ARTICLE
Auteur(s) : Daniela
Bruch-Gerharz1, Michael Hertl2, Thomas
Ruzicka3
1Department of Dermatology,
Heinrich-Heine-University, P.O. Box 101007, D-40001 Duesseldorf,
Germany
2Department of Dermatology, Faculty of Medicine,
Philipps-University of Marburg, Germany
3Department of Dermatology, Faculty of Medicine,
Ludwig-Maximilians-University of Munich, Germany
accepté le 4 Janvier 2007
Clinical course and manifestations
A patient’s presenting symptoms and the temporal evolution of the
clinical findings may suggest the correct diagnosis. In
relapsing-remitting mucous membrane pemphigoid, symptoms and signs
typically evolve over a period of several weeks, stabilize, and
then often extend over many years with periods of activity followed
by quiescent phases every few months [1-4]. The disease most
commonly begins in the fifth or sixth decade of life and has a
female predominance [5, 6].
Mucous membrane pemphigoid typically starts with recurring
vesicles or bullae on either a mucous membrane (figure 1A-D) or a skin
area (figure 1E,
F) usually adjacent to one of the orifices, and exhibits a
pronounced tendency to scarring. Many patients have primary oral
involvement of gingiva, buccal mucosa, alveolar ridge, hard and
soft palate (figure
1D), tongue and lower lip. The most common oral
manifestation is desquamative gingivitis, characterized by gingival
erythema and glaze [7]. Severe involvement is manifested by
desquamation with blisters or ulcers [3]. Postinflammatory atrophy
in the mouth may imitate the white tracery of lichen planus.
Adhesions between the buccal mucosa and the alveolar process or
around the uvula and tonsillar fossae suggest the diagnosis.
Extension of the disease to the larynx or esophagus can give rise
to strictures necessitating surgical intervention [8]. Deafness
from involvement of the middle ear may develop [9].
The conjunctiva is the second most common site of involvement.
Conjunctival lesions usually start in one eye but involve the other
within a few years (figure 1A). The onset of
symptoms may be a simple catarrhal conjunctivitis which lasts for
years, with alternating periods of activity and remission.
Typically, development of the conjunctival blisters leads to
symblepharon (fusion of the bulbar and palpebral conjunctiva) (figure 1B). Patients
who have ocular involvement often present with dry eyes that result
from blocked tear gland openings, accompanied by conjunctival
scarring and inverted lashes. These complications worsen gradually
and tend to lead to corneal ulceration and consequently
opacification (figure
1C) [10, 11].
Some patients have recurring genital lesions (adhesions between
the prepuce and the glans penis, and in the female between the
labia majora) that are highly suggestive of mucous membrane
pemphigoid (figure
1E) [2, 11]. Eventually, urethral stenosis, narrowing of
the vaginal orifice, and other manifestations of external genital
dysfunction may become troublesome. Patients who have anal lesions
often present with spasm and pain on defecation [1]. Anal vesicles
and erosions can lead to scarring and in severe cases may cause
anal stenosis.
Prominent skin lesions (recurring vesicles or bullae) and
extramucosal signs only rarely dominate the clinical picture [12].
Two types of skin lesions may occur, the most common being a
generalized bullous eruption on the head and upper aspect of the
trunk similar to that of bullous pemphigoid, but of transient
nature. The second is a localized erythematous plaque, which often
manifests near affected mucosal surfaces and becomes the site of
recurring bullae with significant scarring. On the scalp,
cicatricial alopecia may develop [6]. Occasionally, patients with
widespread skin lesions present with vegetating and
vesiculo-pustular lesions (“vegetating cicatricial pemphigoid”)
[13]. Milia formation may be associated with secondary scarring
(figure 1G).
Phenotypic variants
There is a marked degree of variability in the clinical and
immunological features of mucous membrane pemphigoid suggesting the
existence of several phenotypic variants. Four major subgroups of
mucous membrane pemphigoid are characterized by distinct clinical
features and diverse target antigens may correlate with these
phenotypic variants [4].
A first group of patients shows pure ocular disease. These
patients rarely show circulating immunoglobulin (Ig) G antibodies
of IgG reactive against the classical bullous pemphigoid (BP)
antigens. It is noteworthy, however, that patients with predominant
ocular pemphigoid may produce IgG antibodies against the β4
integrin subunit [14] or IgA antibodies reacting with an as yet
uncharacterized 45 kd antigen [15]. Another group is represented by
the concomitant appearance of mucosal and skin lesions as well as
circulating IgG and IgA autoantibodies. These patients demonstrate
serologic reactivity against bullous pemphigoid (BP) antigens and
the soluble extracellular domains of BP180 [16]. The oral
pemphigoid variant BP180 includes patients with oral involvement
but no skin or other mucosal involvement. Most of these patients
show linear basal membrane zone deposits of IgG on direct
immunofluorescence, and only recently circulating antibodies
directed against an epitope within the integrin α6 subunit has been
identified [17]. Oral pemphigoid may respond to topical therapy
with glucocorticoids and tacrolimus or systemic treatment with
dapsone. Another major group includes patients with blistering at
multiple mucosal surfaces, without any cutaneous involvement.
A last subgroup is immunochemically distinct and includes
patients with anti-laminin 5 antibodies [18]. These patients have
circulating IgG autoantibodies which bind to the dermal side of
saline-split human skin (see below) and recognize laminin 5
(epiligrin), a component of the laminina lucida of the
dermoepidermal basement membrane zone. Laminin 5 is a ligand for
BP180 and also interacts with collagen VII of the anchoring
fibrils, thus connecting basal keratinocytes via the basement
membrane zone with the dermis. Patients with anti-laminin 5 mucous
membrane pemphigoid seem to have an increased risk of internal
malignancy [18, 19].
Pathological features and pathogenesis
Mucous membrane pemphigoid is a chronic immune-mediated disease
characterized by subepithelial blisters and autoantibodies directed
against specific adhesion molecules located in hemidesmosomes of
basal epidermal keratinocytes and lamina lucida of the
dermoepidermal basement membrane zone [1, 20].
The pathological hallmark of mucous membrane pemphigoid is a
subepithelial loss of adhesion, which can result in permanent
scarring of the affected area, particularly the conjunctiva [2].
Lesions have a predilection for the mucous membranes and they are
histologically indistinguishable from bullous pemphigoid.
Inflammatory cells are typically perivascular in location, but they
may diffusely infiltrate the stroma. The composition of the
infiltrate varies depending on the stage of disease activity and
the affected site. In general, it is composed of lymphocytes,
histiocytes, scattered neutrophils and eosinophils (figure 2A) [21]; plasma
cells predominate in oral, genital and anal lesions, whereas ocular
lesions reportedly contain substantial numbers of mast cells. In
ocular lesions, extensive fibrin deposition has been found that may
sustain a continuous pathologic wound healing process; fibrosis is
present in more developed lesions, in which the stroma is being
degraded [21-24].
Ultrastructural analysis has demonstrated that blister formation
occurs within the lamina lucida. In ocular lesions, the normal
loosely-connected conjunctival epithelial cells become closely
interconnected with increased numbers of desmosomes [25, 26].
Early symptoms of mucous membrane pemphigoid are widely believed
to result from an antibody-mediated process of epithelial
detachment, although the underlying molecular mechanisms are
largely unknown [20]. Experimental in vivo and in vitro models of
blister formation suggest that the autoantibodies target adhesion
molecules within the basal membrane, interfering with their
structural integrity and function [27, 28]. In some lesions,
autoantibodies may impair keratinocyte adhesion through steric
hindrance or by eliciting a complement-mediated inflammatory
reaction at the basement membrane zone [29]. In others, additional
amplification factors including inflammatory cytokines or activated
CD4+ T cells may be necessary to induce the disruption
of the basement membrane zone.
Collectively, the patterns of epithelial detachment are
heterogeneous among patients, but homogenous within active lesions
from the same patient. Consequently, mucous membrane pemphigoid may
not be a distinct disease entity, but rather a series of syndromes
with different causes and pathogenetic mechanisms (e.g. antibody-
and complement-mediated injury, cellular-mediated immune injury, or
primary keratinocyte abnormality). Translationed evidence suggests
that IgG autoantibodies are the initiators of the immune
pathogenesis since IgG titers against BP180 and laminin 5 were
found to relate to the clinical activity of the pemphigoids, but
also IgG antibodies against laminin 5 in mucous membrane
pemphigoid, as recently suggested [30, 31].
Etiology
Unequivocal evidence indicates that genetic and environmental
factors have a substantial effect on susceptibility to mucous
membrane pemphigoid. Common major histocompatibility complex (MHC)
class II markers and extended MHC haplotypes have been found in
distinct clinical variants of mucous membrane pemphigoid, including
HLA-DR4, -DR5, -DQw3, -A2, -B8, -B35, and -B49 [32]. Since 1989, it
has been recognized that the presence of the HLA-DR4 allele
substantially increases the risk of ocular disease [32, 33].
Furthermore, a prevalence of HLA-DQB1*0301 was first described in
patients with pure ocular mucous membrane pemphigoid [34-36]. This
allele, however, was later found to be associated with all clinical
sites of involvement and possibly to be linked to antibasement
membrane IgG production. Interestingly, these studies also
suggested a role for this allele in disease severity [37].
Epidemiological evidence to support the premise of an underlying
genetic factor comes from the observation that patients with mucous
membrane pemphigoid have a higher prevalence of other autoimmune
diseases [33]. Recent studies, however, have shown that monozygotic
twins are discordant for mucous membrane pemphigoid which argues
against genetic susceptibility as the only major risk factor of the
disease [38]. The nature of putative environmental factors remains
unclear in most cases. According to the concept of molecular
mimicry, antibodies to viruses or drugs with structural
similarities to an endogenous antigen within the basal membrane
zone may cause an autoimmune process. The availability of
epithelial basement membrane zone antigens for immune processing
may also be influenced by severe mucosal injury, for example from
burns and severe drug eruptions such as Stevens-Johnson syndrome
[39]. Furthermore, the involvement of different tissues in mucous
membrane pemphigoid may be determined by factors within the local
environment. However, each of the reported observations has
potential confounders that preclude a definite conclusion regarding
the importance of genetic or environmental factors.
Immunological features
Immunopathological techniques may be helpful in characterizing the
underlying pathogenetic processes in mucous membrane pemphigoid.
Direct and indirect immunofluorescence are sensitive but
non-specific indicators for mucous membrane pemphigoid, because
findings are often indistinguishable from those seen in patients
with other subepithelial blistering diseases. Immunochemical
techniques, including immunoblotting, immunoprecipitation and
enzyme-linked immunosorbent assay (ELISA), have simplified the
diagnostic process and have identified novel protein targets
recognized by autoantibodies in different subgroups of mucous
membrane pemphigoid. These novel, more refined diagnostic
techniques, however, are not yet commercially available, but can be
performed by research laboratories in specialized academic centers.
ELISA with recombinant BP180 and native laminin 5 have been
recently established; a BP180-NC16a-ELISA is commercially available
(MBL, Japan).
Direct immunofluorescence
In the vast majority of patients (80-100%) with mucous membrane
pemphigoid, direct immunofluorescence (DIF) of perilesional skin or
mucosa displays a linear, continuous band along the basement
membrane zone of IgG (figure 2B) and/or
complement (C3), and occasionally of IgA [29, 40-43]. DIF is
helpful in characterizing the underlying pathologic processes in
mucous membrane pemphigoid but the findings are not diagnostic.
Bullous pemphigoid, herpes gestationis, epidermolysis bullosa
acquisita and bullous systemic lupus erythematosus can all display
similar DIF patterns, and further evaluation is necessary. The best
DIF results are obtained from perilesional mucosal biopsies, but
perilesional skin specimens may also be used. In patients with
exclusive ocular disease, a conjunctival biopsy should be performed
for DIF to establish the diagnosis of mucous membrane pemphigoid as
early as possible.
Indirect immunofluorescence
It is currently well-established that the sensitivity of indirect
immunofluorescence (IIF) can be increased by using salt-split
normal skin or oral mucosa as a substrate. Circulating
anti-basement membrane zone IgG antibodies binding to the epidermal
side of salt-split skin and mucosa have been found in more than 50%
of patients with mucous membrane pemphigoid and are generally
associated with anti-BP180 IgG (figure 2C) [44]. Patients
with anti-laminin 5 mucous membrane pemphigoid have IgG antibodies
that bind to the dermal (figure 2E) or epidermal
and dermal (figure
2D) side of salt-split human skin [18]. Blister mapping
with type IV collagen is another useful diagnostic technique,
because it allows determination of where the disruption of the
basement membrane has developed. Typically, in mucous membrane
pemphigoid the blister is located within the lamina lucida.
Utilizing the blister mapping technique mucous membrane pemphigoid
can be distinguished from epidermolysis bullosa acquisita, which
may have a similar, mucous membrane-dominated clinical picture.
However, in epidermolysis bullosa acquisita the blister is formed
within the sub-lamina densa region [45].
The clinical subsets of mucous membrane pemphigoid have been
shown to vary in their IIF sensitivity. Positive results were found
in 81% of patients with mucocutaneous disease, 18% of patients with
mucosal disease only, and 7% of patients with ocular disease only
[4]. Korman and Watson developed a technique that utilizes
concentrated serum as substrate in salt-split IIF studies to detect
very low titer antibodies in patients with suspected but previously
unproven autoimmune-mediated diseases of the mucous membranes [46].
An analysis using an indirect enzyme-linked immunosorbent assay
with monoclonal antibodies identified IgG1 and IgG4 as the main IgG
subclasses [47].
Immunoelectron microscopy
Immunoelectron microscopy has identified two distinct patterns with
immune deposits either in the lower lamina lucida and lamina densa
or in the area of hemi-desmosomes and basal keratinocyte plasma
membranes [48-50]. Again, immunoelectron microscopic studies
underline the heterogeneity within the spectrum of mucous membrane
pemphigoid. Patients with IgG binding to the epidermal side had IgG
autoantibodies localized to the hemidesmosomes and the basal
keratinocyte plasma membranes and negative immunoprecipitation. In
contrast, patients with IgG binding to the dermal side of
salt-split skin in IIF had IgG autoantibodies at the interface
between the lower lamina lucida and the lamina densa and
immunoprecipitated laminin 5 (epiligrin) [48].
Target autoantigens
Mucous membrane pemphigoid displays substantial immunological
complexity, and several distinct antigen-antibody interactions are
implicated. Immunochemical techniques have identified laminin 5,
bullous pemphigoid antigen 2 (BP180 or type XVII collagen), and the
β4 integrin subunit as the major targets of autoantibodies in
mucous membrane pemphigoid (figure 3):
Laminin 5 (epiligrin), an adhesion molecule composed of α3, β3
and γ2 chains, is localized to anchoring filaments within the
lamina lucida and acts as a ligand for α3β1 and α6β4 integrins as
well as BP180 [51-53]. It also binds the NC domain of type VII
collagen, thereby linking the hemidesmosomes of basal epidermal
keratinocytes (via α6β4 integrin and BP180) and the anchoring
fibrils of the dermis (via type VII collagen). Experimental
evidence indicates that autoantibodies against laminin 5 interfere
with the adhesive function of this molecule causing detachment of
keratinocytes from the basal membrane zone. By the use of
immunoprecipitation it has been demonstrated that mucous membrane
pemphigoid patients with anti-laminin 5 autoantibodies may also
have autoantibodies against laminin 6, which shares the same α3
subunit suggesting that both are co-targets for these
autoantibodies [54, 55]. Although some studies suggest that
patients with anti-laminin 5 antibodies may represent a minority of
patients with mucous membrane pemphigoid, further work will be
necessary to clarify this point. Interestingly, one case of mucous
membrane pemphigoid has been reported with autoantibodies directed
against both laminin 5 and BP180, which indicates a possible role
for epitope spreading within these ligands in the dermoepidermal
basement membrane zone [56].
Bullous pemphigoid antigen 2 (BP180 or type XVII collagen) forms
a part of the anchoring filament complex together with laminin 5,
and also appears to function as an adhesion molecule [57]. BP180
has been shown to span the lamina lucida and to interact with
laminin 5 in the lamina densa. Immunoblotting studies have
identified at least two epitopes on the extracellular domain of
BP180 recognized by mucous membrane pemphigoid autoantibodies
located in the NC16a domain and the COOH-terminus which are also
targets recognized by autoantibodies in bullous pemphigoid [30, 31,
58]. Electron microscopy localized BP180 autoantibodies of mucous
membrane pemphigoid at the lower lamina lucida and lamina densa,
whereas BP180 autoantibodies of bullous pemphigoid were found at
the upper lamina lucida immediately below the hemidesmosome [59].
The different localization of target epitopes may help to explain
the fact that lesions in bullous pemphigoid are not scarring,
whereas mucous membrane pemphigoid has a propensity for scarring
and tissue destruction. Possibly, in mucous membrane pemphigoid the
basement membrane zone is disrupted at a location deeper than in
bullous pemphigoid, resulting in an inflammatory response in the
area of the lamina densa. Further investigations will be needed to
determine the precise mechanism by which scarring in mucous
membrane pemphigoid occurs.
The β4 integrin subunit in association with the α6 subunit forms
a transmembrane integrin that is an integral part of the epidermal
hemidesmosome and is involved in signal transduction [17, 60].
Autoantibodies directed against the β4 integrin subunit are
presumably pathogenic in a subgroup of patients with ocular mucous
membrane pemphigoid [14, 61]. In addition, immunoblotting revealed
168 kd and 45 kd antigens in mucosal pemphigoid that have to be
further characterized [15, 62].
In summary, there is evidence that the autoantibodies in mucous
membrane pemphigoid interfere with the adhesive function of their
target molecules causing detachment of keratinocytes from the basal
membrane zone [20, 21]. Supporting evidence comes from the
observation that mutations in the genes encoding for the
polypeptide chains of these molecules cause the lethal (laminin 5)
and also non-lethal variants (laminin 5, BP180,β4 integrin subunit)
of junctional epidermolysis bullosa [63-65]. These severe,
inherited subepidermal blistering diseases also affect the skin,
oropharynx and other epithelial-lined tissues and are associated
with secondary atrophy (scarring).
Diagnosis and prognosis
The diagnosis of mucous membrane pemphigoid is difficult and
requires the correlation of clinical, histological and
immunopathological criteria. Mucous membrane pemphigoid may be
suggested clinically by a chronic relapsing course and typical
symptoms, but immunopathological and immunochemical studies are
essential to exclude other immune-mediated blistering diseases [21,
30, 66]. Thus, bullous pemphigoid, epidermolysis bullosa acquisita,
linear IgA bullous disease and bullous systemic lupus erythematosus
can be identified by appropriate immunopathological and
immunochemical studies, including immunoprecipitation and
immunoblotting [66-72]. Utilizing immunoblot technology, the
detection of different target epitopes may clarify the diagnosis in
patients having autoantibodies against the same basement membrane
antigen.
Probably through immunological effects, a number of drugs
(topical glaucoma medications, clonidine, practolol) have been
found to be capable of producing an eruption strikingly similar to
mucous membrane pemphigoid, but limited only to the eyes [73, 74].
The MHC class II genes associated with this so-called pseudo-ocular
pemphigoid are different from those with ocular mucous membrane
pemphigoid and there are definitive serological differences
[74].
Table 1 provides a representative
list of findings in other autoimmune bullous skin disorders that
are clues to specific diagnoses. When the initial evaluation does
not suggest a definite diagnosis, repeated mucosal or skin biopsies
and immunoserological analyses after several months are
advised.
The evolvement of symptoms and the clinical course of mucous
membrane pemphigoid in an individual patient is largely
unpredictable. However, a combination of both initial clinical
score and initial IIF data may provide valuable prognostic
information [75]. Irreversible epithelial injury and scarring of
the mucosal surfaces may result from repeated episodes of disease
flares and the ability of corticosteroids to speed recovery from
relapses often diminishes with time. Persistent signs of epithelial
injury are fibrous adhesions of the upper aerodigestive tract or
corneal opacities, and the majority of patients with eye
involvement eventually develop amaurosis [76].
Studies on the natural history of the disease have provided
important prognostic information that is useful in the assessment
and management of mucous membrane pemphigoid. Frequent relapses in
the first years, a progressive course from the onset, and early
permanent ocular lesions are predictive of a more severe clinical
course [4, 76]. Patients with serious secondary complications
(recurrent infection and malnutrition) have a poor prognosis. Life
expectancy may be shortened slightly; in rare cases, patients with
fulminant disease die within months after the onset of disease.
Table 1 Differential diagnosis of mucous membrane
pemphigoid (MMP)
|
Bullous pemphigoid (BP)
|
|
Clinical findings: Usually non-scarring lesions (tense bullae)
primarily affecting the skin and only rarely the oral mucosa
(10-20%)
|
|
Histology: Subepidermal blister, eosinophilic spongiosis, mixed
perivascular and interstitial cell infiltrate
|
|
DIF: Linear deposition of IgG (50-90%) and complement (C3) at the
basement membrane zone
|
|
IIF: Circulating IgG (90%) antibodies binding to the epidermal and
rarely (< 10%) the dermal side of salt-split skin
|
|
Immunoblotting and immunoprecipitation: 180-kd (BP180) and/or
230-kd antigen (BP230)
|
|
Blister mapping: Intra-lamina lucida split formation
|
|
Epidermolysis bullosa acquisita (EBA)
|
|
Clinical findings: Localized eruption of mainly non-inflammatory
blisters at sites of trauma with secondary atrophy and milia or
widspread eruption of inflammatory blisters involving flexural
surfaces (BP-like phenotype).
|
|
Mucous membranes frequently involved (> 50%) (MMP-like
phenotype)
|
|
Histology: Subepidermal blister with a mixed cellular
infiltrate
|
|
DIF: Linear deposition of IgG (100%) or IgA (< 10%) and C3
(100%) at the basement membrane zone
|
|
IIF: Circulating IgG antibodies binding to the dermal side of
salt-split skin (50%)
|
|
Immunoblotting and immunoprecipitation: 290-kd antigen (type VII
collagen)
|
|
Blister mapping: Sub-lamina densa blister
|
|
Linear IgA bullous disease (LABD)
|
|
Clinical findings: Generalized tense bullae on normal or
erythematous skin, often sausage-shaped and in herpetiform
clusters. Oral and ocular lesions occur in 10-20%
|
|
Histology: Subepidermal blister with a mixed cellular infiltrate
and occasionally papillary neutrophilic microabscesses
|
|
DIF: Linear deposition of IgA (100%) and C3 at the basement
membrane zone
|
|
IIF: Circulating IgA antibodies usually binding to the epidermal
(90%) or dermal (10%) side of salt-split skin
|
|
Immunoblotting and immunoprecipitation: 97-kd, 180-kd (BP180),
230-kd (BP230), 285-kd, 290-kd antigen (type VII collagen)
|
|
Blister mapping: Intra-lamina lucida or sub-lamina densa (type VII
collagen) blister
|
|
Bullous systemic lupus erythematosus (Bullous SLE)
|
|
Clinical findings: Rare, non-scarring, vesiculobullous skin lesions
usually in a herpetiform pattern. Four or more ARA criteria of
systemic lupus erythematosus
|
|
Histology: Subepidermal blister with a mixed inflammatory cell
infiltrate at the dermoepidermal junction and neutrophilic
microabscesses in dermal papillae
|
|
DIF: Linear or mixed linear-granular deposition of IgG (100%), C3
(80-100%), IgA (70%) and/or IgM (50%)
|
|
IIF: Occasionally circulating IgG antibodies usually binding to the
dermal side of salt-split skin
|
|
Immunoblotting and immunoprecipitation: 290-kd antigen (type VII
collagen)
|
|
Paraneoplastic pemphigus (PNP)
|
|
Clinical findings: Ocular and oral blisters and erosions, similar
to those in mucous membrane pemphigoid, in patients with underlying
malignancy (lymphoma, thymoma, etc.). Generalized skin lesions
similar to pemphigus, erythema multiforme or lichen planus
|
|
Histology: Features of pemphigus and erythema multiforme-like or
lichenoid interface dermatitis
|
|
DIF: Binding of IgG to the cell surface of stratified squamous
epithelia or in a linear pattern at the basement membrane zone
|
|
IIF: Circulating IgG antibodies reactive with the cell surface of
simple or transitional epithelia
|
|
Immunoblotting and immunoprecipitation: desmoglein 1, desmoglein 3,
plakins (desmoplakin I and II, envoplakin, periplakin), 180-kd
(BP180), 230-kd (BP230), 210-kd antigen, 170-kd (not yet identified
antigen)
|
|
Pseudo-ocular pemphigoid
|
|
Clinical findings: Scarring ocular lesions, most commonly
uni-ocular. Unusual complication of long-term use of topical
eyedrops (glaucoma treatment) often in diabetic patients.
|
|
Histology: Indistinguishable from cicatricial pemphigoid
|
|
DIF, IIF, and immunochemical findings: Negative
|
Treatment
Principles of therapy
Patients with mucous membrane pemphigoid face enormous prognostic
uncertainty, and they must become well informed about their
disorder. This is perhaps best accomplished with a
multidisciplinary approach involving dermatologists,
ophthalmologists, otolaryngologists and gastroenterologists with
expertise in mucous membrane pemphigoid. Treating physicians must
continually assess the need for psychological support for patients,
since visual impairment, chronic pain, difficulty in eating, and
other physical aspects of the disease have a major impact on the
patient’s quality of life. With the use of systemic
corticosteroids, blistering formation commonly ceases within
several days. Prednisone is the most useful drug, because of its
potent anti-inflammatory and immunosuppressive effects, and rapid
effects can be seen at a dose of 1 mg/kg daily [77, 78]. Dapsone as
an adjuvant has a steroid-sparing effect [79-81]. In addition,
azathioprine 1-2 mg/kg daily and mycophenolate mofetil 2-3 g/daily
are effective [82, 83]. More aggressive treatment with
cyclophosphamide 1-2 mg/kg daily is required in severe ocular
mucous membrane pemphigoid or primary progressive course of disease
[84-86]. Because surgical intervention may provoke disease
exacerbation, it should only be performed in patients in whom
mucous membrane pemphigoid is fully controlled by medical therapy.
Relapsing mucous membrane pemphigoid and the management of
symptoms
The treatment of patients with relapsing disease depends on the
extent and severity of the disease and requires careful
consideration of the tissues involved.
Ocular Lesions. The extent and progression of ocular disease as
well as treatment options can be monitored according to the staging
system of Foster [11]. A potentially useful topical therapy for
ocular lesions is tacrolimus [87], although most patients with
ocular pemphigoid require systemic therapy. Oral corticosteroids
(for example a brief course of oral methylprednisolone) are often
used to treat clinically significant relapses of ocular disease in
an attempt to hasten recovery. The use of dapsone with or without
corticosteroids has also been recommended as a first-line therapy
for patients with moderate ocular disease [79, 88]. The combination
of corticosteroids and cyclophosphamide is indicated for severe
ocular disease [89]. Intralesional corticosteroid injections may
produce short-term remission, but lack long-term benefits and even
may induce cataract formation [90]. Topical corticosteroids are
ineffective in controlling the progression of disease and should be
avoided for treatment of acute relapses. Frequent lubrication with
artificial tears is helpful, and the lids and conjunctiva should be
controlled regularly to exclude bacterial infections.
Oral Lesions. Mild disease limited to the oral cavity may be
initially managed with topical therapies and the occasional use of
systemic corticosteroids during exacerbation [1, 2, 91]. Topical
FK506 (tacrolimus) have also been shown to be of benefit,
especially when used under dentures which facilitate application
and provide an occlusive effect that increases potency [92, 93].
Local anesthetics (e.g. viscous lidocaine) used several times daily
for rinsing the mouth may alleviate mouth pain and difficulties in
swallowing [94]. In severe oral disease, oral corticosteroids
together with dapsone or mycophenolate mofetil are needed [83, 88].
Careful mouth hygiene and avoidance of trauma is important to
prevent infection.
Esophageal and laryngeal lesions. Systemic treatment with
prednisone and cyclophosphamide is necessary for patients with
severe esophageal or laryngotracheal lesions to prevent the serious
complications of esophageal stenosis and asphyxiation [84].
Anogenital Lesions. Patients with anogenital lesions may require
in most instances systemic corticosteroids. Major morbidity occurs
when anogenital lesions result in scarring, and these patients
should be treated systemically with the combination of prednisone
and cyclophosphamide [84].
Cutaneous Lesions. Potent topical corticosteroids such as
clobetasol may be of some benefit when applied to skin lesions.
Intradermal corticosteroid injections can be performed in
recalcitrant lesions of the skin; for example triamcinolone (5
mg/mL) applied every 2 to 4 weeks with a maximum of 40 mg [3].
Systemic corticosteroids or mycophenolate mofetil may be required
in the treatment of localized skin lesions as well as for the
control of generalized bullous eruptions [83].
Progressive mucous membrane pemphigoid
Progressive disease involving mucous membranes generally requires
the use of systemic corticosteroids combined with immunosuppressive
agents for their purported steroid-sparing effects [82-84].
Given that there are no long-term studies confirming that
anti-inflammatory or immunosuppressive agents delay the progression
of disability, the treating physician must consider the patient’s
individual risk of clinically significant early disability and the
patient’s anticipated tolerance of treatment-related side effects.
Indications for systemic therapy include progressive ocular,
laryngeal or esophageal involvement and/or the presence of
progressive oral or cutaneous disease unresponsive to less
aggressive topical measures.
In a recent study in ten patients with progressive, otherwise
treatment-resistant ocular pemphigoid, intravenous immunoglobulin
(2 g/kg/month) therapy was shown to be an effective therapy, but
data on the long-term efficacy and safety of this treatment
modality are not yet available [95-97].
Control of treatment-related side effects
Systemic corticosteroids are potent anti-inflammatory and
immunosuppressive agents [21]. Their long-term use, however, has to
be limited, because of severe side effects, including increased
risk of infections, osteoporosis, hypertension, diabetes mellitus,
peptic ulcers, cataract formation, psychosis, suppression of the
hypothalamic-pituitary-adrenal axis, and pseudotumor cerebri.
Several steroid-sparing agents are used to minimize the steroid
dosage, but harbour risks of their own.
Cyclophosphamide is of great value in controlling both ocular
and oral involvement but may provoke hemorrhagic cystitis, bone
marrow suppression, infections, hair loss, sterility, amenorrhea,
and the development of secondary malignancies (bladder carcinomas
and lymphomas). The use of pulse cyclophosphamide in combination
with corticosteroids, therefore, appears to be more appropriate
[85].
Patients treated with azathioprine have an increased risk for
bone marrow suppression with acute bone marrow failure,
gastrointestinal diseases, liver damage, infections and lymphatic
malignancies [98]. In general, treatment with azathioprine can be
considered as safe; thiopurine methyl transferase serum activity
should be determined prior to initiation of treatment to avoid
severe side effects such as pancytopenia and hepatopathy.
Because of its lower toxicity profile and its selective
mechanism of action, mycophenolate mofetil is a promising advance
in the immunotherapy of mucous membrane pemphigoid.
Myelosuppression, hepatotoxicity, or nephrotoxicity and minor signs
of gastrointestinal intolerance may also occur. An increased
incidence of bacterial or viral infections has not been
demonstrated [83].
Major toxicities of dapsone include methemoglobinemia,
hemolysis, leukopenia, hypersensitivity syndrome, hepatitis,
nephrotoxicity, and peripheral neuropathy. Before onset of dapsone
treatment, patients require a screening for their
glucose-6-phosphatase dehydrogenase activity to prevent severe side
effects [99].
Treatment of complications
The management of mucous membrane pemphigoid involves not only the
control of the disease process but also the treatment of
complications and the restoration of function in cases with
disabilities or mutilations [100]. In patients with ocular mucous
membrane pemphigoid, entropion, trichiasis, symblepharon formation,
and keratinization of the cornea may develop [11]. For the
treatment of severe ocular lesions, mucous membrane or corneal
grafts, allograft limbal or amniotic transplantations,
keratoprosthesis and tarsorrhaphy supplemented with the use of
serum-derived tears should be considered [101-103].
Esophageal and laryngeal strictures may develop in patients with
mucous membrane pemphigoid of the upper aerodigestive tract. In
these cases dilation of the esophagus or resection of laryngeal
stenosis becomes necessary. Tracheostomy may prevent asphyxiation
in patients with severe tracheal involvement.
There are moderately effective treatments for several of the
complications of genital mucous membrane pemphigoid. Surgery may
occasionally be required for severe scarring involving the urethral
or anal orifices. Sexual dysfunction and chronic pain are common
and may respond to appropriate symptom-based treatment
strategies.
Localized skin erosions on the scalp or face rarely respond to
medication but can be healed permanently by full thickness skin
grafts [104].
Challenges in basic research and future directions
Mucous membrane pemphigoid remains a challenging disease to study
because the cause is unknown, the pathophysiological mechanisms are
diverse, and the chronic, unpredictable course of the disease makes
it difficult to determine whether the favorable effects of
short-term treatment will be sustained.
Clinical trials should be designed to evaluate whether
combinations of drugs with different mechanisms of action are more
effective than single agent therapy and to identify promising
agents as well as those that are toxic or ineffective. So far, most
published studies are small (usually including fewer than twenty
patients per group) and brief (less than three years of follow-up)
and there is an urgent need to determine whether the currently
approved, effective immunomodulatory therapies reduce the degree or
delay the development of disability in patients with severe
esophageal or ocular disease and progressive mucous membrane
pemphigoid [82-84]. Although no controlled clinical trials have
proven the usefulness of intravenous immunoglobulins, significant
clinical experience supports this approach [95-97]. Other
immunomodulatory approaches include inhibitors of pro-inflammatory
cytokines, such as tumor necrosis factor-α. Two recent reports have
demonstrated that the tumor necrosis factor-α inhibitor,
etanercept, can be successfully applied in patients with mucous
membrane pemphigoid [105, 106]. Other approaches focus on
inhibiting the de novo-synthesis of pathogenic autoantibodies by
depletion of peripheral B cells with the monoclonal anti-CD20
antibody, rituximab [107, 108].
Acknowledgements
Financial support: none
Conflict of interest: none
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