Disorders of Epidermal and

Dermal -Epidermal Cohesion,

and Vesicular and bullous
Disorders

Sheila Jean Willkomm-Serina , MD,DPDS

 Pemphigus Vulgaris
• PV is more common in Jews and probably in
people of Mediterranean descent and from the
Middle East
• The primary lesion of PV is a flaccid blister,
which may occur anywhere on the skin surface,
but typically not the palms and soles (Fig. 54-2).
• Usually, the blister arises on normal- appearing
skin, but it may develop on erythematous skin.
Because PV blisters are fragile, the most
common skin lesions observed in patients are
erosions resulting from broken blisters.
• These erosions are often quite large, as they
have a tendency to spread at their periphery
(Fig. 54-3).
• A characteristic finding in pemphigus patients is
Nikolsky’s sign
Pemphigus Vulgaris

Nikolsky’s sign
 The mucous membranes most often affected by PV
Pemphigus Vulgaris are those of the oropharyngeal cavity (see Fig. 54-
2B). As with cutaneous lesions, intact blisters are
rare.
Oropharyngeal erosions can be so painful that the
patient is unable to eat or drink.
The inability to eat or drink adequately may
require inpatient hospitalization for disease control
and intravenous fluid and nutrient repletion.
In the majority of patients, painful mucous
membrane erosions are the presenting sign of PV
and may be the only sign for an average of 5
months before skin
lesions develop.
However, the presenting symptoms may vary; in a
study from Croatia, painful oral lesions were the
presenting symptom in 32% of patients.
Most of these patients progressed to a more
generalized
eruption in 5 months to 1 year; however, some
had oral lesions for more than 5 years before
generalization
 Gastrointestinal tract :
 esophagus, stomach, duodenum, and anus

 other mucous membranes :

vulvovaginal, nasal, laryngeal, and
conjunctival mucosa
 Pemphigus Vulgari

Vegetating lesions
• Vegetating /granulomatous lesions intertriginous, scalp, face
pemphigus vegetans of Hallopeau and pemphigus vegetans of
Neumann.
• However, the subsequent analysis of vegetating skin lesions by
histology and immunofluorescence suggests that these cases are
simply clinical variants of PV.1,97
• In the Hallopeau variant, vegetating and often pustular lesions are
present from the outset of disease, are not preceded by bullae, and
favor flexural regions (see Fig. 54-4B).
• Generally, the prognosis for these patients is thought to be better,
with neelder disease and a higher chance of remission compared to
typical PV patients.98 In patients with the Neumann variant, ordinary
PV erosions heal with papillomatous formations, with prognosis
related to the extent of disease activity. The vegetating type of
response may also appear in certain lesions that tend to be resistant
to therapy and remain for long periods of time in one place. Thus,
vegetating lesions seem to be one reactive pattern of the skin to the
autoimmune insult of PV.
 The characteristic clinical lesions of PF are scaly,
Pemphigus Foliaceous crusted erosions, often on an
erythematous base. In more localized and early
No mucosal lesions disease, these lesions are usually well
Seborrheic areas demarcated and scattered in a seborrheic
distribution, including the face, scalp, and upper
Burning sensation trunk

small flaccid vesicle

Pemphigus -Erythematosus
• Senear-Usher syndrome
• immunologic overlap
• features; by definition all demonstrate the cell surface
• staining pattern classic for pemphigus, approximately
30% have positive antinuclear antibody titers, and 80%
have positive lupus band tests, although the latter test
is only positive in 20%–40% of biopsies on nonsunexposed
skin.
• As most patients with pemphigus
erythematosus do not develop systemic signs or symptoms
of lupus, and some may progress from localized
disease to generalized PF, the diagnosis of pemphigus
erythematosus is largely one of historic
NEONATAL PEMPHIGUS

 Infants born to mothers with PV may display

clinical, histologic, and immunopathologic signs
of PV
 The degree of involvement varies from none to
severe enough to result in a stillbirth. If the infant
survives, disease tends to remit as maternal
antibody is catabolized.
 Mothers with PF may also transmit their
autoantibodies to the fetus
Disease Association
• Myasthenia gravis
• Thymoma

Laboratory
PV

Suprabasilar acantholysis
Rows of tombstones
Normal skin histology
Desmosome

Desmosomes are primarily responsible for epidermal adhesion

Laboratory

PV

Suprabasilar acantholysis
Laboratory Subcorneal blister

PF

Acantholysis in the granular layer. B

PF

Subcorneal pustule
Immunofluorescence
IgG

Indirect IF

Direct immunofluorescence shows

immunoglobulin G (IgG) on the
Direct IF keratinocyte
cell surface of the patient’s skin; indirect
immunofluorescence shows IgG in patient
serum that binds the cell surface of normal
keratinocytes.
Laboratory

• Enzyme –linked immunosorbent Assay (ELISA)

-More sensitive and specific, titers correlate with disease activity and
can differentiate between PV and Pf, problem is availability

Prognosis
 Infection is cause of death
 PV (MR is 10 %); lesser for PF
 40 patients with PV : 2 (5%) died
17% long lasting remission
37% relapsed
others required continuous TX
159 pts in croatia, only 12% ha longterm remission, most relapsed
Treatment

• Prednisone ( 0.5-1.0 MKD single daily dose)

• Azathioprine (start 50-100mg/day up to 2.5 mg/kg/day
• Mycophenolate mofetil (2-3 g/day)
• Cyclophosphamide (1.1- 2.5 MKD)
• Rituximab (monoclonal anti CD20 antibody)
• IV immunoglobulin
• Plasmapheresis
• Pulsed IV methylprednisolone
Notes
• Aza- blood and liver monitoring TPMT ; risk of infection
Mycophenolate, cyclophosphamide bladder CA
Paraneoplastic Pemphigus

More necrosis and lichenoid changes

• Intractable stomatitis (Figs. 55-2A and 55-2B). It is the earliest pre-
senting sign and the one feature that persists through- out the course of
the disease, even after treatment and is extremely resistant to therapy.
This nding is so con- sistent that in its absence, PNP should not be
consid- ered in the differential diagnosis.
• his stomatitis consists of erosions and ulcerations that can affect all
surfaces of the oropharynx. The lesions differ from those seen in
pemphigus vulgaris in that they show more necrosis and lichenoid
change. They also preferentially localize to the lateral borders of the
tongue, and characteristically extend onto and involve the vermilion of
the lips. Occasionally, oral lesions are the only manifestation of the
disease. However, it is important to note that erythema multiforme and
TEN are self-limited events that evolve and resolve over several weeks,
whereas PNP is a relentlessly progressive and evolves continuously over
months. NP is the only form of pemphigus that involves non- strati ed
squamous epithelium. Approximately 30%– 40% of cases develop
pulmonary injury, often with a fatal outcome
Paraneoplastic Pemphigus

• 44% NHL
• 19% CLL
• 16% Castleman disease (giant follicular hyperplasia)
• 8% thymoma (malignant and benign)
• 7% sarcomas that are retroperitoneal and often poorly
differentiated
• 4% Waldenström’s macroglobulinemia
• 2% the neoplasms were too poorly differentiated to
categorize
• This mechanism occurs in several neurologic paraneoplastic syndromes.3
This antitumor immune response may be initiated by reactivity against
plakin proteins, and the antitumor immune response may cross-react with
normal consti- tutive proteins of epithelia. However, to date, there are no
data to support this hypothesis.
• It is more likely that this autoimmune disease is a result of more complex
interactions between the tumor cells, the immune system, and speci c
genetic background. In many autoimmune diseases, speci c genetic
predispositions have been found, and HLA studies performed on two
different series of PNP patients revealed a signi cant predominance of HLA-
class II DRB*03 and HLA-class I Cw*14 genes.
• Almost all patients with PNP have autoantibod- ies against desmogleins,
demonstrable by enzyme- linked immunosorbent assay (ELISA), and when
the desmoglein autoantibodies from these patients are af nity puri ed and
injected into neonatal mice, acan- tholytic skin lesions are induced.10
However, none of features of the disease that appear to be induced by cell-
mediated autoimmunity are recreated by the immunoglobulin injections. No
internal organs, like the lungs, are involved, and there are no ndings of
lymphocyte-mediated lichenoid or interface epithelial injury. This is another
indication that humoral immu- nity alone reproduces features of
acantholysis, but pas- sive transfer of autoimmune cells from these patients
may be necessary to induce the complete spectrum of the disease in
animals.
Paraneoplastic Pemphigus
• Approximately one-third of patients have an occult
malignancy at the time they develop PNP. Neoplasms
that would not be detected by routine complete blood
count, serum chemistries, and physical examination are
most likely to be intra-abdominal lymphoma, intratho-
racic or retroperitoneal Castleman tumors, or retroperi-
toneal sarcomas. The most effective and ef cient method
for screening for these tumors is either computer-aided
tomography or magnetic resonance imaging of the
body from the neck to the base of the bladder. If avail-
able, Positron emission tomography/ computer tomog-
raphy (PET/CT) using uorodeoxyglucose (FDG) as a
biologically active molecule can be more speci c in the 605
Indirect immunoflourescence

IgG,C3

Simple, columnar and transitional

Epithelium
(rodent bladder epithelium)
• Serum autoantibodies that bind to the cell surface
of skin and mucosae in a pattern typical of
pemphigus, but in addition, bind to simple,
columnar, and transitional epithelia…Serum
autoantibodies directed against plakin proteins that
are detected by indirect immunofluorescence
against rodent bladder epithelium.
PNP Prognosis

• Sepsis, gastrointestinal bleeding, “multi- organ failure,”

and respiratory failure. Patients with autoimmune
disease associated with B-cell neoplasms are known to
have a high frequency of autoimmune cytopenias, and
some fatal episodes of sepsis are suspected to have
occurred because of sudden and unexplained
neutropenia, possibly due to this mechanism.
Respiratory failure is a common terminal event.
Notes
• High mortality rate, with death due to sepsis,
complications of treatment, or bronchiolitis obliterans.
PNP Treatment
Bullous Pemphigoid

Tense vesicles. Neg nikolsky sign…. Usually start at

flexures…can be localized… 10 persent buccal involvement
spares the vermillon, and is non scarring… 60-70 age group
peak 70…but can occur in children although rare
Triggers

•Most occur without trigger

•Triggers :
•Following UVB or PUVA or radiation
therapy
•Medications: penicillamine, efalizumab,
etanercept, and furosemide

Notes
•Most cases are sporadic
Disease Association

•Neurological disease

Notes
•Especially in 80 years and above
•Malignancy none
BP Histopathology
Early small blister

Subepidermal blister, with eosinophils

BP

A lot of infiltrates lymphocytes, histiocytes, characteristically contain

eosinophils… seldom form microabcesses like in d H)
 Direct Immunoflouresence

C3

Linear band of IgG to epidermal basement

membrane
Laboratory
 Elevated total serum IgE levels
 Direct immunofluorescence shows
immunoglobulin (Ig) G and C3 at epidermal
Basement membrane of perilesional skin,
 Indirect immunofluorescence shows IgG
antibasement membrane autoantibodies in
the serum.
Prognosis
• prior to the availability of systemic
corticosteroids, Lever reported that 8 of 30 adults with bullous pemphigoid
went into remission after approximately 15 months (range, 3–38 months)
of active disease.
In treated patients, the length of disease ranges
from 9 weeks to 17 years with a median treatment
period of 2 years and 50% remission rates in patients followed for at least 3
years
Notes
• 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.162,18High ELISA titers
and, to a lesser degree, positive direct IF at the time of therapy cessation
has been associated with a high risk of relapse within the first year
following cessation of therapy.182
• At least one of these tests should be performed before therapy is
discontinued.
• Old age, poor general health, presence of anti BP180 antibody, poor
prognosis
• Untreated -25% mortality rate
 BP
Treatment
• CORTICOSTEROIDS
• High potency topical steroids
• Prednisone (.75-1 mkd)
• OTHER IMMUNOSUPPRESSIVE AGENTS
• Azathioprine (2.5mg/kg)
• Mycophenolate mofetil (0.5-1 g bid)
• Others: methotrexate, (low dose 5mg/week), cyclophosphamide
• MODULATORS OF ANTIBODY LEVELS
• Intravenous γ-globulin
• Plasmapheresis
• OTHER
• Tetracycline (2g) or erythromycin ( adult dose 1000-3000 mg)and
nicotinamide(1500mg)
• Dapsone(50-200mg/day)
• Sulfapyridine (1-1.5g/day)
• Topical tacrolimus
• Reports have described successful treatment of some
• bullous pemphigoid patients with tetracycline and nicotinamide
• or variations on this theme, such as erythromycin
• and nicotinamide or tetracycline alone.214–216
• In small numbers
• Mainstay pred dose is 1 mkd… supression seen in 1-4 weeks…then taper…5m
per week…to reach about 30mg a day….75-1 mkd severe, .5 moderate, .3 if
mild/local…..adverse effects are dose dependent …give gastric
protection…vit D and ca….extensive disease is >10 new blisters a day

• Topical, 20g bid even on non lesional skin

• Mortality higher with >40 mg prednisolone per day in elderly

• Tetracycline 500-2000 mg/day….azt thiopurine
methyltransferase…myelotoxicity
• Doxy 200-300 per day
• Small rct for antibioic….10% has used it as firt line(germany)…erythro esp for
children… benefits in 1-3 weeks…combi with topical steroids…still no
evidence as effective as sole treatment…no rct for dapson sulfa…steroid
sparing….IVIg immunomodulatory-41 pts as experience…sole treatment
rapid and dramatic short lived effect.used with pred and other agents.well
tolerated but very expensive…cyclophosphamide 3 cases very toxic..only for
refractory cases …..rituximab.biologics, anti cd20, tumor necrosis factor
alpha
Cicatricial Pemphigoid

 painful erosive lesions one or more mucosal site, some skin lesions
 The mouth is the most frequent site of involvement
• 1 in a million, t in patients with cicatricial pemphigoid; it
is often the first (and only) site affected. Lesions often
involve the gingiva, buccal mucosa, and palate (Fig. 57-
2); other sites such as the alveolar ridge, tongue, and
lips are also susceptible.9,43
• A frequent oral manifestation is desquamative gingivitis.
• Other lesions may present as tense blisters that rupture
easily or as mucosal erosions that form as a
consequence of epithelial fragility.
• Lesions in the mouth may result in a delicate white
pattern of reticulated scarring. Adhesions in severe
cases….early to mid sixties
 Cicatricial Pemphigoid

Ocular involvement in patients with

cicatricial pemphigoid is common and
may become sight threatening. Begins as
conjuctivitis, then scarring…may start
unilaterally then becomes bilateral
Cicatricial Pemphigoid

Symblepharon
formation,,,
alopecia
scarring,,,scalp
head and neck
trunk..ruptures
easily… crusting

skin is involved 25-35 % of the time…

Cicatricial Pemphigoid

 Other sites that may be affected by

cicatricial pemphigoid
- nasopharynx
- larynx
 -esophagus
 - anogenital area
A cohort of 35:
patients with antiepiligrin cicatricial pemphigoid (also
called antilaminin 332 cicatricial pemphigoid) was
shown to have an increased relative risk for cancer.47,48
Ten patients in this cohort had solitary solid cancers
(three lung, three gastric, two colon, two endometrial);
eight patients developed cancer after the onset of cicatricial
pemphigoid (six within a year, seven within
14 months). The time between blister onset and cancer
diagnosis was approximately 14 months in nine of the
ten patients. Eight patients in this cohort died as a consequence
of their cancer. All deaths occurred within 21
months.
Laboratory

• Histologic findings, DIF and IIF results are similar in CP,BP and EBA

• Differentiation is clinical
• DIF: continous deposit of any one or combination of the following
along the epithelial basement membranezone ; igG, IgA and/or C3.
-IIF: circulating antibasement membrane zone specific for IgG in 20%
of time . Titers are usually low.

-Immunoblot (western blot), immunoprecipitation

-Evaluate upper airway or esophagus : e.g.CT scan, barium swallow :
malignancy search
Dif in non lesional mucosa: mouth buccal
CP Prognosis

•Cicatricial pemphigoid is typically a

chronic and progressive disorder,
although involvement may be
limited to a given anatomic site
Notes
•Rarely goes into spontaneous
remission
• MILD INVOLVEMENT
• Sites Local Care Measures
• Mouth Topical corticosteroid (gels or ointments) bid/qid; topical corticosteroids
• under occlusion (e.g., dental trays); topical calcineurin inhibitors; intralesional
• corticosteroids
• Nose Irrigation with isotonic saline bid/tid; nasal lubricants; topical corticosteroids
• (e.g., via sprays, inhalers)
• Anogenital region Topical corticosteroids; topical calcineurin inhibitors
• Skin Topical corticosteroids; topical calcineurin inhibitors
• MODERATE INVOLVEMENT
• Sites Therapeutic Options
• Mouth, eyes, nose, larynx, esophagus,
• anogenital region
• Local care measures outlined above plus dapsone 50–200 mg daily, prednisone
• 20–60 mg each morning, or both of these agents simultaneously
• SEVERE INVOLVEMENT
• Sites Therapeutic Options
• Mouth, eyes, nose, larynx, esophagus,
• anogenital region
• Local care measures outlined above plus prednisone (1 mg/kg each morning),
• intravenous immunoglobulin (2 g/kg body weight over 2–3 days every 2–6 week
• for 4–6 months), or both of these agents simultaneously in conjunction with azathioprine
• (2–2.5 mg/kg/day), mycophenolate mofetil (1–2.5 g/day), cyclophosphamide
• (1–2 mg/kg/day), or rituximab (375 mg/m2 weekly × 4 then every 4–6
• months as needed, or 1000 mg on days 1 and 15 and then 500 mg at month 6).
Linear Immunoglobulin
A Dermatosis and Chronic Bullous
Disease of Childhood
Linear Immunoglobulin
A Dermatosis and Chronic Bullous
Disease of Childhood

presence of homogeneous linear deposits

of IgA at the cutaneous basement membrane
Linear IgA dermatosis
Linear IgA dermatosis

Heterogenous,with
combinations of annular or
grouped papules, vesicles,
and bullae (Figs. 58-2 and
58-3).

Typically, these
lesions are distributed
symmetrically on extensor
surfaces,
Including elows knees and
buttocks. pruritic
 Linear IgA dermatosis
Heterogenous,with
combinations of annular
or grouped papules,
vesicles,
and bullae (Figs. 58-2 and
58-3). Typically, these
lesions are distributed
symmetrically on
extensor surfaces,
Including elows knees
and buttocks. pruritic

May have significant mucosal lesions

Drug-induced Linear IgA
*vancomycin is most closely
associated

Recovery has been

 Lithium
reported with
 phenytoin discontinuation of the
 offending agent alone,
sulfamethoxazole/trimethoprim,
but these patients may
 Furosemide benefit from dapsone
 Atorvastatin therapy (see Section
 captopril “Treatment and
 diclofenac Prognosis
Chronic Bullous
Disease of Childhood

“Cluster of jewels”
• Development of large numbers of tense blisters, which
may rupture and become secondarily infected.
• CBDC differs from linear IgA bullous dermatosis of
adults in its typical clinical appearance, relative paucity
of serious mucosal involvement, and good prognosis.31
• Rarely, patients with linear IgA dermatosis may present
with an acute febrile illness with arthritis, arthralgias,
and generalized malaise.45,46
• The tense bullae, often on an inflammatory base.15
• These lesions occur most frequently in the perineum
and perioral region and often may occur in clusters,
giving a “cluster of jewels” appearance (Figs. 58-5–58-
7).
• New lesions sometimes appear around the periphery of
previous lesions, with a resulting “collarette” of blisters.
Chronic Bullous
Disease of Childhood

Colarrette of blisters
 Linear IgA dermatosis and Chronic Bullous
Disease of Childhood
• 70% of linear IgA patients may have oral mucosal lesions
Notes:
• Oral lesions may occur in up to 70% of patients with linear IgA
disease.20
• Mucosal invasion with complication is less often seen in CBDC.31
• Although most patients with linear IgA dermatosis and mucosal
involvement have significant cutaneous disease, cases have been
reported in the literature in which the presenting and
predominant clinical manifestations are lesions of the mucous
membranes.48,49
• These patients may present with desquamative gingivitis and oral
lesions consistent with those seen in patients with cicatricial
pemphigoid (see Chapter 57).
• Patients also may present with conjunctival disease and scar
formation typical of that seen in patients with cicatricial
pemphigoid (see Chapter
 Linear IgA dermatosis and associated
diseases
• ulcerative colitis
• Crohn’s disease
• Lymphoid malignancies
• Non lymphoid malignancies
Notes
• Oral lesions may occur in up to 70% of patients with linear IgA disease.
• Mucosal invasion with complication is less often seen in CBDC.31
• Although most patients with linear IgA dermatosis and mucosal
involvement have significant cutaneous disease, cases have been
reported in the literature in which the presenting and predominant
clinical manifestations are lesions of the mucous membranes.48,49
• These patients may present with desquamative gingivitis and oral
lesions consistent with those seen in patients with cicatricial pemphigoid
(see Chapter 57).
• Patients also may present with conjunctival disease and scar formation
typical of that seen in patients with cicatricial pemphigoid (see Chapter
Differential Diagnosis

 Dermatitis herpetiformis
 Bullous pemphigoid
 Epidermolysis bullosa acquisita
 Bullous eruption of systemic lupus erythematosus
 Cicatricial pemphigoid
 Lichen planus
 Toxic epidermal necrolysis
Prognosis

 LAD : unpredictable course

 CBDC: self limited, remission in 2 years

Notes

• Adults with linear IgA dermatosis have an unpredictable

course.4,20 Many patients have disease that continues for
years, with few, if any, episodes of remission.
• Occasionally, patients may have a spontaneous remission with
loss of clinical features of the disease and disappearance of the
linear IgA deposits in the skin. Patients with severe mucosal
disease, especially of the eyes, may have persistent problems
with symblepharon formation and resulting structural
problems with the eyelids and cornea, even after active
blistering has remitted.
Histopathology of lesional skin from a patient
with linear immunoglobulin A dermatosis showing a
subepidermal
blister filled with neutrophils
Treatment

• dapsone or sulfapyridine (response

usually occurs within 24–48 hours)
-low dose steroid
-mycophenolate mofetil
-topical tacrolimus
-Sulfonamides
Dicloxacillin
erythromycin
flucloxacillin
Pemphigoid Gestationis
(Herpes Gestationis)

Later part of pregnancy or immediately

post partum
• Pemphigoid gestationis (PG) is the least common, yet best-characterized, dermatitis
specific to pregnancy.1 It classically presents as an intensely pruritic, urticarial rash
during the later part of pregnancy or the immediate postpartum period, then rapidly
progresses to a pemphigoid-like, vesiculobullous eruption.
• The rash may wax and wane during pregnancy, only to flare during labor and delivery.
PG appears to be mediated by a specific immunoglobulin (Ig) G directed against the
cutaneous basement membrane zone (BMZ).
• PG occurs in approximately 1 in 50,000 pregnRapid progression to a generalized,
pemphigoid-like eruption, sparing only the face, mucous membranes, palms, and soles
is the rule (although any site may be involved). Starts at abdomen…Flares occur with
delivery in approximately 75% of patients and may be dramaticanciesthe time of
delivery.
• Others develop relatively trivial urticarial lesions during one pregnancy, only to suffer
characteristic blistering during a subsequent gestation.
• Still others develop classic disease during one pregnancy, then no disease during the
next. The frequency of such “skip pregnancies” approximates 5% to 10%.36 Recurrences
associated with menstruation are common, particularly during the first several months
after delivery, and flares during the subsequent use of oral contraceptives occur in at
least 25% of patients..2,3Most disease remits spontaneously over weeks to months
following delivery, although there are isolated reports of protracted postpartum
involvement. It has often been said that once gestational pemphigoid develops, it tends
to occur earlier and with greater severity during subsequent gestations, but there are
no data to support this contention. No clear pattern of paternal contribution
 Results of routine laboratory
investigations are normal.
Histopathology classically reveals a
subepidermal vesicle with a
perivascular infiltrate of lymphocyte s
and eosinophils (Fig. 59-3). Eosinophils
may be lined up along the dermal–
epidermal junction and typically fill
the vesicular space. However, classic
findings are seen only in the minority
of cases. A nonspecific mixed cellular
infiltrate containing a variable number
of eosinophils is more common. The
presence of eosinophils is
the most constant histologic feature of
PG.

Subepidermal vesicle
Laboratory

 C3, with or without IgG, in a linear band along

the BMZ of perilesional skin Direct
immunofluorescence: linear
 deposition of C3, with or without
immunoglobulin (Ig) G, along the basement
membrane zone of the epidermal fragment
of salt-split skin
• No significant maternal morbidity or mortality
• Associated with a slight increase in premature
• and small-for-gestational-age births.
Notes:
• No increase in maternal morbidity or mortality has been documented,
although the impression of such remains from a review of published
case reports.
• Cutaneous disease in the newborn is typically selflimited and rarely
requires intervention. Although there is an increased risk of premature
and small-forgestational- age births,33 there are no data to suggest that
treatment with systemic corticosteroids alters the risk of premature
delivery. That being the case, it is imperative that the risks of therapy be
balanced against the severity of the symptoms.
• Women with a history of PG appear to be at increased risk for the
subsequent development of Graves disease.
Differential Diagnosis

 Most Likely
 Urticarial pemphigoid gestationis
 Pruritic urticarial papules and plaques of pregnancy
 Contact dermatitis
 Drug eruption
 Consider
 Urticaria
 Erythema multiforme
 Dermatitis herpetiformis
 Rule Out
 Pemphigus vulgaris
 Varicella
PG Treatment :
Prednisone .5 MKD
• Systemic corticosteroids remain the cornerstone of
therapy.
• Most patients respond to 0.5 mg/kg of prednisone
(prednisolone) daily. Maintenance therapy,
generally at a lower dosage, may or may not be
required throughout gestation.
• As noted earlier, many patients experience
spontaneous disease regression during the third
trimester, only to experience flare during
parturition
PG Prognosis

- recurrent involvement during

 subsequent gestations are likely to develop
symptoms and during the use of oral
contraceptives.
 Women who have experienced PG need not
avoid additionalpregnancies. However, they
should be counseled that recurrent disease is the
rule.
Dermatitis Herpetiformis
• The primary lesion of DH is an erythematous papule, an
urticaria-like plaque, or, most commonly, a vesicle (Figs. 61-
1–61-3).
• Large bullae occur infrequently.
• Vesicles, especially if they occur on the palms, may be
hemorrhagic. The continual appearance and disappearance
of lesions may result in hyperpigmentation and
hypopigmentation.
• Patients may present with only crusted lesions, and a
thorough search may not reveal a primary lesion.
• The herpetiform (herpes-like) grouping of lesions is often
present in some areas
Dermatitis Herpetiformis
• Symptoms vary considerably from the usually severe burning
and itching in most patients to the almost complete lack of
symptoms in a rare patient.
• Most patients usually can predict the eruption of a lesion as
much as 8–12 hours before its appearance because of
localized stinging, burning, or itching.
• The usual symmetric distribution of lesions on elbows,
knees, buttocks, shoulders, and sacral areas is seen in most
patients at one time or another (see Figs. 61-1–61-4).
• Although these regions are affected most commonly, most
patients have scalp lesions Figure 61-1 Dermatitis
herpetiformis. Extensive eruption
DH Histopathology

dermal papillary collections

of neutrophils

Early lesion
• The histology of an early skin lesion (clinically nonvesicular)
is characterized by dermal papillary collections of
neutrophils (microabscessesAt times, early lesions may be
difficult or impossible to differentiate from those of linear
IgA disease (see Chapter 58), the bullous eruption of lupus
erythematosus (see Chapter 155), bullous pemphigoid (see
Chapter 56), or the neutrophil-rich form of epidermolysis
bullosa acquisita).
• Immunofluorescent localization and ultrastructural studies
of the site of blister formation in DH have demonstrated that
the blister forms above the lamina densa—within the lamina
lucida.
• This is thought to occur because the lamina lucida is the
most vulnerable component of the dermal–epidermal
junction.
Laboratory After Cormane demonstrated that both perilesional
and uninvolved skin of patients with DH contained
granular Ig deposits located in dermal papillary tips,
van der Meer found that the most regularly
detected Ig class in DH skin was IgA (Fig. 61-5).35,36
Although most patients have granular IgA deposits
in their skin, recent studies have suggested that a
distinct fibrillar pattern of IgA deposits can be found
in some patients with DH.37 The potential clinical
significance of this difference is not . Finding
granular IgA deposits in normal-appearing skin is
the most reliable criterion for the diagnosis of
DH.26,40 These IgA deposits are unaffected by
treatment with drugs, but may decrease in intensity
or disappear after long-term adherence to a gluten-
free diet.

Direct immunofluorescence showing

granular dermal papillary deposits of
immunoglobulin A.
 DH disease association
• Gluten sensitive enteropathy
• Celiac Disease
• atrophic gastritis Those with lymphomas
• pernicious anemia adhered to a gluten-free
diet less strictly than
• thyroid disease patients
• insulin-dependent diabetes without lymphoma
• lupus erythematosus,
• Sjögren syndrome
• Vitiligo
• gastrointestinal lymphomas
 Ddx DH
be more difficult to
 Consider differentiate clinically
 Eczema and histologically, but it is
 Atopic dermatitis distinctive immunologically.
 Papular urticaria A high index of suspicion is
 Neurotic excoriations very helpful in
 Bullous pemphigoid that even in the absence of
 Pemphigoid gestationis primary lesions, DH can be
diagnosed based on the
 Linear immunoglobulin A
typical in vivo–bound
dermatosis
granular
 Atopic dermatitis IgA deposits in normal-
 Rule Out appearing skin.
 Scabies
Treatment

•Dapsone 100-150 mg per day

•Sulfapyridine 1.0–1.5 g daily
• patients intolerant of dapsone, in elderly
patients, and in those with cardiopulmonary
problem

•Gluten free diet (pr in wheat, barley, and rye)

Treatment DH
Studies in small numbers of DH patients have indicated
that elemental diets (composed of free amino
acids, short-chain polysaccharides, and small amounts
of triglycerides) can be very beneficial in alleviating
the skin disease within a few weeks. The beneficial
effect on the skin disease may be achieved even if the
patient ingests large amounts of gluten. Unfortunately,
elemental diets are difficult to tolerate for long
periods.
Interestingly, complete resolution of the skin
lesions of DH has also been reported by adherence to
the high-protein, unlimited fat, low-carbohydrate diet
popularized as the “Atkins Diet.” Further studies are
needed to confirm this report.
Epidermolysis Bullosa
Acquisita
Although it is an acquired disease that usually
begins in adulthood, it was placed in the
category epidermolysis bullosa (EB)
approximately 100 years ago because
physicians were struck by how similar the
clinical lesions of EBA were to those seen in
children with hereditary dystrophic forms of
EB. Anchoring fibrils anchor the epidermis and
its underlying BMZ to the papillary dermis.
Patients with hereditary forms of dystrophic EB
(see Chapter 62) and EBA have decreased
numbers of anchoring fibrils in their DEJ.
Epidermolysis bullosa acquisita (EBA) is a
sporadic autoimmune bullous disease of
unknown etiology and with no gender, ethnic,
or geographic predisposition.
skin fragility, subepidermal
blisters, milia formation,
and scarring.
EBA
• 1) a classic presentation
• (2) a bullous pemphigoid (BP)-like presentation
• (3) a cicatricial pemphigoid (CP)-like presentation
• (4) a presentation reminiscent of Brunsting–Perry
pemphigoid
• with scarring lesions and a predominant head and neck
distribution
• (5) a presentation reminiscent
of linear IgA bullous dermatosis or chronic
bullous disease of childhood.
Classic EBA
The classic presentation
(Figs. 60-2 and 60-3A) is
of a noninflammatory
bullous disease with an
acral distribution that
heals…. The classic form
of EBA is thus a
mechanobullous
disease marked by skin
fragility.

severe blistering, erosions, scarring,

and milia formation on trauma-
prone areas of her skin. It is non-
inflammatory.
Bullous Pemphigoid –like EBA
CP –like EBA
Both the classic and BP-like
forms of EBA may have
involvement of mucosal
surfaces. However, EBA also may
present with such predominant
mucosal involvement
that the clinical appearance is
reminiscent of CP (see Fig. 60-
3C).24 These patients usually
have erosions and scars on the
mucosal surfaces of the mouth,
upper esophagus, conjunctiva,
anus, or vagina with or without
similar lesions on the glabrous
skin
Brunsting–Perry pemphigoid-like EBA
 An epidermolysis bullosa
EB acquisita patient demonstrating
two presentations of the
disease: the classic
mechanobullous presentation
with erosions, scarring, and
milia over the elbows and the
more inflammatory bullous
pemphigoid-like lesions on her
trunk However, both the classic
and BP-like forms of the disease
may coexist in the
same patient (Fig. 60-5). The
clinical phenotype of EBA
that is reminiscent of pure CP
occurs in fewer than 10%
of all EBA cases.
EBA

Direct immunofluorescence staining for Ig deposits in perilesional skin of

an epidermolysis bullosa acquisita patient
• IgG is the predominant immunoglobulin class, but deposits of complement, IgA,
IgM, factor B, and properdin also may be detected. The DIF staining demonstrates
an intense linear fluorescent band at the DEJ. Yaoita et al2 have suggested that a
positive DIF and IgG deposits within the sublamina densa zone are necessary
criteria for the diagnosis of EBA.
• Patients with PCT, which may mimic EBA clinically, frequently have IgG and
complement deposits at the DEJ similar to those of EBA patients (see Chapter
132). However, the DIF feature that distinguishes PCT from EBA is that PCT skin
also demonstrates immune deposits around the dermal blood vessels.
• Patients with EBA may have autoantibodies in their blood directed against the
DEJ.3 Thes antibodies can be detected by IIF of the patient’s serum on substrate
of monkey or rabbit esophagus or human skin and stain the DEJ in a linear fashion
that may be indistinguishable from BP ser
• When human skin is incubated in 1 M NaCl, the DEJ fractures cleanly through the
lamina lucida zone.
• This 8 Section 8 :: Disorders of Epidermal and Dermal–Epidermal Adhesion
fracture places the BP antigen on the epidermal side of the split and all other
basement membrane structures on the dermal side of the separation. Salt-split
skin substrate can be used to distinguish EBA and BP sera.3
• If the serum antibody is IgG and labels the epidermal roof, the patient does not
have EBA and BP should be considered. If, on the other hand, the antibody labels
the dermal side of the separation, the patient usually has either EBA or bullous
SLE. The latter can be ruled out by other serology and by clinical criteria.
Ddx EBA

• Most Likely
• Porphyria cutanea tarda
• Pseudoporphyria cutanea tarda
• Bullous pemphigoid
• Cicatricial pemphigoid
• Consider
• Linear immunoglobulin A bullous disease
• Brunsting–Perry pemphigoid
• Bullous systemic lupus erythematosus

NOTES
• can be ruled out by a urine or plasma test for uroporphyrins.
• Pseudo-PCT, usually caused by drugs such as nonsteroidal anti-inflammatory
agents, can look similar to EBA with skin fragility, erosions, and blisters over
trauma-prone areas, scarring, and milia formation. Nevertheless, the DIF
appears different in that pseudo-PCT, like PCT, shows IgG deposits at both
the BMZ at the DEJ and around dermal blood vessels (which are not stained
in E
Diagnostic Criteria for Epidermolysis
Bullosa Acquisita

•No family history of a bullous disorder.

•Histology showing a subepidermal blister.
•Deposition of immunoglobulin G deposits within
•the dermal–epidermal junction (i.e., a positive direct
•immunofluorescence of perilesional skin).
•Immunoglobulin G deposits localized to the lower lamina
densa and/or sublamina densa zone of the dermal–
epidermal junction when perilesional skin is examined by
direct immunoelectron microscopy.
Treatment EBA

Medication, Dose Range

•Colchicine 0.6–3.0 mg/day
•Cyclosporine A 6 mg/kg/day
•Dapsone 100–300 mg/day
•Cytoxan 50–200 mg/day
•Prednisonec 1.0–1.5 mg/kg
•Intravenous immunoglobulind
• 3 g/kg divided over 5 days
•Infliximab 5 mg/kg at 0, 2, 4, and 6 week
• EBA usually responds poorly to treatment. Supportive therapy is
warranted in all patients with EBA. This includes instruction in
open wound care and strategies for avoiding trauma. Patients
should be warned not to over wash or overuse hot water or harsh
soaps and to avoid prolonged or vigorous rubbing of their skin
with a washcloth or towel. In some patients, it appears that
prolonged sun exposure may aggravate or promote new lesions on
the dorsal hands and knuckles. Thus, avoidance of prolonged sun
exposure and the use of sunscreens are helpful. The patient
should be educated to recognize localized skin infections and to
seek medical care and antibiotic therapy promptly when they
occur. EBA patients are often refractory to high doses of systemic
glucocorticoids, azathioprine, methotrexate, and
cyclophosphamide, especially when they have the classic
mechanobullous form of the disease. These agents may be
somewhat helpful in controlling EBA when it appears as an
inflammatory BP-like disease. Some EBA patients improve on
dapsone, especially when neutrophils are present in
Salt split IIF (1M NaCL)

BP

EBA
Laboratory

• Skin punch biopsy

• Perilesional biopsy (for DIF)
• Blood serum for (IIF)

• Elisa
• Immunoblotting
Treatment
•Wound management
•Watch out for superinfections
•Monitor for drug adverse effects or side
effects
 Disorders of
Epidermal and
Dermal -Epidermal
Cohesion
 Pemphigus
Histopathology Target DIF IIF
PV suprabasal Desmoglein 3 IgG keratinocyte IgG keratinocyte
acantholysis. Desmoglein 1 surface surface

PF subcorneal desmoglein 1. IgG keratinocyte IgG keratinocyte

acantholysis. surface surface

PNP vacuolar interface desmoplakins, immunoglobulin G

change and envoplakin, to the cell surface
suprabasilar periplakin, of transitional
acantholysis Desmogleins 3, epithelial cells
desmoglein 1 (rodent urinary
bladder)

This can be accomplished by indirect immunofluorescence of patient serum

on rodent urinary bladder demonstrating binding of immunoglobulin G to the
cell surface of transitional epithelial cells.
Desmosome

Desmosomes are primarily responsible for epidermal

adhesion
Desmosomes

The major components of desmosomes are

 desmosomal cadherins (desmogleins

and desmocollins)
 plakins (desmoplakin, envoplakin, and
periplakin),
 armadillo family proteins (plakoglobin and
plakophilins)
 Inner dense plaque

desmoplakin
desmocollin plakoglobin

desmoglea
Inner dense
plaque

plakophilins
odp Outer dense plaque
desmoglein Dense midline
keratin filaments Plasma membrane
 Inner dense plaque

PV and PF

desmoglea Inner dense

plaque

odp Outer dense plaque

desmoglein
keratin filaments
 Inner dense plaque Desmosomal cadhedrins and
desmosomal plaque protein
PNP
desmoplakin
plakoglobin

desmoglea
Inner dense plaq

odp Outer dense plaque

desmoglein Dense midline
keratin filaments Plasma membrane
PV (DIF) PF(IIF)
Hemidesmosome
Bullous Pemphigoid
 Bullous Pemphigoid

BPAG1

BPAG2/type XVII collagen

BP
 Cicatricial Pemphigoid

A variety of antigens
Cicatricial Pemphigoid Can also have IgG

DIF: linear deposit of C3 in epidermal basement membrane

Epidermolysis Bullosa Aquisita
Epidermolysis Bullosa Aquisita

Anchoring
fibrils
Epidermolysis Bullosa Aquisita
Salt split IIF (1M NaCL)

BP

EBA
 Herpes Pemphigoides

BPAG2/type XVII collagen

Transmembrane molecule bpag2

Herpes Pemphigoides

Dif: Linear band of C3, with or without IgG

EXERCISE
Pemphigus Vulgaris
IgG
4 year old female
 IgA

Subepidermal blister with neutrophils

Dermatitis Herpetiformis
Thank you