Mucocutaneous Diseases

Michal Kuten-Shorrer, DMD, DMSca, Reshma S. Menon, BDS, DMSc

b,
*,
Mark A. Lerman, DMDc

KEYWORDS
 Lichen planus  Pemphigus vulgaris  Mucous membrane pemphigoid
 Oral mucocutaneous diseases  Dermatoses  Oral cavity

KEY POINTS
 Oral manifestations of mucocutaneous diseases may be the first, only, and/or most signif-
icant sign of disease.
 Although some clinical features are pathognomonic for a specific disease, others are
nonspecific. Diagnostic tests, including histopathology and immunofluorescence studies,
are crucial in achieving a definitive diagnosis.
 Because of the systemic nature of mucocutaneous diseases, a multidisciplinary approach
in management is necessary.

INTRODUCTION

The oral mucosa originates in large part from an invagination of the ectoderm and is
therefore comparable with the skin. Both structures are composed of highly special-
ized stratified squamous epithelium, mainly comprising keratinocytes adhering to one
another and to the underlying basement membrane and connective tissue. Mucocu-
taneous conditions are a group of disorders mostly confined to the epithelium, thereby
involving the skin and oral mucosa. Other mucosal sites, such as genital mucosa,
nasal mucosa, and conjunctiva, are also affected.
Oral mucosal manifestations vary and may be the initial feature, most prevalent and/
or symptomatic feature, or only sign of disease. Although mucocutaneous disorders
are mainly observed in the dermatology practice, a multidisciplinary approach is crit-
ical for effective care. Based on the clinical presentation, the dental practitioner may
be the first to identify oral lesions and hence plays an important role in the early diag-
nosis and management of disease.

Disclosure: The authors have nothing to disclose.

a
Division of Oral Medicine, Department of Diagnostic Sciences, Tufts University School of
Dental Medicine, 1 Kneeland Street, Boston, MA 02111, USA; b Department of Oral Medicine,
Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston,
MA 02115, USA; c Division of Oral Pathology, Department of Diagnostic Sciences, Tufts Uni-
versity School of Dental Medicine, 1 Kneeland Street, Boston, MA 02111, USA
* Corresponding author.
E-mail address: [email protected]

Dent Clin N Am - (2019) -–-

https://doi.org/10.1016/j.cden.2019.08.009 dental.theclinics.com
0011-8532/19/ª 2019 Elsevier Inc. All rights reserved.
2 Kuten-Shorrer et al

Mucocutaneous disorders can be broadly categorized based on cause into devel-

opmental (genodermatoses), infectious, inflammatory, immune-mediated or autoim-
mune, and neoplastic conditions. These diseases are autoimmune/immune
mediated or inflammatory, and are characterized by frequent and early involvement
of the oral mucosa. This article discusses the more common and clinically significant
mucocutaneous conditions and provides overview information on less common con-
ditions (Box 1).

LICHEN PLANUS
Epidemiology
Lichen planus (LP) is a chronic inflammatory disorder that most frequently involves the
skin and/or oral mucosa.1,2 Compared with cutaneous disease, oral LP (OLP) tends to
be more chronic, with a mean age at onset in the fifth to sixth decades and a slight
female predilection.1,3 Data on the prevalence of OLP are limited, with estimates
ranging between less than 1% and up to 3% of the population, making OLP the
most common mucocutaneous condition in the mouth.4

Pathobiology
OLP is considered a T cell–mediated reaction directed against epithelial basal cells,
but the target antigen, whether endogenous or exogenous, is unknown.5–10 Following
antigen recognition, both cluster of differentiation (CD) 41 T-helper cells and CD81
cytotoxic T cells are activated, with a predominance of CD81 cells within the epithe-
lium. The exact mechanism of the ensuing basal keratinocytes apoptosis remains un-
known; however, it is thought to be triggered by granzyme B release, tumor necrosis
factor alpha secretion, and Fas Ligand expression. Aside from these antigen-specific
processes, the development of OLP also is thought to involve mast cell degranulation
and matrix metalloproteinase activation, leading to basement membrane disruption
and migration of lymphocytes through the epithelium.
Several causal factors have been implicated in OLP, including (1) psychological
stress; (2) local and systemic inducers of cell-mediated hypersensitivity; and (3) infec-
tious agents. Acute exacerbations of OLP have been linked to psychological stress,
and anxiety and depression are reported to be more common in patients with OLP
compared with normal controls.11,12 Lichenoid mucositis is an umbrella term for

Box 1
Mucocutaneous diseases

Most common
Lichen planus
Pemphigus vulgaris
Mucous membrane pemphigoid
Less common
Erythema multiforme
Systemic lupus erythematosus
Epidermolysis bullosa
Psoriasis
Chronic ulcerative stomatitis.
 Mucocutaneous Diseases 3

lichenoid hypersensitivity reactions, presenting with clinical and histologic features

almost identical/very similar to OLP.10,13–16 Oral lichenoid contact lesions (OLCLs)
are typically triggered by dental restorative materials (mainly amalgam) or food
flavoring (usually cinnamic aldehyde). Oral lichenoid drug reactions (OLDRs) arise in
temporal association with exposure to certain medications, such as oral hypoglycemic
agents, diuretics, angiotensin-converting enzyme inhibitors, or nonsteroidal antiin-
flammatory drugs.15–17 Strong evidence suggests an association between hepatitis
C virus (HCV) infection and OLP in some geographic regions, such as southern Europe
and Japan.18–20 The mechanism underlying this association is not clear but may be
related to a pattern of immune dysregulation and could involve a cytotoxic immune
response to epithelial cells infected with HCV.21

Clinical Presentation
Classic cutaneous LP presents with violaceous papules, sometimes polygonal, and
often covered by a network of fine white lines (Wickham striae). Lesions appear mainly
on the flexural aspect of the wrists and ankles and in the lumbar region. They are char-
acteristically pruritic and self-limiting, remitting within 1 to 2 years in most cases.1,2,22
Although up to 60% of patients with cutaneous LP may show oral disease, only 15%
of patients with OLP develop cutaneous lesions.1 In these cases, lesions develop
within several months after the appearance of oral disease.23 OLP is characterized
by roughly symmetric and bilateral distribution, typically affecting the buccal mucosa,
gingiva, and/or tongue. This characteristic distribution allows differentiation of OLP
from OLCLs (Table 1). Although histopathologically similar to OLP, OLCLs are often
unilateral in presentation, occurring in direct topographic relationship with the offend-
ing agent (Fig. 1).24,25
OLP can be classified into 6 subtypes based on clinical appearance. These sub-
types may present individually or concurrently: reticular, atrophic, erosive, papular,
plaque, and bullous.26 A more recent classification groups lesions into only 3 clinical
subtypes: reticular, atrophic/erythematous, and ulcerative (Table 2, Fig. 2).27 By far,
the reticular subtype is the most common, presenting with Wickham striae, and is
generally asymptomatic. Atrophic and ulcerative forms are usually accompanied by
reticulation, facilitating the differentiation process from other mucocutaneous dis-
eases, such as pemphigus vulgaris or mucous membrane pemphigoid (MMP).
When affecting the gingiva, atrophic OLP often presents as desquamative gingivitis,
with painful diffuse erythema, erosion, and desquamation of the attached and mar-
ginal gingiva. Although OLP is the leading cause, other mucocutaneous disorders
can lead to desquamative gingivitis and these cases can be clinically indistinguishable
(Box 2).28,29
When more than 1 site is concurrently involved, the severity of the oral disease does
not necessarily correlate either with the extent of involvement or with the severity of
the disease in the other sites. Furthermore, the intensity of symptoms in the oral cavity
is variable and, in some cases, symptoms are expressed only when triggered by spicy
or acidic foods. A sense of mucosal roughness or reduced mucosal flexibility may also
be noted.

Diagnosis and Assessment

Definitive diagnosis of OLP relies on both clinical and histopathologic features. The
clinicopathologic correlation is especially important considering the various OLP
mimics that may present with similar clinical and/or histopathologic characteristics
(see Table 1).15
 4
Table 1
Clinical and histologic mimics of oral lichen planus

Kuten-Shorrer et al
Characteristic Immunofluorescence
Entity Common Clinical Presentation Typical Histopathology Findings
OLP  Bilateral, roughly symmetric  Basal cell degeneration with presence  DIF: usually negative; shaggy deposits of
distribution of cytoid bodies fibrinogen at BMZ and IgM-positive
 Reticular, atrophic, or erosive subtypes  Bandlike lymphocytic infiltrate at colloid bodies
(see Table 2) interface  IIF: negative
 Sawtooth rete ridges
 Subepithelial clefting
OLCLs  Individual lesions similar to OLP  Similar to OLP  DIF: similar to OLP
 At site of irritation, often unilateral  Eosinophils or perivascular/paravascular  IIF: negative
inflammation may be noted
OLDRs  Similar to OLP Similar to OLP  DIF: similar to OLP
 Temporal relationship with medications  IIF: negative
Mucous membrane  Desquamative gingivitis, ulcers, bullae  Subepithelial clefting with preservation  DIF: continuous linear deposits of IgG,
pemphigoid formation of basal cells IgM, C3, and/or IgA along the BMZ
 Positive Nikolsky sign  Variable chronic inflammation  IIF: often negative
LP pemphigoides  Combined features of MMP and OLP  Similar to OLP, MMP, or both  DIF: similar to MMP
 IIF: IgG at BMZ
Pemphigus vulgaris  Diffuse ulcers and erosions,  Suprabasilar clefting and acantholysis  DIF: intercellular deposits of IgG and C3
desquamative gingivitis  Variable inflammation in the lamina  IIF: intercellular IgG
 Positive Nikolsky sign propria
Chronic graft-versus-  Similar to OLP  Similar to OLP  DIF: similar to OLP
host disease  History of allogeneic hematopoietic  Lymphocytic band is usually sparse  IIF: negative
stem cell transplant
Lupus  Usually asymmetric lesions  Similar to OLP  DIF: granular deposits of IgG, IgM, and/
erythematosus  Central ulceration surrounded by  BMZ thickening or C3 at BMZ
radiating striae  Perivascular inflammatory infiltrate  IIF: negative in discoid LE; systemic LE
commonly ANA, anti–double-stranded
DNA, anti-SM, RNP, Ro/SSA, and La/SSB,
anti-antiphospholipid, and cardiolipin
positive

Abbreviations: ANA, antinuclear antibody; BMZ, basement membrane zone; DIF, direct immunofluorescence; IIF, indirect immunofluorescence; LE, lupus erythe-
matosus; MMP, mucous membrane pemphigoid.
Data from Refs.14–16
 Mucocutaneous Diseases 5

Fig. 1. Amalgam-associated OLCLs of the left lateral tongue (A) and posterior buccal mucosa
(B) presenting with erythema and white striations/plaques. The amalgam is in direct contact
with the affected areas. (Courtesy of Daliah Salem, DMD, MMSc, Boston University Goldman
School of Dental Medicine, Boston, MA.)

Histopathology
The 2003 modified World Health Organization (WHO) diagnostic criteria for OLP
outline 2 hallmark features (Fig. 3)30:
1. A well-defined, bandlike zone of lymphocytic infiltration confined to the superficial
lamina propria
2. Liquefactive degeneration (squamatization) of the basal cell layer
Other microscopic features include hyperparakeratosis and/or orthokeratosis,
acanthosis, sawtooth-rete ridges, and cytoid (colloid or Civatte) bodies. Subepithelial
clefting may occur and is a common artifact caused by the weakened basal cell adhe-
sion to the connective tissue.

Immunofluorescence
Tissue diagnosis may be challenging because the histopathologic features of OLP
may be influenced by a variety of factors, including the clinical subtype and the
severity of disease at the time of the biopsy. The use of direct immunofluorescence
(DIF) is thus recommended as a diagnostic adjunct, and can facilitate, for example,
the differentiation of OLP from vesiculobullous diseases (see Table 1). This differenti-
ation is of particular importance in the case of OLP presenting solely as desquamative
gingivitis,31 or in the rare case of LP pemphigoides of the pemphigoid family,

Table 2
Oral lichen planus: clinical patterns

Type Clinical Appearance and Common Sites Comments

Reticular White striations (Wickham striae), Most common manifestation
papules, or plaquelike lesions on the of disease
buccal mucosa, ventral and dorsal
tongue, labial mucosa, or gingiva.
Usually asymptomatic
Atrophic Areas of erythema, particularly on the Usually in conjunction with
gingiva (desquamative gingivitis). reticular lesions
May be painful
Ulcerative Ulcerations, rare bullae. May cause In conjunction with reticular
significant pain and erythematous lesions
6 Kuten-Shorrer et al

Fig. 2. Clinical patterns of OLP. Reticular (with Wickham striae) (A); atrophic (B); ulcerative
(C); atrophic form presenting as desquamative gingivitis (D).

characterized by the development of vesiculobullous lesions on areas affected by

LP.32 DIF requires submission of tissue in Michel solution as opposed to the 10%
formalin used to transport tissue for routine hematoxylin-eosin (H&E) staining. To
this end, 2 samples should be obtained. OLP is characterized by deposition of fibrin-
ogen in a shaggy pattern along the basement membrane zone (BMZ) with variable
deposition of immunoglobulin (Ig) and complement.

Treatment
Management of OLP focuses on symptom alleviation, because no cure exists.
Although not specific for OLP, patients benefit from elimination of local factors that
may trigger or exacerbate symptoms. These factors may include sharp or rough res-
torations, ill-fitting dentures, or plaque-induced gingival disease. Oral lichenoid

Box 2
Differential diagnosis: desquamative gingivitis

1. OLP and lichenoid lesions

2. Vesiculobullous diseases
a. Mucous membrane pemphigoid
b. Pemphigus vulgaris
c. Less common: paraneoplastic pemphigus, epidermolysis bullosa acquisita, and linear
immunoglobulin A disease
3. Plasma cell gingivitis
 Mucocutaneous Diseases 7

Fig. 3. OLP histopathology. (A) Hyperkeratosis, epithelial atrophy, and a dense bandlike lym-
phohistiocytic infiltrate in the superficial lamina propria (original magnification 200). (B)
Squamatization and degeneration of basal cells with scattered eosinophils in the inflamma-
tory infiltrate (original magnification 400). (C) Squamatization of the basal cells and a sub-
epithelial cleft with a moderately dense lymphohistiocytic infiltrate in the lamina propria
(original magnification 400). (D) Acanthotic epithelium, colloid bodies, and sawtooth-
shaped rete ridges with weakened cell adhesions in the basal cell layer (original magnifica-
tion 400).

reactions may resolve following identification and removal of the offending agent.
Patch testing can further assist in determining alternative materials to use.

Pharmacologic therapy
Although asymptomatic OLP requires no treatment other than periodic observation,
symptomatic cases are managed pharmacologically based on the extent and severity
of disease. Topical corticosteroids are first-line therapy.33–36 The potency of the agent,
coupled with the delivery formulation, significantly affect the effectiveness of the treat-
ment (Table 3), and maximal efficacy is ensured by providing the patient with clear in-
structions for use. For refractory and symptomatic localized ulcerative lesions,
intralesional injections of triamcinolone acetonide (10–40 mg/mL) can be used. Alter-
natively, tacrolimus 0.1%, a calcineurin inhibitor, can be used topically either as an
ointment or a compounded solution when topical corticosteroids alone are insuffi-
cient. Topical retinoids, tretinoin 0.1% or isotretinoin 0.1%, can also be considered
as second-line treatment.33 Because topical immunosuppressive treatment increases
the risk of secondary candidiasis, prophylactic topical or systemic antifungal therapy
may be required and should be considered on a case-by-case basis.37
The addition of systemic therapy is considered during acute severe exacerbations
of localized disease, or in cases involving extraoral sites as well (eg, genitalia, skin,
8 Kuten-Shorrer et al

Table 3
Topical corticosteroids commonly used for the management of oral manifestations of
mucocutaneous diseases

Medicationa Instruction of Useb Comments

Topical Gels, Creams, and Ointments
Clobetasol 0.05% Apply to lesions 2–4 times per Gels are preferred for
Fluocinonide 0.05% day. intraoral use and are
Betamethasone dipropionate Gels can be applied with effective in managing
0.05% gauze and left in place 10– limited areas of
Triamcinolone 0.1%–0.5% 15 min involvement
Extensive gingival lesions can
be treated with occlusive
trays that hold the gel on
the affected areas
Topical Solutions
Dexamethasone 0.1 mg/mL Hold solution and swish in For mild to moderate cases in
(5 mL) mouth for 4–6 min before which lesions are diffuse,
Prednisolone 3 mg/mL (5 mL) expectoration. Repeat 2–4 numerous, or inaccessible
times per day to topical application
a
Drugs are listed in a descending order of potency.
b
For all cases of topical therapy, patients are instructed to wait 10 to 15 minutes after application
before eating/drinking or brushing teeth.

or esophagus). Systemic prednisone (1 mg/kg/d) is generally effective and should be

used for the shortest possible duration in order to mitigate potential adverse effects. If
used for longer than 2 weeks, a taper is needed. Evidence to support the use of other,
steroid-sparing systemic agents is sparse and generally weak.36,38 These agents
include hydroxychloroquine,39 azathioprine,40,41 and mycophenolate mofetil.42

Prognosis and Monitoring

OLP is a chronic condition, characterized by waxing and waning severity. Patients
are typically followed at least annually, with the frequency of follow-up visits
increasing proportionally with disease activity and symptoms. The importance of
long-term monitoring and periodic repeat biopsy is further emphasized by the re-
ported risk of malignant transformation, especially in the erosive subtype of dis-
ease. Depending on the study, the transformation rate varies between 0.4% and
5.8% over periods of observation from 0.5 to more than 20 years.43 This variability
primarily stems from the lack of concordance in the diagnostic criteria of OLP and is
at the heart of the controversy surrounding its malignant potential.38 In a recent
attempt to address this problem, Aghbari and colleagues44 conducted a meta-
analysis limited to studies using the modified WHO diagnostic criteria, showing
an overall 0.9% transformation rate.

PEMPHIGUS VULGARIS
Epidemiology
Pemphigus refers to a group of autoimmune acantholytic blistering disorders that
affect the mucosa and skin.45 Several variants of pemphigus have been described
based on clinicopathologic correlation, including pemphigus vulgaris (PV), pemphigus
foliaceus, paraneoplastic pemphigus (PNP), and other less common varieties.46 Only
PV and PNP typically have oral involvement. PV is the most common variant, prefer-
entially affecting women in their fifth and sixth decades of life.47,48 Showing a strong
 Mucocutaneous Diseases 9

genetic component, PV is more prevalent in certain ethnic groups, particularly Ashke-

nazi Jews and individuals of Mediterranean and south Asian origin. The incidence of
PV is extremely variable and ranges between 0.5 and 50 cases per million based on
the population evaluated.49–52

Pathobiology
Pemphigus is understood to be predominantly familial, although sporadic cases have
been reported. Many human leukocyte antigen (HLA) genetic profile studies have been
performed and associations have been noted for HLA-DRB1*0402/1401/1404,
DQB1*0503, and DRB1*03/07/15 in distinct populations, among several others.53
Although many of these phenotypes have associated risks, the correlation between
the HLA status and patients’ clinical outcomes is still vague.54
Historically, PV is thought to result from antibody-mediated acantholysis leading to
suprabasal blistering. According to the compensation hypothesis, IgG serum autoan-
tibodies are directed against desmogleins (Dsg) 1 and 3, members of the cadherin
family of molecules that are present in desmosomes and are normally responsible
for maintaining the structural integrity of stratified squamous epithelium.45,55,56 In
normal mucosa and skin, these are expressed throughout the thickness of the epithe-
lium with a predominance of Dsg3 in oral mucosa. This differential expression profile of
autoantibodies significantly corresponds to the patient’s clinical presentation and
extent of mucous membrane and cutaneous involvement. Hence, patients with oral
mucosal involvement have chiefly anti-Dsg3 autoantibodies that lead to defective
cell adhesion and acantholysis.48,56,57
Nowadays, it is thought that the pathogenesis of PV is more complex, with factors
other than autoantibodies against Dsg1 and Dsg3 contributing to the development of
disease.58–60 Studies on mechanistic pathways of Dsg antibody generation have led to
the identification of a synergistic model formed from a trifecta of autoantibody-guided
steric hindrance of Dsg-mediated adhesion, altered desmosome assembly, and
altered signaling pathways.46,59

Clinical Presentation
The lesions in PV typically present in a mucocutaneous fashion with extremely rare
cases involving only the skin.61 The oral mucosal lesions are usually the first to appear,
followed by mucosal lesions in other sites, such as the larynx, esophagus, conjunctiva,
nose, anus and genitals, or the skin. Cutaneous lesions present as flaccid bullae and
erosions, commonly presenting on the head, trunk, and groin.
Exclusive oral mucosal involvement is estimated to occur in 50% of cases,62–64 con-
sisting of flaccid blisters, painful erosions, and superficial ulcers (Fig. 4). A recent
study of 31 cases of PV revealed that nongingival lesions were present more frequently
(55% of cases) and desquamative gingivitis was noted in less than a third of the
cases.65 These data are consistent with previous reports of site-specific oral mucosal
involvement of PV.63,66,67

Diagnosis and Assessment

The extent of involvement of mucosal and skin lesions should be assessed along
with the disease-related damage and functional impairment, as part of the physical
examination. Nikolsky sign, a perilesional mechanical manipulation leading to the
formation of a new vesicle, is commonly positive. Although this test is only moder-
ately sensitive, it has been reported to show high specificity for the diagnosis of
PV.68,69
10 Kuten-Shorrer et al

Fig. 4. Diffuse erosion and desquamative gingivitis (A) and superficial ulcers (B) of PV.

Histopathology and immunofluorescence

A biopsy of a vesicle that was first noted less than 24 hours before the visit or of the
perilesional mucosa is recommended. Suprabasilar clefting and acantholysis with
Tzanck cells within the cleft are characteristic of PV (Fig. 5). Variable degrees of
chronic inflammation may be noted.
In addition to routine histologic analysis, DIF studies should be submitted from
lesional/perilesional tissue. In PV, these show intercellular deposits of IgG in a
meshlike pattern; IgA may also be noted (Fig. 6). In patients with positive DIF, sero-
logic studies can further support the diagnosis. Indirect immunofluorescence (IIF)
microscopy uses monkey esophagus to detect the presence of autoantibodies to
intracellular structural proteins of keratinocytes.70 ELISA (enzyme-linked immuno-
sorbent assay) can also help confirm the presence of IgG autoantibodies and is
positive in more than 90% of cases.71,72 Because the levels of circulating autoan-
tibodies frequently correlate with the course of disease, IIF and ELISA aid with
monitoring disease activity and response to treatment. However, active disease
may infrequently occur in the absence of detectable IgG autoantibodies73; in
contrast, up to 40% of patients in clinical remission may have detectable levels
of antibodies.74,75

Fig. 5. PV histopathology. (A) Suprabasilar clefting and villouslike connective tissue papillae
with acantholytic cells (original magnification 100). (B) Rounded acantholytic (Tzanck) cells
protruding into the cleft with scattered acute and chronic inflammatory cells (original
magnification 400).
 Mucocutaneous Diseases 11

Fig. 6. Intercellular deposition of IgG in PV.

PNP (paraneoplastic autoimmune multiorgan syndrome [PAMS]), a rare variant of

pemphigus associated with malignancy, may present with similar oral findings to
PV. Differentiation can be facilitated by the identification of clinical features such as
highly symptomatic, therapy-refractory hemorrhagic mucositis of the lip and tongue
mucosa (Fig. 7). The reported cohort is of patients in the fourth to seventh decades,
with both sexes affected equally.76–78 Extensive mucocutaneous involvement is com-
mon, often with a heterogeneous clinical course and presentation. It is crucial for a
thorough diagnostic work-up to rule out an occult malignancy.78 In addition to devel-
oping the characteristic IgG autoantibodies to Dsg1 and/or Dsg3, other antigens from
the plakin family have also been implicated.76,79 A severe complication of PNP/PAMS
is the development of bronchiolitis obliterans, related to the disease-associated cyto-
toxic T-cell activity.80,81

Treatment
Therapy in patients with PV is designed to produce symptomatic improvement either
via direct reduction of serum autoantibodies or immunosuppression. Similar to OLP,
topical corticosteroids may be considered if the oral findings are localized (see
Table 3).

Fig. 7. Widespread superficial ulcers and crusting of lips in PNP.

12 Kuten-Shorrer et al

Because the first priority during the initial phase of therapy is to attain rapid disease
control, systemic corticosteroids are often used in addition to or instead of topical
agents, with a starting dosage of prednisone of 0.5 to 1.5 mg/kg/d82 This treatment
can be supplemented with steroid-sparing, immunosuppressive adjuvants, particu-
larly in patients with the risk of developing complications associated with therapy or
prolonged corticosteroid use.69 The first-line corticosteroid-sparing immunosuppres-
sive agents, azathioprine and mycophenolate mofetil, show relative safety and effi-
cacy.83 More recent add-ons to first-line treatment are anti-CD20 monoclonal
antibodies, rituximab and ofatumumab. Introduction of rituximab in a patient’s thera-
peutic regimen is warranted in patients with moderate to severe disease and in cases
without successful clinical remission with systemic corticosteroids and immunosup-
pressive therapy. In long-term follow-up studies, up to 45% of patients who were
treated with rituximab remained in remission even when taken off of systemic
therapy.84–86
Other steroid-sparing agents currently used include intravenous Ig (IVIG) adminis-
tered at 2 g/kg over 2 to 5 days per month. Patients receive IVIG in combination
with first-line systemic corticosteroids and/or immunosuppressive agents. Although
the significant cost of IVIG has been cited as a concern to patients and physicians,
it is cost-effective when considering the reduction in side effects associated with con-
ventional immunosuppressive therapy.87 Cyclophosphamide and other modalities,
such as immunoadsorption, are used as the last resort if all other options fail.69

Prognosis
Until the introduction of corticosteroids as first-line therapy for patients with
pemphigus, the mortalities were as high as 90%, but have since drastically reduced
to between 5% and10%.88–90 The use of corticosteroids has associated comorbidities
such as Cushing syndrome/hypercortisolism, osteoporosis, and adrenal insuffi-
ciency.90 With the introduction of other first-line therapies, these are seen less often.
The ultimate goal for PV management is long-term remission after the discontinua-
tion of therapy. With the use of immunosuppressive adjuvants and the addition of rit-
uximab to the treatment arsenal, complete remission off therapy is achievable. The
outcomes vary vastly based on the treatment modalities used.

MUCOUS MEMBRANE PEMPHIGOID

Epidemiology
MMP is an uncommon autoimmune subepithelial blistering disorder that belongs to
the group of pemphigoid diseases, along with at least 7 other distinct entities.91
Although the epidemiology of MMP is unclear, some studies estimate the incidence
to be around 1.3 to 2.0 per million people, and the prevalence is almost twice in
women.92–94 Most patients with MMP are in the fifth to seventh decades of life at
the time of diagnosis.94,95

Pathobiology
The most widely accepted theory for the development of MMP is based on the devel-
opment of circulating antibodies in response to altered immunologic tolerance to
structural proteins located in the basement membrane of epithelium/epidermis.96
At least 6 target antigens have been identified and include BP180, laminin 332, lam-
inin 311, BP230, both subunits of a6b4 integrin, and type VII collagen.91 Specifically,
IgG and IgA autoantibodies were found most commonly against BP180 in patients
with MMP (50%–75%) and patients with ocular lesions presented with reactivity to
 Mucocutaneous Diseases 13

b4 integrin (>85%).97 The binding of autoantibodies to BMZ antigens leads to the

weakening of the attachment of the hemidesmosomes to the basement membrane
and ultimately the development of a subepithelial cleft. A potential contributing fac-
tor, increased prevalence of HLA-DQB1*0301, has been reported in patients with
MMP.98

Clinical Presentation
The hallmark feature of MMP is the presence of clinically evident bullae, erosions, and
secondary scarring of the mucosa and, less often, the skin.99 However, the oral mu-
cosa tends to be spared from the scarring effects of the disease process.91 The clinical
severity is extremely variable and can present as a discrete bulla, widespread lesions,
or desquamative gingivitis. Lesions present most frequently in the oral cavity (85%),
followed by other mucosal sites such as conjunctiva (65%), nasal cavity (20%–
40%), anogenital area (20%), pharynx (20%), and larynx (5%–10%).91
Oral MMP typically presents with erythematous patches and erosions with/without
a pseudomembrane.99 The detection of intact vesicles or bullae is uncommon
because they tend to quickly rupture, leaving irregularly shaped erosions. The most
common presentation of oral lesions in MMP is that of desquamative gingivitis (84%
of cases; Fig. 8), and extragingival lesions are noted in less than 10% of cases.65,100

Diagnosis and Assessment

The diagnosis of MMP must be rendered based on a combination of the clinical pre-
sentation, histopathology, and immunofluorescence studies.99 The occurrence of
desquamative gingivitis in a patient should prompt the physician to include MMP in
the list of differentials (see Box 2).29 Although unreliable and not included as a diag-
nostic criterion, Nikolsky sign may be positive in oral MMP.99,101

Histopathology and immunofluorescence

A biopsy of an intact blister or perilesional tissue in proximity to the erosion is obtained
and submitted for routine H&E and DIF studies.102 A subepithelial cleft or detached
fragments of epithelium showing intact basal cells are characteristically noted. Vari-
able epithelial thickness and inflammation may be present (Fig. 9). DIF studies of
MMP show linear deposition of IgG, C,3 and IgA in the BMZ (Fig. 10). IIF is rarely
used because circulating antibodies are rarely detectable in patients (5%–25%) with
MMP.

Fig. 8. Desquamative gingivitis of MMP.

14 Kuten-Shorrer et al

Fig. 9. MMP histopathology. (A) Hyperkeratosis, variable epithelial hyperplasia, a subepithe-

lial cleft and scattered inflammatory cells (original magnification 100). (B) Subepithelial
clefting with preservation of basal cells (original magnification 400).

Treatment
Therapy for oral MMP includes a combination of topical and systemic agents designed
to reduce disease severity and symptoms without tipping the balance in favor of
immunosuppression. Patients are stratified as high or low risk to help guide therapeu-
tic decisions. The classification is based on the site of disease involvement, severity,
and progression of disease, and indicates the risk of developing sequelae from scar-
ring.99 Involvement of the oral mucosa, with or without the skin, renders the patient low
risk and a more conservative approach is indicated.
Topical corticosteroids are first-line therapy for localized disease (see Table 3). An
occlusive tray is recommended for gingival disease. Alternatively, gauze may be used
to help keep the medication in close contact with the lesions. Topical tacrolimus 0.1%
ointment also may be used in refractory cases.
Systemic therapy primarily comprises corticosteroids and steroid-sparing agents
and is administered to high-risk patients with MMP and low-risk patients who fail
topical therapeutics (Table 4). Other systemic agents have been reported to be
used for treatment of oral MMP and include tetracycline, nicotinamide, and

Fig. 10. Linear C3 at the BMZ in MMP.

 Mucocutaneous Diseases 15

Table 4
Mucous membrane pemphigoid: risk stratification

Risk
Class Criteria Treatment
Low Oral mucosa/oral mucosa Moderate-dose to high-dose topical corticosteroids
and limited skin (see Table 3)
High  Ocular, genital, Mild disease
nasopharyngeal,  Dapsone (50–200 mg/d) or
esophageal, and/or  Sulfamethoxypyridazine (0.5–1 g/d) or
laryngeal mucosae; or  Sulfapyridine (0.25–1 g/d)
 Rapid disease progression Severe disease
 Prednisone (0.5–1.5 mg/kg/d)
Adjuvant therapies:
 Cyclophosphamide (1–2 mg/kg/d) or
 Azathioprine (1–2 mg/kg/d) or
 Mycophenolate mofetil (1–2 g/d in divided
doses)

Data from McMillan R, Taylor J, Shephard M, et al. World Workshop on Oral Medicine VI: a system-
atic review of the treatment of mucocutaneous pemphigus vulgaris. Oral surgery, oral medicine,
oral pathology and oral radiology. 2015;120(2):132–42.e161; and Chan LS, Ahmed AR, Anhalt GJ,
et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic
criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol.
2002;138(3):370–9.

methotrexate.103 IVIG and rituximab have also been used to treat ocular MMP suc-
cessfully; large studies are yet to be published on therapeutic protocols for these
agents in oral MMP.82,91
Prognosis
MMP may result in debilitating or life-threatening disease in the absence of treatment.
However, even with treatment, prognosis is unpredictable because response differs
among individuals and relapse is common. Based on clinical evidence gathered
over the past several decades, prognostic predictors are now recognized for MMP
and serve as a guide for therapeutics and patient counseling. The site of involvement,
presence and titers of dual isotypes of autoantibodies (IgG and IgA), and the antigen-
specific autoantibodies are prognostic indicators of disease severity.99

ERYTHEMA MULTIFORME
Epidemiology
Erythema multiforme (EM) is an acute, self-limiting, immune-mediated disorder
affecting the skin and/or mucosal surfaces. The oral mucosa is the most frequently
involved mucosal site, with a reported frequency of up to 70%.104,105 EM usually oc-
curs in healthy young adults with a peak age at onset in the 3rd to 4th decades of life,
although up to 20% of cases occur in children.106,107 While epidemiological data is
scarce, the annual incidence of EM is estimated to be far less than 1 percent.106
Most cases are transient and resolve without long-term sequelae, but a subset of pa-
tients experience repeated episodes over many years, leading to recurrent EM.104,107
Pathobiology
A hypersensitivity reaction, EM is primarily triggered by infectious agents (approxi-
mately 90% of cases), with herpes simplex virus (HSV) most frequently implicated, fol-
lowed by Mycoplasma pneumonia (PM) which is also the major cause of EM in
16 Kuten-Shorrer et al

children.108,107 Drugs are the second most frequently suspected cause of EM.109,110
Implicated medications include sulfonamides, NSAIDs, and penicillins.
The underlying pathogenesis of HSV-related EM is the most studied and is thought
to involve a cell-mediated immune reaction against HSV DNA fragments in the skin or
mucosa.111–113 Following a recurrent HSV infection, the virus is present in the blood
and phagocytosed by circulating mononuclear cells, particularly circulating CD341
Langerhans cell precursors. The engulfed viral DNA is then transported to the epithe-
lium, where the expression of HSV DNA fragments, notably the viral pol gene, leads to
activation of HSV-specific T cells and production of effector cytokines. This step initi-
ates an inflammatory cascade that promotes the lysis of HSV-infected cells and
recruitment of autoreactive T cells. The specific immune response to the viral Pol pro-
tein, which is synthetized and expressed for only a few days, may explain the transient
nature of EM lesions.

Clinical presentation
EM is characterized by acute targetoid erythematous lesions with symmetric, acral
distribution and can be classified into isolated cutaneous (EM minor, EMm) and muco-
cutaneous forms (EM major, EMM). Mucosal involvement alone is rare.109,110 Typical
targetoid lesions are regular, well-defined round papules or plaques consisting of at
least three concentric zones: a central disk, a peripheral pale ring, and an erythema-
tous halo.114 Lesions generally measure less than 3 cm in diameter. Atypical raised
target lesions may also appear, manifesting as elevated, palpable lesions with only
two zones and/or an ill-defined border. By definition, less than 10% body surface
area (BSA) is affected in EM. Lesions are generally asymptomatic, although burning
or itching may be reported, and persist for one week or longer before healing without
scarring.
Oral involvement is primarily seen in EMM, whereas the lips alone may be involved in
EMm. The lips tend to become swollen and show pathognomonic hemorrhagic crust-
ing.115,116 Intraorally, diffuse areas of erythema and/or superficial ulcerations typically
affect the lingual, buccal, and labial mucosa, particularly in the anterior parts of the
mouth. Occasional intact vesicles may be seen. Lesions are painful, compromising
speech and alimentation. They usually occur simultaneously with skin lesions, and,
similarly, heal without scarring.117

Diagnosis and assessment

The diagnosis of EM is based on clinical presentation. Patients’ history should be
reviewed for evidence of a triggering factor, with special emphasis on a recent
HSV infection.110,114,118 Laboratory work up is not required, as there are no specific
diagnostic tests for EM, however aids in identification of causal agents and exclusion
of other disorders.
Stevens-Johnson syndrome (SJS) can be differentiated from EMM primarily based
on clinical appearance (Table 5).115,119,120 Painful, predominantly macular atypical
target lesions are characteristic. Other differentiating criteria include constitutional
symptoms, distribution of lesions, and clinical severity, with SJS considered a life-
threatening reaction.
Confirmation of active HSV infection in HSV-associated EM can be achieved using
viral culture, cytology, or direct fluorescent antibody (DFA) testing. In cases where a
clear relationship to HSV is not supported by history and clinical examination, serology
for HSV antibodies excludes HSV-associated EM when negative. Positive serology
coupled with molecular testing (polymerase chain reaction [PCR] or in-situ hybridiza-
tion) for HSV on tissue specimens indicates subclinical HSV reactivation, and possible
 Mucocutaneous Diseases 17

Table 5
Erythema multiforme major versus Stevens-Johnson syndrome: different diseases with
distinct features

Prodromal
Cause Symptoms Cutaneous Lesions Mucosal Involvement
EMM Likely Usually  Distribution: localized, Often limited to oral mucosa:
infectious absent acral; <10% BSA erythema, ulceration, and
 Pattern: typical targets, hemorrhagic crusting
raised atypical targets
 Nikolsky sign: negative
SJS Likely Common,  Distribution: widespread,  At least two sites involved
drugs flu-like including central trunk;  Oral cavity almost always
<10% BSA affected: extensive
 Pattern: flat atypical ulceration with hemorrhagic
targets, macules crusts
 Nikolsky sign: positive

Abbreviations: BSA, body surface area; EMM, erythema multiforme major; SJS, Stevens-Johnson
syndrome.

HSV-associated EM. In patients with respiratory symptoms, molecular or serologic

testing for M. pneumoniae infection are indicated to support a diagnosis of M. pneu-
moniae-related EM. Finally, tissue biopsy and immunofluorescent studies allow to
differentiate EM from other vesiculobullous disorders.

Histopathology and immunofluorescence

Histological features are often nonspecific and if a biopsy is mandated, the epithelium
shows spongiosis, keratinocyte apoptosis and necrosis, lymphocyte satellitosis and
degeneration of basal cells. Variable chronic inflammation is noted, and eosinophils
are often present. As mentioned earlier, the diagnosis is primarily based on clinical
findings and a biopsy may be performed in order to rule out a vesiculobullous disorder.

Treatment
The goals of treatment are two-fold: 1) to reduce the duration of acute EM and prevent
complications, and 2) to prevent or reduce the frequency and severity of recurrences.
Thus, the management of EM depends on the severity of the disease and its course, as
well as the underlying cause. Evidence to support the various treatments derives pri-
marily from retrospective series or small controlled trials.114,121
In suspected drug-induced EM, the first measure is to discontinue the offending
drug and avoid re-exposure. Mild disease, manifesting with only cutaneous involve-
ment or nondisabling, limited oral mucosal involvement, is managed with focus on
symptomatic relief. Topical corticosteroids serve as first-line therapy (Table 3) along-
side topical anesthetics, as needed. Short-term systemic corticosteroids are often
used in severe cases with extensive oral mucosal involvement and risk of dysphagia,
although controlled studies are lacking. Hospitalization for nutrition and pain control
may be required.
In cases of recurrent HSV-associated EM, continuous antiviral therapy with sys-
temic acyclovir, valacyclovir, or famciclovir is effective at suppressing at-
tacks.104,105,122 Prophylactic antiviral therapy should also be considered in patients
with idiopathic recurrent EM, when subclinical HSV infection cannot be excluded. Ev-
idence is lacking to support specific recommendations for treatment duration in cases
with favorable response. For patients with recurrent EM resistant to continuous
18 Kuten-Shorrer et al

antiviral therapy, second-line therapies include azathioprine, mycophenolate mofetil,

or dapsone.114,121

Prognosis
Acute EM is usually self-limiting, with complete resolution within weeks without signif-
icant sequelae. Some patients, however, experience recurrences. The severity and
frequency of attacks is highly variable and unpredictable. In a large case series, Scho-
field et al. reported an average of six attacks per year, and an overall mean duration of
disease of 9.5 years.105 Several features have been associated with a less favorable
prognosis for disease control in patients with recurrent EM.104 These include severe
oral involvement, inability to identify a specific cause, lack of improvement with contin-
uous antiviral therapy, extensive corticosteroid therapy, and immunosuppressive ther-
apy with two or more agents.

SUMMARY

Oral lesions may be the first and occasionally the only manifestation of mucocuta-
neous diseases. As such, oral health practitioners are integral members of the multi-
disciplinary team caring for patients with mucocutaneous disease. Early and proper
diagnosis is crucial to prevent systemic progression and to ameliorate outcomes.
Although some oral features are pathognomonic for the specific condition, others
are nonspecific, making diagnosis difficult to achieve based on clinical examination
only. Aside from the routine histologic examination, diagnostic tools such as immuno-
fluorescence and serologic testing aid in achieving an accurate diagnosis.

REFERENCES

1. 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 1999;88(4):431–6.
2. Le Cleach L, Chosidow O. Lichen planus. N Engl J Med 2012;366(8):723–32.
3. Carbone M, Arduino PG, Carrozzo M, et al. Course of oral lichen planus: a retro-
spective study of 808 northern Italian patients. Oral Dis 2009;15(3):235–43.
4. McCartan BE, Healy CM. The reported prevalence of oral lichen planus: a re-
view and critique. J Oral Pathol Med 2008;37(8):447–53.
5. Thornhill MH. Immune mechanisms in oral lichen planus. Acta Odontol Scand
2001;59(3):174–7.
6. Lodi G, Scully C, Carrozzo M, et al. Current controversies in oral lichen planus:
report of an international consensus meeting. Part 1. Viral infections and etiopa-
thogenesis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100(1):
40–51.
7. Lehman JS, Tollefson MM, Gibson LE. Lichen planus. Int J Dermatol 2009;48(7):
682–94.
8. Farhi D, Dupin N. Pathophysiology, etiologic factors, and clinical management
of oral lichen planus, part I: facts and controversies. Clin Dermatol 2010;
28(1):100–8.
9. Payeras MR, Cherubini K, Figueiredo MA, et al. Oral lichen planus: focus on
etiopathogenesis. Arch Oral Biol 2013;58(9):1057–69.
10. Kurago ZB. Etiology and pathogenesis of oral lichen planus: an overview. Oral
Surg Oral Med Oral Pathol Oral Radiol 2016;122(1):72–80.
 Mucocutaneous Diseases 19

11. Rojo-Moreno JL, Bagan JV, Rojo-Moreno J, et al. Psychologic factors and oral
lichen planus. A psychometric evaluation of 100 cases. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 1998;86(6):687–91.
12. Pippi R, Romeo U, Santoro M, et al. Psychological disorders and oral lichen pla-
nus: matched case-control study and literature review. Oral Dis 2016;22(3):
226–34.
13. Issa Y, Duxbury AJ, Macfarlane TV, et al. Oral lichenoid lesions related to dental
restorative materials. Br Dent J 2005;198(6):361–6 [disussion: 549]; [quiz: 372].
14. Khudhur AS, Di Zenzo G, Carrozzo M. Oral lichenoid tissue reactions: diagnosis
and classification. Expert Rev Mol Diagn 2014;14(2):169–84.
15. Cheng YS, Gould A, Kurago Z, et al. Diagnosis of oral lichen planus: a position
paper of the American Academy of Oral and Maxillofacial Pathology. Oral Surg
Oral Med Oral Pathol Oral Radiol 2016;122(3):332–54.
16. Muller S. Oral lichenoid lesions: distinguishing the benign from the deadly. Mod
Pathol 2017;30(s1):S54–s67.
17. Halevy S, Shai A. Lichenoid drug eruptions. J Am Acad Dermatol 1993;29(2 Pt
1):249–55.
18. Carrozzo M, Pellicano R. Lichen planus and hepatitis C virus infection: an up-
dated critical review. Minerva Gastroenterol Dietol 2008;54(1):65–74.
19. Lodi G, Pellicano R, Carrozzo M. Hepatitis C virus infection and lichen planus: a
systematic review with meta-analysis. Oral Dis 2010;16(7):601–12.
20. Alaizari NA, Al-Maweri SA, Al-Shamiri HM, et al. Hepatitis C virus infections in
oral lichen planus: a systematic review and meta-analysis. Aust Dent J 2016;
61(3):282–7.
21. Harden D, Skelton H, Smith KJ. Lichen planus associated with hepatitis C virus:
no viral transcripts are found in the lichen planus, and effective therapy for hep-
atitis C virus does not clear lichen planus. J Am Acad Dermatol 2003;49(5):
847–52.
22. Tziotzios C, Lee JYW, Brier T, et al. Lichen planus and lichenoid dermatoses:
Clinical overview and molecular basis. J Am Acad Dermatol 2018;79(5):
789–804.
23. Eisen D, Carrozzo M, Bagan Sebastian JV, et al. Number V oral lichen planus:
clinical features and management. Oral Dis 2005;11(6):338–49.
24. 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 2006;35(4):233–40.
25. Montebugnoli L, Venturi M, Gissi DB, et al. Clinical and histologic healing of li-
chenoid oral lesions following amalgam removal: a prospective study. Oral
Surg Oral Med Oral Pathol Oral Radiol 2012;113(6):766–72.
26. Andreasen JO. Oral lichen planus. 1. A clinical evaluation of 115 cases. Oral
Surg Oral Med Oral Pathol 1968;25(1):31–42.
27. Eisen D. The clinical manifestations and treatment of oral lichen planus. Derma-
tol Clin 2003;21(1):79–89.
28. Lo Russo L, Fedele S, Guiglia R, et al. Diagnostic pathways and clinical signif-
icance of desquamative gingivitis. J Periodontol 2008;79(1):4–24.
29. Maderal AD, Lee Salisbury P 3rd, Jorizzo JL. Desquamative gingivitis: clinical
findings and diseases. J Am Acad Dermatol 2018;78(5):839–48.
30. 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 2003;32(9):
507–12.
20 Kuten-Shorrer et al

31. Suresh L, Neiders ME. Definitive and differential diagnosis of desquamative

gingivitis through direct immunofluorescence studies. J Periodontol 2012;
83(10):1270–8.
32. Sultan A, Stojanov IJ, Lerman MA, et al. Oral lichen planus pemphigoides: a se-
ries of four cases. Oral Surg Oral Med Oral Pathol Oral Radiol 2015;120(1):
58–68.
33. Al-Hashimi I, Schifter M, Lockhart PB, et al. Oral lichen planus and oral lichenoid
lesions: diagnostic and therapeutic considerations. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2007;103(Suppl):S25.e21-12.
34. Lodi G, Carrozzo M, Furness S, et al. Interventions for treating oral lichen planus:
a systematic review. Br J Dermatol 2012;166(5):938–47.
35. Davari P, Hsiao HH, Fazel N. Mucosal lichen planus: an evidence-based treat-
ment update. Am J Clin Dermatol 2014;15(3):181–95.
36. Tziotzios C, Brier T, Lee JYW, et al. Lichen planus and lichenoid dermatoses:
Conventional and emerging therapeutic strategies. J Am Acad Dermatol
2018;79(5):807–18.
37. Tejani S, Sultan A, Stojanov I, et al. Candidal carriage predicts candidiasis dur-
ing topical immunosuppressive therapy: a preliminary retrospective cohort
study. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122(4):448–54.
38. Lodi G, Scully C, Carrozzo M, et al. 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
2005;100(2):164–78.
39. Eisen D. Hydroxychloroquine sulfate (Plaquenil) improves oral lichen planus: an
open trial. J Am Acad Dermatol 1993;28(4):609–12.
40. Lear JT, English JS. Erosive and generalized lichen planus responsive to azathi-
oprine. Clin Exp Dermatol 1996;21(1):56–7.
41. Silverman S Jr, Gorsky M, Lozada-Nur F, et al. A prospective study of findings
and management in 214 patients with oral lichen planus. Oral Surg Oral Med
Oral Pathol 1991;72(6):665–70.
42. Wee JS, Shirlaw PJ, Challacombe SJ, et al. Efficacy of mycophenolate mofetil in
severe mucocutaneous lichen planus: a retrospective review of 10 patients. Br J
Dermatol 2012;167(1):36–43.
43. van der Meij EH, Schepman KP, Smeele LE, et al. A review of the recent litera-
ture regarding malignant transformation of oral lichen planus. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 1999;88(3):307–10.
44. Aghbari SMH, Abushouk AI, Attia A, et al. Malignant transformation of oral lichen
planus and oral lichenoid lesions: a meta-analysis of 20095 patient data. Oral
Oncol 2017;68:92–102.
45. Amagai M. Pemphigus. In: Bolognia J, Jorizzo J, Schaffer J, editors. Derma-
tology, vol. 1. Elsevier; 2012. p. 461–74.
46. Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Pemphigus. Nat Rev Dis
Primers 2017;3:17026.
47. Alpsoy E, Akman-Karakas A, Uzun S. Geographic variations in epidemiology of
two autoimmune bullous diseases: pemphigus and bullous pemphigoid. Arch
Dermatol Res 2015;307(4):291–8.
48. Shah AA, Seiffert-Sinha K, Sirois D, et al. Development of a disease registry for
autoimmune bullous diseases: initial analysis of the pemphigus vulgaris subset.
Acta Derm Venereol 2015;95(1):86–90.
49. Simon DG, Krutchkoff D, Kaslow RA, et al. Pemphigus in Hartford County, Con-
necticut, from 1972 to 1977. Arch Dermatol 1980;116(9):1035–7.
 Mucocutaneous Diseases 21

50. Asilian A, Yoosefi A, Faghini G. Pemphigus vulgaris in Iran: epidemiology and

clinical profile. Skinmed 2006;5(2):69–71.
51. Michailidou EZ, Belazi MA, Markopoulos AK, et al. Epidemiologic survey of
pemphigus vulgaris with oral manifestations in northern Greece: retrospective
study of 129 patients. Int J Dermatol 2007;46(4):356–61.
52. Meyer N, Misery L. Geoepidemiologic considerations of auto-immune
pemphigus. Autoimmun Rev 2010;9(5):A379–82.
53. Yan L, Wang JM, Zeng K. Association between HLA-DRB1 polymorphisms and
pemphigus vulgaris: a meta-analysis. Br J Dermatol 2012;167(4):768–77.
54. Sinha AA. The genetics of pemphigus. Dermatol Clin 2011;29(3):381–91, vii.
55. Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial
cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 1991;67(5):
869–77.
56. Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the staphylococcal
scalded-skin syndrome. N Engl J Med 2006;355(17):1800–10.
57. Koch PJ, Walsh MJ, Schmelz M, et al. Identification of desmoglein, a constitutive
desmosomal glycoprotein, as a member of the cadherin family of cell adhesion
molecules. Eur J Cell Biol 1990;53(1):1–12.
58. Mao X, Nagler AR, Farber SA, et al. Autoimmunity to desmocollin 3 in
pemphigus vulgaris. Am J Pathol 2010;177(6):2724–30.
59. Grando SA. Pemphigus autoimmunity: hypotheses and realities. Autoimmunity
2012;45(1):7–35.
60. Schmidt E, Spindler V, Eming R, et al. Meeting report of the pathogenesis of
pemphigus and pemphigoid meeting in Munich, September 2016. J Invest Der-
matol 2017;137(6):1199–203.
61. Yoshida K, Takae Y, Saito H, et al. Cutaneous type pemphigus vulgaris: a rare
clinical phenotype of pemphigus. J Am Acad Dermatol 2005;52(5):839–45.
62. Laskaris G, Sklavounou A, Stratigos J. Bullous pemphigoid, cicatricial pemphi-
goid, and pemphigus vulgaris. A comparative clinical survey of 278 cases. Oral
Surg Oral Med Oral Pathol 1982;54(6):656–62.
63. Mignogna MD, Lo Muzio L, Bucci E. Clinical features of gingival pemphigus vul-
garis. J Clin Periodontol 2001;28(5):489–93.
64. Santoro FA, Stoopler ET, Werth VP. Pemphigus. Dent Clin North Am 2013;57(4):
597–610.
65. Sultan AS, Villa A, Saavedra AP, et al. Oral mucous membrane pemphigoid and
pemphigus vulgaris-a retrospective two-center cohort study. Oral Dis 2017;
23(4):498–504.
66. Shklar G, Frim S, Flynn E. Gingival lesions of pemphigus. J Periodontol 1978;
49(8):428–35.
67. Said S, Golitz L. Vesiculobullous eruptions of the oral cavity. Otolaryngol Clin
North Am 2011;44(1):133–60, vi.
68. Uzun S, Durdu M. The specificity and sensitivity of Nikolskiy sign in the diag-
nosis of pemphigus. J Am Acad Dermatol 2006;54(3):411–5.
69. Murrell DF, Pena S, Joly P, et al. Diagnosis and management of pemphigus: rec-
ommendations by an international panel of experts. J Am Acad Dermatol 2018.
[Epub ahead of print].
70. van Beek N, Rentzsch K, Probst C, et al. Serological diagnosis of autoimmune
bullous skin diseases: prospective comparison of the BIOCHIP mosaic-based
indirect immunofluorescence technique with the conventional multi-step single
test strategy. Orphanet J Rare Dis 2012;7:49.
22 Kuten-Shorrer et al

71. Amagai M, Komai A, Hashimoto T, et al. Usefulness of enzyme-linked immuno-

sorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of
pemphigus. Br J Dermatol 1999;140(2):351–7.
72. Schmidt E, Dahnrich C, Rosemann A, et al. Novel ELISA systems for antibodies
to desmoglein 1 and 3: correlation of disease activity with serum autoantibody
levels in individual pemphigus patients. Exp Dermatol 2010;19(5):458–63.
73. Schmidt E, Zillikens D. Modern diagnosis of autoimmune blistering skin dis-
eases. Autoimmun Rev 2010;10(2):84–9.
74. Kwon EJ, Yamagami J, Nishikawa T, et al. Anti-desmoglein IgG autoantibodies
in patients with pemphigus in remission. J Eur Acad Dermatol Venereol 2008;
22(9):1070–5.
75. Naseer SY, Seiffert-Sinha K, Sinha AA. Detailed profiling of anti-desmoglein au-
toantibodies identifies anti-Dsg1 reactivity as a key driver of disease activity and
clinical expression in pemphigus vulgaris. Autoimmunity 2015;48(4):231–41.
76. Anhalt GJ, Kim SC, Stanley JR, et al. Paraneoplastic pemphigus. An autoim-
mune mucocutaneous disease associated with neoplasia. N Engl J Med
1990;323(25):1729–35.
77. Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol 1997;12:77–96 [discus-
sion: 97].
78. Yong AA, Tey HL. Paraneoplastic pemphigus. Australas J Dermatol 2013;54(4):
241–50.
79. Schepens I, Jaunin F, Begre N, et al. The protease inhibitor alpha-2-
macroglobulin-like-1 is the p170 antigen recognized by paraneoplastic
pemphigus autoantibodies in human. PLoS One 2010;5(8):e12250.
80. Nousari HC, Deterding R, Wojtczack H, et al. The mechanism of respiratory fail-
ure in paraneoplastic pemphigus. N Engl J Med 1999;340(18):1406–10.
81. Hoffman MA, Qiao X, Anhalt GJ. CD81 T lymphocytes in bronchiolitis obliterans,
paraneoplastic pemphigus, and solitary Castleman’s disease. N Engl J Med
2003;349(4):407–8.
82. McMillan R, Taylor J, Shephard M, et al. World workshop on oral medicine VI: a
systematic review of the treatment of mucocutaneous pemphigus vulgaris. Oral
Surg Oral Med Oral Pathol Oral Radiol 2015;120(2):132–42.e1.
83. Beissert S, Mimouni D, Kanwar AJ, et al. Treating pemphigus vulgaris with pred-
nisone and mycophenolate mofetil: a multicenter, randomized, placebo-
controlled trial. J Invest Dermatol 2010;130(8):2041–8.
84. Feldman RJ, Ahmed AR. Relevance of rituximab therapy in pemphigus vulgaris:
analysis of current data and the immunologic basis for its observed responses.
Expert Rev Clin Immunol 2011;7(4):529–41.
85. Colliou N, Picard D, Caillot F, et al. Long-term remissions of severe pemphigus
after rituximab therapy are associated with prolonged failure of desmoglein B
cell response. Sci Transl Med 2013;5(175):175ra130.
86. Wang HH, Liu CW, Li YC, et al. Efficacy of rituximab for pemphigus: a systematic
review and meta-analysis of different regimens. Acta Derm Venereol 2015;95(8):
928–32.
87. Daoud YJ, Amin KG. Comparison of cost of immune globulin intravenous ther-
apy to conventional immunosuppressive therapy in treating patients with auto-
immune mucocutaneous blistering diseases. Int Immunopharmacol 2006;6(4):
600–6.
88. Langan SM, Smeeth L, Hubbard R, et al. Bullous pemphigoid and pemphigus
vulgaris–incidence and mortality in the UK: population based cohort study.
BMJ 2008;337:a180.
 Mucocutaneous Diseases 23

89. Huang YH, Kuo CF, Chen YH, et al. Incidence, mortality, and causes of death of
patients with pemphigus in Taiwan: a nationwide population-based study.
J Invest Dermatol 2012;132(1):92–7.
90. Hsu DY, Brieva J, Sinha AA, et al. Comorbidities and inpatient mortality for
pemphigus in the U.S.A. Br J Dermatol 2016;174(6):1290–8.
91. Schmidt E, Zillikens D. Pemphigoid diseases. Lancet 2013;381(9863):320–32.
92. Bernard P, Vaillant L, Labeille B, et al. Incidence and distribution of subepider-
mal autoimmune bullous skin diseases in three French regions. Bullous Dis-
eases French Study Group. Arch Dermatol 1995;131(1):48–52.
93. Bertram F, Brocker EB, Zillikens D, et al. Prospective analysis of the incidence of
autoimmune bullous disorders in Lower Franconia, Germany. J Dtsch Dermatol
Ges 2009;7(5):434–40.
94. Hubner F, Recke A, Zillikens D, et al. Prevalence and age distribution of
pemphigus and pemphigoid diseases in Germany. J Invest Dermatol 2016;
136(12):2495–8.
95. Scully C, Lo Muzio L. Oral mucosal diseases: mucous membrane pemphigoid.
Br J Oral Maxillofac Surg 2008;46(5):358–66.
96. Kourosh AS, Yancey KB. Pathogenesis of mucous membrane pemphigoid. Der-
matol Clin 2011;29(3):479–84, x.
97. Oyama N, Setterfield JF, Powell AM, et al. Bullous pemphigoid antigen II
(BP180) and its soluble extracellular domains are major autoantigens in mucous
membrane pemphigoid: the pathogenic relevance to HLA class II alleles and
disease severity. Br J Dermatol 2006;154(1):90–8.
98. Delgado JC, Turbay D, Yunis EJ, et al. A common major histocompatibility com-
plex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphi-
goid. Proc Natl Acad Sci U S A 1996;93(16):8569–71.
99. Chan LS, Ahmed AR, Anhalt GJ, et al. The first international consensus on mu-
cous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors,
medical treatment, and prognostic indicators. Arch Dermatol 2002;138(3):
370–9.
100. Bagan J, Jimenez Y, Murillo J, et al. Oral mucous membrane pemphigoid: a clin-
ical study of 100 low-risk cases. Oral Dis 2018;24(1–2):132–4.
101. Gallagher G, Shklar G. Oral involvement in mucous membrane pemphigoid. Clin
Dermatol 1987;5(1):18–27.
102. Scully C, Carrozzo M, Gandolfo S, et al. Update on mucous membrane pemphi-
goid: a heterogeneous immune-mediated subepithelial blistering entity. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88(1):56–68.
103. Xu HH, Werth VP, Parisi E, et al. Mucous membrane pemphigoid. Dent Clin
North Am 2013;57(4):611–30.
104. Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics,
etiologic associations, and treatment in a series of 48 patients at Mayo Clinic,
2000 to 2007. J Am Acad Dermatol 2010;62(1):45–53.
105. Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema multiforme: clinical fea-
tures and treatment in a large series of patients. Br J Dermatol 1993;128(5):
542–5.
106. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of
characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;
8(6):763–75.
107. Heinze A, Tollefson M, Holland KE, et al. Characteristics of pediatric recurrent
erythema multiforme. Pediatr Dermatol 2018;35(1):97–103.
24 Kuten-Shorrer et al

108. Howland WW, Golitz LE, Weston WL, et al. Erythema multiforme: clinical, histo-
pathologic, and immunologic study. J Am Acad Dermatol 1984;10(3):438–46.
109. Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, et al. Current perspectives on er-
ythema multiforme. Clin Rev Allergy Immunol 2018;54(1):177–84.
110. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema
multiforme: a review for the practicing dermatologist. Int J Dermatol 2012;51(8):
889–902.
111. Aurelian L, Kokuba H, Burnett JW. Understanding the pathogenesis of HSV-
associated erythema multiforme. Dermatology 1998;197(3):219–22.
112. Ono F, Sharma BK, Smith CC, et al. CD34+ cells in the peripheral blood trans-
port herpes simplex virus DNA fragments to the skin of patients with erythema
multiforme (HAEM). J Invest Dermatol 2005;124(6):1215–24.
113. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema
multiforme (HAEM): a viral disease with an autoimmune component. Dermatol
Online J 2003;9(1):1.
114. Roujeau J-C, Mockenhaupt M. Erythema multiforme. Chapter 43. In: Kang S,
Amagai M, Bruckner AL, et al, editors. Fitzpatrick’s dermatology. 9th edition.
McGraw-Hill Education; 2019.
115. Al-Johani KA, Fedele S, Porter SR. Erythema multiforme and related disorders.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(5):642–54.
116. Samim F, Auluck A, Zed C, et al. Erythema multiforme: a review of epidemiology,
pathogenesis, clinical features, and treatment. Dent Clin North Am 2013;57(4):
583–96.
117. Ayangco L, Rogers RS. Oral manifestations of erythema multiforme. Dermatol
Clin 2003;21(1):195–205.
118. Scully C, Bagan J. Oral mucosal diseases: erythema multiforme. Br J Oral Max-
illofac Surg 2008;46(2):90–5.
119. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical
patterns and causes of erythema multiforme majus, Stevens-Johnson syn-
drome, and toxic epidermal necrolysis: results of an international prospective
study. Arch Dermatol 2002;138(8):1019–24.
120. Assier H, Bastuji-Garin S, Revuz J, et al. Erythema multiforme with mucous
membrane involvement and Stevens-Johnson syndrome are clinically different
disorders with distinct causes. Arch Dermatol 1995;131(5):539–43.
121. de Risi-Pugliese T, Sbidian E, Ingen-Housz-Oro S, et al. Interventions for ery-
thema multiforme: a systematic review. J Eur Acad Dermatol Venereol 2019;
33(5):842–9.
122. Tatnall FM, Schofield JK, Leigh IM. A double-blind, placebo-controlled trial of
continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol
1995;132(2):267–70.