Transcript bullous pemphigoid - Pediatrics

IMMUNE BULLOUS DERMATOSIS OF
CHILDHOOD
CASE PRESENTATION
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Johan Jams- a 7 years old Indian boy- was
admitted to the pediatric inpatient ward on
03/03/12 for a 5 days history of vesiculobullous
non itchy eruption, initially on the elbows that
progressed to involve the upper and lower limbs,
the axilla and groin, the eyelids and the lips.
Initially in a private clinic he was prescribed
zithromax and topical bactroban.
Lesions were getting more extensive and
parents revised the Dermatology clinic in
Farwaniya Hospital. He was diagnosed as
shingles??
CASE PRESENTATION
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Later the parents revised the Infectious Disease
Hospital and he was referred back to Farwaniya
Hospital as Steven Jhonson Syndrome case.
Dermatologists requested a skin biopsy which
revealed a linear pattern of deposition of IgA
together with C3 at the BMZ consistent with the
diagnosis of Chronic Bullous Disease Of
Childhood (CBDC).
NORMAL SKIN, with labels
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Vesicles and bullae are accumulations of fluid within
or under the epidermis.
Subepidermal blisters
Occur between the dermis and the epidermis.
 Their roofs are relatively thick and so they tend to be tense
and intact.
 They may contain blood.
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Intra-epidermal
blisters appear within the spinosum or granulosum cell
layer of the epidermis
 So have thin roofs and rupture easily
 Leave an oozing denuded surface.
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Subcorneal blisters
Form just beneath the stratum corneum at the
outermost edge of the epidermis
 Have even thinner roofs
 Tendency to break is more marked
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BLISTERING DISORDERS IN INFANCY AND
CHILDREN
Epidermolysis Bullosa
 Herpes Simplex and
Zoster
 Epidermolytic
Hyperkeratosis
 Incontinentia
Pigmenti
 Mastocytosis
 Bullous Impetigo
 Staphylococcal
Scalded Skin
Syndrome
 Erythema Multiforme

Toxic Epidermal
Necrolysis
 Scabies
 Suction blisters
 Immunobullous
Disorders
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Pemphigus
Bullous pemphigoid
Dermatitis
herpetiformis
Epidermolysis Bullosa
Acquisita
Linear IgA dermatoses
AUTOIMMUNE BULLOUS DISORDERS
Pemphigus
 Bullous Pemphigoid (BP)
 Dermatitis Herpetiformis (DH)
 Epidermolysis Bullosa Acquisita (EBA)
 Linear IgA Dermatoses (Chronic Bullous Disease Of
Childhood –CBDC)
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Clinically they may be indistinguishable in children
Immunobullous diseases in childhood are
uncommon but should be considered if the
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blistering condition has been persistent for
longer than a month, particularly if unresponsive
to antibiotic therapy.
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Diagnosis is made by correlating the histologic
findings with the direct immunofluorescence
(DIF).
Blisters may appear flaccid, tense or may
present as erosions
IMMUNE - MEDIATED
INTRAEPIDERMAL
BULLOUS DISEASES
PEMPHIGUS VARIANTS
PEMPHIGUS VULGARIS
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Autoimmune blistering disease of the skin and
mucous membranes with intraepidermal blisters.
Very rare in childhood.
Painful fragile blisters occur in lower epidermis,
just above the basal layer, anywhere on the body,
arising on normal or erythematous skin.
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o
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Nikolsky sign is positive.
Mucous membrane lesions (particularly in the
mouth) occur in 50-70% and may be the sole sign
for an average of 5 months before skin lesions
develop.
Erosions may involve the pharynx or the
larynx, causing hoarseness.
Neonatal PV occurs when maternal IgG crosses
the placenta, and remits when maternal
antibodies decrease (~6–12 months).
OTHER PEMPHIGUS VARIANTS
 Pemphigus
foliaceus
 Endemic pemphigus (Fogo selvagem [in
Brazil])
 Paraneoplastic pemphigus (PNP) [Seen with
lymphoma & leukemia]
 Drug-induced pemphigus (caused by
penicillamine or captopril)
 Pemphigus erythematosus (Senear-Usher
syndrome [SUS]– Hybrid between PV & SLE)
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Pathogenesis
IgG autoantibodies are directed against
desmosomes (cell adhesion proteins) in epidermis.
Acantholysis (loss of cell-to-cell adhesion) in areas
of deposition of IgG.
Diagnosis
DIF is positive for IgG and C3 along keratinocyte
surfaces.
Histology:
Suprabasilar acantholysis in PV / NP and
Granular cell layer acantholysis in PF, and
pemphigus erythematosus .
TREATMENT
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Prednisone 1–2 mg/kg per day.
Steroid-sparing agents: cyclophosphamide,
azathioprine, cyclosporine, methotrexate, or gold
High-potency topical steroids might be helpful for
localized disease
Intravenous immunoglobulins (IVIG) may be a
promising therapy.
Prognosis
Prognosis without treatment is poor. Infection is
often the cause of death.
IMMUNE-MEDIATED SUBEPIDERMAL
BULLOUS DERMATOSES
Bullous
Pemphigoid
Epidermolysis Bullosa
Acquisita
IgA Mediated Disorders
1.
DERMATITIS HERPETIFORMIS
2. LINEAR IgA DISEASE
BULLOUS PEMPHIGOID
Large, tense blisters arising on normal or
erythematous skin.
 Mucous membrane involvement in 10–35%.
 Sites of predilection: lower abdomen, inner
thighs, flexor forearms or generalized.
 Bullae may have clear or hemorrhagic fluid.
 Nikolsky sign is negative.
 Early lesions tend to look urticarial and are
quite pruritic.
 Very rare in childhood.
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Pathogenesis
BP antigens are proteins in hemidesmosomes (cell-to-matrix
adhesion proteins) in BMZ. IgG can activate complement,
causing leukocyte adherence to the BM, and subsequently
leading to dermal–epidermal separation.
Diagnosis
DIF: linear pattern of IgG and C3 at BMZ.
Indirect immunoflourescence: 70–80% of patients
will have circulating IgG which binds to stratified
squamous epithelium.
GENERALIZED DISCRETE AND CONFLUENT ANNULAR EDEMATOUS RED PLAQUES WITH
CRUSTED PAPULES AND VESICLES AT THE PERIPHERY IN A 6-YEAR OLD GIRLSHE WAS
TREATED FOR PRESUMED LINEAR IGA BULLOUS DISEASE OF CHILDHOOD WITH ORAL DAPSONE
WITHOUT IMPROVEMENT. THE BIOPSY SHOWED A SUBEPIDERMAL VESICLE, AND DIRECT
IMMUNOFLUORESCENCE REVEALED C3 AND IMMUNOGLOBULIN G ALONG THE BASEMENT
MEMBRANE ZONE TYPICAL OF BULLOUS PEMPHIGOID.
Histology
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subepidermal blister without necrosis.
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Treatment
Prednisone 1–2 mg/kg per day.
Steroid-sparing agents: cyclophosphamide,
azathioprine, cyclosporine, methotrexate, or gold
Localized BP can be treated with high-potency
topical steroids
Prognosis
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BP may be self-limited and can last several
months to many years.
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pemphigus
Very rare in childhood
 Clinical features:
monomorphic
 Blisters:
flaccid,ruptures easily
 Content of blisters:
fluid filled.
 Oral lesion :are
common
 Nikolsky’s
sign:Positive
 Acantholytic cells are
seen
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pemphigoid
Very rare in childhood
 Polymorphic
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Tense ,firm
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Mostly hemmorhagic
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Less common
Negative
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No acantolytic cells.
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EPIDERMOLYSIS BULLOSA ACQUISITA
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Epidemiology
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Pathophysiology
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Few isolated cases of children seen
Autoimmune Subepidermal Blistering condition
Signs
Trauma prone areas more commonly affected
 Tense Blisters and Erosions over extensor surfaces
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Knuckles
 Dorsal hands
 Elbows
 Knees
 Ankles
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Mucosal involvement
Oral, nasal, and esophageal mucosa
 Conjunctival mucosa
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THE FAMILY OF IGA-MEDIATED
BULLOUS DERMATOSIS
Dermatititis herpetiformis
Linear IgA Disease
(Bullous Disease of
Childhood)
DERMATITIS HERPETIFORMIS
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Most common immunobullous disease in children
Characterized by intensely pruritic chronic
papules and vesicles located symmetrically over
extensor surfaces, scalp hairline and posterior
nuchal area.
Primary lesions: erythematous papules,urticarial
plaques or vesicles, but crusted lesions are
frequently the only lesions seen. Large bullae
infrequent.
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Mucous membrane involvement uncommon.
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Onset is usually in adolescence or later.
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Most have GI abnormality similar to celiac
disease (villous atrophy of the small intestine)
but are asymptomatic.
Lesions can be exacerbated by gluten or oral
iodides
Sometimes associated with GI lymphomas, or
autoimmune disease (e.g.thyroid disease,
diabetes, SLE, Sjögren syndrome, or vitiligo).
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Pathogenesis
IgA deposits are complexes of immunoglobulins
and GI-derived antigens which react with an
unidentified skin antigen.
IgA activates complement, causing chemotaxis
of neutrophils which release enzymes causing
blistering.
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Diagnosis
Histology: dermal papillary collections of
neutrophils with subepidermal blisters within
lamina lucida of BMZ.
DIF shows granular IgA and C3 deposits.
Circulating Antireticulin antibodies of IgA and
IgG classes can be detected in the majority of
patients.
Circulating IgA autoantibodies to endomysium,
tissue transglutaminase (tTG) and gliadin are
also detected.
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Treatment
Dapsone 2mg/kg per day.
Gluten-free diet may be effective.
Prognosis
Lifelong disorder, persisting indefinitely with
varying severity.
CHRONIC BULLOUS DISEASE OF CHILDHOOD
(LINEAR IGA DERMATOSIS)
Background
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Linear immunoglobulin A (IgA) dermatosis
(LAD) is an autoimmune subepidermal
vesiculobullous disease that may be idiopathic or
drug-induced. Children and adults are affected,
with disease of the former historically referred to
as chronic bullous dermatosis of childhood
(CBDC). It is the second most common
immunobullous disease in childhood.
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The clinical presentation is heterogeneous and
appears similar to other blistering diseases, such
as bullous pemphigoid and dermatitis
herpetiformis.
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Pathophysiology
Caused by linear deposition of IgA to a 97-kDa
antigen in lamina lucida of BMZ.
Antibody deposition leads to complement
activation and neutrophil chemotaxis, which
eventuates in loss of adhesion at the dermalepidermal junction and in blister formation.
Associations
1. Drugs: vancomycin, lithium, diclofenac
2. Lymphoid and nonlymphoid malignancies
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Diagnosis
Usually overlooked initially, because of its
confusion with bullous impetigo.
Histology:
Subepidermal bulla with neutrophils along the
BMZ, often in papillary tips.
DIF: IgA in a homogeneous linear pattern along
BMZ; occasional IgG and C3.
Three patterns of IgA deposition (found on
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electron microscopy): in lamina lucida (similar
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to BP); at or below lamina densa (similar to
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epidermolysis bullosa acquisita).
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Low titer IgA serum autoantibodies can
sometimes be detected.
Epidermal Basement Membrane Zone Antigens in Bullous Diseases
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Mortality/Morbidity
The mean duration is 3.9 years, ranging from 2.17.9 years. Remission has been reported to occur
in 64% of children, in most cases within 2 years.
The disease tends to wax and wane in severity.
Drug-induced cases typically resolve quickly once
the causative agent is withdrawn. Cutaneous
lesions usually heal without scarring, while
mucous membranes lesions heal with scarring.
Ocular linear IgA dermatosis may lead to
blindness. Nose, pharynx, larynx, oesophagus
and rectum can be involved.
Sex
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The female-to-male ratio is 1.6:1.
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Age
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Disease in children commences at ages ranging
from 6 months to 10 years, with a mean of 3.3-4.5
years.
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History
 Some patients note a prolonged period of
prodromal itching before lesions appear.
 Patients with ocular manifestations may complain
of pain, or discharge.
 Rash latency in vancomycin-induced cases of
linear IgA dermatosis ranges from 1-13 days after
first dose .
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Physical
The classic primary lesions of linear IgA
dermatosis are clear and/or hemorrhagic vesicles
or bullae on normal, erythematous, or urticarial
skin.
Cutaneous manifestations may also include
erythematous plaques, blanching macules and
papules, or targetoid erythema multiforme–like
lesions.
The diagnosis is not dependent on the presence of
vesicles and/or bullae and a morbilliform variant
has been described.
Physical
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Bullae may be discrete or arranged in a
herpetiform pattern, often described as the
cluster of jewels sign. Alternatively, vesicles and
bullae may be seen at the edge of annular lesions,
the appearance of which has been described as
the string of beads sign.
Lesions in children are typically localized to the
lower abdomen and anogenital areas with
frequent involvement of the perineum. Other
sites of involvement include the feet, the hands,
and the face, particularly the perioral area
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Oral lesions include vesicles, ulcerations,
erosions, desquamative gingivitis, or erosive
cheilitis, and they may precede skin lesions.
children and adults frequently complain of ocular
symptoms, such as burning, or discharge.
Ophthalmologic findings even in the absence of
ocular complaints may include subconjunctival
fibrosis , symblepharon formation, and cicatricial
entropion .
Bullous lesions on the genital area in a child with linear IgA
dermatosis
cluster of jewels
ANNULAR LESIONS DEMONSTRATING THE
STRING OF BEADS SIGN.
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Treatment
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Dapsone 2mg/kg per day
Prednisone 1–2 mg/kg per day
Most cases respond to combination of prednisone
and dapsone
Topical antibiotics and nonstick gauze covering
if lesions are oozing or crusted
Other drugs: colchicine, sulfapyridine
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Prognosis
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Usually lasts several years and then remits.
Occasionally, persists into puberty.
DIFFERENTIAL DIAGNOSIS
•
Bullous impetigo
 • Pemphigus
 • Bullous pemphigoid
 • Epidermolysis bullosa
 • Erythema multiforme
 • Bullous systemic lupus erythematosus
EPIDERMOLYSIS BULLOSA
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EB is a group of genetic diseases where mild
trauma induces blister formation, presenting
usually in the neonatal period.
EB is divided into scarring (dystrophic) and
nonscarring (simplex and junctional) types.
Non scarring types demonstrate an intra
epidermal separation (EB simplex) or a
separation at the dermal–epidermal junction
(junctional EB).
Scarring types: subepidermal blisters are found
in dystrophic EB.