GROSS APPEARANCE/
CLINICAL VARIANTS |
CHARACTERIZATION |
| General |
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| VARIANTS |
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| CHILDHOOD |
Clin Exp Dermatol 1993;18:483-5.
J Am Acad Dermatol 1994;30:884-8.
Int J Dermatol 1991;30:339-42
J Am Acad Dermatol 1988;19:366-7.
The major clinical, histopathologic, and immunologic features of childhood
BP are considered indistinguishable from adult BP
Mucous membrane involvement was more frequent than in the adult form
and all infants 1 year of age or younger had marked palmoplantar and
facial involvement
Systemic corticosteroid therapy (prednisolone 1-2 mg/kg per day) is
the treatment of choice in childhood BP |
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Bullous pemphigoid in infancy: Clinical and epidemiologic characteristics.
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Pediatric Dermatology Unit, Schneider Children's Medical Center of Israel, Petah-Tiqva, Israel.
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J Am Acad Dermatol. 2008 Jan;58(1):41-8. Abstract quote
BACKGROUND: Recent cases of infants with bullous pemphigoid (BP) prompted us to explore the clinical and laboratory features of childhood BP.
OBJECTIVES: We sought to explore the characteristics of infantile BP and compare them with childhood BP.
METHODS: All new consecutive cases of infantile BP referred to dermatologic departments in Israel during 2004 to 2006 were retrospectively reviewed. All reported cases in the English- and foreign-language medical literature were gathered and statistical analysis of all cases was performed.
RESULTS: Reports on infantile BP are rapidly increasing. Among 78 reported children with BP, 42 (53%) occurred in the first year of life. The incidence of infantile BP in Israel in the last years is 2.36:100,000/y. Predisposition for acral involvement is significantly higher in infantile BP than in childhood BP (79% vs 17%, P < .001), whereas genital involvement is very rare (5% vs 44%, P = .002). Laboratory parameters were not significantly different, except for a more frequent IgM deposition at the dermoepidermal junction in childhood BP (29% vs 10%, P = .042).
LIMITATIONS: Statistical analyses of published cases may not be representative and could be affected by possible reporting biases.
CONCLUSIONS: Infantile BP may not be as rare as commonly stated. Age-related differences in regional distribution of lesions in BP were demonstrated. No major differences regarding laboratory results, treatment, and prognosis were found.
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Childhood bullous pemphigoid: a clinicopathologic study and review of
the literature.
Fisler RE, Saeb M, Liang MG, Howard RM, McKee PH.
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Am J Dermatopathol. 2003 Jun;25(3):183-9 Abstract quote Bullous pemphigoid
(BP) is an acquired bullous disorder that predominantly affects the
elderly. It is rare in children but when it occurs, there is considerable
clinical and histologic overlap with other acquired or congenital blistering
disorders.
A definitive diagnosis of childhood BP requires direct immunofluorescence
and, in some cases, characterization of the target antigen. Three cases
of childhood BP are presented, with their histologic and immunofluorescence
findings. The first was a 5-month-old male infant who presented with
erythema and bullae of the palms and soles and was found to have linear
deposition of IgG and C3 along the dermoepidermal junction on direct
immunofluorescence (DIF).
Histopathologic examination revealed a subepidermal blister containing
eosinophils. Type IV collagen was demonstrated along the floor of the
blister cavity by a direct immunoperoxidase technique.
The second case was an 8-month-old female infant who presented with
a blistering eruption of her palms and soles that then became widespread.
Direct immunofluorescence showed linear IgG and C3 at the dermoepidermal
junction, with laminin deposition at the base of the blister.
The third case was a 7-year-old female with bullae and erosions on the
vulva and vaginal mucosa. A subepidermal blister was seen on microscopic
examination whereas immunofluorescence demonstrated linear IgG and C3
deposition at the basement membrane zone (BMZ). A literature review
uncovered 50 cases of childhood BP confirmed by direct or indirect immunofluorescence,
or both, and often with evidence of autoantibodies against either the
180 kD or the 230 kD human bullous pemphigoid antigens (BP180 or BP230).
This review was used to delineate characteristics of childhood BP, including
the newly proposed subtypes: infantile BP and childhood localized vulval
BP. Infantile BP presents within the first year of life and is characterized
by BP-like lesions on erythematous or normal acral skin. Localized vulval
BP is a self-limited, nonscarring BP-like process that involves only
the vulva. Both subtypes are normally self-limited and respond well
to either topical or systemic steroids, if treatment is initiated before
the disease becomes widespread. |
| Childhood bullous pemphigoid developed
after the first vaccination |
J Am Acad Dermatol 2001;44:348-50
In the last 5 years, 10 adult and 2 infantile BP cases with a close
relation of vaccination have been reported
Anti-influenza vaccine, tetanus toxoid booster, and tetracoq vaccine
were the possible causes of these cases
3.5-month-old BP case in whom the lesions developed 24 hours after the
first tetracoq vaccine
Conclusion:
Suggest that vaccination may be the triggering factor of BP of any age
by stimulating the immune system with an unexplained mechanism |
| Vesicular pemphigoid |
Chronic eruption of small pruritic vesicles resembling dermatitis
herpetiformis. |
| Pemphigoid vegetans |
Resembles pemphigus vegetans
with verrcuous vegetating lesions in intertriginous areas
May be asociated with ulcerative colitis |
| Polymorphic pemphigoid |
Combines features of dermatitis herpetiformis and bullous
pemphigoid
Some cases may represent linear IgA disease |
| Pemphigoid nodularis |
Combines features of prurigo nodularis and bullous pemphigoid
May resolve with scarring
Variant with hyperkeratotic islands within areas of blisters called pemphigoid
en cocarde. |
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Subacute prurigo variant of bullous pemphigoid: autoantibodies show
the same specificity compared with classic bullous pemphigoid.
Schmidt E, Sitaru C, Schubert B, Wesselmann U, Kromminga
A, Brocker EB, Zillikens D.
Department of Dermatology, University of Wurzburg,
Josef-Schneider-Strasse 2, 97080 Wurzburg, Germany. |
J Am Acad Dermatol 2002 Jul;47(1):133-6 Abstract quote
We describe a 76-year-old white woman with a 6-month history of intensive
pruritus and excoriated papules resembling subacute prurigo. Histopathology
showed signs of chronic dermatitis, whereas findings by direct and indirect
immunofluorescence microscopy were compatible with bullous pemphigoid
(BP).
The patient's serum contained IgG autoantibodies that recognized epitopes
on both BP180 and BP230 by Western blot analysis of epidermal extracts.
In addition, we found strong reactivity with recombinant NC16A, an immunodominant
region of BP180 targeted in the majority of BP sera, whereas no antibodies
against the keratinocyte-derived soluble BP180 ectodomain (LAD-1) or
the recombinant intracellular domain of BP180 were detected. The patient's
disease responded well to oral methylprednisolone and mycophenolate
mofetil. Disease activity correlated with enzyme-linked immunosorbent
assay reactivity of antibodies to BP180 but not with titers of antibodies
to the dermoepidermal junction as determined by indirect immunofluorescence
on salt-split skin.
Our findings suggest that the subacute prurigo form of BP is a true
variant of BP. |
| HISTOLOGICAL TYPES |
CHARACTERIZATION |
| General |
Subepidermal bulla with eosinophils and a lesser degree of neutrophils
Eosinophilic spongiosis may be present on the periphery of lesions
but also in early urticarial, non-bullous lesions
If the blister is older, re-epithelialization of the base may occur,
mimicking an intraepidermal blister
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| VARIANTS |
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Generalized pruritic eruption with suprabasal acantholysis preceeding
the development of bullous pemphigoid
María A.Barnadas1, Ramón M.Pujol1, RománCurell2, XavierMatías-Guiu2
and AgustínAlomar1
Departments of 1Dermatology and 2Pathology, Hospital de la Sta.
Creu i St. Pau, Barcelona, Spain
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J Cutan Pathol 2000;27 (2), 96-98 Abstract quote
We report a patient who presented with a papular pruritic eruption
of a 3-month duration that histologically showed suprabasal acantholysis
accompanied of an eosinophilic inflammatory infiltrate that was consistent
with the diagnosis of Grover's disease. Later, erythematous plaques
and vesicles appeared which showed a histopathological pattern of eosinophilic
spongiosis.
The direct immunofluorescence (DIF) study showed linear IgG and C¢3
at the dermal epidermal junction which was consistent with the diagnosis
of bullous pemphigoid. No anti-intercellular deposits of immunoglobulin
G (IgG) or C¢3 were observed.
We consider that suprabasal acantholysis may represent the early phase
of bullous pemphigoid.
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Pemphigoid nodularis associated with autoantibodies to the NC16A
domain of BP180 and a hyperproliferative integrin profile
Marianne Schachter, MD
Joaquin C. Brieva, MD
Jonathan C. R. Jones, PhD
Detlef Zillikens, MD
Christian Skrobek, MD
Lawrence S. Chan, MD
Chicago, Illinois, and Wuerzburg, Germany
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J Am Acad Dermatol 2001;45:747-54 Abstract quote
Pemphigoid nodularis, a rare variant of bullous pemphigoid, has clinical
features resembling prurigo nodularis, with blisters arising from normal-appearing
or nodular skin. The fine antigenic epitope of the autoantibodies and
the mechanism accounting for the nodular phenotype has not been delineated.
We describe a patient with pemphigoid nodularis that fulfilled the
criteria of bullous pemphigoid by histopathologic examination and direct
and indirect immunofluorescence studies. Immunopathologic examination
also revealed in situ deposition and circulating autoantibodies of all
IgG subclasses, except IgG3, and both light chains to the patient's
skin basement membrane. By immunoblotting, the patient's IgG autoantibodies
labeled BP180, BP230, and an unidentified 150-kd epidermal protein and
mapped the BP180 epitope to the MCW-1, region 2 of the NC16A domain.
The nodular plaque skin showed expression of -6 and -1 integrin subunits,
mediators of matrix-cell signaling and proliferation, at the basal and
the suprabasal epidermis, a pattern found in psoriasis, which is the
prototype of hyperproliferative dermatoses.
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| PROGNOSIS AND TREATMENT |
CHARACTERIZATION |
| PROGNOSIS |
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Prediction of survival for patients with bullous pemphigoid: a prospective study.
Joly P, Benichou J, Lok C, Hellot MF, Saiag P, Tancrede-Bohin E, Sassolas B, Labeille B, Doutre MS, Gorin I, Pauwels C, Chosidow O, Caux F, Esteve E, Dutronc Y, Sigal M, Prost C, Maillard H, Guillaume JC, Roujeau JC.
Department of Dermatology, Institut National de la Sante et de la Recherche Medicale U 519, University of Rouen, Rouen, France.
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| Arch Dermatol. 2005 Jun;141(6):691-8. Abstract quote |
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OBJECTIVE: To identify the prognostic factors of bullous pemphigoid (BP).
DESIGN: Prospective study of patients with BP included in a randomized, controlled trial.
SETTING: Twenty dermatology departments in France.Patients One hundred seventy patients with BP initially treated with a 40-g/d dosage of clobetasol propionate cream (testing sample) and 171 patients initially treated with oral corticosteroids at a dosage of 0.5 or of 1.0 mg/kg per day, depending on the extent of BP (validation samples).
MAIN OUTCOME MEASURES: The end point was overall survival during the first year after BP diagnosis. From the testing sample, associations of clinical and biological variables with overall survival were assessed using univariate and multivariate analyses. Selected predictors were included in a prognostic model. To verify that these predictors were not dependent on the treatment used, the model was then validated independently on the 2 series of BP patients treated with oral corticosteroids.
RESULTS: Median age of the BP patients included in the testing sample was 83 years. The 1-year Kaplan-Meier survival rate was 74%. From univariate analysis, the main deleterious predictors were demographic factors (ie, older age and female sex), associated medical conditions (ie, cardiac insufficiency, history of stroke, and dementia), and low Karnofsky score, which is a measure of the patient's general condition. No factors directly related to BP, in particular extent of cutaneous lesions, were shown to be related to the patients' prognosis. From multivariate analysis, only older age (P = .02) and low Karnofsky score (P<.001) appeared independently predictive of death. From the Cox model including these 2 predictors, the predicted 1-year survival rates were 90% (95% confidence interval [CI], 85%-96%) for patients 83 years or younger with Karnofsky score greater than 40, 79% (95% CI, 69%-90%) for patients older than 83 years with Karnofsky score greater than 40, 65% (95% CI, 50%-86%) for patients 83 years or younger with Karnofsky score of 40 or less, and 38% (95% CI, 26%-57%) for patients older than 83 years with Karnofsky score of 40 or less. Kaplan-Meier survival distributions of patients from the validation samples appeared clearly separated according to these 4 categories and were in close agreement with corresponding predicted 1-year survival rates obtained from the testing sample.
CONCLUSIONS: The prognosis of patients with BP is influenced by age and Karnofsky score. These predictors are easy to use and should facilitate the management of BP.
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Risk factors for lethal outcome in patients with bullous pemphigoid:
low serum albumin level, high dosage of glucocorticosteroids, and old
age.
Rzany B, Partscht K, Jung M, Kippes W, Mecking D, Baima B, Prudlo
C, Pawelczyk B, Messmer EM, Schuhmann M, Sinkgraven R, Buchner L, Budinger
L, Pfeiffer C, Sticherling M, Hertl M, Kaiser HW, Meurer M, Zillikens
D, Messer G.
Department of Dermatology, Fakultat fur Klinische Medizin Mannheim
der Universitat Heidelberg, Mannheim, Germany.
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Arch Dermatol 2002 Jul;138(7):903-8 Abstract quote
BACKGROUND: Although bullous pemphigoid (BP) is the most frequent autoimmune
bullous disease and is associated with a considerable case-fatality
rate, little is known about factors that influence its prognosis.
OBJECTIVE: To identify prognostic factors for lethal outcome in the
first year after the initial hospitalization in patients with BP.
DESIGN: A multicenter retrospective cohort study.
SETTING: Seven dermatologic university hospitals in Germany.
PARTICIPANTS: A total of 369 patients diagnosed as having BP between
January 1, 1987, and December 31, 1997.
STATISTICS: Univariate (Kaplan-Meier) and multivariate (Cox regression)
analysis.
RESULTS: Of the 369 patients with BP, 209 (57%) died, 106 (29%) within
the first year after hospitalization. Fifty-four percent were women.
The mean +/- SD age at entry was 77.3 +/- 11.1 years. The patients with
BP were followed up to 10.5 years, with a median time of 1.8 years to
death or interview (25th and 75th quartiles, 0.5 and 4.0 years). The
major risk factors for lethal outcome in the first year after hospitalization
were an increased age, with a multivariate risk estimate of 3.2 (95%
confidence interval [CI], 1.9-5.2) for age greater than 80.4 years (median);
a daily glucocorticosteroid dosage of more than 37 mg (75th quartile)
at discharge, with a multivariate risk estimate of 2.5 (95% CI, 1.5-4.3);
serum albumin levels of 3.6 g/dL or less (25th quartile), with a multivariate
risk estimate of 2.6 (95% CI, 1.5-4.4); and an erythrocyte sedimentation
rate greater than 30 mm/h (75th quartile), with a multivariate risk
estimate of 1.7 (95% CI, 1.1-2.8).
CONCLUSIONS: There is a considerable case-fatality rate in patients
with BP. Older patients who require a higher dosage of oral glucocorticosteroids
at hospital discharge and who have low serum albumin levels are at greater
risk of death within the first year after hospitalization. These prognostic
factors should be considered in the care of patients with BP as well
as in the design of future clinical trials.
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| TREATMENT |
Corticosteroids are mainstay of therapy
Steroid sparing medications include:
Azathioprine
Mycophenolate mofetil
Dapsone |
| GENERAL |
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A Systematic Review of Treatments for Bullous Pemphigoid
Nonhlanhla P. Khumalo, MD; Dedeé F. Murrell, MD; Fenella Wojnarowska,
MD; Gudula Kirtschig, MD |
Arch Dermatol. 2002;138:385-389 Abstract quote
Objective
To assess the effectiveness of treatments for bullous pemphigoid.
Methods
The Cochrane Library search strategy was used to identify randomized
controlled trials from MEDLINE and EMBASE, from their inception to September
30, 2001. All randomized controlled trials on interventions for bullous
pemphigoid, confirmed by immunofluorescence studies, were included.
Results
We found 6 randomized controlled trials with a total of 293 patients.
Two trials, one comparing prednisolone, 0.75 mg/kg per day, with prednisolone,
1.25 mg/kg per day, and the other comparing methylprednisolone with
prednisolone, did not find any significant difference in effectiveness.
The higher dose of prednisolone, however, was associated with more severe
adverse effects. Combination treatments of prednisone with azathioprine
in one trial and of prednisolone with plasma exchange in another were
useful in halving the corticosteroid dose required (mean SD, 0.52 0.28
mg/kg in the plasma exchange–treated group vs 0.97 0.33 mg/kg in
the prednisolone only–treated group). However, a fifth trial, including
all 3 treatment groups (prednisolone alone, prednisolone and azathioprine,
and prednisolone and plasma exchange), failed to confirm the benefit
of combination treatment over prednisolone alone. A trial of 20 patients,
comparing prednisone with tetracycline and niacinamide, found no statistically
significant difference in response between the 2 groups, but the prednisone-treated
group had more serious adverse effects.
Conclusions
There is inadequate evidence for a recommendation of a specific treatment
for bullous pemphigoid, and there is a need for larger randomized controlled
trials with adequate power. Starting doses of prednisolone greater than
0.75 mg/kg per day do not seem to give additional benefit, and it seems
that lower doses may be adequate for disease control. The effectiveness
of the addition of plasma exchange or azathioprine to corticosteroids
has not been established. Combination treatment with tetracycline and
niacinamide seems useful, although this needs further validation.
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| IMMUNOGLOBULIN |
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Comparison Between Intravenous Immunoglobulin and Conventional Immunosuppressive
Therapy Regimens in Patients With Severe Oral Pemphigoid Effects on
Disease Progression in Patients Nonresponsive to Dapsone Therapy
A. Razzaque Ahmed, MD, DMSc; José E. Colón, DMD
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Arch Dermatol. 2001;137:1181-1189 Abstract quote
Context
Mucous membrane pemphigoid has a wide clinical spectrum. The clinical
context was to determine whether pemphigoid disease that initiates in
the oral cavity progresses to involve other mucosae and to determine
the influence of systemic therapy on such progression.
Objective
To determine the clinical outcomes and disease progression in patients
with oral pemphigoid for whom dapsone therapy was impossible.
Design
Retrospective analysis of a cohort of 20 patients with immunopathologic-proven
oral pemphigoid studied between September 1, 1994, and October 31, 2000.
Twelve patients received conventional therapy that consisted of a combination
of oral prednisone with an immunosuppressive agent. Eight patients in
whom such therapy was contraindicated received intravenous immunoglobulin
therapy. Patients were followed up for 33 to 62 months (mean follow-up,
47.5 months).
Setting
Patients were treated in an ambulatory tertiary medical care facility
of a university-affiliated hospital.
Patients
The 20 patients had pemphigoid disease limited to the oral cavity only
at the initial clinical presentation and when enrolled in the study.
Main Outcome Measures
The following variables were compared between the 2 groups of patients:
(1) duration of treatment, (2) frequency of relapses, (3) induction
of remission, (4) adverse effects of therapy, (5) extra oral involvement,
and (6) quality of life.
Results
Using the aforementioned factors, the group treated with intravenous
immunoglobulin had statistically significant shorter treatment duration,
fewer relapses, higher remission rate, fewer adverse effects, no extraoral
involvement, and a better quality of life compared with the group who
received conventional therapy.
Conclusions
Intravenous immunoglobulin is a safe and effective modality to treat
mucous membrane pemphigoid. It seems to be a good option for patients
who cannot be treated with dapsone and in whom conventional therapy
is contraindicated or results in the development of serious adverse
effects. In patients with progressive mucous membrane pemphigoid, intravenous
immunoglobulin therapy may arrest disease progression.
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Intravenous immunoglobulin therapy for patients with bullous pemphigoid
unresponsive to conventional immunosuppressive treatment
A. Razzaque Ahmed, MD
Boston, Massachusetts
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J Am Acad Dermatol 2001;45:825-35 Abstract quote
Background: Up to 24% of patients with bullous pemphigoid (BP) do not
respond to conventional therapy consisting of oral prednisone alone
or combined with corticosteroid-sparing immunosuppressive agents (ISAs).
They cannot sustain a prolonged clinical remission and continue to have
relapses.
Objective: Fifteen patients with recurrent BP who had experienced several
significant side effects resulting from conventional therapy were treated
with intravenous immunoglobulin (IVIg) therapy.
Methods: A preliminary dose-finding study tested 7 additional patients
to ascertain the optimal IVIg dose of 2 gm/kg per cycle. Objective parameters
to determine clinical outcomes were recorded before and after IVIg therapy:
doses of prednisone and ISAs, their duration, side effects, clinical
course, frequency of relapses and recurrence, response to therapy, number
of hospitalizations, total days hospitalized, and quality of life. Results:
While receiving IVIg as monotherapy, all study subjects achieved a sustained
clinical remission. A statistically significant difference was noted
in all the variables studied before and after IVIg therapy. IVIg had
a corticosteroid-sparing effect and improved quality of life and did
not produce any serious side effects.
Conclusion: IVIg appears to be an effective alternative in treating
patients with severe BP whose disease is nonresponsive to conventional
therapy. IVIg may be particularly useful, if treatment is begun early,
in patients who are at risk of experiencing serious or potentially fatal
side effects from conventional immunosuppressive therapy. After clinical
control is achieved, IVIg therapy should be gradually withdrawn and
not abruptly discontinued. (.)
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| LEFLUMONIDE |
Arch Dermatol 2000;136:1204-1205
Novel immunomodulatory agent used in preventing organ transplantation
and treating rheumatoid arthritis
Two patients where standard steroid therapy treatment failed and both
refused corticosteroid sparing therapy-both responded with initial doses
of 20 mg/d allowing tapering of steroids
Converted into active metabolite A771726, a malononitrilamide, which
inhibits:
Dihydro-orotate dehydrogenase, a mitochondrial enzyme critical for de
novo synthesis of pyrimidines-critical for proper function of T and
B lymphocytes and this drug inhibits cytotoxic T cells and the synthesis
of antibodies
Lymphocyte tyrosine kinase activity upon mitogen stimulation or activation
of the interleukin 2 receptor
Tumor necrosis factor-activated nuclear factor kappa B-dependent gene
expression
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| STEROIDS |
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A comparison of oral and topical corticosteroids in patients with bullous
pemphigoid.
Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E,
Vaillant L, D'Incan M, Plantin P, Bedane C, Young P, Bernard P; The
Bullous Diseases French Study Group.
Department of Dermatology and Biostatistics, INSERM Unite 519, University
of Rouen, Rouen, France.
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N Engl J Med 2002 Jan 31;346(5):321-7 Abstract quote
BACKGROUND: Bullous pemphigoid is the most common autoimmune blistering
skin disease of the elderly. Because elderly people have low tolerance
for standard regimens of oral corticosteroids, we studied whether highly
potent topical corticosteroids could decrease mortality while controlling
disease.
METHODS: A total of 341 patients with bullous pemphigoid were enrolled
in a randomized, multicenter trial and stratified according to the severity
of their disease (moderate or extensive). Patients were randomly assigned
to receive either topical clobetasol propionate cream (40 g per day)
or oral prednisone (0.5 mg per kilogram of body weight per day for those
with moderate disease and 1 mg per kilogram per day for those with extensive
disease). The primary end point was overall survival.
RESULTS: Among the 188 patients with extensive bullous pemphigoid,
topical corticosteroids were superior to oral prednisone (P=0.02). The
one-year survival rate was 76 percent in the topical-corticosteroid
group and 58 percent in the oral-prednisone group. Disease was controlled
at three weeks in 92 of the 93 patients in the topical-corticosteroid
group (99 percent) and 86 of the 95 patients in the oral-prednisone
group (91 percent, P=0.02). Severe complications occurred in 27 of the
93 patients in the topical-corticosteroid group (29 percent) and in
51 of the 95 patients in the oral-prednisone group (54 percent, P=0.006).
Among the 153 patients with moderate bullous pemphigoid, there were
no significant differences between the topical-corticosteroid group
and the oral-prednisone group in terms of overall survival, the rate
of control at three weeks, or the incidence of severe complications.
CONCLUSIONS: Topical corticosteroid therapy is effective for both moderate
and severe bullous pemphigoid and is superior to oral corticosteroid
therapy for extensive disease.
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