Bullous pemphigoid
Salient
features
- Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease, and its onset is often after 60 years of age
- It is usually a chronic disease, with spontaneous exacerbations and remissions, which may be accompanied by significant morbidity
- BP is associated with tissue-bound and circulating autoantibodies directed against BP antigen 180 (BP180, BPAG2 or type XVII collagen) and BP antigen 230 (BP230 or BPAG1e), components of junctional adhesion complexes called hemi-desmosomes that promote dermal–epidermal cohesion
- The spectrum of clinical presentations is extremely broad. Characteristically, BP is an intensely pruritic eruption with widespread blister formation. In early stages, or in atypical variants of the disease, only eczematous or urticarial lesions (either localized or generalized) are present or just excoriations due to intense pruritus. Occasionally, patients present with just pruritus. Oral mucous membrane erosions occur in a minority of patients
- Skin pathology shows subepidermal blisters with eosinophils and other inflammatory cells.
- Diagnosis relies on immunopathologic examinations, particularly direct immunofluorescence (IF) showing C3 and immunoglobulin (Ig) G at epidermal basement membrane zone of perilesional skin and Indirect IF showing IgG anti–basement membrane autoantibodies in the serum as well as ELISA for anti-BP180/BP230 autoantibodies
- Therapy includes topical and systemic corticosteroids and immunosuppressives
Pemphigoid diseases. Autoantibody specificities and
diagnostically relevant clinical signs. Main target antigens are indicated in
bold: for target antigens in italics.
Introduction
BP
is the most common autoimmune subepidermal blistering disease of the skin. It
mainly affects elderly people although younger patients may also be affected. It is usually a chronic self-limiting
disease, with spontaneous exacerbations and remissions, which may be
accompanied by significant morbidity. It often starts with generalized pruritus and
urticated and erythematous lesions (either localized or generalized). Later,
tense blisters are characteristic both on erythematous and on normal skin.
Mucosal involvement only develops in a minority of patients and is not
predominant. Histopathology of a lesional biopsy reveals subepidermal
splitting. Auto antibodies, chiefly IgG, recognize two proteins of the hemidesmosomes
– the junctional adhesion complexes found in skin and mucosae, BP180 (type XVII
collagen) in almost all patients and, in about half of them, BP230.
BP has emerged as a paradigm of organ-specific autoimmune
disease.
Epidemiology
BP is typically a disease of the elderly, with an onset
after 60 years of age. The annual incidence has been
estimated to be at least 6–13 new cases per million populations; however,
recent studies suggest a three-fold higher incidence, most likely due to
improved survival amongst the elderly as well as the recognition of non-bullous
variants. It has higher predominance in men than in women. The disease also
occurs in children, but rarely. Certain HLA class II alleles are more prevalent
in patients with BP than in the general population.
Pathogenesis
BP is an example of an immune-mediated disease that is
associated with a humoral and cellular response directed against two well characterized
self-antigens: BP antigen 180 (BP180, BPAG2 or type XVII collagen) and BP
antigen 230 (BP230 or BPAG1e). While the former is a transmembrane protein with
a large collagenous extracellular domain, the latter is a cytoplasmic protein
belonging to the plakin family. These two antigens are components of the
hemidesmosomes, which are adhesion complexes promoting epithelial–stromal
adhesion in stratified and other complex epithelia. Immunoelectron
microscopy studies have demonstrated that in vivo-deposited
IgG antibodies are localized to the hemidesmosomal plaque and to the outside of
the basal cell plasma membrane beneath the hemidesmosome, in a distribution
corresponding to the locations of BP230 and of BP180, respectively.
Humoral and cellular responses
Almost all patients with BP have circulating IgG
autoantibodies that bind to BP180. The anti-BP 180 antibodies belong to the IgG
class (IgG1 and IgG 4 subclasses) as well as the IgE class. More specifically,
it is the non-collagenous NC16A domain, a region of BP180 located
extracellularly but close to the transmembrane domain, that constitutes the
immunodominant region. However, additional antigenic sites exist within both
the extracellular and intracellular domains of BP180, and they are recognized
by up to 70% of BP sera. Patients with BP also exhibit significant auto reactivity
to intracellular BP230, and BP230-reactive autoantibodies bind predominantly to
the C-terminal region of this autoantigen. The presence of several antigenic
sites throughout BP180 and BP230 is most likely results from the phenomenon
known as “epitope spreading”. This phenomenon may also account for the finding
that patients' sera rarely contain autoantibodies targeting additional
components of the BMZ.
Patients with BP develop an auto reactive T-cell response
to BP180 and BP230, and this is probably crucial for stimulating B cells to
produce autoantibodies. The responsiveness of anti-BP180 auto reactive T cells
is restricted by certain HLA class II alleles (e.g. HLA-DQB1*0301), which are
prevalent in BP patients. These T lymphocytes, whose major relevant epitopes
seem to be harbored within the NC16 domain, have a CD4+ phenotype and produce
both Th1 (e.g. interferon-γ) and Th2 cytokines (e.g. interleukin [IL]-4, IL-5
and IL-13. Th2, as well as more recently identified
Th17, cytokines may be particularly relevant to the pathophysiology of
BP; they predominate within lesional tissue and in patients' sera. Also, the
IgG4 subclass, the secretion of which is regulated by Th2 cytokines, is one of
the major isotypes of the anti-BP180 autoantibodies.
Upon binding of autoantibodies to their
target antigens, subepidermal blister formation results from a cascade of
events in which Fc receptor-mediated mechanisms, via BP180–anti-BP180 antibody
complexes, are critical. The latter involve complement activation and
recruitment of inflammatory cells, with
liberation of their proteases including matrix metalloproteinase-9, neutrophil
elastase, and mast cell proteases. These proteinases proteolytically
degrade various extracellular matrix proteins as well as BP180. Infiltrating innate immune cells (macrophages, neutrophils,
mast cells, and eosinophils) contribute to tissue damage via the release of
proinflammatory cytokines, e.g. IL-4, -5, -8, -17, and eotaxin, which further
enhance the inflammatory response. Autoantibodies
to BP180 can also amplify the inflammatory response by directly stimulating
keratinocytes to express inflammatory cytokines (e.g. IL-6 and IL-8). Finally, IgG auto antibodies reduce hemidesmosomal BP180
content and thereby contribute in a complement-independent manner to weakening
of dermal–epidermal cohesion.
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Sequence
of events leading to blister formation in bullous pemphigoid
Binding of autoantibodies (green) against BP180 (orange)
initiates Fc‐independent
events resulting in the secretion of interleukin (IL)‐6
and IL‐8
from basal keratinocytes as well as in internalization and decreased expression
of BP180 (1). Complement is activated at the dermal–epidermal junction (DEJ)
(2) and mast cells degranulate (3). Complement activation and chemokine
gradients trigger the infiltration of inflammatory cells into the upper dermis
(4). Their secretion of additional inflammatory mediators further increases the
inflammatory reaction. Finally, granulocytes at the DEJ release reactive oxygen
species and proteases (5) that ultimately induce dermal–epidermal separation (6).
Clinical Features
Non-bullous phase
The cutaneous manifestations of BP can be
extremely polymorphic. A prodromal non‐bullous
phase usually precedes the development of tense generalized blisters. In this phase
of the disease, signs and symptoms are frequently nonspecific, with mild to
severe intractable pruritus alone or in association with excoriated,
eczematous, papular and/or urticarial lesions that may persist for several
weeks or months. Importantly, these nonspecific skin
findings may remain as the only signs of the disease; at least 20% of patients
have neither obvious blisters nor erosions due to ruptured bullae at the time
of diagnosis.
Bullous phase
The bullous stage of BP is characterized by intense
pruritus and development of widespread vesicles and bullae on apparently normal
or erythematous skin together with urticarial and infiltrated papules and
plaques that occasionally assume an annular or figurate pattern. The blisters
are tense, firm-topped, oval or round, up to 1–4 cm in diameter; contain a
clear fluid and may persist for several days. Occasionally, the blister fluid becomes
blood-tinged. After mechanical irritation, Bullae ruptures, sometimes
producing large, bright red, oozing and bleeding erosions. Usually bullae
collapse and transform into yellowish or hemorrhagic crusts. The Nikolsky sign
is negative. Pruritus, which may be incapacitating, is almost constantly
present. The lesions frequently have a symmetrical
distribution pattern, and they predominate on the flexural aspects of the
extremities and abdomen. Within intertriginous zones, vegetating plaques
can be observed (pemphigoid vegetans). Residual post inflammatory changes
include hyper- and hypopigmentation and, only occasionally, milia. Involvement
of the oral cavity is observed in 10–30% of patients and the lesions are less
severe, less painful and less easily ruptured than in pemphigus. The mucosae of
the eyes, nose, pharynx, and esophagus and ano‐genital
areas are rarely affected. Without severe super infection all lesions heal
without scarring. Erythema may persist at the sites of previous blisters for
many weeks or months. In approximately 50% of patients, a peripheral blood
eosinophilia is noted.
Clinical variants
Several clinical variants of BP have been
described. Pemphigoid gestationis (or gestational pemphigoid) is
also a variant of BP, which typically occurs during pregnancy. Localized lesions may remain
localized or develop into classical BP.
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UNUSUAL CLINICAL
VARIANTS OF BULLOUS PEMPHIGOID |
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Also
referred to as “stump“pemphigoid. |
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† |
Radiotherapy
can also provoke generalized form of pemphigoid. |
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‡ |
Also
variant of mucous membrane (cicatricial) pemphigoid. |
Childhood bullous pemphigoid
Two peaks of incidences of BP in childhood are reported:
in the first year of life (infantile BP), and around the age of 8 years
(childhood BP). While the individual lesions of BP in infants and in older
children (infantile and childhood BP) are similar to those observed in the
elderly, the sites of involvement can differ. In infants, bullae often first
appear acrally, in particular palmar and plantar skin and then can generalize
to other sites, including the face. In older children, involvement of the
genital region (e.g. vulvar childhood pemphigoid) occurs in almost half of the
cases. No immunopathological differences between BP in childhood and adults
have been reported. Autoantibodies mainly target the NC16A domain of BP180.
Generally, infants and children with BP have a good prognosis with remissions
within weeks to a few months under therapy. For treatment, systemic
corticosteroids are usually combined with dapsone or sulfapyridine.
Associated Diseases
The association of internal malignancies with BP is
probably related primarily to the older age of the patient, with increased
frequency of certain cancers (e.g. digestive tract, urinary bladder, and lung)
as well as lymphoproliferative disorders.
Rarely, BP has been described in patients with
inflammatory bowel disease or other autoimmune disorders such as rheumatoid
arthritis, Hashimoto's thyroiditis, dermatomyositis, lupus erythematosus and
autoimmune thrombocytopenia. It is thought that these associations reflect a
genetically determined susceptibility to develop autoimmune diseases.
BP has also been found in association with certain
dermatoses, such as psoriasis and lichen planus, and the bullae may be
localized to the psoriatic plaques. It has been speculated that a chronic
inflammatory process at the dermal–epidermal junction results in the exposure
of antigens to auto reactive T lymphocytes, leading to a secondary immune
response (epitope spreading phenomenon).
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Finally, BP is significantly associated with neurological
disorders, such as Parkinson's disease, dementia, psychiatric disorders, and
stroke. A strong association with multiple sclerosis was also observed in a
population-based study. It should be noted that neuronal variants of BP230 are
expressed in the central and peripheral nervous systems.
Predisposing factors
In some patients, BP appears to be triggered by trauma,
burns, radiotherapy or UV irradiation (including PUVA). Furthermore, about 20
case reports have described the association of vaccination with the onset of
BP, most frequently against influenza.
Drug-induced bullous pemphigoid
In certain patients, systemic medications can lead to the
development of BP. Drug-induced bullous pemphigoid
(BP) may occur up to three months after initial administration of a new
medication, and it can resemble the spontaneous form of this autoimmune
disorder. However, drug-induced BP is characterized by a younger age-of-onset
and cutaneous lesions may have an erythema multiforme-like appearance.
Responsible drugs include diuretics (e.g. furosemide, spironolactone), NSAIDs,
antibiotics (e.g. amoxicillin, ciprofloxacin),
D-penicillamine, potassium iodide, gold and captopril, TNF-α inhibitors,
dipeptidyl peptidase 4 inhibitors (“gliptins” [hypoglycemic agents]), and
anti-PD-1/PD-L1 antibodies. The histologic and direct immunofluorescence
findings are similar to those observed in bullous pemphigoid, and it is the
clinician who has to consider the diagnosis of drug-induced disease, especially
in younger patients (<60 years of age). Hence, in all patients, a careful drug history
is mandatory to exclude the triggering effect of a drug, since its prompt
discontinuation may result in rapid improvement.
The mechanisms by which drugs favor the development of BP
remain to be elucidated. It is likely that the drugs act as triggers in
patients with an underlying genetic susceptibility by either modifying the
immune response or altering the antigenic properties of the epidermal basement
membrane.
Diagnosis
The diagnosis of BP is based upon the typical
clinical presentation, compatible histologic features, and, most importantly,
positive direct immunofluorescence (DIF) microscopy studies. Further support
for the diagnosis of BP requires the detection of specific circulating IgG auto
antibodies (anti-BP180, anti-BP230) via either indirect immunofluorescence
(IIF) microscopy or ELISA. In the vast majority of patients, these tests allow
for the correct classification of patients. However, in a minority of patients
(~10%) in whom both IIF microscopy and ELISA are negative, additional
immunopathological studies, e.g. n-serration versus u-serration pattern
analysis (see below), can be employed to demonstrate an autoantibody response
to BP180 and/or BP230 and thereby exclude other autoimmune bullous diseases.
Light microscopy and electron microscopy
In the non-bullous phase or in atypical variants of BP,
light microscopy studies may provide less specific information, since only sub epidermal
clefts, eosinophilic spongiosis and/or dermal infiltrates of eosinophils may be
found. Some of the eosinophils have lined up at the dermal–epidermal junction,
a typical finding in the urticarial stage of BP.
In biopsy specimens of an early bulla, a sub epidermal
blister accompanied by a dermal inflammatory infiltrate composed of eosinophils
and mononuclear cells is typically observed. The infiltrate favors the
uppermost dermis, and the cavity of the bulla contains a net of fibrin, eosinophils
and mononuclear cells. Electron microscopy studies have shown that sub epidermal
blister formation occurs at the level of the lamina lucida.
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Direct immunofluorescence microscopy (DIF)
In almost all patients, direct IF microscopy studies of
perilesional, uninvolved skin will characteristically demonstrate the presence
of fine, linear, continuous deposits of IgG and/or C3 along the epidermal
basement membrane. IgG4 and IgG1 are the predominant IgG subclasses. Two additional studies are helpful in distinguishing BP
from other autoimmune blistering disorders: (1) close analysis of the linear
fluorescence pattern at the BMZ in order to determine if it is n-serrated (BP and linear IgA bullous dermatosis)
versus u-serrated (epidermolysis bullosa acquisita); and
(2) the salt-split skin assay in which perilesional skin is examined after
treatment with 1 M NaCl. In BP, immune
deposits are found in the epidermal side (roof) or in both the epidermal and
dermal sides of the split. Although not routinely available, the computer-aided
fluorescence overlay antigen mapping (FOAM) technique allows one to determine
more precisely the localization of deposited immunoreactants.
Direct immunofluorescence microscopy of
bullous pemphigoid. In a perilesional biopsy, linear binding of immunoglobulin
G (IgG) at the dermal–epidermal junction is seen (a). At higher magnification
and in thin sections (4 μm), IgG deposition is no longer linear but appears
curved with arches closed at the top referred to as ‘n‐serrated’ pattern (b; inset).
Indirect immunofluorescence
(IIF) microscopy
For IIF
studies in sub epidermal blistering diseases, salt-split normal human skin is
the substrate of choice, rather than intact normal human skin or monkey
esophagus. Circulating anti-basement membrane auto antibodies of the IgG class
and, less frequently, of the IgA and IgE classes, are detectable in 60–80% of
patients. These autoantibodies typically bind to the epidermal side or, less
frequently, to both the epidermal and dermal sides of saline-separated normal
human skin.
 Immunofluorescence microscopy (indirect) utilizing
salt-split human skin. (A) Circulating IgG auto antibodies from BP
patients bind to the epidermal side (roof) of the salt-induced split
(arrows); the artificial separation is indicated by an asterisk. (B) IgG auto
antibodies from patients with EBA, anti-p200 pemphigoid and certain forms of
mucous membrane pemphigoid (e.g. with antibodies against laminin 5/332) react
with the dermal side (floor) of the blister (arrows). |
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Enzyme-linked immunosorbent assays (ELISA)
Bullous pemphigoid (BP) BP180 and BP230 ELISA are
sensitive, objective, and specific tests that should be considered as an
initial screening test in the diagnosis of pemphigoid and its variants.
Antibody titer correlates with disease activity. Patients with severe disease
have high titers of antibodies to BP. Titers decrease with clinical
improvement. Therefore assaying reactivity to BP180 may be a helpful guide for
disease management.
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ELISAs utilizing
recombinant proteins that encompass specific regions of the BP antigens and the
target antigens include the NC16A domain of BP180 and the C-terminus (+/− the
N-terminus) of BP230. These test have been found to be fairly specific
(>90%). Occasionally, low-titer, false-positive results are observed in
healthy subjects and elderly patients with pruritic cutaneous eruptions. When
performed in unselected BP patients, the overall sensitivity of the BP180-NC16A ELISA is comparable
to that of IIF (with salt-split skin as a substrate). Combining the ELISA for
BP230 with the BP180-NC16A ELISA increases the overall sensitivity by ~10% so
the former is only recommended in the setting of a negative BP180 ELISA.
Immunoblot and
immunoprecipitation studies
In
immunoblot and immunoprecipitation studies of keratinocyte extracts, 60–100% of
patients’ sera contain IgG auto antibodies that bind to BP180 and BP230,
respectively. Patients’ sera also frequently contain specific IgA and IgE auto antibodies.
In general, recombinant forms of BP180 and BP230 expressed in prokaryotic or
eukaryotic systems are used for the detection of autoantibodies
A summarizes the approach to the
laboratory diagnosis of bullous pemphigoid.
DIAGNOSTIC CRITERIA FOR BULLOUS PEMPHIGOID
Because the clinical findings in the
non-bullous phase of BP may be nonspecific, they can resemble a variety of
dermatoses, including drug reactions, contact dermatitis, prurigo (simplex and
nodularis), urticarial dermatoses, arthropod reactions, and scabies. These
disorders are usually distinguished on the basis of the clinical history and
setting, pathologic features, and the negative findings with IF microscopy. The
pemphigus group, paraneoplastic pemphigus, and dermatitis herpetiformis can be
differentiated on the basis of distinctive immunopathologic findings and
clinical context. A recent study found that, in patients with a sub epidermal
blistering disorder associated with linear deposits of IgG or C3 along the
epidermal basement membrane, the presence of the following four clinical
criteria strongly indicated a diagnosis of BP: (1) absence of skin atrophy, (2)
absence of mucosal involvement, (3) absence of head and neck involvement, (4)
age greater than 70 years.
Differences between pemphigus vulgaris and bullous pemphigoid
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Disease course and
prognosis
BP is a
chronic disease
characterized by a waxing and waning course with occasional spontaneous
remission in the absence of treatment. Untreated pemphigoid may remain localized or
it may become generalized. Localized disease often resolves spontaneously, but spontaneous remission
can even occur in patients with more generalized disease. Clinical remission
with reversion of direct and indirect IF to negative has been noted in
patients, even those with severe generalized disease, treated with oral
corticosteroids alone or with azathioprine. Approximately 30% of BP patients have a
relapse during their first year of treatment, with extensive disease and
associated dementia as independent risk factors for relapse. Furthermore, after
cessation of therapy, ~50% of patients experience a relapse, most often within
the first 3 months.
Generalized BP has a poor prognosis, especially in older
patients,those in poor general condition and the presence of anti-BP180 antibodies. The
disease duration is usually 3–6 years, with most patients achieving complete
remission off treatment.
Because of the intractable pruritus, and the presence of
bullous, eroded or impetiginized lesions, the disease is often accompanied by
significant morbidity with a profound impact on quality of life.
Mortality is considerable among elderly
patients.The estimated death rate during the first year varies
between 10% and 40%, depending on the series.
Risk factors for lethal outcome are old age (greater than 80 years),
extensive disease, high doses of prednisolone (>35 mg/day), serum albumin
levels of less than 3.6 g/dL, a Karnofsky score of 40 or less, and the presence
of heart disease, diabetes, or neurological diseases.
Monitoring
The practicality
of using the results of quantitative serologic tests, such as the BP180 ELISA,
as a means of guiding treatment remains to be established. That said, serum
levels of IgG auto antibodies to BP180 did correlate with disease severity in
several ELISA-based studies. Furthermore, determination of anti-BP180 IgG
antibody levels by ELISA at days 0, 60, and 150 appeared to help predict
disease relapse – a small (<20%) decrease in serum autoantibody levels
between days 0 and 60 was associated with relapse during the first year of
therapy. Finally, a high BP180-NC16A ELISA score (>27 U/ml) and, to a lesser
degree, positive DIF findings at the time of therapy cessation are both good indicators of future
relapse of BP. At
least one of these tests should therefore be performed before therapy is
discontinued.
Treatment
Therapeutic ladder
Definition of disease
activity: Localized and mild disease: involvement of
<10% of body surface; moderate disease: involvement of 10–30% of body
surface; extensive disease: may be considered with >10 blisters/day or
involvement of >30% of body surface.
Localized and mild disease
Lesional very potent topical corticosteroids 2×/day
Moderate disease
First line
Very potent topical corticosteroids on the whole body
surface 2×/day
Second line
Very potent topical corticosteroids on the whole body
surface 2×/day
Plus (in alphabetical order)
Azathioprine 2.5 mg/kg/day (with normal TPMT activity) or
Dapsone 1.0–1.5 mg/kg/day or
Doxycycline 200 mg/day ± nicotinamide 2 g/day or
Methotrexate 10–20 mg/week or
Mycophenolates (mofetil 2 g/day, gastro‐resistant
mycophenolic acid (Myfortic®) 1.44 g/day)
Or
Prednisolone 0.5 mg/kg/day tapering, with or without
Azathioprine, dapsone, doxycycline, methotrexate,
mycophenolates
Extensive disease
First line
Very potent topical corticosteroids on the whole body
surface 2×/day
Plus
Azathioprine, dapsone, doxycycline, methotrexate,
mycophenolates
Or
Very potent topical corticosteroids on the whole body
surface 2×/day
Plus
Prednisolone 0.5 mg/kg/day tapering, with or without
Azathioprine, dapsone, doxycycline, methotrexate,
mycophenolates
Second line
In case of insufficient response treat with oral prednisolone, increase the dose to 0.75 mg/kg/day and, if still insufficient, to 1.0 mg/kg/day
Third line
Plus immunoadsorption, rituximab or IVIG
Bullous pemphigoid is usually a
self-limited inflammatory sub epidermal blistering disorder of the elderly, in
which circulating auto antibodies to epitopes in the basement membrane zone
bind to this region and initiate a cascade of inflammatory events resulting in
urticarial and bullous lesions. The therapeutic strategy is to reduce auto
antibody production and to control the inflammatory reaction. Because bullous
pemphigoid is not life threatening and agents that reduce auto antibody
formation are inherently high risk, the initial goal of therapy is to control
inflammation and reduce blister formation to a level consistent with individual
patient comfort with the minimum dose of drugs necessary.
In contrast to PV,
BP is a much milder disease requiring lower doses of systemic steroids. Treatment
of bullous pemphigoid depends greatly on the extent of disease. For
localized and mildto moderate disease, potent topical steroids plus the
systemic anti-inflammatory (tetracyclines and nicotinamide) may be sufficient. Unless there is glucose-6-phosphate dehydrogenase deficiency,
the use of dapsone may also be warranted, particularly in the presence of
mucosal involvement. The benefit of topical immunomodulators, such as
tacrolimus, remains to be confirmed. For more severe cases, systemic
steroids alone or combined with immunosuppressives may be needed to control the
disease. Finally, in treatment-resistant cases, IVIg,
anti-CD20 immunotherapy (rituximab), which is relatively specific in
targeting the antibody-producing B cells or
omalizumab may be tried. Use of the latter is based upon the presence of
IgE anti-BP180 auto antibodies in patients with BP that likely contribute to
tissue damage.
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THERAPEUTIC LADDER
FOR BULLOUS PEMPHIGOID |
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Mild and/or localized
disease |
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First-line Super potent topical
corticosteroids Second-line Oral corticosteroids Minocycline,
doxycycline or tetracycline, alone or in combination with nicotinamide Erythromycin Dapsone Topical
immunomodulators (e.g. tacrolimus) |
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Extensive/persistent
cutaneous disease |
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First-line, as primary
treatment Super potent topical
corticosteroids Oral corticosteroids† Second-line, or as adjunctive
therapy Azathioprine Mycophenolatemofetil Methotrexate§ Chlorambucil Cyclophosphamide IVIg Plasma exchange Rituximab Omalizumab Immunoadsorption |
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Note: Super potent topical
corticosteroids should be considered in any patient and may be combined with
a systemic therapy. |
† Prednisone
doses of at least 0.5–0.75 mg/kg/day seem to be necessary to control extensive
disease, but increase serious side effects, including mortality. For mild
disease, 0.5 mg/kg/day is sufficient.
§ In
elderly patients, low-dose regimen (2.5–10 mg/wk) can be effective
First line or initial Steps
Patients who do not
control their conditions with topical steroids and systemic anti-inflammatory
agents or patients having more extensive disease are usually treated with oral prednisone. Despite the lack of randomized controlled trials,
oral prednisone remains the mainstay of therapy.
For extensive disease, defined as either >10 new
blisters/day or inflammatory lesions involving >30% of body surface area, a
regimen of oral prednisone at a dose of 0.5–1 mg/kg/day is often recommended. Start with
oral prednisone alone at 0.5mg/kg/day in a single morning
dose. A dramatic clinical response will be seen in 70–80% of patients after 2–3
weeks. Once there have been no new blisters or
pruritus for at least 2 weeksand
the previous lesions are 80% healed, the dose may be decreased by 20% every 2
weeks, as long as no new lesions occur. The majority can be managed on doses of less
than 10 mg/day prednisolone, which can be slowly withdrawn. One reducing
regimen is reduction by 1 mg/month once the dose is below 10 mg/day. However, the use of systemic corticosteroids, especially
in the elderly, is associated with significant side effects.
Some recent studies suggest that
potent topical steroids, such as clobetasol
proprionate
cream 0.05% applied twice daily, are also effective in both moderate and severe
bullous pemphigoid with the same efficacy as oral corticosteroids, and, most
importantly, with fewer systemic side effects and reduced mortality. Thus, these patients received a daily dose of
40 g of clobetasol propionate applied twice daily to the entire
surface of the body until 15 days after control of the disease had been
attained. High-potency topical treatment did result in significant systemic
absorption and therefore may act via local and systemic effects. Such topical
therapy can be expensive and difficult to apply, which may prove prohibitive in
many patients. Widespread use of high potent TCS (group 1 bd) (40gm/day) is about
as effective as oral prednisolone 0.5mg/kg daily while avoiding systemic adverse
effects from systemic corticosteroids.
Second line or as adjunctive
therapy
Immunosuppressive
therapies can serve as steroid-sparing agents and are employed when
corticosteroids alone fail to control the disease. I.e. if sufficient
clinical response is not achieved after 3 weeks,
there are contraindications to the use of systemic corticosteroids, and/or
comorbidities exist that limit the dosage of corticosteroid (e.g. diabetes
mellitus, osteoporosis, psychosis). The
most frequently employed agents are methotrexate, azathioprine and mycophenolate
mofetil. In each case, continue
the immunosuppressive agent for at least 2 months before abandoning it as
ineffective. Once the steroid-sparing agent has begun to work, the dose of
systemic steroids is gradually tapered following the protocol above. The choice
of immunosuppressive agent is determined by the patient's coexistent medical
conditions, the side-effect profile, and the
cost. There is no evidence that one agent is superior to another. Azathioprine
is the best established immunosuppressant and ideally
thiopurinemethyltransferase (TPMT) activity testing should be assessed prior to
initiation of treatment to guide dosage.
Methotrexate (MTX)
MTX alone or in combination with topical
steroids or oral steroids is reported to be effective. Dosages vary from 2.5 to
15 mg/week. MTX causes myelosuppression, hepatotoxicity, and pneumonitis. MTX
is excreted via kidney,so in the elderly, the dose of
methotrexate requires careful monitoring as renal function is often
significantly reduced. Elderly patients should start treatment with the
lowest dose. Folic acid 5 mg on the non-MTX days is often prescribed to reduce
toxicity. Low-dose oral pulse methotrexate may be an effective alternative in
patients with generalized bullous pemphigoid. Initiate treatment with oral
methotrexate (10 mg/week). The methotrexate treatment is modified according to
the following responses: (1) if the number of blisters increases, the dosage is
increased by 2.5 mg/week; (2) if severe itching is present, a potent topical
corticosteroid (0.5% clobetasol) is added, to a maximum of 20 gm/day, and its
use is discontinued if the itching stops; and (3) if a positive response
appears to be permanent, the dosage is reduced by 2.5 mg/week every 2 months,
and then discontinued.
Azathioprine
Azathioprine can be considered as an adjunctive
treatment to oral steroids where the response has been inadequate and the
disease is not suppressed, or when the side effects of existing therapy are
troublesome and unacceptable. Azathioprine as a single agent may be considered
for older patients with more significant disease who do not respond to dapsone
or antibiotics and who do not tolerate prednisone. Younger patients are usually
not treated with azathioprine because of the increased risk of malignant
neoplasms. Patients respond within 3 to 6 months of treatment. Treatment may
then be stopped and restarted with disease flares. The
dosage of azathioprine (0.5–2.5 mg/kg/day) should be adjusted according to the
level of thiopurine methyltransferase, in order to increase efficacy and reduce
myelosuppression. The risk of azathioprine-induced myelosuppression can
be predicted by detecting patients with intermediate or low thiopurine methyltransferase
(TPMT) activity. TPMT levels are evaluated to ensure the patient receives
adequate amounts of azathioprine. Monitor blood counts and liver function
tests.
Mycophenolate mofetil
(MMF)
MMF is a well-tolerated immunosuppressive
agent. It has been prescribed in doses of 0.5 to 1 gm. twice daily both as an
adjunct to oral steroid and as a monotherapy following disease relapse.
Systemic anti-inflammatory
drugs
a. Doxycycline/Minocycline 100mg bd plus niacinamide 250-500 mg three
times daily ( the antibiotic probably reduce
inflammation, rather than altering antibody production). Bulla formation may
decrease or stop within 3 weeks. Antibiotics are continued for 1 or 2 months
and slowly tapered once control is achieved. These drugs may suppress the
inflammatory response at the BMZ, inhibit neutrophil chemotaxis, and increase
cohesion of the dermoepidermal junction. The effect may be enhanced by the
synergetic effect of nicotinamide. This may be adequate alone to control mild
disease or may provide additional anti-inflammatory effect without causing
additional immunosuppression.
b.
Dapsone Dapsone
50 to 200 mg daily may be used either as the initial and
sole treatment of BP, particularly when there are contraindications to the use
of corticosteroids or immunosuppressants or in combination with topical steroids, oral
steroids, or azathioprine. Glucose-6-phosphate dehydrogenase deficiency
predisposes to hematologic side effects and should be excluded. Vit E 600IU daily is added to reduce hemolysis. Start at low doses
(50 mg daily) and increase over 2 or 3 weeks to a maximum of 150 to 200 mg
daily (usual dose is 100 mg/day). Patients who have a neutrophil-predominant
infiltrate may be the best candidates for this drug. The response occurs within
2 weeks. The dosage is regulated according to the patient’s response.
While the optimal duration of therapy has not
been established, BP patients usually need to be treated for a range of 6–12
months, depending upon the severity of the disease and therapeutic response.
The exception is steroid-resistant or steroid-dependent disease. This time
period includes a maintenance phase in which low-dose oral prednisone
(<10 mg/day) or topical clobetasol propionate (10 g/week) is continued for 1
to 6 months after cessation of clinically active disease. Finally, in all
patients with BP, it is important to minimize the complications of both the
cutaneous lesions and the systemic treatment, including using osteoporosis
prophylaxis and gastric protection.
For patients treated with systemic corticosteroid for
longer than 1 month, a combined supplement of calcium and vitamin D should be
instituted to prevent osteoporosis. In addition to calcium and vitamin D
supplementation, patients on long-term treatment with systemic corticosteroids
should be taking bisphosphonate, a specific inhibitor for osteoclast-mediated
bone resorption (e.g., alendronate).
Corticosteroid therapy has lowered the
morbidity from the disease considerably and most patients achieve permanent
remission after therapy and do not require
further therapy;
but significant mortality of bullous pemphigoid still remains at 15–40%, and is
nearly always treatment related or related to the general condition and age of
the patients.
