This document discusses bullous diseases of the skin. It describes different types of bullous diseases including autoimmune bullous diseases like pemphigus and bullous pemphigoid. Pemphigus can be superficial or deep and is caused by antibodies against desmogleins. Bullous pemphigoid typically affects elderly patients and is characterized by large tense subepidermal blisters caused by antibodies against the basement membrane. Diagnosis involves skin biopsy and detection of antibodies. Management involves topical and systemic steroids, immunosuppressants, and monitoring of clinical response and antibody titers.

1. Bullous disease of the skin

2. • Blister; is accumulation of fluid within or under the
epidermis. It has many causes and a correct clinical
diagnosis must be based on a closed clinical study of
physical sign.
• Classification
• 1. Auto immune bullous disease; when there are
immunological factors in the form of antibodies or T
lymphocyte involved in the pathogenesis of the disease
• 2. Erythema multiforme
• 3. Hereditary mechanobullous disease
• 4. Miscellaneous bullous disease.

3. • The site of bullae could be either
• 1. Sub corneal bullae; bullous impetigo, miliaria
crystalline, staphylococcus scalded skin syndrome
• 2. intraepidermal bullae; pemphigus, acute
eczema, viral vesicle
• 3. subepidermal bullae; bullous pemphigiod,
pemphigiod gestations, dermatitis herpitiforme,
bullous erythema multiforme, bullous lichen
planus ,bullous lupus erythematosus , linear IGA
disease, epidermolysis bullosa

4. Auto immune bullous disease
1. Pemphigus
• There are two types of this disease which is either
• Superficial like
1. p. foliacous
2. p. erythematosus
• Or deep (suprabasal)
1. p.vulgaris
2. p.vegetans
• This disease affects young people in Iraq around 30-40
years of age. (In other countries it is a disease of
elderly people).

5. Etiology;
• 1. The etiological factors of this disease are
antibodies of IGg type directed toward the
desmosome between the keratinocyte, antibodies
bind to desmogleins, transmembrane glycoprotiens
in the desmosomes. Keratinocyte will spilt and float
inside the malpigian layer forming intra epidermal
vesicles. This antibodies found in both involved and
clinically normal skin. The antibodies titers correlated
with the severity of the disease and if the titers are
very high it is lethal

6. • 2. Drugs had shown to induce pumphigus like
penicillamine, captopril, penicillin, thiopronine
and rifampicin, ultraviolet light may exacerbate
pumphigus .
• 3. Many studies indicated genetic predisposition
to pemphigus and its association with HLA
phenotype DR 4 or DR6 in addition to the
predisposition of developing other autoimmune
disease like myasthenia gravis and thymoma.

7. Clinical feature
• Any area of the body can be affected from the
scalp to the sole but the most affected area is
the oral cavity that is affected in 60% of the
cases in the initial phase but along the course
of the disease 100% of the cases will be
affected with oral lesion.
•

8. • The oral lesions are of short lived bullae quickly
ruptured to involve most of oral cavity with
painful erosions. The lesion may extend to the
lips forming heavy fissures, crusts on the
vermilion. Involvement of the throat produces
hoarseness of the voice and difficulty in
swallowing. The mouth odor is offensive and
unpleasant, rarely the esophagus involved with
sloughing of the entire lining lead to esophagitis
dissecance superficialis.

11. • The skin lesion is variable some time we see flaccid
easily ruptured bullae that appear on either apparently
normal skin or mucous membrane or on an erythematous
bases. the fluid in the bullae are first clear later become
hemorrhagic or even seropurulent the bullae soon rupture
to form erosions (row surfaces that is ooze and bleeds
easily) and these lesions gradually covered with
generalized crustations that have little or no tendency to
heal and because the bullae is very superficial so mostly
the patient present with generalized crustation rather than
flaccid bullous stage.

14. • There is no itching at all with rash but usually
there is superadded infections because the
patient with no skin so lack the barriers for the
entrance of microorganism spread cause
bacteremia and then septicemia that is the first
cause of death in this condition .

15. • There is absence of cohesion in the epidermis
manifested firstly by nickolesky sign by which the
upper layers can easily made to slip laterally by
slide presser or rapping or it is removed by
twisting pressure with the finger tip leaving moist
surface.
• Secondly bullae spread phenomena that is by the
pressure on the intact bullae gently forcing the
fluid to wonder under the lesion away from the
pressure site ( asboe-hansen sign).

16. • Histopathology; the characteristic finding
consist of acantholytic cells , intra-epidermal
cleft and blister formation and this
acantholytic cell lining the bullae as well as
lying free in the bullae cavity and these cells
show no intercellular bridges,

18. Investigations
• 1- Skin biopsy firstly to see the intra-epidermal
vesicles and acantholysis and then do
immunoflourescent technique which is either :
• a- Direct immunoflourescent test by taking a sample
of skin lesion and see the immunoglobulin depositions
around the keratinocyte.
• b- Indirect immunoflouresnce technique by taking the
serum with their antibodies and put it on normal skin
to see immunoglobulin deposition.

19. • DDX
• If only mouth lesions are present; aphthae,
mucosal lichen planus and erythema
multiforme, differential diagnosis includes all
forms of acquired bullous diseases

20. • Treatment
• 1- Local treatment
• - prolong daily bath help to removed the thick
crust and reduce the foul odor
• - Topical antimicrobial agent (silver sulphadiazine
1%) .
• - benadryl ( equal parts of malox and elexire of
diphenhydramine hydrochloride or viscous
xylocain for mouth lesion specially befor meals
• Topical and intralesional glucocorticoids

21. 2-systemic steroids;
• use high dose of prednisolone tablet 2-3mglkg body
weight daily alone or in combination with
immunosuppressive drugs until cessation of new blister
formation and disappearance of nikolsky sign. Then
rapid reduction to about half the initial dose until
patient is almost clear, followed by very slow tapering
of the dose to minimal effective maintenance dose.
Pemphigus antibody titer is performed every 4 weeks
watching for fall in titer. Medication is continued until
clinical disease is suppressed and pemphigus antibody
disappear from serum and when both DIF and IF
become negative.

22. • 3-concomitant immunosuppressive therapy;
• Immunosuppressive agents are given concomitantly for
their glucocorticoid-sparing effects, they may be used
as single agents when corticosteroid is contraindicated
or only when there is limited disease but combined
treatment is superior in control the disease.
• Azathioprine, 2-3 mg/kg body weight until complete
clearing then tapering of dose to 1 mg/ kg
.azathioprine alone is continued even after cessation of
glucocorticoid treatment and may have to be
continued for many months or years.

23. • Methotrexate either orally or intramuscularly
in dose of 25-35 mg/ kg l week, dose
adjustment are made as with azathioprine
• Cyclophosphamide, 100-200 mg daily with
reduction to maintenance doses of 50-100
mg/ day.

24. • 4-gold therapy; have S.E of bone marrow
suppression and nephrotoxicity given in a dose of
25-50 mg l week
• 5-plasmapharesis in conjunction with
glucocorticoids and immunosuppressive agents in
poorly controlled patients, in the initial phases of
the treatment to reduce antibody titers.
• 6. mycophenolate mofetile 1 gm twice daily has
been reported to be beneficial

25. • 7. High dose intravenous immunoglobulin
2gm/kg body weight every 3-4 weeks has
been reported to be have a glucocorticoid-
sparing effect.
• 8. Rituximab (monoclonal antibody to CD 20)
given IV once a week for 4 weeks show
dramatic effect in some patients

26. • 9-extracorporeal photochemotherapy
• 10-dapson as steroid sparing agent or
maintenance therapy
• 11-intralesional steroid injection may control
limited recalcitrant lesions such as lesion in
scalp or mouth.
• Other measure is to correct fluid and
electrolyte imbalance.

27. Monitoring
• Clinical, for improvement of skin lesion and
development of drug related SE
• Laboratory monitoring of pemphigus antibody
titers and for hematological and metabolic
indicators of glucocorticoid and or
immunosuppressive- induced adverse effects.

28. 2. Bullous pemphigoids
• It is less common than pemphigus and happens
in elderly patients between 65-70 years old.
Usually it started as dermatitis with sever itching
and then bullous lesion appear. Manifested as
pruritic papular and or urticarial lesion with large
tense sub epidermal bullae contain serous or
hemorrhagic fluid.

29. • Area of predilection are the inner thigh and
the flexure surfaces of the arms, axillae,
groins, lower abdomen and the oral cavity
that is less involved and usually 9-39% of the
cases are with mouth lesion along the course
of the disease

33. • The disease is usually mild and the mortality
rate is low with periodic exacerbation and
remission even with no treatment, so it is self
limiting condition, antigens directed against
lamina lucida, circulating anti basement
membrane antibody of I gG type present in
70% of the cases in which no correlation
between titer of antibody and clinical disease
activity

34. • Many variants of bullous pemphigiod
• 1. It may begin at localized site such as shin
and remain so during the course of the
disease
• 2. It may localized to the sole as vesicular
eruption (dyshidrosiform pemphigiod
• 3. localized vulval lesion and ulcer
• 4. May be limited to the area of radiation and
burn

35. • 5. Vesicular varients(vesicular
pemphigiod)tens small grouped blisters
• 6. Papules and nodules on scalp and
extremities resembling prurigo nodularis
• 7. erythrodermic pemphigiod
• 9. Non bullous variants manifested as pruritic
eczema or urticarial eruption

36. • Histopathology of BP;
• Subepidermal bulluea, absences of
acantholysis, superficial dermal infiltration
contain eosinophils

38. • Laboratory Investigations
• Dermatopathology;
• Light microscopy; accumulation of
eosinophils, neutrophils and lymphocyte in
the papillary dermis and sub epidermal bullae
• Electron microscopy; split occurs in the lamina
lucida of basement membrane

39. • Immunopathology; linear IgG deposits along
the BM zone also c3 which may occur in the
absence of IgG.
• Serum; circulating antibasement membrane
IgG antibodies detected by IIFT in 70% of
patients, titer do not correlate with course of
disease.
• Hematology; eosinophilia

40. • Diagnosis and DDX
• Clinical appearance, histopathology, and
immunology permit a differentiation from
other bullous diseases

41. Treatment
• Similar to pemphigus,
• 1. steroid use in a lesser dose and shorter course as
50-100 mg prednisolone daily continued until clear
either alone or combined with
• 2. Azathioprine 150 mg/day for remission induction
and 50-100 mg for maintenance
• 3 . In refractory cases IVIG, plasmapharesis
• 4. dapson 100-150mg l day , MTX 2.5-10 mg l week
orally is effective and safe in elderly and in mild cases.

42. • 5. Topical corticosteroid, topical tacrolimus
therapy may be beneficial in very mild cases
• 6. Tetracycline + nicotinamide has been
reported to be effective in some cases
• The disease is usually self limiting within 5-6
years period

43. 3. Herpes gestation
• A pruritic inflammatory bullous disease has
many similarities to bullous pemphigoid, with
onset either during pregnancy or at post
partum period, mostly occur during second
trimester of pregnancy, average at 21 week of
gestation.

44. • presented as urticarial plaques and papules s.t
associated with vesicles and bullue around
umbilicus and extremities sparing the face,
scalp ,and the oral mucosa, associated with
sever pruritis that is flare few days after
delivery and remit spontaneously to reoccur in
subsequent pregnancy , subsequent
menstrual cycle or with the use of oral
contraceptive pills

47. • The Effect on infant usually results in
premature and small for gestational age baby.
5% of babies have urticarial, vesicular or
bullous lesion .The disease may also
associated with hydatiform mole and
choriocarcinoma

48. Histopathology
• Sub epidermal blister with heavy linear
deposition of c3 along the basement membrane
zone with concomitant IgG deposition in 30% of
patients
Diagnosis
• Also by skin biopsy with direct and indirect IFT
which show antibasement membrane antibodies
of IgG type directed against antigen deposition in
lamina lucida

49. Differential diagnosis;
• 1. PUPPP(Pruritic urticarial papules and
plaques of pregnancy)
• 2. Disease occur coincidentally and non
specific for pregnancy include erythema
multiformi, bullous pemphigiod, pemphigus,
and drug reaction

50. • Treatment
• In mild cases topical steroid
• In severe cases systemic steroid 40 mg daily is
effective

51. Dermatitis herptiformi
It is a chronic relapsing severely pruritic disease ,
characterized by grouped symmetrical
polymorphus papular , papulovesicular,
vesiculobullous, bullous or urticarial lesion on an
erythematous base. Itching is severe and
provokes scratching to the point of bleeding and
later scarring. Predilection site; scalp, nuchal
area, forearm, post axillary fold, back and
buttock. The disease had equal male to female
ratio and it is common between 20 -40 years old.
The course of the disease is life long with
prolonged remission being a rare event,

54. • DH associated with gluten- sensitive
enteropathy and those patients have
abnormality of jejunal mucosa and if given a
high gluten diet all the patients will develop
abnormal findings indistinguishable from
celiac disease

55. • Diagnosis: circulating IgA antibodies against
smooth muscle cells endomuceium present in
70% of DH patient.
• DIF of non-involved skin revealed IgA
deposition alone or with C3.arranged in
granular pattern in the dermal papillae.
• Histopathology; subepidermal bullae found at
the tip of dermal papillae.

56. • Treatment ; dapson and sulphapyridine 50-
300 mg daily , side effect of the drugs
hemolytic anemia leukopaenia ,
methomoglobin anemia , agranulocytosis and
peripheral neuropathy, usually started with
100 mg daily and then increase the dose
gradually to the effective level or until the side
effect appear.

57. Chronic benign bullous disease of childhood
• This is a disease of childhood at preschool age and it is
a self limiting disease within 2-3 years, clinically appear
as tense large bullae usually seen around the mouth,
pelvis and limbs could be non itchy rash or may cause
severe itching.
• On immunoflurescent study IgA deposition at dermo
epidermal junction which result in sub epidermal
bullae
• Treatment
• Reassure the mother and we may use dapson with or
without steroid

58. II. Erythema multiforme
• It is a self limiting recurrent disease usually of
young adult occurring in the spring, there is
no or mild prodrome last 1-4 weeks. Clinically
it is divided into two types;
• 1. Erythema multiforme simplex or ordinary
type
• 2. Steven Johnson syndrome a sever type with
mucosal involvement
• .

59. • Ordinary type appears as sharply marginated
erythematous macules which become raised
oedematous papules over 24-48 hour. Later
the lesion takes a shape of iris with three
zones; central dusky purpura which may
blister and elevated oedematous pale ring and
a surrounding macular erythema

60. • The lesion appear symmetrically on dorsal feet,
extensor limb, elbow, knee, palms and soles, with
oral involvement in 25% of cases to differentiate
it from Steven Johnson syndrome. The last one
usually with high fever and loss of appetite and
the patient is toxic, eruption occur at all ages
which is diffuse on the trunk and prominent oral
involvement. The course of Steven is much
protracted which may take one month and the
patient may require hospitalization

64. Etiology
• 1. infections; viral , bacterial and fungal, The
commonest viral cause is herpes simplex labialis, which
fallowed by EM lesion five days after the appearance of
HS lesions usually cause erythema multiforme minor.
• 2. Drugs; sulphonamides, non-steroidal anti-
inflammatory drugs, allopurinol and anticonvalsent
drugs, usually cause Stevens Johnson syndrome.
• 3. Inflammatory bowel disease, Crohn’s disease and
ulcerative colitis.
• 4. Sun light.
• 5. Radiations

65. • Management
• 1. Antibiotic covers if the cause is infection
• 2. Topical steroid
• 3. Antihistamine
• 4. Mouth wash
• 5. Systemic steroids, especially in SJS which
may be used in a high dose 1100mg daily with
intravenous fluid nutrients

66. III. mechanobullous disease (
epidermolysis bullosa)
• A. hereditary epidermolysis bullosa;
• it is a spectrum of rare genodermatosis in
which a disturbed coherence of the epidermis
and or dermis leads to blister formation
following trauma. Classification based on the
site of blister formation divided into 3 groups;
• 1. EP simplex
• 2. Junctional EB
• 3. Dystrophic EB

67. EB simplex
• A trauma induced intra epidermal blistering, based on
mutations of the genes for keratins 5 and 14 resulting in
cytolysis of basal keratinocyte and a cleft in basal cell
layer.
Two subtypes are identified
• Generalized EBS which is dominantly inherited with
onset at birth or early infancy. There is generalized
blistering following trauma with a predilection for
traumatized body sites such as feet, hands, elbows and
knees, blisters are tens or flaccid at first lead to erosions
, there is rapid healing with minimal scarring. Nail,
teeth, and oral mucosa are usually spared

68. Localized EBS
• It is the most common form with onset in
childhood or later and may not present until
adulthood manifested as thick wall blisters on
the feet and hands occur after excessive
exercise, manual work, military training
associated with hyperhidrosis of palm and
sole, secondary infection of blisters.

69. Junctional EB
• Blister formation occur within the lamina
lucida of the basement membrane, mutations
are in the gene for collagen XVII and laminin, it
is autosomal recessive

70. Dystrophic epidermolysis bullosa
• Blistering occur below the basal lamina
healing therefore accompanied by scarring
and milia formation. Occur due to mutations
in anchoring fibril type VII collagen which is
therefore rudimentary or absent. It is either
dominant or recessive

71. Management
• Supportive skin care and supportive care to
other organ systems, systemic therapies for
complications, wound management,
nutritional support and infection control are
key to the management of all EB patients

72. EB acquisita
It is a chronic sub epidermal bullous associated with
autoimmunity to type VII collagen within the anchoring
fibrils in the basement membrane zone classified into 4
types;
1. Classical mechanobullous type; presented as non
inflammatory blistering eruption with acral distribution
heals with scarring and milia formation associated with
skin fragility, erosion and scars .
2. Bullous pemphigoid – like presentation; a wide spread
vesiculo- bullous eruption on erythematous or even
urticarial base involving the trunk, central body, skin
folds in addition to extremities

73. 3.Cicatricial pemphigoid – like presentation with
prominent mucosal involvement- erosion and
scarring in the mouth, esophagus, conjunctiva,
anus and vagina
4.The IgA bullous dermatosis- like presentation ;
vesicles arranged in an annular fashion

74. • Histopathology
• Sub epidermal blister with clear separation
between epidermis and dermis
• Immunopathology
• Reveals linear IgG+IgA+IgM at the dermo
epidermal junction
• Salt split –skin IIFT show circulating anti
basement membrane AB bind floor of blister,
ELISA a very specific test to type VII collagen

75. • Treatment
• Very difficult and refractory to all treatment
regime specially in patient with mechano-
bullous presentation

80. IV. Miscellaneous bullous disease
When the primary disease is not a bullous disease
but during the course of the disease blisters
appear as in:
1-Bullous dibeticorum ; it is a very common
condition in Iraq found in association with
diabetes millets , seen in middle age and elderly ,
present as huge bullous lesion affecting the feet
which may be present acutely . Treated by rest
and supportive treatment and usually heal.
Sometime managing diabetes mellitus may help
in clearing or decreasing the next attack.

81. 2-Bullous SLE .
3-Bullous LP.
4-Bullous dermatosis of haemodialysis
resmpling porpheria cutanea tarda.
5-Drug eruption.