrurksa C.
Efficacy of topical retinoic acid compared
with topical fluocinolone acetonide in the
treatment of oral lichen planus. Oral Surg.
Oral Med. Oral Pathol. Oral Radiol. Endod.
83(1), 21–25 (1997).
119 Carbone M, Goss E, Carrozzo M et al.
Systemic and topical corticosteroid
treatment of oral lichen planus: a
comparative study with long-term
follow-up. J. Oral Pathol. Med. 32(6),
323–329 (2003).
120 Frieling U, Bonsmann G, Schwarz T,
Luger TA, Beissert S. Treatment of severe
lichen planus with mycophenolate mofetil.
J. Am. Acad. Dermatol. 49(6), 1063–1066
(2003).
121 Torti DC, Jorizzo JL, McCarty MA. Oral
lichen planus: a case series with emphasis on
therapy. Arch. Dermatol. 143(4), 511–515
(2007).
122 Chang AL, Badger J, Rehmus W,
Kimball AB. Alefacept for erosive lichen
planus: a case series. J. Drugs Dermatol.
7(4), 379–383 (2008).
123 Rebora A, Parodi A, Murialdo G.
Basiliximab is effective for erosive lichen
planus. Arch. Dermatol. 138(8), 1100–1101
(2002).
124 Cheng A, Mann C. Oral erosive lichen
planus treated with efalizumab. Arch.
Dermatol. 142(6), 680–682 (2006).
493
 Review Carrozzo & Thorpe
125 Yarom N. Etanercept for the management
of oral lichen planus. Am. J. Clin.
Dermatol. 8(2), 121 (2007).
126 Moss AC, Treister NS, Marsee DK,
Cheifetz AS. Clinical challenges and images
in GI. Oral lichenoid reaction in a patient
with Crohn’s disease receiving infliximab.
Gastroenterology 132(2), 488, 829 (2007).
127 Choonhakarn C, Busaracome P,
Sripanidkulchai B, Sarakarn P. The efficacy
of aloe vera gel in the treatment of oral lichen
planus: a randomised controlled trial.
Br. J. Dermatol. 158(3), 573–577 (2008).
128 Guyot AD, Farhi D, Ingen-Housz-Oro S
et al. Treatment of refractory erosive oral
lichen planus with extracorporeal
photochemotherapy: 12 cases.
Br. J. Dermatol. 156(3), 553–556 (2007).
129 Axéll T, Henriksen BM. Treatment of
gingival lichen with free palatal grafts.
J. Oral Pathol. Med. 36(2), 105–109 (2007).
494
View publication stats
130 Huerta Leteurtre N, Bagan Sebastian JV,
Cardona Tortajada F, LloriaDe Miguel E,
Jimenez Soriano Y, Basterra Algeria J. Oral
lichen planus plaques and homogeneous
leukoplasia: comparative results oftreatment
with CO2 laser. Acta Otorrinolaringol. 50(7),
543–547 (1999).
131 Trehan M, Taylor CR. Low-dose excimer
308-nm laser for the treatment of oral lichen
planus. Arch. Dermatol. 140(4), 415–420
(2004).
132 Kollner K, Wimmershoff M, Landthaler M,
Hohenleutner U. Treatment of oral lichen
planus with the 308-nm UVB excimer laser
– early preliminary results in eight patients
Lasers Surg. Med. 33(3), 158–160 (2003).
133 Katz J, Goultschin J, Benoliel R, Rotstein I,
Pisanty S. Lichen planus evoked by
periodontal surgery. J. Clin. Periodontol.
15(4), 263–265 (1988).
Affiliations
• Marco Carrozzo
Professor, Department of Oral Medicine,
School of Dental Sciences, University of
Newcastle upon Tyne, Framlington Place,
Newcastle upon Tyne, NE2 4BW, UK
Tel.: +44 191 222 6797
Fax: +44 191 222 6137
marco.carrozzo@ncl.ac.uk
• Rebecca J Thorpe
Department of Oral Medicine, School of
Dental Sciences, University of Newcastle
upon Tyne, Framlington Place, Newcastle
upon Tyne, NE2 4BW, UK
Tel.: +44 127 486 0030
Fax: +44 191 222 6137
dr.thorpe@westfieldfs.co.uk
Expert Rev. Dermatol. 4(5), (2009)