Australian Dental Journal

The official journal of the Australian Dental Association

Australian Dental Journal 2010; 55:(1 Suppl): 23–38

doi: 10.1111/j.1834-7819.2010.01196.x

Oral mucosal diseases: the inflammatory dermatoses

M Schifter,* S-C Yeoh,  H Coleman,* A Georgiou*
*Oral Medicine ⁄ Oral Pathology Unit, Westmead Centre for Oral Health, Westmead Hospital, Sydney.
 Oral Medicine ⁄ Oral Pathology, Liverpool and Royal Prince Alfred Hospitals and The Sydney Dental Hospital, Sydney.

ABSTRACT
The oral inflammatory dermatoses is a term used to describe a number of predominantly immune-mediated disorders: lichen
planus (LP), erythema multiforme (EM), the vesiculobullous diseases pemphigoid (MMP), pemphigus (PV) and
epidermolysis bullosa acquisita (EBA). These conditions are characterized by frequent involvement of the oral mucosa
and often associated with extraoral manifestations, particularly of the skin, but can involve the eyes, both the conjunctiva
and sclera, the nasal and pharyngeal mucosa, as well as the genitals. Given their frequent, and sometimes initial involvement
of the oral mucosa, oral health professionals need to be both familiar with the clinical features and presentations of these
conditions, and appreciate their critical role in management.
This paper reviews the clinical features and presentation of the oral dermatoses, provides guidance as to the appropriate
investigations needed to differentiate and correctly diagnose these conditions, details the aetio-pathology of these diseases
and discusses their management.
Keywords: Autoimmune, blister, bullae, corticosteroids, dermatoses, desquamative, erosion, immune-mediated, immunosuppression,
steroid-sparing, vesicles, vesiculobullous, ulcers.
Abbreviations and acronyms: ADCC = antibody dependent cellular cytotoxicity; BMZ = basement membrane zone; CDC = complement
dependent cytotoxicity; cGVHD = chronic graft-versus-host disease; DIF = direct immuno-fluorescence; DLE = discoid lupus
erythematosus; EB = epidermolysis bullosa; EBA = epidermolysis bullosa acquisita; EM = erythema multiforme; c-IFN = gamma-
interferon; MMP = mucous membrane pemphigoid; OCP = ocular cicatricial pemphigoid; OLCL = oral lichenoid contact lesions; OLDR =
oral lichenoid drug reactions; OLP = oral lichen planus; OMMP = oral mucous membrane pemphigoid; PUVA = psoralen ultraviolet A light;
PV = pemphigus vulgaris; SJS = Stevens Johnson syndrome; TEN = toxic epidermal necrolysis; TNF-a = tumour necrosis factor alpha.

‘‘contact’’ lesion, is not understood, but all the lesions

ORAL LICHEN PLANUS
Lichen planus is a chronic systemic disease of estab-
lished immune-mediated pathogenesis.1 It most com-
monly, and most protractedly, involves the mucosa of
the oral cavity, hence it is of interest and concern to
dentists, but it can involve other sites, namely the skin,
the scalp (with inflammation around and affecting the
hair follicles resulting in alopecia), the nails as well as
the genital area – the vulval and vaginal mucosa, and
the glans penis. There are six recognized oral presen-
tations of lichen planus: (1) reticular; (2) papular; and
(3) plaque-form; and the (4) atrophic; (5) ulcerative
(erosive) and rare (6) bullous form. These latter three
forms can be associated with significant discomfort
requiring either topical and ⁄ or systemic immunosup-
pressive therapy.2
The cause(s) of the various oral lichenoid lesions,
ranging from idiopathic oral lichen planus (OLP) to the
ª 2010 Australian Dental Association
are characterized histologically by a typical ‘‘lichenoid
tissue reaction’’ featuring a band-like lymphohistiocytic
infiltrate within the lamina propria and liquefaction
degeneration of the basal keratinocytes. These reactions
may be the result of several diverse possible triggers,
but all culminate in a common pathologic process, that
of T-lymphocyte directed, immune-mediated, damage
to the oral epithelial basal cells.1,2
Epidemiology
OLP is a common condition. To date there have been
no studies of the prevalence of OLP in Australia.
Overseas data from comparable countries indicate a
prevalence of between 0.5 to 2.2% of the population.2
However, OLP most frequently presents in women, by
a ratio of approximately 3:1 to 3:2 compared with men,
aged 40 years and above.
23
M Schifter et al.

MANAGEMENT

Diagnosis
The diagnosis of OLP is usually made on clinical
features alone. However, careful attention to the
clinical history is essential, to ensure assessment, and
if warranted, the appropriate management, of the
extraoral manifestations of lichen planus.1
The signs and symptoms can vary considerably. Lichen
planus of the oral mucosa occurs most often in the
absence of skin lesions. Symptomatically, OLP can also
vary, with patients presenting with complaints of mild
but noticeable intolerance to particularly salty, spicy or
acidic foods (such as any form of curry). Rarely, patients
will present with widespread oral mucosal ulceration
that is spontaneously very painful and so elicit their
presentation. The reticular, papular, and plaque forms of
OLP are often asymptomatic, and are often detected
coincidentally by the dentist. Given the concern about
Fig 1. Characteristic white interlacing striae seen with oral lichen
the potential for OLP to undergo malignant transforma- planus present on the buccal mucosa.
tion,1,3–5 and the critical role of the dentist in oral cancer
detection, opportunistic screening by dentists for all
forms of oral mucosal disease is strongly encouraged. and monitoring, biopsy would be prudent clinical
Mucosal lesions are usually multiple and almost practice, particularly when the disease does not present
always have a bilateral, symmetrical distribution. They with its typical manifestations, or when there is concern
commonly take the form of minute white papules that and therefore need, to exclude dysplasia or malignancy.1
gradually enlarge and coalesce to form either a reticular, Furthermore, in severe disease warranting treatment
annular, or plaque-like pattern. A characteristic feature with high-dose systemic corticosteroid therapy or potent
is the presence of slender white lines (Wickham’s striae) ‘‘steroid-sparing’’ immune-suppressant agents, then a
radiating from the papules. In the reticular form, there is confirmatory biopsy would be highly appropriate.
a lace-like network of slightly raised white lines, often
interspersed with papules or rings (Fig 1). The plaque-
Laboratory investigations
like form may be difficult to distinguish from leukopla-
kia. In some patients, the lesions are erythematous or These are indicated in patients with severe OLP
frankly ulcerated. Oral lesions of lichen planus may also warranting high-dose systemic corticosteroids, with
include bullae, but this is rare. These different forms can the need to exclude underlying infectious diseases that
merge or coexist in the same patient.1 The gingivae are can be reactivated by the corticosteroids (e.g., HIV,
commonly the site of erythematous ⁄ erosive OLP. Hepatitis B and C, and tuberculosis). Similarly, if
Involvement of the gingivae is described clinically as considering treatment with a suitable ‘‘steroid-sparing’’
desquamative gingivitis, but is not unique to OLP and systemic agent (e.g., hydroxychloroquine, azathioprine
may feature in the presentation of other oral dermato- or methotrexate), then routine full blood count, and
ses, especially pemphigoid and pemphigus. testing of liver and renal function may be worthwhile
for baseline assessment and monitoring in patients
needing long-term management.
Special investigations

Biopsy and histopathological investigations Differential diagnoses

The clinical features alone may be sufficiently diagnos-
tic, particularly when presenting with the ‘‘classic’’
reticular form. The evidence regarding the need and
value of biopsy for histological confirmation of the
diagnosis is not definitive. Studies have shown variability
in both inter-observer and intra-observer reliability in
the clinicopathological assessment of OLP.6 As OLP is a
chronic disorder that often requires long-term treatment
There is a spectrum of oral lesions that resembles OLP
both clinically and histopathologically.7 These ‘‘lichen
planus-like’’ (‘‘lichenoid’’) lesions include the following
conditions: (1) oral lichenoid contact lesions (OLCL) as
a result of allergic contact stomatitis (delayed immune
mediated hypersensitivity). They are seen in direct
topographic relationship to dental restorative materials,
such as amalgam. In regards to the approach to oral

24 ª 2010 Australian Dental Association


lichenoid contact lesions, the value of patch testing
remains controversial;7–11 (2) oral lichenoid drug
reactions (OLDR), wherein oral and ⁄ or cutaneous
lesions arise in temporal association with the taking
of certain medications, e.g., oral hypoglycaemic agents,
angiotensin-converting enzyme inhibitors, and non-
steroidal anti-inflammatory agents. Confirmation of
the diagnosis of an oral lichenoid drug reaction may be
difficult, since empiric withdrawal of the suspected drug
and ⁄ or its substitution by an alternative agent may be
complicated;12,13 (3) oral lichenoid lesions (OLL-
GVHD) of graft-versus-host disease are confined to
allogeneic haematopoietic stem cell transplant recipients
who have developed acute, or more commonly, chronic
graft-versus-host disease (cGVHD). There is evidence
that there is a greater risk of malignant transforma-
tion with OLL-GVHD than seen with OLP.14
The oral presentation of discoid lupus erythematosus
(DLE) can also present with reticular or plaque-like
lesions, but it is an uncommon condition that tends to
present very much unilaterally, so indicating biopsy for
histopathological and direct immune-fluorescence
investigations, the latter being most useful in distin-
guishing OLP from DLE.15
Additional measures
Referral for examination by a dermatologist or gynae-
cologist should be considered, depending on the
presenting signs and symptoms reported by the patient.
Treatment
An essential first step is patient education as to the
chronic nature of OLP and that therapy is not curative,
but directed at relieving their symptoms. For treatment
to be effective, patients require education regarding the
need to be compliant with the recommended therapy.
Instilling in patients the need for ongoing monitoring,
not only for the patients’ response to treatment, but for
malignant transformation is also important.
Supportive measures
The elimination of precipitating or provoking factors is
an important initial step in the management of symp-
tomatic OLP. The undertaking of active measures to
resolve or minimize mechanical trauma from dental
procedures, sharp cusps, rough dental restorations, and
ill-fitting prostheses, or chemical trauma from acidic,
spicy, or strongly flavoured foods and beverages should
be encouraged. Of themselves, such supportive mea-
sures can lead to symptomatic improvement, or, more
rarely, resolution of the disease.
The accumulation of bacterial plaque, often as a
result of the discomfort associated with oral hygiene
ª 2010 Australian Dental Association
Inflammatory dermatoses
procedures in patients with gingival involvement, may
also exacerbate the condition. The use of supplemental
oral hygiene measures, including the use of alcohol-free
chlorhexidine gluconate mouthrinses, may be helpful in
such cases.16
Patch testing and removal of lichenoid-inducing
dental restorative materials
Idiopathic OLP needs to be distinguished from OLCL,
most commonly seen in direct topographic relationship
with amalgam. Cutaneous patch testing, undertaken by
a clinician skilled and experienced in ‘‘reading’’ the
cutaneous response to a variety of test agents can be
useful to confirm the diagnosis of an OLCL,7,8 espe-
cially in severe, symptomatic cases, in which wide-
spread replacement of the amalgam fillings is being
considered, given the expense in time and money to the
patient concerned. The benefit of such patch testing is
to ensure that the alternate dental restorative materials
also, in turn, do not incite a lichenoid contact reaction
(e.g., as has been seen with gold and even composite
materials). In select cases, and if practical, consider-
ation should be given to the replacement of those
isolated restorations, seemingly in direct topographic
relationship with a lichenoid oral mucosal lesion,
particularly if symptomatic, with an alternate material,
but the patient needs to be counselled that this may not
necessarily prove beneficial. As an interim step, tempo-
rary coverage of the suspected inciting material may be
considered to determine if resolution of the OLCL
occurs before undertaking definitive removal and
replacement of the suspected inciting material.
Pharmacotherapy (Table 1)
Given the immune-mediated aetiology of OLP (and
similar conditions such as mucous membrane pemphig-
oid (MMP)), the aim of therapy is to minimize or
‘‘restrain’’ the body’s immune-mediated inflammatory
response, but without risking the activation of oppor-
tunistic infections. Treatment should be kept as simple
as possible and should not inordinately burden the
patient with complex, unwieldy or protracted treat-
ments that result in non-compliance. Therefore, topical
corticosteroids remain the mainstay of treatment.1,17
Unfortunately, there are only limited evidence-based
studies regarding the therapeutic interventions in OLP,
and so treatment remains largely empirical.1
Topical treatments: home remedies and
over-the-counter (OTC) preparations
Patient prepared saline mouthwashes are of very limited
clinical utility, somewhat palliative, and do not address
the aetiological factors seen in OLP, but may facilitate
25
M Schifter et al.

Table 1. Therapeutic agents useful in treating oral dermatoses

Pre-therapeutic
Medication Dose Contraindications investigations Monitoring Adverse reactions

Corticosteroids prednisolone: n% Active infectious Tb, HIV, HBV, Systemic: hypertension,

(‘‘steroids’’) (1) ½–1 mg per kg ⁄ diseases: Tb, HIV, HCV hypertension, psychosis, diabetes
bodyweight of the HBV, HCV psychosis, diabetes mellitus, weight
patient for 4 days mellitus, weight gain, cataracts
(or longer in gain, cataracts Oral mucosa:
pemphigus) with Oral mucosa: candidiasis,
rapid taper until candidiasis, mucosal mucosal atrophy
clinical remission atrophy
occurs n%
(2) <7.5 mg ⁄ daily

Calcineurin- Topical application A causal relationship has not been established with malignancy. Skin irritation, pruritis
inhibitors: only thin layer to cancer and lymphoma have been reported in patients treated with and erythema on
pimecrolimus affected mucosa topical calcineurin inhibitors, including pimecrolimus 1% cream. application
(Elidel) twice daily

Lysosomotropic 200–400 mg pre-existing baseline visual annual baseline UV (sun)

amines: hydroxyl- (once daily) retinopathy acuity testing (for visual acuity testing light–initiated
chloroquine psoriasis macular FBC and LFTs lichenoid cutaneous
(Plaquenil) porphyria degeneration) by an weekly for first reactions
G6PD deficiency ophthalmologist 4 weeks; thereafter, Note: slow onset of
FBC, G6PDH levels, only if indicated action of up to
LFTs 3 months

azathioprine 1.0–2.0 mg per kg recent use of live thiopurine FBC weekly for first severe adverse reaction
(Imuran) bodyweight ⁄ daily vaccines methyl-transferase 8 weeks; thereafter with xanthine oxidase
(once daily) pregnancy (Category (TPMT) assay monthly inhibitors of which
D) (including (determines risk of the most potent is
partner of male bone marrow allopurinol (Progout
patient) aplasia) Zyloprim)
concomitant FBC, LFTs, E ⁄ U ⁄ C
allopurinol

mycophenolate max 2 g ⁄ day (once pregnancy n% HIV, HBV, HCV FBC and LFTs malignancy risk, e.g.
(CellCept, daily or divided (Category D) weekly for first skin cancer,
Myfortic) dose) 4 weeks; thereafter, lymphoma; infection;
only if indicated progressive multifocal
leuco-encephalopathy;
bone marrow
depression

dapsone (Dapsone) maintenance dose: FBC, G6PDH levels, FBC, LFTs weekly dose related haemolysis,
50–100 mg daily LFTs for the first month, especially in G6DP
(‡300 mg daily) HIV, HBV, HCV monthly for six deficient patients;
dapsone months and agranulocytosis; toxic
hypersensitivity semi-annually hepatitis and
thereafter cholestatic jaundice

methotrexate 10 to 25 mg ⁄ pregnancy n% FBC, LFTs, E ⁄ U ⁄ C FBC weekly for first hepato ⁄ nephrotoxicity;
(Methoblastin) Weekly only until (Category D) HIV, HBV, HCV 8 weeks, thereafter ulcerative stomatitis;
adequate response liver ⁄ renal monthly bone marrow
is achieved impairment depression;
HIV, HBV, HCV immune-suppression
immune-deficiency;
concomitant
retinoinds

Rituximab 375 mg ⁄ m2 (body Murine (mouse) Tb, HIV, HBV, infection progressive multifocal
(Mabthera) surface area) once protein HCV leucoencephalopathy
weekly for 4 weeks hypersensitivity (PML)

Abbreviations: Tb = tuberculosis; HIV = human immune-deficiency virus; HBV = hepatitis B virus; HCV = hepatitis C virus; G6PDH = glucose-6-
phosphate dehydrogenase; FBC = full blood count; LFTs = liver function tests; UV = ultraviolet light; E ⁄ U ⁄ C = electrolytes ⁄ urea ⁄ creatinine.

oral hygiene. Patients often self-prescribe and use a
variety of OTC antimicrobial mouthwashes in the
mistaken understanding that OLP may be infective in
nature, but often complain of their astringency,
26
especially the alcohol-containing mouthwashes (and a
useful clue as to the diagnosis).
Kenalog in Orabase is one topical corticosteroid
(0.1% triamcinolone) preparation that has the distinct
ª 2010 Australian Dental Association

advantage of being mixed with a vehicle for applying
medication to the oral surfaces – Orabase (composed
of gelatin, pectin and carmellose in a Plastibase
(hydrocarbon gel ointment base)).1 The use of such an
adhesive addresses an important therapeutic issue in
treating OLP, i.e., having sufficient ‘‘contact time’’
between the medicament and the mucosal lesion(s) of
OLP. It maintains the medication in close contact with
the lesion and provides a protective covering that
augments the effects of the corticosteroid.
Prescription treatments: topical corticosteroid
preparations
Topical corticosteroids come in a range of strengths,
rated from mild (hydrocortisone) to moderate (beta-
methasone valerate) to highly potent (clobetasone) and
means of delivery by pastes, ointments, gels or as
inhaled agents (as used in asthma treatment). All
agents, used in a variety of delivery methods have
demonstrated some efficacy in treating OLP.1 How-
ever, the basic principles guiding topical corticoster-
oids therapy is firstly to use the lowest strength agent
possible to achieve a therapeutic benefit, and secondly,
for oral mucosal lesions (as opposed to skin condi-
tions), to favour the use of adhesive-containing
preparations to prolong contact time, and so avoid
the agent being simply washed away by the ever-
present saliva.
Compounded preparations
Empirically, patients report modest to good responses
to the use of moderate, to highly potent topical
corticosteroids such as betamethasone valerate mixed
with an equal amount (by weight) of Orabase, used two
to four times daily (after meals) given they are suitably
adhesive. One limitation is that they often need to be
prepared by specialist compounding pharmacists. A
second limitation is many patients find this mixture
unpleasant and ‘‘tacky’’. Use of specially fabricated
modified topical fluoride trays, with extended coverage
of the gingiva and adjacent alveolar mucosa to hold
topical agents in place in the treatment of the desqua-
mative gingivitis form of OLP are reported to be
helpful, but again, patient compliance can be poor.1
Potent corticosteroids, such as dexamethasone, com-
pounded as a mouthwash suspension (0.1% strength –
40 mg Dexamethasone mixed with 400 ml sterile
water) are better tolerated by patients.18 However,
patients must be carefully instructed in their use,
emphasizing that it is to be used as a rinse, for at least
three minutes (for sufficient therapeutic contact time),
at most four times a day (after meals) and to spit out
well, to minimize systemic uptake of this highly potent
corticosteroid and thereby avoid its adverse effects.
ª 2010 Australian Dental Association
Inflammatory dermatoses
Antifungal agents
Supplemental use of antifungal agents, such as *Dakt-
arin (miconazole) Oral Gel, or chlorhexidine-con-
taining mouthwashes is warranted given the risk of
candidial overgrowth and possible infection secondary
to the use of the corticosteroids (whether they be used
topically or systemically).
Systemic agents: corticosteroids
Systemic corticosteroids are used in two ways: firstly, as
a short-term ‘‘pulse’’ dose of prednisolone up to 0.5 mg
per kilogram (of the patients’) body weight for a short
period of time (four days or less and then rapidly
tapered) to bring about control of severe ulcerative OLP
or in patients with multiple, highly active, sites of lichen
planus. Secondly, longer-term, to supplement topical
therapies, at sub-physiological doses (equal or less than
7.5 mg prednisone (or equivalent) daily.1 Monitoring
for the principle side effects (and other adverse effects)
of systemic corticosteroid therapy, hypertension, dia-
betes mellitus, gastric ulceration and osteoporosis is
essential and should be undertaken by clinicians skilled
in the use of such agents and familiar with their side
effects.
Corticosteroid alternatives
Retinoids (topical and systemic)
Overall, the published studies suggest that retinoids are
potentially effective in the treatment of OLP, but
probably inferior to corticosteroids.19 Systemic reti-
noids are associated with a number of serious adverse
effects that would prohibit their routine use for the
management of OLP, and include elevated ⁄ deranged
transaminase levels, hyperlipidaemia, cheilitis, dryness
and desquamation of the skin, alopecia, and dystrophic
nail formation, as well as being teratogenic and
therefore their use in women of child-bearing age is
contraindicated.
Topical calcineurin inhibitors
Cyclosporine is one of the oldest of such agents, but it
is relatively expensive and unpleasant tasting, with
studies showing an improvement in the oral symptoms
that is not significantly better than 1% triamcinolone
paste.20
Tacrolimus and pimecrolimus
Tacrolimus and pimecrolimus are newer calcineurin
inhibitors,21 with an improved safety profile in com-
parison with cyclosporine but there are only limited
*Azoles (topical or systemic) are contraindicated in patients taking
Warfarin.
27
M Schifter et al.
studies as to their benefits. They are expensive and the
United States Food and Drug Administration (FDA) has
a ‘‘black box’’ warning attached to the use of these
agents because of a theoretical increased risk of
malignancy (squamous cell carcinoma and lymphoma)
in patients using topical tacrolimus ⁄ pimecrolimus for
cutaneous psoriasis. Therefore, the use of these agents
should be restricted and patients should be made aware
of these concerns.22
Phototherapy
There is a single study of the benefits of phototherapy
using psoralen ultraviolet A light (PUVA) and which
was included in a recent Cochrane review. However,
UV light has a known oncogenic potential and there-
fore, its use for OLP is questionable.23
Other and ⁄ or ‘‘steroid-sparing’’ systemic medications
These agents are indicated in patients with refractory
LP, confined to the oral cavity, or also involving extra-
oral sites, requiring systemic corticosteroids for control.
There is limited evidence supportive of a few potentially
useful agents and the use of such agents is best restricted
to clinicians highly familiar with these drugs and,
importantly, their adverse effects: (1) lysosomotropic
amines (the antimalarials chloroquine and hydroxy-
chloroquine): hydroxychloroquine, at doses of 200 to
400 mg daily, have been effective for OLP;24 (2)
azathioprine is a successful ‘‘steroid-sparing’’ agent
for cutaneous lichen planus, but there is limited
published evidence suggesting it may have a similar
role in recalcitrant OLP at doses ranging from 1–2 mg
per kilogram (patients’ bodyweight) daily; (3) other
systemic agents: a variety of other immune-suppressant
or immune-modifying agents have been trialled in OLP,
including Dapsone (diamino-diphenyl sulfone – an
antituberculotic ⁄ antileprotic medication), systemic cal-
cineurin-inhibitors, such as cyclosporine and more
recently the chemotherapeutic agent and the folinic
acid inhibitor, methotrexate. Evidence for the use of
such agents is poor, limited to case series or case
reviews, and these agents all have significant, poten-
tially highly adverse side effects that would demand
great caution in their use for OLP.
PROGNOSIS AND OUTCOME
Protracted involvement is typical for OLP, averaging on
eight years, and ranging up to 20 or more years. In
many cases, OLP inexplicably ‘‘burns out’’ allowing for
the cessation of any therapeutic interventions. How-
ever, some patients may suffer from the cycle of chronic
inflammation followed by healing with scarring, with
resultant microstomia, if the bucco-labial mucosa is
involved, or loss of buccal sulcal depth, making the
28
provision of oral hygiene by the use of a toothbrush
difficult for the patient. In such cases, elective removal
of the more posteriorly placed teeth, especially unop-
posed, non-functional molar teeth may merit consider-
ation. Plastic surgery interventions to relieve the
microstomia are sometimes indicated but are painful
and can be of limited benefit.
Malignant transformation
The potential for OLP to undergo malignant transfor-
mation is controversial. If there is a risk, the risk is very
difficult to quantify and possibly so low that it is very
difficult to determine if OLP is truly associated with a
significant risk for malignant transformation. Prudence
dictates treating OLP as a potentially malignant lesion.1
If this approach is favoured, then ongoing, and at the
least, annual monitoring, of the oral mucosa by a
clinician experienced in the management of OLP is
indicated. Any lesion suspected to harbour dysplasia
and ⁄ or frank malignancy (oral squamous cell carci-
noma) merits biopsy, and histopathological assessment,
preferably by a pathologist experienced in oral patho-
logy. Clinical suspicion should be aroused in the case
of a lesion (or lesions) not typical for OLP, a lesion that
is heterogeneous in texture and colour (a mixture of
erythema and keratosis), or any isolated area of mucosa
that remains unresponsive to therapeutic interventions,
such as persistent ulceration despite clinical improve-
ment in the remainder of the mucosa affected by the
OLP. Before undertaking a biopsy, consideration
should be given to a trial of topical (and if indicated
systemic) corticosteroids and anti-fungal treatments to
lessen any associated inflammatory or infectious
changes that, on histopathological assessment, may
mask the degree of dysplasia or malignancy within the
lesion.
Dentists have a crucial role in the diagnosis of OLP, a
common immune-mediated disorder and its manage-
ment, especially initiating supporting measures, of what
can be a chronic and very troubling condition for the
patient. Management entails patient education as to its
immune-mediated inflammatory nature, the chronicity
of the condition and the value and limitations of any
therapeutic intervention. The mainstay of treatment is
topical corticosteroid therapy that relies on patient
compliance, that is regular and, when required, used
frequently, to be effective. Systemic corticosteroid
treatment has a role, as does select systemic alternate
or ‘‘steroid-sparing’’ agents but these are best used by
specialist clinicians familiar with their proper use and
the adverse side effects of such agents. All clinicians
involved in the delivery of dental ⁄ oral health care to a
patient with OLP need to provide monitoring of the
oral mucosa for any changes that may herald malignant
transformation.
ª 2010 Australian Dental Association
 Inflammatory dermatoses

Table 2. Clinical spectrum of erythema multiforme (adapted from Ayangco L, Rogers RS25 and Al-Johani KA,
Fedele S, Porter SR26)
Type Course Trigger Cutaneous involvement Mucosal involvement Duration Prognosis ⁄ outcome

EM minor acute, self-limiting, infections >10% BSA typical
rarely recurrent symmetrical target
lesions* and ⁄ or acrally
distributed atypical
raised target lesions
EM major acute, self-limiting infections >10% BSA typical
can be recurrent symmetrical target
lesions* and ⁄ or acrally
distributed atypical
raised target lesions
SJS acute, progressive drugs >10% BSA widespread
systemic disease small blisters, purple
macules or flat atypical
target lesions
predominantly found
on the torso*
TEN prodromal mucosal drugs >30% BSA widespread
involvement small blisters, purple
followed by acute macules or flat atypical
deterioration and target lesions
widespread skin predominantly found
lesions on the torso*
absent, or limited to 1–3 weeks remits, full recovery
one mucosal site
usually oral; oral
lesions: mild-severe
erosions ⁄ ulcers
involvement of at least 1–6 weeks generally remits
2 mucosal sites; oral
mucosal involvement
usual and the most
prominent feature of
the disease
involvement of at least 2–6 weeks 10% mortality
2 mucosal sites; usually
extensive and heals
with scarring
involvement of at least 2–6 weeks 30% mortality
2 mucosal sites; usually
severe and extensive;
heals with scarring

Abbreviations: EM = erythema multiforme; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; BSA = body surface area.
Description* of skin lesions: Typical target lesions: targets: individual lesions less than 3-cm diameter with a regular round shape, well-defined
border, and at least 3 different zones, i.e., 2 concentric rings around a central disk, with one ring palpably oedematous and paler than the central
disk. Atypical target lesions: round, oedematous, palpable lesions, similar to ‘‘typical’’ target lesions but with only 2 zones and ⁄ or a poorly defined
border. Flat atypical target lesions: as for ‘‘atypical’’ target lesions, but non-oedematous, with central blister.

cyte cells, probably mediated by epithelial surface

ERYTHEMA MULTIFORME
Erythema multiforme (EM) is part of a spectrum of
complex, immune-mediated, reactive, muco-cutaneous
disorders that often presents with oral, especially, labial
mucosal erythema, blistering and ulceration.25,26 This
spectrum encompasses a range of four clinical conditions
(Table 2) that overlap in regards to their clinical features
and suspected aetiology and pathogenesis: (1) EM minor
with predominantly cutaneous involvement with the
appearance of the classic ‘‘target lesions’’ and infre-
quently, only mild oral mucosal involvement; (2) EM
major with cutaneous and mucosal involvement of at
least one other site, apart from the oral mucosa (Figs 2a
and 2b). Both of these conditions are relatively benign,
self-limiting diseases thought to be more strongly
associated with an infectious trigger; (3) Stevens Johnson
syndrome (SJS) is a more severe, fulminating condition
with involvement of up to 10% of a patients’ body
surface area; and (4) toxic epidermal necrolysis (TEN) is
characterized by epidermal denudement in excess of
30% of the body’s surface area. These latter two
conditions are more likely to be triggered by a drug
(50 and 95%, respectively) (Table 2).25,26
The aetiology and pathogenesis of EM remain
obscure. Regardless of what serves as the ‘‘trigger’’,
the process culminates in cytotoxic CD8+ T-cell
induced apoptosis and necrosis of the basal keratino-
ª 2010 Australian Dental Association
antigens common to, or shared with the triggering
infectious agent or drug. Cytokines, mostly tumour
necrosis factor alpha (TNF-a), are found in the lesional
tissue although in herpes simplex virus associated EM,
gamma-interferon (c-IFN) predominates and mediates
the epidermal damage.27
Histologically, early classic EM with cutaneous target
lesions have a prominent dermal inflammatory reaction
with oedema, vasodilation and a lymphohistiocytic
infiltrate around the blood vessels. With more severe
disease, dramatic necrosis of the whole dermis may be
seen, with subdermal blister formation with character-
istic hydropic degeneration and necrosis of the individ-
ual basal keratinocyte cells. Histologically, the mucosal
lesions demonstrate similar, non-specific, inflammatory
changes but with marked epithelial necrosis. The direct
immuno-fluorescence findings are also non-specific but
can be useful in differentiating EM from other condi-
tions such as pemphigoid and pemphigus.26
Epidemiology
There are only limited reliable data. Hospital admis-
sions for EM and its associated conditions have been
reported as low as 4.2 per million patients per annum.28
Stevens Johnson syndrome is uncommon, possibly
affecting 1–6 per million people per year with the
29
M Schifter et al.
(a)
(b)
Fig 2. (a) Typical haemorrhagic crusting of the lips seen with
erythema multiforme. (b) Typical cutaneous ‘target lesions’ of
erythema multiforme.
reported incidence of TEN in Western Australia being
0.4 cases per million head of population.28,29
Overall, the peak age of occurrence for EM and
related disorders, apart from TEN, is in the teenage
years through to the early 20s and predominantly in
young males. The mean peak age of onset for TEN is
reported to be 63 years with a predominantly female to
male ratio of 3:2.29,30
MANAGEMENT
Diagnosis
EM and its variants are diagnosed principally by their
abrupt clinical presentation and features, with special
30
investigations such as biopsy for histopathology and
direct immunofluorescence useful in excluding condi-
tions such as pemphigoid, pemphigus, and bullous
lichen planus that may present with similar clinical
characteristics. In EM major, the oral mucosa is the
most commonly involved mucosal site, but any mucosa
can be involved, including the epithelial lining of the
trachea, bronchi, and gastrointestinal tract, as well as
the genitalia. Erythematous macules precede vesiculo-
bullous formation of the mucosa that rupture, leaving
irregular superficial painful ulcers, with a marked
erythematous halo, or develop into broad areas of
white, desquamating, necrotic mucosa. The lip lesions
are characteristically, markedly haemorrhagic.25,26
SJS is a more severe disease, characterized by
significant oral mucosal involvement, plus conjunctival
and ⁄ or genital mucosal involvement, and more exten-
sive skin involvement that generally follows several
days later. The muco-cutaneous lesions last up to six
weeks and reflecting the more significant disease
process can heal with scarring, so resulting in laryngeal,
conjunctival and vaginal strictures.25,26
TEN presents with the oral lesions typical for EM
major, but the skin involvement is extensive, with
consequently up to 30% of the body surface denuded,
and resembling second degree burns. Indeed, optimal
care for patients with TEN is in a specialized burns
unit, with attention to the critical issues of fluid loss,
electrolyte disturbance and secondary infection.30
Special investigations
There are no tests that are pathognomonic for EM and
its variants. Biopsy for histopathology and direct
immune-fluorescence are only useful in excluding con-
ditions that can present similarly. Laboratory investi-
gations are directed in determining any recent infection
that may have triggered the EM. Human Herpes Viruses
1 and 2 (HSV-1 and 2) are a very common trigger,
preceding the presentation of EM major by up to
14 days, reportedly in some 70% of cases. The other
commonly reported infectious trigger is Mycoplasma
pneumoniae infection. For SJS and TEN, drugs, partic-
ularly anti-convulsants such as carbamazepine (Tegre-
tol), phenytoin (Dilantin), phenobarbitol and sodium
valproate are frequently implicated.26
Treatment
There are no systematic reviews detailing the best
treatment for EM major, or its more severe variants.
The key aspects of care are firstly, identification and, if
practical, treatment of the infectious trigger, or identi-
fication (from the history) and withdrawal of the
suspected causative drug. Secondly, the use of im-
mune-modulating therapy of which historically the
ª 2010 Australian Dental Association
 Inflammatory dermatoses

mainstay has been systemic corticosteroid therapy.
However, the use of systemic corticosteroids is mired
in controversy, with some authors claiming a higher
rate of adverse outcomes for patients placed on
systemic corticosteroids, particularly in SJS and TEN.30
The extent of the supportive measures are scaled to
the severity and extent of the muco-cutaneous involve-
ment and include in general, effective pain control,
often necessitating opiates, limiting alimentation, and
considering enteral feeding, intensive nursing, especially
skin care, antibiotics, wound management, including
debridement, and attention to maintenance of patient
fluid and electrolyte balance.
PROGNOSIS AND OUTCOME
For EM major the muco-cutaneous lesions remit by six
weeks, usually healing with little if any scarring. For SJS
and TEN, healing only starts to occur some two, even
six weeks after onset, with a substantial risk of scarring.
Mortality is reported to be as high as 70% for patients
with TEN, predominantly from infection.30 Recurrent
forms of EM major, SJS and TEN have been reported.
Dental practitioners have a critical role in the
diagnosis of EM major and its more severe, potentially
life-threatening variants, SJS and TEN, as well as
having a role in supportive care, especially pain control
and ensuring proper alimentation.
MUCOUS MEMBRANE PEMPHIGOID
Pemphigoid is the general term applied to several
chronic conditions that are classified as immune-
Table 3. Pemphigoid subtypes as determined by clinical features and antigen binding sites (adopted from Bagan J31)
Clinical
Clinical subtype presentation ⁄ sites
mediated sub-epithelial blistering diseases characterized
by vesicles or bullae that break down to leave ragged
ulcers that affect epithelial surfaces, particularly the
mouth. Historically, pemphigoid was broadly subdi-
vided into only two main conditions: (1) ‘‘bullous
pemphigoid’’ that predominantly affects the skin, and
rarely, mucosa; and (2) ‘‘benign mucous membrane
pemphigoid’’ also known as cicatricial pemphigoid, but
now more simply as ‘‘mucous membrane pemphigoid’’
(MMP), that conversely, overwhelmingly affects mu-
cosa and infrequently the skin.31,32
Mucous membrane pemphigoid is an antibody med-
iated autoimmune disease. To understand MMP, it
needs to be appreciated that auto-antigenic antibodies,
predominantly, IgG (although IgA variants are known)
are directed against various antigenic sites found on the
complex array of proteins that make up the structure of
the hemidesmosome. The hemidesmosome is the sub-
microscopic structure, seen best under electron micros-
copy that anchors the basal epithelial cells to the
basement membrane. Immunologically, MMP is char-
acterized by the deposits of predominantly IgG anti-
body (97%) with complement factor C3 and to a lesser
extent with IgA (27%) or IgM (12%) antibodies
directed at a variety of differing antigens (that make
up the varying subtypes of MMP) within the basement
membrane zone.32 It is now apparent that at least six
subsets of MMP exist, on the basis of different patterns
of immunopathology and antigenic specificity (targets)
of the autoantibodies (Table 3).32 The result of this
antibody-complement complex is seen histologically,
with separation at the junctional epithelial basement
membrane zone, giving rise to a sub-basilar split. This is
Direct immuno- Indirect immuno-
fluorescence (DIF) fluorescence (IIF)
findings findings Main target antigens

Cicatricial pemphigoid (CP) oral mucosa, other IgG and C3 frequent 230 kDa (BP1 Ag)
mucosal sites, skin deposition at BM 180 kDa (BP2 Ag)
b4 Integrin sub-unit
Laminin5
Oral mucous membrane oral (only) IgG and C3 rare 230 kDa (BP1 Ag)
pemphigoid (OMMP) deposition at BM 180 kDa (BP2 Ag)
Laminin 5 and 6
a6 Integrin sub-unit
168 kDa
Ocular cicatricial ocular (only) IgG and C3 rare Laminin 5
pemphigoid (OCP) deposition at BM 205 kDa
Anti-laminin 5 pemphigoid oral mucosa, other mucosal IgG and C3 rare Laminin 5
sites, rarely skin deposition at BM
Anti-p200 pemphigoid ? ? ? 200 kDa protein of
the dermo-epidermal
junction (distinct
from other antigen
sites)
Not yet specified ? ? ? antibodies against more
than one antigen

Abbreviations: BM = basement membrane; BP = bullous pemphigoid; C3 = complement component; kDa = kiloDalton.

ª 2010 Australian Dental Association 31
M Schifter et al.
seen clinically as a blister underlying the full thickness
of the epithelium, and which can last hours to days if
left undisturbed, before breaking down to leave a
painful ulcer.
Occasional drug-induced MMP has been reported,
associated with penicillamine (D-Penamine), a heavy-
metal chelator used in rheumatoid arthritis and the loop
diuretic agent, frusemide (Lasix, Urex).32
Epidemiology
The epidemiology of MMP is unclear. Retrospective
immune-fluorescent studies suggest that MMP has an
annual incidence of 1.5–9.6 · 105 population (esti-
mated to be up to three times more frequent than
pemphigus).32
MMP is predominantly a disease of women, with a
mean age at onset of 51–62 years.32 Children are rarely
affected.
MANAGEMENT
Diagnosis
The clinical phenotype known as MMP is not a single
entity. It includes patients with oral lesions only, and
others with involvement of the skin and ⁄ or other mucous
membranes, or occasionally other systems. The most
common areas of involvement are the oral cavity (85%)
and conjunctivae (64%).32 The oral mucosa is often the
initial site of MMP lesions. The term ‘‘oral mucous
membrane pemphigoid’’ (OMMP) is often used when
MMP is limited to the oral cavity with no other mucosal
involvement and ‘‘ocular cicatricial pemphigoid’’ (OCP)
is used when MMP is limited to the conjunctivae.
Oral mucosal lesions
Patients present with bleeding, pain, dysphagia or
desquamation of the oral mucosa. Vesicles or bullae
may occur anywhere on the oral mucosa, and there may
Fig 3. ‘‘Desquamative gingivitis’’, a clinical presentation (not a
condition) seen with oral lichen planus, and on occasion, mucous
membrane pemphigoid.
32
be a positive ‘‘Nikolsky sign’’, where firm sliding
pressure with a finger separates normal-appearing
epithelium from the underlying lamina propria, result-
ing in the immediate formation of a vesicle or erosion.
The blisters rupture leading to pseudo-membrane
covered, irregularly shaped ulcers with a yellowish
slough and surrounded by an erythematous, inflamma-
tory halo. The gingiva is the commonest site involved
(Fig 3), followed by the hard and soft palate, buccal
mucosa, and tongue. The oral lesions rarely scar.31,32
Ocular lesions
Ocular manifestations have been reported to occur in 3
to 48% of patients with oral lesions.33 Ocular involve-
ment usually begins as chronic conjunctivitis with
symptoms of burning, irritation, photophobia and
excess tearing. Vesicles are rarely seen in the conjunc-
tiva and ulceration is seen only in advanced aggressive
disease. Scarring following repeated fibrosis can lead to
symblepharon (partial or complete adhesion of the
palpebral conjunctiva of the eyelid to the bulbar
conjunctiva of the eyeball), ankyloblepharon (fusion
of the sclera and palpebral conjunctivae), and great
discomfort from entropion (the eyelids fold inward to
rub the corneal surface) and trichiasis (malpositioned
eyelashes touching the cornea or conjunctiva). The
combination of entropion and trichiasis may lead to
blindness.32
Other sites
Cutaneous involvement is uncommon (up to 25% of
patients) and is limited to the face, neck, scalp, axilla,
trunk and extremities. Some patients may develop
lesions affecting the larynx, oesophagus, nasal and
genital mucosa.32–34
Clinically, there are a number of differential diagno-
ses to consider and include pemphigus, oral lichen
planus, erythema multiforme (and its variants), angina
bullosa haemorrhagica, dermatitis herpetiformis or
linear IgA disease, and ⁄ or epidermolysis bullosa acqui-
sita (EBA).31,32,34
Special investigations
Biopsy (histopathological and DIF investigations)
Definitive diagnosis is based on biopsy of perilesional
tissue with histological and direct immuno-fluores-
cence (DIF) examination.31,32,34 Histologically, MMP
is characterized by junctional separation at the level
of the basement membrane giving rise to a sub-basilar
split as in other forms of pemphigoid. The findings
from the DIF microscopy are the most useful. The
DIF shows deposits of IgG and C3 in a homogeneous
ª 2010 Australian Dental Association

linear manner in the basement membrane zone
(BMZ) along the epithelial-connective tissue junc-
tion.31,32
Laboratory investigations
As for OLP, these are generally not required, except
for patients with severe MMP, warranting high-dose
systemic corticosteroids with the need to exclude
underlying infectious diseases that can be reactivated.
A similar approach is required and if considering
suitable ‘‘steroid-sparing’’ systemic agents such as
azathioprine or, for MMP in particular, cyclophosph-
amide, is warranted for long-term management.
Indirect immunofluorescence
Indirect immunofluoresence findings using the sub-
basement membrane antigen titre can be inconsistent,
and so usually, unhelpful. However, IIF done on salt-
split epithelial substrates (ss-IIF) can be useful in
distinguishing MMP from EBA. Salt-split substrates
use epithelium, in which the lamina lucida of the
basement membrane has been split at the middle, leaving
exposed the target antigens for MMP and ⁄ or EBA. In
MMP the circulating antibodies bind to the roof, base, or
both, of the salt-split epithelial substrate, consistent with
the heterogeneous nature of the target antigens seen in
MMP. In contrast, in EBA the circulating antibodies only
bind to the base and so ss-IIF can be useful in
differentiating MMP from EBA.31,32
Treatment
The treatment for MMP, especially oral MMP is
consistent with that already outlined for the treatment
of OLP. The exception is that the tetracycline antibi-
otics and derivatives, such as minocycline (at doses of
50 mg ⁄ day), and the nitrogen mustard analogue and
alkylating agent, cyclophosphamide (at 2 mg per kilo-
gram bodyweight per day), are more useful as possible
steroid-sparing agents, for intractable disease.35,36
Prognosis
Remission can be induced with treatment although
relapse, especially of the ocular form, is common, so
patients will need ongoing monitoring and education
about the need to return if ⁄ when they have recurrence
of their disease. MMP has no known predilection to
undergo malignant change, as is the concern with OLP.
PEMPHIGUS VULGARIS
The word ‘‘pemphigus’’ is derivative from the Greek
term ‘‘pemphix’’ meaning bubble or blister. Pemphigus
ª 2010 Australian Dental Association
Inflammatory dermatoses
is a group of autoimmune diseases (Table 4) character-
ized by intra-epithelial blistering, resulting in superficial
vesicles or bullae that easily rupture, resulting in
ulceration of mucosal and ⁄ or cutaneous sites. Pemphi-
gus vulgaris (PV) is the most common and clinically the
most aggressive variant, being associated with signifi-
cant morbidity and mortality, composing 70% of all
reported cases.37 Pemphigus vulgaris commonly and
initially affects the oral mucosa and then the skin.
Other mucosal sites may also be involved, including the
mucosa of the conjunctivae, nose, oesophagus, pharynx
and larynx, and genitalia.37
Epidemiology
Pemphigus vulgaris affects 0.1–0.5 patients per 105
population per year.37 It is more prevalent in certain
ethnic groups, in particular Ashkenazi Jews and people
of Mediterranean and South Asian background. This is
reflected in the association with certain HLA subtypes:
HLA-DR4 (DRB1*0402) especially seen in Ashkenazi
Jews, and DRx14 (DRB1*1041) and DQB1*0503 in
patients of European and Asian backgrounds, respec-
tively.38
The male to female ratio is approximately equal. The
mean age of onset is between 50 to 60 years of age,
although the condition has been described in children
and elderly patients.37
Pemphigus vulgaris is an autoantibody-mediated
condition, similar to pemphigoid, but the antibody-
complement complexes are directed at the inter-
epithelial attachment of the epithelial cells and not
the attachment of the basal epithelial cells to the
basement membrane that characterizes MMP. Specific
to PV, the IgG serum autoantibodies are directed
against a cadherin-type cell adhesion molecule in the
stratified squamous epithelium that binds keratino-
cytes to one another. The main adhesion molecule
antigen target seen in PV is desmoglein 3 (Dsg3).
However, 50% of patients also have autoantibodies to
Dsg1.39 Oral epithelium expresses high concentrations
of Dsg3 whereas skin expresses both Dsg3 and Dsg1.
As a result, oral lesions develop at an early stage.
However, once Dsg1 antibodies are evident, the
disease progresses to involve skin and other mucosal
sites.39 The proportion of Dsg1 and Dsg3 antibodies
appears to be related to the clinical severity of PV;
those with only Dsg3 antibodies have oral lesions
predominantly.39
This antigen-antibody interaction activates the com-
plement cascade by the release of inflammatory medi-
ators and recruitment of activated T cells. Damage to
the intercellular area between keratinocytes leads to
apoptosis, resulting in loss of cell-to-cell adhesion
(acantholysis) and subsequent intra-epithelial blister-
ing.37
33
M Schifter et al.

Table 4. Clinical and immunohistochemical variants of pemphigus

Clinical presentation
Disease and subtype(s) Natural history ⁄
(alternate terms) Oral Cutaneous prognosis ⁄ outcome Target antigens

Pemphigus vulgaris Common. Commonest and most aggressive form of pemphigus: Fatal if untreated Desmoglein 3
(PV) Usually the first oral mucosal involvement common and often first site Good with (Dsg 3 is more
site involved of presentation leading to extensive skin involvement. treatment common in oral
Pemphigus vegetans Rare (in all 3 Uncommon and less aggressive clinical variant of PV: Often progresses epithelium)
forms of presents with large verrucous confluent plaques and to pemphigus (& Desmoglein 1
pemphigus pustules localized to flexural areas (axilla ⁄ groin). vulgaris (Dsg-1 & 3 are
Pemphigus vegetans vegetans) Often begins and ends as typical PV. Needs more Frequent relapses both found in
of Neumann intense immune-suppression than seen with PV, with (even with skin))
patients troubled by chronic relapses (and remissions). treatment)
Pemphigus vegetans Relatively benign, usually very well localized disease. Prolonged
of Hallopeau remission (with
treatment)
Pemphigus foliaceus Rare All forms of PF are characterized clinically by superficial More benign Desmoglein 1
(PF) cutaneous blisters and erosions seen on histology as course than PV,
subcorneal acantholysis. with prolonged
Pemphigus Very rare condition with the combined features of remission.
erythematosus pemphigus foliaceus and SLE.
(‘‘Senear-Usher
syndrome’’)
Endemic pemphigus PF and FS are identical clinically, histologically, and
(‘‘Brazillian serologically but differ significantly, epidemiologically,
pemphigus’’ or with marked geographic clustering in Brazil, being a
‘‘Fogo Selvagem’’ diseases of people resident in ⁄ or near the rainforests.
(FS)) The autoimmune response in FS is thought to be
triggered by a putative environmental factor.
IgA pemphigus Rare (all 3 forms Rare, characterized by pruritic, flaccid vesicles and ⁄ or Recalcitrant to Desmoglein 3 (&
of IgA pustules in annular pattern with central crusting, treatment with Desmoglein 1)
pemphigus) sometimes hypopyon* of the eye. Pathogenesis: related corticosteroids
to the neutrophilic infiltrate in the epidermis rather
than solely to the binding of IgA to target epidermal
antigens. DIF: IgA (cf IgG seen in all other forms of
pemphigus) deposits in lower epithelium or entire
epidermal cell surfaces.
Subcorneal pustular Subcorneal (beneath the stratum corneum) blister
dermatosis containing neutrophils with epidermal acanthosis and
(‘‘Sneddon- spongiosis, results in superficial fragile blistering.
Wilkinson
disease’’)
Intraepidermal Deeper, intra-epidermal blister containing neutrophils
neutrophilic with epidermal acanthosis and spongiosis, results in
IgA dermatosis more marked blistering and consequent ulceration.
Paraneoplastic Common & very Polymorphous skin eruption, consisting of blisters, Fatal Desmoglein 3,
pemphigus severe erosions, and targetoid lesions; severe mucous Desmoplakin 1,
membrane involvement. Desmoplakin 2,
DIF: IgG deposits on entire epidermal cell surfaces + ⁄ ) BP 230,
granular-linear complement auto-antibodies to rat evoplakin,
bladder epithelium in 75% of cases. periplakin,
others
Familial benign Rare Not a true form of pemphigus, as it is not antibody chronic, Desmocollin 1
chronic pemphigus mediated. AD pattern of inheritance relapsing–
(‘‘Hailey-Hailey It presents a chronic recurrent bullous and vesicular remitting course
disease’’) dermatitis of intertriginous areas that is characterized
histologically by suprabasilar acantholysis.
Pathogenesis: heterozygous mutations of the ATP2C1
gene leads to a malfunction of the encoded protein
hPMR1 - hPMR1 being a high-affinity calcium
transport ATPase pump of the Golgi complex. A low
level of intracellular Ca2+ induces premature
keratinocyte proliferation, which leads to
dysfunctional desmosomal proteins and thus abnormal
keratinocyte adhesion.

Abbreviations: PV = pemphigus vulgaris; PF = pemphigus foliaceous; SLE = systemic lupus erythematosus; FS = Fogo Selvagem; DIF = direct
immuno-fluorescence; cf = in contrast; BP = bullous pemphigoid; AD = autosomal dominant; Ca2+ = calcium ion.
*hypopyon = sterile leukocytic exudate; seen in the anterior chamber of the eye.
34 ª 2010 Australian Dental Association

Some drugs have been reported to induce PV,
including the anti-mycobacterial antibiotic, rifampicin.
More recently, associations have been reported with
penicillamine as well as the anti-hypertensive ACE
(angiotensin-converting enzyme) inhibitor, captopril,
and other thiol-containing compounds.37
Paraneoplastic pemphigus is the rarest, but most
serious form of pemphigus, that presents with features
typical for PV. Paraneoplastic pemphigus is again an
immune-mediated disorder, initiated by an underlying
lympho-reticular or haematological malignancy. It is
hypothesized that antibodies principally evoked and
directed against the malignant cells, inadvertently
target antigens that share characteristics with the
tumour cells, but are found instead in the mucosa and
skin. Paraneoplastic pemphigus has a poor prognosis
with a mortality rate, regardless of treatment,
approaching 90%.40
MANAGEMENT
Diagnosis
Pemphigus vulgaris presents with oral lesions in 50–
70% of cases. Oral mucosal lesions may be the first and
only sign of disease, and often precede cutaneous
involvement by an average of five months.
Oral mucosal lesions may present initially as intact
vesicles or bullae that readily rupture, forming painful
ill-defined, irregularly shaped erosions and ulcers
(Fig 4)41 that may affect any part of the oral mucosa,
although gingival, buccal or palatal lesions are most
common. These lesions are painful and slow to heal,
but do not scar. Advanced manifestations usually
comprise severe desquamative or erosive gingivitis,
Fig 4. Pemphigus vulgaris – typical oral presentation with shallow
ulceration of the soft palate.
ª 2010 Australian Dental Association
Inflammatory dermatoses
where bullae have ruptured to leave areas of peeling
tissue with red erosions and ulcers.
All oral mucosal sites may be involved, and lesions
may spread to involve the oropharynx and larynx.
Other mucosal surfaces, including the conjunctiva,
oesophagus, and genitalia may also become involved.
Many patients develop cutaneous lesions, often
presenting as a flaccid blister containing clear fluid,
which arises on normal-appearing skin. Due to their
fragile nature, being intra-epithelial (in contrast to the
sub-epithelial nature of the blisters seen in pemphigoid),
intact blisters are uncommon in PV, rupturing quickly
to produce painful erosions.
Patients can be Nikolsky sign positive on examina-
tion of the mucosa and the skin.
Special investigations
Clinical suspicion that a patient has one of the vesiculo-
bullous diseases warrants biopsy of perilesional tissue,
with histological and DIF examination being essential
in establishing the diagnosis.
Biopsy, histopathological and direct immuno-
fluorescence investigations
Histopathology demonstrates intra-epithelial vesicle
formation. The earliest changes consist of intercellular
oedema with loss of intercellular attachments in the
basal layer. Suprabasal keratinocytes separate from the
basal cells to form clefts and blisters. Basal cells are
separated from one another and stand like a ‘‘row of
tombstones’’ on the floor of the blister, but they remain
attached to the basement membrane. Acantholytic
(Tzanck) cells may be seen within the vesicle.37
Direct immuno-fluorescence performed on fresh
tissue demonstrates IgG deposited on the surface of
the keratinocytes forming a ‘‘basket weave’’ appear-
ance. IgM and complement components such as C3
may also be present.
Laboratory investigations
These are required in the patient in whom PV is
suspected. Indirect immuno-fluorescence is essential in
detecting the circulating IgG autoantibodies that bind
to epithelium. These are present in 80–90% of patients
with PV. Antibody titres may also help guide prognos-
tication and therapy. The preferred substrate for IIF is
monkey oesophagus or salt-split normal human skin
substrate.42 In paraneoplastic pemphigus, the circulat-
ing antibodies not only bind to squamous epithelial cell
surfaces (skin and oesophagus substrates) but also
attach to transitional epithelium, such as rat bladder,
and this is useful in differentiating PV from paraneo-
plastic pemphigus.40
35
M Schifter et al.
In addition, as high-dose systemic corticosteroids
serve as the mainstay of initial therapy for PV, there is
the need to exclude underlying infectious diseases that
can be reactivated by the corticosteroids (HIV, Hepa-
titis B and C, and tuberculosis). In addition, screening
for the diseases initiated or exacerbated by high-dose
steroids, such as hypertension, diabetes mellitus and
osteoporosis is also required.
For long-term management, almost inevitably, pa-
tients with PV will need to be changed to a suitable
steroid-sparing systemic agent, namely azathioprine,
mycophenolate and ⁄ or rituximab (Mabthera).43
PROGNOSIS ⁄ OUTCOME
The severity and natural history of PV is variable, but
before the advent of corticosteroids, most patients died.
Treatment with systemic steroids has reduced the
mortality rate to 5–15%.37
Most deaths occur during the first few years of
disease, and if the patient survives five years, the
prognosis is good. Early disease is probably easier to
control than widespread disease, and mortality may be
higher if therapy is delayed. Morbidity and mortality
are related to the extent of disease, the maximum dose
of systemic corticosteroids required to induce remis-
sion, and the presence of other diseases. Prognosis is
less favourable in patients with extensive disease and in
older patients. Complications secondary to the use of
high-dose corticosteroids contribute to the mortality
rate, therefore steroid-sparing agents should be intro-
duced as quickly as practical once clinical remission is
achieved. Both azathioprine and mycophenolate, purine
inhibiting cytostatic agents, with particular activity
against T and B lymphocytes have been shown to be
successful as steroid-sparing agents for PV. Both have a
delayed onset of action, of up to 3–4 months, so that
slow tapering of the corticosteroids is required, corre-
lated to the clinical signs of disease, in conjunction with
the introduction of these steroid-sparing agents.
Rituximab (Mabthera) is a genetically engineered
chimeric murine ⁄ human monoclonal antibody that
binds specifically to the antigen, CD20, a transmem-
brane molecule located on pre-B and mature B lym-
phocytes. This results in B-cell lysis by complement
dependent cytotoxicity (CDC) and antibody dependent
cellular cytotoxicity (ADCC), as well as possibly
inducing apoptosis, causing the elimination of all
circulating B-lymphocytes. As a result, they cannot
transform into active, antibody-producing plasma cells.
The net result is no autoantibody is produced that can
target the intra-epithelial, desmoglein proteins, so
inducing a remission of the PV.43
The incidence and duration of true remissions in
pemphigus is uncertain. The question remains if
treatment simply suppresses the manifestations of the
36
disease and therefore must be continuously adminis-
tered, or induces complete remissions, so allowing
therapy to be discontinued. However, a recent long-
term longitudinal study has been undertaken of
complete and long-lasting remissions (defined as
lesion-free with no systemic therapy for at least six
months) in 40 patients with PV treated conventionally
and followed up for an average of 7.7 years. Five
patients (5%) died of the disease but complete and
long-lasting remissions were induced in 25, 50 and
75% of patients at 2, 5 and 10 years, respectively,
after diagnosis.44 Most of the remaining patients were
in partial remission or had mild disease controlled with
only a small dose of corticosteroids. It is therefore
possible to eventually induce complete and durable
remissions in most patients, permitting systemic ther-
apy to be safely discontinued without a flare in disease
activity in approximately 75% of patients after
10 years.44
It is notable that early diagnosis and the introduction
of treatment, so that the PV remains confined to the
oral mucosa, appears to have a critical effect on
prognosis and outcome. This again emphasizes the
important role dentists have in screening and recogniz-
ing various oral mucosal diseases, such as PV.
EPIDERMOLYSIS BULLOSA ACQUISITA
Epidermolysis bullosa acquista (EBA) is a very rare
non-inheritable, mechano-bullous condition character-
ized by the development of autoantibodies that target
the Type VII collagen found in the basement mem-
brane.45 In contrast, epidermolysis bullosa (EB) is an
inherited form of the disease. Both diseases are
characterized by the problem that even the slightest
mechanical irritation, or trauma of the skin and ⁄ or the
mucosal surfaces of the oral cavity and upper aero-
digestive tract, results in the formation of blisters that
only heal with scarring and severe atrophy of the
affected tissues. In EB the defect is a genetically-
induced molecular derangement of the keratin fila-
ments, hemidesmosomes and anchoring filaments and
fibrils that attach the epidermis to the deeper dermis.
Clinically, EBA manifests very similarly to the inher-
ited, but more severe and devastating, EB, but has later
onset, usually in early adulthood, and so can be
confused clinically with other blistering conditions,
especially pemphigoid and its variants. The diagnosis
rests on the history, biopsy with DIF to exclude
pemphigoid and other blistering diseases, and IIF
undertaken on salt-split epithelial substrates (that
show typical antigen binding to the base of the
epithelial cells).45 Treatment is usually successful with
high-dose corticosteroids often required in combina-
tion with other immunosuppressant agents and ⁄ or
dapsone.45 The oral complications, especially those
ª 2010 Australian Dental Association

resulting in microstomia can be most severe and
warrant the minimization of any dental treatment, or
the use, immediately prior to any dental treatment, of
a bolus of high-dose corticosteroids.
SUMMARY
Dentists need to be very familiar with the range and
number of immune-mediated conditions that can
present with initial or even isolated oral manifestations
given their potential for morbidity, the poor quality of
life of affected patients, and their potential mortality.
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Address for correspondence:
Clinical Associate Professor Mark Schifter
Department of Oral Medicine, Oral Pathology and
Special Needs Dentistry
Westmead Centre for Oral Health
Westmead Hospital
PO Box 533
Wentworthville NSW 2145
Email: mark_schifter@wsahs.nsw.gov.au
ª 2010 Australian Dental Association