VESICULOBULLOUS ERUPTIONS
PROF IHAB YOUNIS
Classification:
A-IMMUNOLOGICAL DISEASES
I-Intraepidermal diseases

Pemphigus

Subcorneal pustular dermatosis
II-Subepidermal diseases




Bull pemphigoid
Pemphigoid gestationis
Linear IgA disease
Dermatitis herpetiformis
B-GENETIC DISEASES

Epidermolysis bullosa

Hailey & Hailey disease
I-INTRAEPIDERMAL DISEASES
PEMPHIGUS
(Etymology: Greek word pemphix meaning bubble)
Types
1.Pemphigus vulgaris
2. Pemphigus vegetans
3. Pemphigus foliaceus
4. Paraneoplastic pemphigus
1-PEMPHIGUS VULGARIS
•
ETIOLOGY
•
An uncommon disease with incidence varies from 0.5-3.2 cases per 100,000
population
•
Incidence is increased in people of Mediterranean origin
•
The male-to-female ratio is approximately equal
•
The mean age of onset is approximately 50-60 years
•
It is an autoimmune disease
•
Antigen: desmoglein 1 and desmoglein 3 which are proteins found on the
surface of keratinocytes
•
Antibodies: Patients with active disease have circulating and tissue-bound
autoantibodies of both IgG1 and IgG4
1
•
Complement:Pemphigus antibody fixes components of complement to the
surface of epidermal cells. Antibody binding may activate complement with
the release of inflammatory mediators and recruitment of activated T cells
•
The binding of autoantibodies results in a loss of cell-to-cell adhesion, a
process termed acantholysis due to destruction of desmosomes
Clinically
I- Skin
•
The primary lesion is a flaccid bulla filled with clear fluid that arises on
healthy skin or on an erythematous base
•
It has a predilection for the scalp, face, axillae, groins and pressure points
•
The bullae are fragile; therefore, intact bullae may be sparse
•
The contents soon become turbid, or the bullae rupture, producing painful
erosions, which is the most common skin presentation
•
Erosions often are large because of their tendency to extend peripherally with
the shedding of the epithelium
•
Nikolsky sign: In patients with active blistering, firm sliding pressure with a
finger separates normal-appearing epidermis, producing an erosion
•
Lesions in skin folds readily form vegetating granulations
•
Healing occurs without scarring
II-Mucous membranes
•
PV presents with oral lesions in 50-70% of patients, and almost all patients
have mucosal lesions at some point in the course of their disease
•
Mucosal lesions may be the sole sign for an average of 5 months before skin
lesions develop, or they may be the sole manifestation of the disease
•
Other mucosal surfaces may be involved, including the conjunctiva,
esophagus and/or dysphagia, labia, vagina, cervix, vulva, penis, urethra, nasal
mucosa, and anus
•
Intact bullae are rare in the mouth. More commonly, patients have ill-defined,
irregularly shaped, gingival, buccal, or palatine erosions, which are painful
and slow to heal
•
The oral cavity is involved in almost all patients and sometimes it is the only
area involved. Erosions may be seen on any part of the oral cavity. Erosions
can be scattered and often are extensive. Erosions may spread to involve the
2
larynx, with subsequent hoarseness. The patient often is unable to eat or drink
adequately because the erosions are so uncomfortable
LABORATORY STUDIES
1-Histopathology
•
Changes start with intercellular edema with loss of intercellular attachments in
the basal layer
•
Suprabasal epidermal cells separate from the basal cells to form clefts and
bullae
•
Basal cells are separated from one another and stand like a row of tombstones
on the floor of the blister, but they remain attached to the basement membrane
•
Blister cells contain some acantholytic cells
2-Direct immunofluorescence (DIF)
•
An antibody against IgG is linked to a fluorescent material (fluorophore) and
added to the skin biopsy
•
In positive cases the antibody recognizes the target molecule and binds to it,
and the fluorescence can be detected via microscopy
•
The best location for DIF testing is on normal perilesional skin as when testing
is performed on lesional skin, false-positive results can be observed. DIF
shows intercellular deposition throughout the epidermis. This pattern is not
specific for pemphigus vulgaris and may be seen in other types of pemphigus
3-INDIRECT IMMUNOFLUORESENCE (IDIF)
•
In IDIF two antibodies are used. An unlabeled 1ry antibody specifically is
added to bind to the IgG of patient. In +ve cases, adding a secondary antibody,
which carries the fluorophore, recognizes the 1ry antibody and binds to it
producing fluorescence
•
IDIF demonstrates the presence of circulating IgG autoantibodies that bind to
epidermis in 80-90% of patients with pemphigus vulgaris. The titer of
circulating antibody correlates with disease course
4-Tzanck preparation
•
A smear is taken from the base of a blister or erosion &stained with Giemsa,
methylene blue
•
+ve cases show acantholytic cells: rounded keratinocytes with hypertrophic nuclei, hazy or absent nucleoli and increased nuclear to cytoplasmic
ratio
3
THERAPY
I-STANDARD TREATMENT
•
Oral prednisolone (Hostacorten H ®) 1.0 mg/kg/day as an initial dose (usually
60 mg/day). Once disease activity is controlled, tapering prednisolone to as
low a dose as possible should be the goal
•
Immunosuppressive agents in combination with oral prednisone (steroid
sparing):
-
Azathioprine(Immuran®) 100 to 300 mg/day
-
Mycophenolate mofetil (Mofetyl® 500 tab)
2–3 g/day:it has a faster effect
that azatioprine but more expensive(110 LE for 8 LE)
-
Cyclophosphamide (Endoxan® 50 mg tab)50 to 200 mg/day. very effective in
controlling severe disease but more toxic than azathioprine
-
Cyclosporine (Sandimmune®, Neoral® 100 cap) 5 mg/kg/day
II-AGGRESSIVE TREATMENT
(for non responding cases)
1-Intravenous pulse therapy
•
Methylprednisolone(Depo-Medrol ® 40mg/ vial), 1 gm is given over 3 hours
/24h for 4 to 5 consecutive days. It can result in long-term remissions but may
lead to cardiac arrhythmias with sudden death, and its use is controversial
•
Cyclophosphamide pulse therapy has also been reported to result in remissions.
The advantage of this therapy over that of daily cyclophosphamide has not
been clearly established
2-Rituximab (Rituxan ®)
•
It is a potent B-cell-depleting anti-CD20 monoclonal antibody
•
CD20 is a transmembrane glycoprotein specifically expressed on B cells
•
Rituximab induces a depletion of CD20+ B cells and a decline in IgG
(including anti-desmoglein autoantibodies)
•
Rituximab leads to a complete remission in most of the patients with
refractory pemphigus vulgaris
•
The
side
effects
of
rituximab,
leukoencephalopathy
•
It is very expensive (88099$)
4
include
progressive
multifocal
3-Plasmapheresis
•
It is sometimes used, in combination with cyclophosphamide or another
immunosuppressive agent
•
NB:Topical potent steroids + K Permengnate can be used to control mild cases
or resistent small areas
PROGNOSIS
•
Untreated, pemphigus vulgaris is often fatal because of the susceptibility to
infection and fluid and electrolyte disturbances
•
Treatment with systemic steroids has reduced the mortality rate to 5-15%.
•
Most deaths occur during the first few years of disease, and, if the patient
survives 5 years, the prognosis is good
•
Early disease probably is easier to control than widespread disease, and
mortality rates may be higher if therapy is delayed
•
Morbidity and mortality are related to the extent of disease, the maximum
dose of prednisolone required to induce remission, and the presence of other
diseases
•
Prognosis is usually better in childhood than in adulthood
2-PEMPHIGUS VEGETANS
•
It is a rare variant
•
Etiology is similar to pemphigus vulagaris
•
Clinically:Involvement of the oral mucosa is almost invariable. Vegetating
lesions are primarily flexural, although vegetations may occur at any site
•
Treatment is similar to pemphigus vulgaris but etretinate may be added if
vegetations persist
•
Histopathologically:The vegetating lesions are hyperkeratotic and acanthotic
with suprabasal clefts containing eosinophils
•
eosinophilic abscesses may be present in older lesions
3-PEMPHIGUS FOLIACEUS
ETIOLOGY
•
It accounts for 10% of cases of pemphigus
•
IgG4 autoantibodies directed against desmoglein 1 destroy desmosomes
5
•
Most cases are idiopathic but drugs containing thiol groups, e.g. ACE
inhibitors have been implicated. Other drugs are nifedipine, the penicillins,
cephalosporins, chloroquine, hydoxychloroquine, rifampicin, and interferon
CLINICALLY
•
It is less severe than pemphigus vulgaris
•
The onset is usually insidious with scattered scaly lesions involving the
‘seborrhoeic’ areas: scalp, face, chest and upper back
•
Localized disease slowly extends. Blistering may not be obvious because the
cleavage is superficial and the small flaccid bullae rupture easily
•
Scales separate leaving well-demarcated crusted erosions surrounded by
erythema
•
Erosions are both painful and offensive
•
Eventually, the patient may become erythrodermic with crusted oozing red
skin
HISTOPATHOLOGY
•
Acantholysis in the granular layer produces subcorneal pustule
•
Bullae contain fibrin, some neutrophils and scattered acantholytic
keratinocytes
•
Older lesions are acanthotic, and hyperkeratotic with focal parakeratosis
•
Dyskeratotic cells in the granular layer of older lesions distinguish PF from
PV
TREATMENT
•
Responds to potent topical or intralesional steroids or, if control is inadequate,
prednisolone 20–40 mg/day
•
Adjuvants include azathioprine, cyclophosphamide and dapsone
•
Prognosis: it responds well to treatment and may remit. However, it can also
pursue a very chronic course over many years and be subject to repeated
relapses
4- PARANEOPLASTIC PEMPHIGUS
ETIOLOGY
•
It occurs in association with a variety of underlying malignant neoplasms,
most commonly B-cell lymphomas
•
Antibodies are predominantly antiplakin antibodies of the IgG1 subclass
6
•
Target antigens are plakins (proteins associated with junctional complexes
that provide connection between cells
CLINICALLY
•
The clinical features overlap with erythema multiforme and lichen planus
pemphigoides
•
Patients have severe mucosal erosions and polymorphous cutaneous signs
including bullae, erosions particularly on the upper body and palmoplanter
target lesions
LABORATORY TESTS
Histopathology
•
Necrosis of keratinocytes or vacuolar interface dermatitis
•
Suprabasal clefting
•
Acantholysis
Direct IF reveals immunoglobulin and/or complement at the BMZ as well as on the
surface of keratinocytes
Indirect IF is positive and antibodies are predominantly antiplakin antibodies of the
IgG1 subclass
TREATMENT
•
It is generally refractory to treatment
•
Most patients die secondary to sepsis, GIT bleeding, multiorgan or
respiratory failure
SUBCORNEAL PUSTULAR DERMATOSIS
ETIOLOGY
•
The etiology is unknown
•
No antibodies are found
•
The accumulation of neutrophils in the subcorneal layer suggests the presence
of chemoattractants in the uppermost epidermis. Interleukin (IL)-1 beta, IL-6,
IL-8, IL-10, leukotriene B4, and complement fragments C5a and C5a are
neutrophil chemoattractants that have been found at increased levels It most
commonly affects woman aged 40 years or older
CLINICALLY
•
Patients typically present with a history of a relapsing pustular eruption
involving the flexural areas of the trunk and proximal extremities
7
•
Pruritus can occur but is not usually prominent
•
The primary lesions are flaccid pustules, measuring several millimeters in
diameter, on normal or mildly erythematous skin. The classic lesion has been
described as a "half-half" blister, in which purulent fluid (sterile pus)
accumulates in the lower half of the blister
•
The most commonly affected areas include the axillae, groin, neck, and
submammary regions
•
Mucous membrane involvement is unusual
•
The pustules can be isolated or grouped and tend to coalesce and form annular,
circinate, or serpiginous patterns
•
The pustules are superficial and rupture easily, resulting in a superficial crust
•
Mild hyperpigmentation often remains after pustular lesions have resolved
•
It is chronic and relapsing but benign
LABORATORY STUDIES
Histopathology
•
The classic histologic finding is subcorneal pustules filled with neutrophils
and occasional eosinophils
•
However, this finding is not specific and can be found in other conditions
such as pustular psoriasis, pemphigus foliaceus, bacterial impetigo, and
dermatophytosis
•
Direct and indirect immunofluorescence studies are typically negative
TREATMENT
•
Dapsone 50 – 150 mg/day is the treatment of choice, with resolution usually
occurring in about 4 weeks. Once disease control has been established, the
dose should be tapered to the lowest dose needed to maintain control
•
Acitretin
has been used successfully and should be considered as an
alternative or additional treatment for those who are intolerant of, or
unresponsive to, dapsone. Once disease control has been established, the dose
should be tapered to the lowest dose needed to maintain control
•
Phototherapy with PUVA, and narrowband UVB alone or in combination with
dapsone and/or retinoids can be successful. Long-term maintenance regimens
may be needed
II- SUBEPIDERMAL DISEASES
BULLOUS PEMPHIGOID
8
ETIOLOGY
•
It is uncommon with an incidence of 6-7 cases per million person-years
•
It primarily affects elderly individuals with an average age at onset of 65 years
in Europe
•
It affects men and women equally
•
Several drugs have been associated with the development of bullous
pemphigoid, including furosemide,spironolactone, penicillins, alfa blockers
and antipsychotics
•
Physical agents, including thermal burns, wounds, PUVA and radiotherapy,
have also been reported to induce bullous
•
Autoantibodies: IgG autoantibodies
•
Antigen: The two major antigens are BP230 and BP180, which are associated
with hemidesmosomes in the BMZ
•
Complement is necessary for blister formation
CLINICALLY
•
It commonly starts with itching and a non-specific rash on the limbs that may
be either urticaria-like or occasionally eczematous
•
This prodrome may last for weeks or months
•
Severe irritation with a faint, dusky erythema in a figurate pattern may
sometimes precede blister formation
•
Sudden generalization of the true eruption of bullous pemphigoid follows the
prodromal phase and most of the body may be affected within a week
•
Blisters may arise on erythematous and on normal skin and may be associated
with dermal edema
•
The blisters are tense and dome shaped, obtaining a diameter of many
centimeters
•
They appear mainly on the flexural aspects of limbs and on the central
abdomen
•
Their contents are usually clear serous exudate, although occasionally this is
bloodstained
•
The blisters are tough and may remain intact for several days
•
Those that rupture leave erosions that heal rapidly, leaving mild
postinflammatory changes
9
•
Fresh crops of small blisters may continue to occur even after apparent control
has been achieved with treatment
•
Mucosal lesions occur less frequently and are less severe than pemphigus
vulgaris
•
They are usually confined to the mouth
•
The oral lesions consist of small blisters that, like those of the skin, may
remain intact and, if they rupture, heal rapidly
LABORATORY STUDIES
HISTOPATHOLOGY
•
The blister is subepidermal with an intact and often viable epidermis forming
the roof
•
Blisters may contain numerous eosinophils and neutrophils
•
Biopsies of blisters and from erythematous areas of skin show a dermal infl
ammatory infiltrate containing many eosinophils and neutrophils with
lymphocytes and histiocytes
Direct IF : Perilesional skin shows linear deposition of C3 and IgG antibodies along
basement membrane zone
Indirect IF: Circulating IgG antibodies to basement membrane zone in 70 – 80 %.
PROGNOSIS
•
Remission may occur within a few months or the eruption may continue for 36 years
•
There may be occasional flares that will require temporary increases in
therapy
•
About one-third of untreated patients die
•
Corticosteroids has lowered the mortality but it still remains at 15–40%, and is
nearly always treatment related or
•
related to the general condition and age of the patients
TREATMENT
•
During prolonged treatment, it is advisable to aim for the presence of a blister
once every few weeks so as to be certain that the patient is not being over
treated
•
For localized cases, very potent topical steroids (Clobetasol, Dermovate®) are
sufficient
10
•
The recommended initial dose of prednisolone is 20 mg/day in localized or
mild disease, 40 mg/day in moderate disease, and 50–70 mg/day in severe
disease
•
Steroid dosage can often be reduced quite quickly over the course of a few
weeks to a dose of 15–20 mg/day and thereafter more slowly. 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
•
Measures to prevent osteoporosis should be implemented from the start of
systemic steroid therapy, whenever practicable
•
For mild to moderate disease, tetracyclines and nicotinamide should be
considered
•
Immunosuppressants should be considered if the steroid dose can not be
reduced to an acceptable level
•
Azathioprine is the best established immunosuppressant
•
Mycophenolate mofetil is a useful alternative immunosuppressant
•
Rituximab has been reported to be both successful and unhelpful in a few
cases
PEMPHIGOID GESTATIONIS
ETIOLOGY
•
It is a rare condition that may affect from one in 10 000 to one in 60 000
pregnancies
•
It is considered that an HLA mismatch between mother and fetus triggers an
immune response that cross-reacts with the maternal skin
•
The autoantibodies are directed at the same hemidesmosome target antigens as
bullous pemphigoid
•
The autoantibodies are IgG antibodies of the IgG1 and IgG3 subclasses
•
These IgG1 antibodies avidly bind C3
•
Autoantibodies react with the amniotic basement membrane
CLINICALLY
•
It begins in the majority of patients in the second and third trimesters
•
Almost half of cases develop in the first pregnancy.
11
•
The condition characteristically begins around the umbilicus, and then spreads
to the abdomen, thighs, limbs, palms and soles
•
Early in its course, the eruption consists of urticated papules, plaques, target
lesions & wheals, associated with marked pruritus
•
Subsequently, vesicles and larger blisters appear
•
Involvement of the oral cavity is relatively rare
•
Neonatal pemphigoid gestationis may occur in 3% pregnancies due to transfer
of antibodies across the placenta. It usually resolves rapidly without treatment
Laboratory Studies
HISTOPATHOLOGY
•
A subepidermal blister with eosinophils and neutrophils
•
The epidermis shows focal spongiosis
IMMUNOFLUORESCENCE
•
DIF:shows linear deposition of C3 along the BMZ of perilesional skin in all
cases
•
IgG is deposited in 30% to 40% of cases
•
IIF:shows binding of C3 and IgG to the BMZ
•
IgG antibodies can be detected in serum by ELISA
PROGNOSIS
•
Usually, the disease lasts several weeks to months, on average 6 months, but
sometimes it can continue for years
•
There is a high risk of recurrence in subsequent pregnancies(20%); the onset is
likely to be earlier than in the previous one
•
In many cases, the disease becomes relatively quiescent in late pregnancy,
only to flare severely immediately postpartum
•
The likelihood of prolonged disease is increased by older age, multiparity and
mucosal involvement
•
There are often flares with menstruation and there are usually dramatic flares
with the use of oral contraceptives, which is contraindicated while the disease
is still active, but can often be used subsequently
•
It is associated with premature delivery and a risk of low birth weight
•
The fetal prognosis is worse when there is early onset of the disease, reflecting
more prolonged duration of placental insufficiency, and when there is
12
blistering, perhaps because of more severe microseparation and placental
damage
TREATMENT
•
In mild cases, topical potent or very potent steroids can be successful
•
They are often combined with a systemic antihistamine (using one suitable for
use in pregnancy: chlorpheneramine is safest)
•
Once the blisters develop, systemic steroids are usually necessary. Moderate
disease responds to 20–30 mg/day of prednisolone, severe disease may need
40–80 mg/day
•
Prednisolone dose can usually be reduced fairly rapidly to a much lower
maintenance dose
•
The use of systemic steroids does not seem to have an adverse effect on
pregnancy outcomes
•
Because postpartum exacerbations are so frequent, it is worth increasing the
corticosteroid dose temporarily at the first sign of a flare
•
In the non-breastfeeding woman there are reports of the successful use of
tetracyclines,
•
Immunosuppressive treatment, including cyclophosphamide and rituximab
have also been used
TREATMENT
•
Dapsone 50 – 150 mg/day is the treatment of choice, with resolution usually
occurring in about 4 weeks. Once disease control has been established, the
dose should be tapered to the lowest dose needed to maintain control
•
Acitretin
has been used successfully and should be considered as an
alternative or additional treatment for those who are intolerant of, or
unresponsive to, dapsone. Once disease control has been established, the dose
should be tapered to the lowest dose needed to maintain control
•
Phototherapy with PUVA, and narrowband UVB alone or in combination with
dapsone and/or retinoids can be successful. Long-term maintenance regimens
may be needed
LINEAR IG A DISEASE
ETIOLOGY
•
Incidence ranges from 1-0.1/250,000/year
13
•
There is a slight female preponderance
•
In children it commences at a mean age of 3.3-4.5 years
•
Disease of adults ranges starts at a mean age of 52 years
•
It has been reported after voncomycin injection, influenza vaccination, some
diseases e.g. typhoid & TB
•
Antigen may be similar to bullous pemphigoid antigen located in the lamina
lucida and sublamina densa, or both
•
Ig A antibody reacting with the antigens leads to complement activation and
neutrophil chemotaxis, which eventuates in loss of adhesion at the dermalepidermal junction and in blister formation
CLINICALLY
•
The classic primary lesions are clear and/or hemorrhagic round or oval
vesicles or bullae on normal, erythematous, or urticarial skin
•
Alternatively, vesicles and bullae may be seen at the edge of annular or
polycyclic lesions, the appearance of which has been described as the string of
beads sign
•
The distribution of lesions differs between adults and children
•
In children lesions 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
•
In adults, the trunk and the limbs are most commonly affected
•
Involvement of the perineum and the perioral area is less frequent than in
children
•
Blisters and ulceration on the lips and inside the mouth affect about 50%. Eye
involvement may result in irritation, dryness, light sensitivity, blurred vision,
corneal scarring and even blindness
LABORATORY INVESTIGATIONS
Histopathology
•
Subepidermal blistering with a predominantly polymorphonuclear infiltrate,
although mononuclear cells and eosinophils may be present
DIF reveals the IgA along BNZ in a linear pattern
IIF for IgA BMZ antibodies is more often positive in children (80%) than adults
(30%)
14
Prognosis
•
Spontaneous remission occurs in the majority of patients after an average of
3–6 years
•
Cases occurring in childhood then extending beyond puberty have been
reported
•
In pregnancy, often there is improvement or remission of the disease from the
second trimester, and the women may be able to discontinue all drugs,
however there is usually a relapse postpartum at about 3 months. There does
not seem to be any fetal damage
Treatment
•
A few patients have mild disease and can be controlled with topical steroids
alone
•
The treatment of the children can be difficult because side effects limit dosage,
but the drugs used are identical in children and adults
•
Erythromycin should be tried as first-line treatment in children
•
Dapsone in doses starting at less than 0.5 mg/kg (giving it as 25 mg on
alternate days) or less in young children, and 25–50 mg/day in an adult, may
be slowly increased to a dose of 1 mg/kg in a child and 100–150 mg in an
adult to keep the patient comfortable and without significant side effects
•
Too rapid an increase in the dose often results in hemolytic anemia
•
Patients at risk of glucose-6-phosphate dehydrogenase deficiency should be
screened prior to treatment
•
Other
reportedly
useful
medications
include
prednisone,
sulfamethoxypyridazine, colchicine, dicloxacillin, mycophenolate mofetil, and
intravenous immunoglobulin
DERMATITIS HERPETIFORMIS (DH)
ETIOLOGY
•
Prevalence of dermatitis herpetiformis has been reported as high as 10 cases
per 100,000 population
•
It occurs more frequently in individuals of Northern European ancestry and is
rare in Asians and Africans
•
Male-to-female ratio is 2:1
15
•
Typically, the onset is in the 2nd to 4th decade; however, persons of any age
may be affected
•
It is an autoimmune blistering disorder associated with a gluten-sensitive
enteropathy (coeliac disease)
•
Which has a genetic background
•
Gluten is a protein found in barley, wheat&rice
•
IgA antibodies to gliadin (a portion of wheat protein) have been noted in 2535% of patients
•
IgA against smooth muscle endomysium are most specific for gluten
sensitivity and are found in 80% of patients with dermatitis herpetiformis
•
HLA studies have conclusively established the presence of a genetic
predisposition for dermatitis herpetiformis
CLINICALLY
•
The diagnosis is suspected based on the distribution of the eruption.
•
Flesh-colored–to–erythematous
excoriated
papules
or
plaques
with
herpetiform (ie, small, clustered) vesicles are symmetrically distributed over
extensor surfaces, including the elbows, knees, buttocks, and shoulders. The
face and and nuchal areas are raely affected. Lesions occur infrequently on the
oral mucosa.Palms and soles are spared.
•
The eruption is intensely pruritic; patients often present with erosions and
crusts in the absence of vesicles, which have ruptured due to excoriation
•
Typical symptoms include intense itching, burning, and stinging
•
There may be associated worsening of disease with dietary intake of gluten.
Many do not report any GI symptoms, even when prompted
•
There are often associated autoimmune diseases, particularly thyroid disease,
pernicious anaemia and diabetes
LABORATORY TESTS
HISTOPATHOLOGY
•
Lesional skin reveals neutrophils in the dermal papillae, with fibrin deposition
and edema. Eosinophils may be present
•
Papillary microabscesses form and progress to subepidermal vacuolization and
vesicle formation
•
Vesicles form in the lamina lucida, the weakest portion of the dermoepidermal
junction, due to neutrophil lysosomal enzymes
16
•
The biopsy sample should be taken from the edge of a lesion for hematoxylin
and eosin staining and from normal-appearing perilesional skin for DIF
staining as results of DIF of lesional skin are often falsely negative because
the vigorous immune response degrades the IgA antibody at the site of the
lesion
DIF shows deposition of IgA in a granular pattern in the upper papillary dermis
IDIF is negative for BMZ or dermal autoantibodies
•
Jejunal biopsy will demonstrate signs of gluten-sensitive enteropathy in
almost all cases manifested by blunting of villi, crypt hyperplasia, and
lymphocyte infiltration of crypts
PROGNOSIS
•
The disease runs a very long course with exacerbations and remissions
•
Life expectancy is normal
TREATMENT
•
Dapsone is the most widely used treatment
•
It is wise to start at 25–50 mg/day and slowly increase to a dose that keeps the
patient comfortable and without significant side effects
•
Too rapid an increase in the dose often results in hemolytic anaemia,
•
The dose needed for the average case is 100–200 mg/day but a few may
require 400 mg/day
•
Although systemic corticosteroids are in the main ineffective
•
and not indicated
•
Topical steroids may be helpful in lessening symptoms
•
Heparin,
with
or
without
tetracyclines,
in
combinationwith
nicotinamide/niacinamide are advocated for patients who cannot tolerate
dapsone
•
A gluten-free diet is the treatment of choice in the long term. It has been
shown not only to improve the enteropathy, but also to allow discontinuation
of drug therapy
GENETIC DISEASES
EPIDERMOLYSIS BULLOSA (EB)
ETIOLOGY
•
Frequency: 00 case/1000,000 live births
17
•
Onset of epidermolysis bullosa is at birth or shortly after
•
Mode of Inheritance:
•
EB simplex:Mainly Dominant
•
Junctional EB: Recessive
•
Dystrophic EB:Recessive and Dominant
•
TYPES OF EB
CLINICALLY
I- EB Simplex
Mild type
•
Blisters usually are precipitated by trauma
•
They can be mild to severe and most frequently occur on the palms and soles
•
Lesions typically heal without scarring
•
Hyperhidrosis can accompany this disorder
Severe type
•
Usually, a generalized onset of blisters occurs at or shortly after birth
•
Hands, feet, and extremities are the most common sites of involvement
•
Palmoplantar hyperkeratosis and erosions are common
•
Oral mucosa may be affected
II- Junctional EB
Lethal Type
•
Characterized by generalized blistering at birth
•
Patients show characteristic periorificial erosions around the mouth, eyes, and
nares, often accompanied by significant hypertrophic granulation tissue
•
Multisystemic involvement of the corneal, conjunctival, tracheobronchial,
oral, pharyngeal, esophageal, rectal, and genitourinary mucosae is present
•
Internal complications of the disease include a hoarse cry, cough, and other
respiratory difficulties
•
Patients are at increased risk for death from sepsis or other complications
secondary to the profound epithelial disadhesion, and usually, they do not
survive past infancy
Non-Lethal Type
•
Patients show generalized blistering & survive infancy and clinically improve
with age
18
•
Usually, these patients do not present with the same type of hoarse cry or other
significant respiratory symptoms as do patients with the lethal form
•
The lesions heal with atrophic scarring
•
Mucous membranes are involved, but less severely than in the lethal form
•
An important sign of this form is the poor hair development; the alopecia
affects the scalp
•
The teeth show severe pitting
•
The nails are dystrophic and frequently missing, especially on the toes
III- Dystrophic EB
Dominant type
•
Generalised blistering is present at birth
•
Blistering becomes localised to hands, feet, elbows or knees as the child grows
older and in response to friction
•
Small white spots (milia) are often present at healed scarred sites
•
Dystrophic or absent nails are common
•
2 variants are described one has an acral distribution and minimal oral or tooth
involvement. Another variant has more extensive blistering, scarlike papules
on the trunk (termed albopapuloid lesions), and involvement of the oral
mucosa and teeth
Recessive Type
•
Generalised severe blistering is more common and involves large areas of
skin and mucous membranes
•
Blisters heal but with scarring and deformity causing limited movement as
fingers and toes may be fused together (mitten hands)
•
Complications such as infection, malnutrition and dehydration may cause
death in infancy and those that survive are at great risk of developing
squamous cell carcinoma
LABORATORY TESTS
MICROSCOPY
1-ELECTRON MICROSCOPE
•
EM is the criterion standard for determining the level of blistering
2-IMMUNOFLUORESCENCE
•
In EB simplex, antigens localize to the floor
•
In junctional EB, antigens localize to the roof and floor of the blister
19
•
In dystrophic EB, antigens localize to the roof of the blister
Prenatal diagnosis
•
Once the mutations are identified in a family, reliable prenatal diagnosis is
possible
•
DNA for prenatal diagnosis can be obtained as a chorionic villi sample as
early as the ninth week of gestation
•
Alternatively, amniotic fluid drawn after the eleventh week can provide the
necessary DNA
TREATMENT
•
There is no specific treatment for any form of EB, and the mainstay of clinical
management is based on protection and avoidance of provoking factors
•
The 1st step is to establish the diagnosis
•
For babies, treatment should be done in a specialist neonatal or pediatric unit,
which has the expertise, staff and resources to manage these cases
•
The erosions are cleaned with sterile normal saline and covered in comfortable
non-adherent dressings
•
Some EB specialists may prefer to use a topical antiseptic such as 1%
chlorhexidine cream, rather than topical antibiotics, because of the risk of
emergence of antibiotic-resistant bacteria.
•
Another preference is to treat open wounds with 1% silver sulfadiazine cream
(Flamazine), or an ointment containing polymyxin B or bacitracin
•
For children and adults special precautions should be taken in the use of
adhesive tapes, sphygmomanometer cuffs, tourniquets and any other
instruments or appliances that might lead to blister formation or shearing of
the skin or mucous membranes
•
The following systems require particular attention by a specialist:oral mucosa,
teeth, eyes, GIT and bones
•
Topical opiates, eg diamorphine, may be effective in the treatment of pain,
reducing the need for powerful systemic analgesia
•
Genetically engineered growth factors and other cytokines that are able to
influence wound healing will soon be available for clinical trials, or even
clinical practice
20
EPIDERMOLYSIS BULLOSA AQUISITA
ETIOLOGY
•
There is an autoimmune reaction
•
The antibodies are IgG type
•
The antigen is type VII collagen within the lamina densa at the BMZ
•
It is very rare with an incidence of about 0.25 per million
•
It can occur at any age
CLINICALLY
•
Patients have erosions, tense blisters within noninflamed skin, and scars over
trauma-prone surfaces such as the backs of the hands, knuckles, elbows, knees,
sacral area, and toes
•
Some blisters may be hemorrhagic or develop scales, crusts, or erosions
•
The lesions heal with scarring and frequently with the formation of milia
within the scarred areas
•
A scarring alopecia and some degree of nail dystrophy may be seen
LABORATORY TESTS
HISTOPATHOLOGY
•
There is a subepidermal blister, ie, a separation has occurred between the
epidermis and the dermis
•
Also, there is a mixture of inflammatory cell dermal infiltrate compsed of
lymphocytes, monocytes, neutrophils, and eosinophils
IMMUNOFLUORESCENCE
•
DIF: performed on perilesional skin biopsy detects a linear band of
immunoglobulin G deposit along the dermoepidermal junction
•
IIF: detects IgG class circulating autoantibodies that bind to the dermal (base)
side of the BMZ
OTHER TESTS
•
Direct and indirect immunoelectron microscopy: They document the
ultrastructural localization of in vivo-bound IgG autoantibodies (by direct
method) or the binding site of circulating IgG autoantibodies (by indirect
method) at the basement membrane
•
ELISA documents the specific basement membrane antigen recognized by the
patient's IgG circulating autoantibodies
21
TREATMENT
•
Oral corticosteroids and immunosuppressants.
•
For patients who are on long-term systemic corticosteroid treatment, daily
calcium, vitamin D supplements and bisphonate (Fosamax tab) are essential
for reducing steroid-induced osteoporosis
•
For patients who do not respond to oral corticosteroids and
immunosuppressives, some other newer, therapeutic options include: IV
immunoglobulin & Rituximab
HAILEY–HAILEY DISEASE
ETIOLOGY
•
It is caused by mutations in one copy of ATP2C1, a gene on chromosome
3q21 that encodes the human secretory-pathway Ca2+/Mn2+-ATPase isoform
1 (hSPCA1)
•
Decreased Ca in epidermis leads to weak adhesions between keratinocytes
CLINICALLY
•
The condition usually presents in the third or fourth decade
•
Flaccid vesicopustules, crusted erosions or expanding circinate plaques
appear in areas exposed to friction such as the sides of the neck, axillae, groins
and perineum
•
Lesions extend peripherally, healing in the centre
•
Flexural disease may be hypertrophic and malodorous with soft, flat, moist
vegetations and fissures
•
Itch and pain are common and flexural disease may be disabling
•
Asymptomatic, longitudinal, white bands are present in the nails of some
patients
•
Mucosal involvement is uncommon
•
Hailey–Hailey disease may koebnerize into inflammatory conditions such as
psoriasis or seborrheic dermatitis
HISTOPATHOLOGY
•
Acantholytic clefts and bullae form above the basal cells
•
The suprabasal cells separate partially from one another, so clusters of loosely
coherent cells float in the bullae
22
•
Widespread acantholysis gives the epidermis the appearance of a ‘dilapidated
brick wall’
TREATMENT
•
Simple measures should be tried to reduce skin friction and keep flexures dry,
including weight loss if appropriate, loose cool clothing and absorbent pads in
skin folds
•
Combinations of moderate to potent topical corticosteroids with antibacterial
and/or antifungal agents may be effective
•
The potency of topical corticosteroids should be reduced as soon as possible to
prevent atrophy
•
Systemic corticosteroids have been recommendead for widespread disease
23