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The management of mucous

membrane pemphigoid
and pemphigusdth_1323 268..280
Richelle M. Knudson, Amer N. Kalaaji & Alison J. Bruce
Department of Dermatology, Mayo Clinic/Mayo Clinic College of Medicine,
Rochester, Minnesota
ABSTRACT: Mucous membrane pemphigoid and pemphigus vulgaris are autoimmune blistering dis-
orders in which many similar drugs and therapeutic strategies are utilized. In general, localized disease
can be treated with topical agents. In contrast, patients with more severe and progressive disease
usually require a combination of systemic corticosteroids and immunosuppressive medications. Oral
corticosteroids, adjuvant immunosuppressive agents, antibiotics such as dapsone and immunomodu-
latory procedures like intravenous immunoglobulin are the main therapeutic agents used in treating
these two disorders. Much of the morbidity and mortality associated with these disorders are related to
the sites involved and to the drugs used for therapy. Treatment should be individualized based on
severity, extent, and rate of progression of disease, comorbidities, and age of the patient. Serum levels
of specic autoantibodies and indirect immunouorescence titers, in certain cases, can be used to
monitor response to therapy.
KEYWORDS: cicatricial pemphigoid, mucous membrane pemphigoid, pemphigus vulgaris, therapy
Mucous membrane pemphigoid (MMP) and pem-
phigus vulgaris (PV) are autoimmune blisteringdis-
orders that can have a signicant impact on a
patients quality of life. Both are characterized by
autoantibodies directed at different regions of the
epithelium. Many of the same drugs and therapeu-
ticstrategies areutilizedinthesetwodiseases. There
are some differences, however, that arise due to
their different characteristics. We reviewthe impor-
tant characteristics of MMP and PV and provide
treatment recommendations. Treatment of MMP
and PV utilizes both topical and systemic therapy.
Treatment should be individualized based on
severity, extent, andrate of progressionof disease as
well as patient comorbidities including age.
MMP is a chronic inammatory subepithelial blis-
tering disease. The incidence of MMP is estimated
to be between 1 in 12,000 and 1 in 20,000 in the
general population with a predilection for the
elderly (60 to 80 years, mean age 62 to 66 years)
(13). However, children may also be affected (4,5).
MMP is characterized by the linear deposition of
IgG, IgA, and/or C3 along the epidermal basement
membrane zone in mucosal and/or cutaneous
biopsy specimens (6). Numerous target antigens in
the hemidesmosome have been associated with
MMP. These include bullous pemphigoid (BP)
antigen 180 (also known as collagen XVII and
bullous pemphigoid antigen [BPAG]2), BP antigen
230 (also known as BPAG1), laminin 5 (laminin
332), laminin 6 (laminin 311), and integrin b4
subunit. The most commonly affected areas are the
Address correspondence and reprint requests to: Alison J.
Bruce, MD, Mayo Clinic, Department of Dermatology,
200 First Street SW, Rochester, MN 55905, or email:
The authors have no conict of interest.
Dermatologic Therapy, Vol. 23, 2010, 268280
Printed in the United States All rights reserved
2010 Wiley Periodicals, Inc.
ISSN 1396-0296
oral and ocular mucosa, but the nasopharynx,
esophagus, larynx, and anogenital mucosa may
also be involved (FIGS. 13). The consequences of
this disease can be severe, including airway con-
striction secondary to laryngeal webs, change in
vision and blindness secondary to ocular scarring,
and urinary and sexual dysfunction (6). The skin of
the face, scalp, extremities, and umbilicus can also
be involved. Mucous membrane lesions can occur
in 10 to 40% of patients with bullous pemphigoid,
but it is not usually a presenting symptom. In con-
trast, oral involvement is often the presenting
symptom of PV (7).
MMP can be localized or extensive and can
affect both cutaneous and mucosal surfaces.
Depending on the area most affected, pemphigoid
can broadly be divided into cutaneous (bullous)
pemphigoid and mucosal pemphigoid, with some
overlap between these two entities. Historically,
mucosal disease has been given many names
depending on the region involved (e.g., gingival,
oral, and ocular, etc.). Further classication has
been based on the tendency to scar hence the
term cicatricial pemphigoid. This latter term is
often used interchangeably with ocular pemphig-
oid as ocular involvement classically leads to scar
formation. However, cutaneous involvement can,
on occasion, produce scarring, as seen with a local-
ized form of pemphigoid involving the head and
neck region known as Brunsting-Perry pemphig-
oid. Furthermore, on rare occasions, oral involve-
ment may also produce scarring, usually at the
commissures of the mouth, although this is not
As mentioned previously, there are numerous
target antigens that have been associated with
MMP. It is now recognized that MMP has several
subsets based on the target antigen involved and,
in reality, likely represents a heterogeneous group
of disorders characterized by a similar subepithe-
lial blistering pathogenesis. Regardless of target
antigen, the clinical result is blister formation. On
mucosal surfaces, this is usually appreciated as a
sloughing or desquamative process. The location
(depth) of the target antigen within the basement
membrane zone may explain why some subsets
portend greater scarring.
On a practical level, therefore, the authors prefer
the term mucosal pemphigoid to include all the
mucosal subtypes, with further descriptors of loca-
tion used in individual patients. The authors also
avoid using the term cicatricial pemphigoid and
prefer to classify disease based on the location, rec-
ognizing that certain regions of involvement have a
greater tendency for scar formation.
Because of the variability in presentation, the
extent of mucosal pemphigoid determines the
approach to therapy. Localized disease may be
easier to control. However, it can progress to exten-
sive disease, which is typically more difcult to
control. Extensive disease can progress rapidly,
FIG. 1. Erythematous, swollen attached gingiva. Note area of
desquamation characteristic of desquamative gingivostoma-
titis in a patient with MMP.
FIG. 2. H&E, MMP: Subepithelial separation.
FIG. 3. Direct immunouorescence, MMP: Linear deposi-
tion of C3 and IgG along the dermoepidermal junction.
Mucous membrane pemphigoid and pemphigus
necessitating more aggressive therapy. Topical
therapy with corticosteroids and/or tacrolimus,
with occasional use of systemic corticosteroids
during exacerbations, is often the appropriate
therapy for those with limited disease. Such disease
has often been termedbenign mucous membrane
pemphigoid, but this terminology is not favored,
as the disease is not benign in its potential
sequelae. For example, severe mouth pain can limit
oral intake, adversely affecting nutritional well-
being. Patients with extensive disease require a
combination of systemic corticosteroids and
immunosuppressive or anti-inammatory medi-
cations (7).
Pemphigus is a group of autoimmune intraepithe-
lial blistering diseases that affect the skin and
mucous membranes. Subtypes include PV, pem-
phigus foliaceus, pemphigus vegetans, pemphigus
erythematosus, and paraneoplastic pemphigus.
The various subtypes are associated with different
target antigens. In mucosal-dominant PV, the
target antigen is desmoglein 3, whereas in the
mucocutaneous type, the target antigen is both
desmoglein 1 and desmoglein 3. In contrast, the
target antigen is desmoglein 1 in pemphigus folia-
ceus and pemphigus erythematosus. Numerous
target antigens have been described with paraneo-
plastic pemphigus. These include desmoglein 3,
desmoglein 1, plectin, desmoplakin I, desmoplakin
II, BPAG1, envoplakin, and periplakin.
The incidence of PV is estimated to range from
one to six new cases per million per year, with the
mean age of onset being 50 to 60 years. The disease
is precipitated by IgG autoantibodies binding to
desmoglein 3 and/or desmoglein 1. PV is the most
common subtype, frequently presenting with oral
involvement including desquamative gingivosto-
matitis or cheilitis due to the erosion of the fragile
mucosal surface (FIGS. 47). Seventy to ninety
percent of patients with PV develop erosions of the
oral mucosa; oral involvement is the presenting
sign in 50% of patients with PV. Other mucosal sur-
faces include the throat, esophagus, conjunctivae,
nasal mucosa, vagina, vulva, penis, and anus (8).
More than half of patients develop skin involve-
ment with accid bullae or erosions. In patients
with pemphigus foliaceus, blisters are limited to
cutaneous surfaces, without mucosal involvement.
Pemphigus erythematosus, a localized form of
pemphigus foliaceus, is characterized by involve-
ment of the malar area of the face and seborrheic
regions. Pemphigus vegetans is a rare variant of PV
characterized by vegetative granulating plaques
involving intertriginous areas. Paraneoplastic
pemphigus usually presents with severe stomatitis
that extends onto the vermilion lip (FIGS. 89).
Before corticosteroids were introduced in the
1950s, the mortality of PV was approximately 75%
FIG. 4. Erythema and desquamation of the attached gingiva
and lips typical of PV.
FIG. 5. Erythema, ulceration and erosions of the palate in a
patient with PV.
FIG. 6. H&E, PV: Acantholysis and intraepithelial separation
with tombstoning of basal keratinocytes.
Knudson et al.
(9). Today, themortality is around10%andis mostly
secondary to complications of therapy, especially
highdoses of corticosteroids usedover long periods
of time to maintain disease control (913).
Overview of therapy of MMP and PV
Topical therapy may be minimally effective, and
although adequate for mild disease, control of
more severe disease frequently requires systemic
therapies. Systemic corticosteroids may be needed
for optimal disease control, with or without
the addition of adjuvant systemic medications
(Tables 1 and 2).
Systemic corticosteroids are the rst line of
therapy for extensive and rapidly progressive MMP
as well as for more severe PV. Adjuvant drugs are
often used for their steroid-sparing effects and may
be used alone to maintain remission. Immunosup-
pressive agents such as azathioprine, mycopheno-
late mofetil (14,15), cyclophosphamide (6,16,17),
and methotrexate (18) have been used in MMP for
their steroid-sparing effects. These four drugs
along with cyclosporine have also been used in PV
(1931). Antibiotics such as dapsone (7,17,32) and
combinations of tetracycline and nicotinamide
(13,33,34) have demonstrated efcacy in both
FIG. 7. Direct immunouorescence, PV: cell surface deposi-
tion of IgG and C3.
FIG. 8. Erosions andcrusting of the lips inpatient withpara-
neoplastic pemphigus.
FIG. 9. Direct immunouorescence, paraneoplastic pem-
phigus: cell surface deposition of IgG and C3 in combination
with linear or granular deposition of IgG and C3 at the base-
ment membrane zone.
Table 1. Recommendations for the treatment of
mucous membrane pemphigoid
Mild, local oral disease
1. Moderate to high potency topical corticosteroids
can be used initially (two to three times daily).
2. If the response to topical therapy is not adequate,
dapsone therapy can be initiated (125 to 150 mg
daily, gradually titrated upward).
3. Alternatively, tetracycline (1 to 2 g per day) and
nicotinamide (2 to 3 g per day) can be used.
4. If disease is not adequately controlled with the
above regimens, oral corticosteroids (prednisone
1 to 2 mg/kg per day) +/- an adjuvant
immunosuppressive agent can be used.
Ocular involvement, severe involvement
, and/or
rapidly progressive disease
1. Initial treatment with oral corticosteroids
(prednisone 1 to 2 mg/kg per day) plus adjuvant
immunosuppressive therapy (azathioprine 1 to
2 mg/kg per day, mycophenolate mofetil 2 to
2.5 g per day divided into two doses, or
cyclophosphamide 12 mg/kg per day) is
2. When the disease becomes adequately controlled,
prednisone is tapered while continuing adjuvant
3. IVIg can be used in resistant disease and in rapidly
progressive ocular disease which threatens vision.
4. Other modalities of therapy, such as the biologics,
can be considered in disease that has been
refractory to all other treatment options.
Severe involvement includes laryngotracheal, esophageal,
and/or anogenital disease.
Mucous membrane pemphigoid and pemphigus
MMP and PV. Gold, an anti-inammatory drug, has
been used in PV but not in MMP (13,3538). Immu-
nomodulatory procedures such as intravenous
immunoglobulin (IVIg) therapy (3949) and plas-
mapheresis (5052) may be effective in MMP or PV.
Extracorporeal photopheresis, another immuno-
modulatory procedure, has been used in PV (53
57). More recently, biologic agents, such as
rituximab (5862), etanercept (63,64), and inix-
imab (65), have been reported to be effective in the
treatment of either MMP or PV. Thalidomide (66)
and subconjunctival mitomycin C injections (67)
have been used with limited evidence in MMP. In
general, most patients with extensive disease
require long-term therapy.
Oral and ocular care
Excellent oral care has been emphasized as being
an important part of the treatment of both MMP
and PV. This consists of brushing the teeth twice
daily using a soft-bristle brush and gentle tech-
nique, ossing on a daily basis, and professional
teeth cleaning performed every 3 to 6 months.
Ahmed et al. have recommended gentle debride-
ment of necrotic mucosal tissue to prevent in-
fection (68). Thus, having a dentist involved in
the patients care is vital. Topical analgesics or
anesthetics and antiseptic mouthwashes are
recommended as further treatment. Various
elixirs containing combinations of viscous lido-
caine (Xylocaine Viscous), diphenhydramine
(Benadryl) and antacids such as Maalox can
be used as an oral rinse to decrease mouth pain
(68,69). Oral trauma can lead to the formation of
new erosions and should be avoided. Poorly tting
dentures are commonly associated with trauma to
the mucosal surface as are dry crackers or hard
candies. Patients should be evaluated to ensure
that all dental appliances t properly.
Ocular care plays a very important role in the
management of ocular MMP. Frequent lubrication
to prevent drying is recommended. This can be
achieved with preservative-free articial tears if
used more than four times daily or with any type of
articial tears if used less frequently. More viscous
solutions, such as Refresh Celluvisc or Genteal
Gel, can be used when the eyes become
extremely dry. A petrolatum-based ointment, such
as Refresh PM, can be used at bedtime. Place-
ment of lacrimal punctal plugs is recommended
if the patients do not already have occluded
puncta secondary to conjunctival scarring. Topical
cyclosporine, also known as Restasis, can be con-
sidered in patients with dry eyes, but burning can
limit compliance. It is also important to clean the
debris and exudate that can accumulate around
the eyes in order to prevent secondary infection.
Articial tears are often adequate, but if further
cleaning is necessary, buffered preserved saline
solutions, such as Eye Wash or Dacriose, can be
used. Eye involvement may result in scarring and
mechanical obstruction, potentially progressing to
blindness. Thus, even with limited or local disease,
aggressive therapy is warranted. Hence, systemic
therapies are always indicated for ocular disease.
Involving a dentist and ophthalmologist in the
management of patients with MMP and PV is very
important. Often, those with ocular MMP are
referred to dermatology by an ophthalmologist for
consideration of systemic therapy. It may also be
important to involve otolaryngology and/or gas-
troenterology if there is development of symptoms
suspicious for upper airway or esophageal involve-
ment. Patients should undergo endoscopy if symp-
toms develop and to monitor the response to
Topical corticosteroid therapy
The rst-line therapy for MMP localized to the oral
cavity, or the oral cavity and the skin, has been
Table 2. Recommendations for the treatment of
mucous membrane pemphigus vulgaris
Mild, nonprogressive oral disease
1. Moderate to high potency topical corticosteroids
can be used initially (two to three times daily).
2. Dapsone therapy (125 to 150 mg daily, gradually
titrated upward) can be introduced early.
3. Alternatively, tetracycline (2 g per day) and
nicotinamide (1500 mg per day) can be considered.
Severe mucous membrane involvement or concurrent
cutaneous involvement
1. Initial treatment with oral corticosteroids
(prednisone 0.5 to 1 mg/kg per day) plus adjuvant
immunosuppressive therapy (azathioprine 1.5 to
3 mg/kg per day, mycophenolate mofetil 2 to 2.5 g
daily divided into two doses, cyclophosphamide 50
to 200 mg per day, cyclosporine 5 mg/kg per day,
or methotrexate 10 to 17.5 mg per week) is
2. When the disease becomes adequately controlled,
prednisone is tapered while continuing adjuvant
3. IVIg is helpful in refractory cases and is used
concurrently with corticosteroids and an
4. Plasmapheresis and rituximab can be considered in
refractory cases.
Knudson et al.
topical corticosteroids. A conservative approach
has been recommended because there is less risk
of scarring in these regions (6). Some patients with
PV may have mild disease with limited inamma-
tion and erosion of the mucosal surfaces. If the
disease appears nonprogressive and restricted to
one body area such as the mouth, topical therapy
alone may be adequate. There are a few recognized
adverse effects associated with the use of topical
corticosteroids in the oral cavity. These include oral
candidiasis and reactivation of herpes simplex
virus. Oral candidiasis can be treated with anti-
fungal agents such as clotrimazole lozenges
(Mycelex), nystatin swish and swallow (Mycosta-
tin), or oral uconazole (Diucan). Clotrima-
zole lozenges are used ves times per day for 7 to 14
days. Nystatin swish and swallow is dosed at 5 mL
four times per day until the patient is asymptom-
atic for 48 hours. Oral uconazole, 100 to 200 mg
daily, is used for 7 to 14 days. If the patient has
frequent recurrent episodes of oral candidiasis,
oral uconazole 100 mg can be used twice weekly
for prophylaxis.
Corticosteroid gels or ointments, such as uoci-
nonide 0.05% (Lidex), desoximetasone 0.25%
ointment or 0.05% gel (Topicort), or clobetasol
0.05%(Temovate), can be used two or three times
per day (7). Gels are often more easily applied and
better tolerated within the oral cavity. Corticoster-
oids can be compounded in an adhesive base, such
as Orabase, to improve adherence (70). Some
patients nd this base too granular to apply effec-
tively. Thus, the authors prefer gels. Patients should
be advised to apply the topical therapy two to three
times per day initially when symptoms are severe
and to gradually taper the frequency of application
once relative improvement occurs. We recommend
using either a Q-tip or ngertip for application,
rubbing the gel or ointment into affected areas
gently for 30 seconds, and then abstaining from
eating or drinking for 30 minutes. Patients should
be made aware that such applications are typically
off-label and the products often stipulate for
external use only. A prosthetic device (such as a
dental tray) that ts over the teeth and gingiva can
be fashioned by a dentist to make application of a
corticosteroid preparation easier. When corticos-
teroids are applied under dentures or such an
appliance, their potency is increased (71). Intrale-
sional corticosteroid injections can be used in the
treatment of MMP and PV with some success.
Injection of triamcinolone acetonide (Kenalog), 5
to 10 mg/mL, every 2 to 4 weeks, is recommended
(68). Corticosteroid injections have also been used
for ocular MMP, but this usually only produces
short-term results and there is signicant risk of
cataract formation. Subconjunctival injections
should only be performed by an ophthalmologist
but are rarely used in practice. Topical corticoster-
oids should not be used alone and are not effective
in controlling disease progression in ocular MMP
Other agents used as topical therapy
Signicant response to the use of topical tacroli-
mus (Protopic) twice daily has been reported for
the treatment of MMP (7376). We have found
topical corticosteroids to be more efcacious. Fur-
thermore, a black box warning associated with tac-
rolimus states that although a causal relationship
has not been established, rare cases of malignancy
(e.g., skin cancer and lymphoma), have been
reported in patients treated with topical cal-
cineurin inhibitors. The risks of this medication
should be reviewed with the patient.
Systemic corticosteroids
Systemic corticosteroids are the rst-line therapy
for the treatment of extensive MMP, rapidly pro-
gressive MMP, or in patients with ocular, laryngeal,
esophageal, severe anogenital, or severe gingival
involvement causing loosening of the teeth (7).
Systemic corticosteroids can prevent severe com-
plications such as loss of vision, airway obstruc-
tion, urinary dysfunction, sexual dysfunction, and
loss of teeth. An initial dose of 0.75 to 1 mg/kg per
day is recommended, and this dose is continued
until the disease is brought under control.
Systemic corticosteroids are the rst-line
therapy for the treatment of severe PV. Before the
advent of corticosteroid therapy in the 1950s, PV
was uniformly fatal. Since then, the mortality of PV
has dropped signicantly, with current rates of 0
to 10% (912,25). The authors typically use 0.75
to 1 mg/kg of oral prednisone given as a single
morning dose. On occasion, higher doses of pred-
nisone may be required to achieve control.
A rapid response is usually noted once treat-
ment is initiated. Even so, treatment may be nec-
essary for an extended period of time and may be
associated with many adverse effects (77). In both
disorders, the initial dose is continued until no new
lesions develop and all lesions have healed. Once
this control is achieved, we recommend a gradual
taper of systemic corticosteroids, 5 to 10 mg incre-
ments per week, over the course of several weeks.
Consideration can be given to using alternate day
corticosteroids. However, the authors do not use
Mucous membrane pemphigoid and pemphigus
this approach whentapering corticosteroids. When
the dose is reduced to 2025 mg daily, we taper
further in smaller increments usually 1 mg every
other week as long as disease remains quiescent.
Should the disease are at any point along the
corticosteroid taper, we return to the dose used
prior to the disease are and maintain that dose for
approximately 4 weeks before proceeding with a
slower taper thereafter. We have found that
patients with PV will require many months of high-
dose systemic corticosteroid therapy before a taper
can be attempted, whereas patients with MMP can
be weaned more rapidly, irrespective of whether
adjuvant therapy is administered. Patients should
therefore be advised that systemic corticosteroids
may need to be used for several months and to
anticipate a protracted course of therapy until
adequate disease control is achieved. Furthermore,
patients should also be advised that bisphospho-
nates, calcium, and vitamin D are necessary even
early in treatment (see below).
The many side effects and the risk of long-term
corticosteroid use in older MMP and PV patients
mandate that the lowest effective dose of corticos-
teroids be used and that adjuvant therapy be
initiated early. When treatment with systemic cor-
ticosteroids is commenced, it is recommended that
an immunosuppressive agent such as azathio-
prine, cyclophosphamide, or mycophenolate
mofetil should also be started. These immunosup-
pressive agents are continued long-term, whereas
corticosteroids are tapered over 6 to 12 months.
The eventual goal is monotherapy with the immu-
nosuppressive agent.
Adjuvant management strategies are recom-
mended to protect against many of the recognized
sequelae of prolonged corticosteroid treatment.
These include use of an H2-blocker or proton
pump inhibitor for ulcer prophylaxis, as well as a
bisphosphonate (daily, weekly, or monthly), and
calcium(1000 to 1500 mg daily) and vitamin D(800
to 1000 IU daily) supplementation for osteoporosis
prophylaxis (78).
Close clinical monitoring is necessary in all
patients while on therapy. Prior to initiating any
systemic immunosuppressive agent, a complete
physical examination and age-appropriate malig-
nancy screening should be performed. Baseline
laboratory data that may be helpful in selecting a
steroid-sparing immunosuppressive agent and
monitoring for potential adverse effects include
complete blood count (CBC) with differential,
renal function tests, liver function tests (LTF),
fasting lipid prole, urinalysis, tuberculin skin test,
QuantiFERON-TB Gold test, hepatitis panel,
glucose-6-phosphate dehydrogenase (G6PD)
enzyme level (for dapsone), and TPMT enzyme
level (for azathioprine). Bone densitometry is indi-
cated for patients on a daily dose of prednisone
5 mg or more for greater than 6 months (78).
Blood pressure, blood glucose, and stool guaiac
should also be monitored (13). Prophylaxis for
Pneumocystis carinii should be considered in those
on long-term oral corticosteroids or other immu-
nosuppressives with the exception of dapsone (79).
Patients should be followed closely for signs or
symptoms of infection or malignancy. If either
occurs, treatment should be instituted early and
Adjuvant corticosteroid pulse therapy
Corticosteroid pulse therapy can be used to induce
remission in patients with severe or recalcitrant PV
(51). Corticosteroid pulse therapy involves the use
of discontinuous intravenous infusions of very
high doses of corticosteroids over a short period of
time (80). It was originally used for PV in the 1980s.
With this type of therapy, intravenous infusions of
500 to 1000 mg of methylprednisolone acetate or
100 to 200 mg infusions of dexamethasone are
given in divided doses on three consecutive days
per month as pulse therapy, in combination with
maintenance scheduled prednisone and other
immunosuppressants such as azathioprine (81).
Pulse therapy can be administered orally rather
than intravenously, with dexamethasone 100 mg
given on 3 consecutive days on a monthly basis.
Toth et al. report success of monthly glucocorticoid
pulses as monotherapy in patients with mild oral
lesions in the early stage of PV (13).
Pulse corticosteroid therapy is associated with
many side effects including mood changes, weight
gain, hypertension, severe electrolyte abnormali-
ties, myocardial infarction, cardiac arrhythmia,
and pancreatitis (82).
Antibiotics such as dapsone, other sulfonamides,
and tetracycline with or without nicotinamide are
effective in the treatment of both MMP and PV.
Dapsone can be used as rst-line therapy in
localized MMP or slowly progressing, extensive
MMP as it may take 10 to 12 weeks before produc-
ing benet (17). Dapsone can be instituted alone
or with concurrent systemic corticosteroids. If
the benet of dapsone is suboptimal, then other
immunosuppressive agents can be added. Once
remission has been achieved and maintained for
Knudson et al.
several months to years, the more aggressive
immunosuppressive agent can be tapered while
continuing dapsone, which has a more favorable
side effect prole. Although some studies have
shown no statistically signicant difference in
remission when dapsone was compared to
placebo, the authors have found dapsone to be
extremely useful in controlling mild-to-moderate
PV or MMP if introduced early in disease evolution.
Dapsone is contraindicated in patients with low
G6PD levels. In patients with normal G6PD levels,
the degree of hemolytic anemia and associated
symptoms may be reduced by gradually increasing
the dose of dapsone. Begin dapsone at 25 to 50 mg
per day for 3 days. Thereafter, the dose can be
increased by 25 mg per day every third day up to
100 mg per day. The patient should then take 100
mg per day for 7 days before increasing to a target
maintenance dose of 125 to 150 mg daily (17). This
gradual titration allows for the bone marrow to
adapt to the hemolytic insult. Doses higher than
150 mg daily usually do not produce incremental
The main side effects of dapsone include meth-
emoglobinemia, hemolytic anemia, agranulocyto-
sis, and hypersensitivity syndrome. Patients should
be counseled that dapsone causes hemolysis, and a
1- to 2-g drop in hemoglobin should be antici-
pated. Most patients tolerate this mild anemia, and
this drop in hemoglobin is not a reason to discon-
tinue therapy. Decreases in hemoglobin greater
than 2 g may necessitate discontinuation of
dapsone. A CBC with differential and reticulocyte
count should be monitored every week for the rst
4 to 6 weeks, every 2 weeks until week 12, and every
3 months thereafter once stable dosing is achieved.
Frequent monitoring of the CBC with differential
is also necessary because agranulocytosis can
occur in approximately 1 in 400 patients and
occurs most often after 8 to 12 weeks of therapy
(83,84). Dapsone hypersensitivity syndrome is an
idiosyncratic reaction characterized by fever,
generalized eruption, hepatitis, and peripheral
eosinophilia; dapsone should be immediately
discontinued. Dapsone also causes a distal motor
peripheral neuropathy, which is usually reversible
upon discontinuation. Therefore, patients should
be monitored for hand and/or leg weakness or
muscle atrophy (7).
Tetracycline, along with nicotinamide, has been
used with some success in patients with minimal
or localized MMP at a dose of 1 to 2 g of tetracycline
per day and 2 to 3 g of nicotinamide per day
(33,34). For mild PV, 2 g per day of tetracycline and
1500 mg per day of nicotinamide are used (13).
This regimens minimal side effect prole is ideally
suited for elderly patients. The adverse effects of
tetracycline include gastrointestinal upset and
phototoxicity. It should not be used inpatients with
renal impairment or in children less than 9 years
old. The adverse effects of nicotinamide include
ushing and pruritus.
Immunosuppressive adjuvant therapy
Numerous immunosuppressive agents have been
used as an adjunct to oral corticosteroids in the
treatment of MMP and PV, particularly in more
severe disease, or whendisease extends beyond the
oral cavity. Adjuvant medications are used for
many reasons. In those patients requiring the ini-
tiation of systemic corticosteroids, an immuno-
suppressive agent should be started concurrently
with the systemic corticosteroid. Adjuvant drugs
decrease the dose of systemic corticosteroids
needed to achieve disease control and facilitate
tapering. Adjuvant therapies may permit better
disease control and maintenance as corticoster-
oids are tapered. Once disease control is achieved,
the corticosteroids can be discontinued while the
immunosuppressive drug is continued. Azathio-
prine, mycophenolate mofetil, cyclophosphamide,
and methotrexate are used in the treatment of
MMP and PV. Cyclosporine is also used in the treat-
ment of PV.
Combination adjuvant immunosuppressive
and/or anti-inammatory therapies can be used
without corticosteroids. Azathioprine or mycophe-
nolate mofetil may each be used with dapsone if
use of the latter alone fails to achieve control.
Azathioprine. Azathioprine (1 to 2 mg/kg per day)
is the rst choice of adjuvant therapy in MMP,
provided the disease is not rapidly progressive or
threatening vision. Azathioprine (1.5 to 3 mg/kg
per day) is used in patients with PV (13,28). When
azathioprine and systemic corticosteroids are
used, remission rates of 2845%and mortality rates
of 1.47%have been reported (9,19,85,86). Azathio-
prine has been used alone; however, its long
latency of onset (up to 8 weeks) limits its initial use
as monotherapy (19,87). Despite the recom-
mended doses mentioned above, azathioprine
dosing should be individualized based on the
patients thiopurine methyltransferase (TPMT)
enzyme activity level (13). TheTPMT assay may not
be widely available but is available at many refer-
ence labs. The main side effects of azathioprine
include hepatotoxicity, hypersensitivity syndrome,
and neutropenia. Patients with low levels of TPMT
Mucous membrane pemphigoid and pemphigus
are at greater risk of developing neutropenia. In
patients with high TPMT levels, doses of up to 3.5
to 4 mg/kg may be needed to achieve clinical effect
(88). Regular laboratory monitoring should include
LFTs and CBC with differential.
Mycophenolate mofetil. Mycophenolate mofetil (2
to 2.5 grams per day intwo divideddoses) is usedin
combination with systemic corticosteroids in both
MMP and PV (14,15,22,88,89). Like azathioprine, it
may take 6 to8 weeks toachieve clinical effect but is
less hepatotoxic (89). Laboratory parameters (CBC
with differential, LFTs) must be monitored regu-
larly. Bothazathioprineandmycophenolatemofetil
can be used in conjunction with dapsone should
the latter provide only partial control.
Cyclophosphamide. Cyclophosphamide (1 to
2 mg/kg per day) is used in MMP when the disease
is aggressive, as it achieves efcacy sooner than
azathioprine or mycophenolate mofetil (6). Con-
current use of cyclophosphamide and systemic
corticosteroids is indicated in patients with severe
esophageal or laryngotracheal lesions, anogenital
lesions, or progressive ocular disease is to prevent
esophageal stenosis, asphyxiation, urinary and
sexual dysfunction, and blindness (16,17).
In patients with PV who cannot tolerate the oral
route, intravenous administration is used. Cyclo-
phosphamide has a steroid-sparing effect at doses
of 50 to 200 mg per day in numerous case series
(20,23,27,29,31). Cyclophosphamide has typically
been used along with systemic corticosteroids as
an adjuvant immunosuppressive medication.
Cyclophosphamide has a higher incidence of
adverse effects when compared to azathioprine or
mycophenolate mofetil. The side effects include
hemorrhagic cystitis, infertility, and bladder cancer
(20,90). Because of its potential toxicity, cyclophos-
phamide should be used as short-termtherapy and
transitioned to an alternate adjuvant immunosup-
pressive agent once disease control is achieved.
Regular laboratory monitoring includes CBC with
differential as well as urinalysis. Oral cyclophos-
phamide is an alternative adjuvant therapy in
patients who have previously been recalcitrant to
azathioprine or mycophenolate mofetil (51).
Methotrexate. Although the use of methotrexate is
fairly straightforward and dermatologists are famil-
iar with its administration, it is not commonly used
as adjuvant therapy in MMP and PV. However, it
has been found to be helpful in some patients
(18,26,30). Methotrexate(10to17.5 mgweekly) may
be considered in patients in whom other adjuvant
medications have failedor are contraindicated. The
major side effect of methotrexate is hepatotoxicity
whichis relatedtototal cumulativedose. Additional
sideeffects includeanemia, leukopenia, pulmonary
toxicity, mucositis, and nausea.
Cyclosporine. Cyclosporine (5 mg/kg per day) is
used concomitantly with prednisone in the treat-
ment of PV (25). Nephrotoxicity, hypertension,
hepatitis, and neurologic changes are known side
effects. Thus, cyclosporine should not be consid-
ered as rst-line adjuvant therapy, but it may be
used to achieve rapid initial control.
Immunomodulatory procedures
IVIg. IVIg may be necessary in patients with rapidly
progressive, extensive, or treatment-resistant MMP
or PV (39,40,44,47,48). There are many theories as
to the mechanism of action of IVIg including selec-
tively decreasing serumautoantibody levels, block-
ing the function of Fc receptors, increasing the
catabolism of immune complexes, and inhibiting
complement-mediated damage (10,91).
IVIg has a very rapid onset of action, and it has
been found to be especially helpful in patients with
progressive ocular MMP in whom vision has dete-
riorated and is threatened (39,40,43,44,47,48). In
some patients, IVIg arrests the progression of eye
disease, maintains vision, and prevents blindness
(44). IVIg is used with oral corticosteroids and an
immunosuppressant drug in patients with refrac-
tory PV. However, efcacy of IVIg in PV is contro-
versial (4143,49).
Indications for IVIg, as determined by consen-
sus, include: failure of conventional therapy with
prednisone at a maximumdose of 60 mg per day or
higher for 6weeks withaconcurrentlyadministered
immunosuppressant agent for 10 to 12 weeks; sig-
nicant adverse effects from the use of conven-
tional therapy; contraindications to high-dose
long-term corticosteroids or immunosuppressant
agents; and life-threatening or severely debilitating
disease despite maximum conventional systemic
therapy (40). The suggested dose is 2 grams/kg per
cycle. Acycleconsists of thetotal dosegiveninthree
equal doses over a period of 3 days. Initially, one
cycle is administered every 3 to 4 weeks, but in
patients with aggressive ocular MMP, the cycle
interval may be shortened to 2 weeks (44). Once the
disease is effectively controlled, the interval
between cycles can be gradually increased with a
proposed end point of two cycles given 16 weeks
apart (40).
Knudson et al.
Treatment with IVIg is extremely expensive.
Adverse events occur in less than 1% of patients
being treated for autoimmune diseases (46). Fever,
chills, ushing, myalgias, nausea, vomiting, and
headache occur during infusion and are related to
the infusion rate. Many of these side effects are
mild and may be managed by slowing the rate of,
or temporarily discontinuing, the infusion. Rare,
serious side effects include acute renal failure,
hemolysis, neutropenia, anaphylactic reactions (in
those with IgA deciency), congestive heart failure
(in those with heart disease), cerebrovascular acci-
dents, and aseptic meningitis (45,46).
Plasmapheresis. Plasmapheresis plays a limited
role in the management of MMP and PV but can be
considered in difcult cases. Plasmapheresis is not
recommended as initial therapy but is best consid-
ered as a short-term bridging therapy to decrease
autoantibody levels while a longer-term therapeu-
tic option is sought (9, 5052).
Extracorporeal photopheresis. Extracorporeal pho-
topheresis has been used in patients with PV; but
outcomes are variable, and results are difcult to
interpret overall (5357).
Other treatment modalities
An increase in tumor necrosis factor alfa (TNF-a)
has been found in the serum and blister uid of
patients with immunobullous disorders (92,93).
Thus, there is rationale for the use of anti-TNF-a
agents (etanercept, iniximab, and thalidomide) in
these conditions. Other less commonly used
agents include subconjunctival mitomycin C, gold,
and rituximab. Rituximab, an anti-CD20 mono-
clonal antibody, is emerging as an effective treat-
ment of immunobullous diseases.
Biologics. Etanercept (25 mg subcutaneously
twice weekly) and iniximab (5 mg/kg given by
infusion at 0, 2, and 6 weeks, then every 8 weeks
thereafter), have been reported to be successful for
MMP in single case reports and small case series
Rituximab, a humanized monoclonal IgG anti-
body against the Bcell-specic cell-surface antigen
CD20, binds to and depletes CD20-expressing B
cells from the circulation for 6 to 12 months (94).
Rituximab has been reported to be successful in
three cases of recalcitrant MMP (59,61,62). In the
treatment of PV, rituximab (375 mg per meter
squared given weekly for 4 weeks) is administered
to patients resistant to or intolerant of standard
regimens (oral corticosteroids and another immu-
nosuppressant drug). Rituximab has also been
used concomitantly with IVIg, other immunosup-
pressants, and oral corticosteroids. After the
4-week induction cycle, long-term therapy with
infusions every 4 or 12 weeks may be continued
(60). It has been noted that most patients respond
within 3 months after starting rituximab, but there
have been reports of delayed response after a year
of treatment (58).
Serious adverse events associated with ritux-
imab, including death and infection, occurred in
13% of patients with immunobullous diseases (PV,
pemphigus foliaceus, and paraneoplastic pemphi-
gus) (60). Rituximab is contraindicated in preg-
nancy, and patients of childbearing age must use
effective contraception during its use and for 12
months thereafter (60).
Thalidomide. Thalidomide has well-known anti-
TNF-a effects. A single case of thalidomide use
(100 mg daily) in refractory MMP has been
reported (66). Thalidomide may be considered as
an alternative treatment option in those not
responding to conventional therapy (66).
Subconjunctival mitomycin C. Subconjunctival
mitomycin C injections have been used by oph-
thalmologists in the treatment of ocular MMP (67).
They are used as a last option in patients in whom
disease is progressing rapidly and not responding
to oral agents, or in those in whom oral agents
cannot be used due to side effects. The effects of
subconjunctival mitomycin C are not permanent,
and injections cannot be given more than one to
three times. If used more often, scleral and con-
junctival ischemia and necrosis may occur. This
can result in permanent damage to the eye.
Gold. Gold (50 mg intramuscularly per week) has
been used in mild-to-moderate cases of PV
as monotherapy or with oral glucocorticoids
(13,36,38). Because of its delayed onset of action,
side effect prole, and relative ineffectiveness, it is
seldom used today. Two early studies reported
complete remission in 15 to 44% in a total of 44 PV
patients. In 15 to 28%, gold was considered to be
ineffective, and 17 to 35% of patients discontinued
the drug because of side effects (35,37).
Diagnosis and response to treatment
Microscopy and appropriate laboratory testing are
used to diagnose and monitor the response to
therapy for MMP and PV. Direct immunouores-
Mucous membrane pemphigoid and pemphigus
cence (DIF) of perilesional skin in MMP shows
linear deposition of IgG, IgA, and/or C3 along the
epithelial basement membrane zone. Indirect
immunouorescence (IIF) reveals serum autoanti-
bodies binding to the epidermal or dermal side of
salt-split skin. Serum levels of autoantibodies to
BP230 and the NC16 domain of BP180 can be
obtained by enzyme-linked immunosorbent assay
(ELISA). Autoantibodies to BP180 and BP230 may
be absent as other target antigens may be involved.
In MMP, IIF titers do not correlate with disease
activity. However, the serum level of autoantibod-
ies to the NC16 domain of BP180 does correlate
with disease activity and can be used to monitor
response to treatment in cases where BP180 is the
target antigen (95).
DIF microscopy of perilesional skin in PV shows
intercellular deposits of IgG and C3 (96). Serum
levels of autoantibodies to desmoglein 1 and/or
desmoglein 3 can be obtained by ELISA, and the
presence of circulating autoantibodies that bind to
intercellular junctions of keratinocytes in sub-
strates such as monkey esophagus can be detected
with the use of IIF microscopy (97). In PV, disease
activity correlates with both IIF titers and serum
levels of desmoglein 1 and/or desmoglein 3
autoantibodies. These tests can therefore be used
to monitor a patients response to treatment (98).
The serologic tests mentioned above should be
obtained at diagnosis. Once therapy is initiated,
these tests can be monitored every few months to
determine the efcacy of treatment. Serologic
testing can be extremely helpful in making treat-
ment decisions about management of MMPandPV,
inconjunctionwiththeclinical status of thepatient.
MMP and PV are disorders that can be mild and
limited, or severe and progressive with devastating
effects on patients. Similar drugs and therapeutic
strategies are used in both disorders. For localized
non-ocular disease, topical therapy is the mainstay
of treatment, whereas more severe and progressive
disease requires systemic therapies. Treatment
should be individualized based on severity and
extent of disease, rate of disease progression,
comorbidities, and age of the patient as well as
physician preference and experience.
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