vesiculobullous disorders

1. M O D E R AT O R : D R R O C H E L L E M
PRE : DR NAVYASHREE S

2. TOPICS
1. BULLOUS PEMPHIGOID
2. CHRONIC BULLOUS DISEASE OF CHILDHOOD
3. DERMATITIS HERPETIFORMIS

3. INTRODUCTION
• Bullous skin disorders are skin conditions characterised
by blister formation.
• A blister is an accumulation of fluid between cells of the
epidermis or upper dermis .
• Causes :
• Genetic
• Physical
• Inflammatory
• Immunologic
• Drugs
• Bullous skin diseases are mostly autoimmune

4. PATHOPHYSIOLOGY
• Keratinocytes of the epidermis are tightly bound together
by desmosomes and intercellular substance to form a
barrier of high tensile strength and stability.
• Beneath the epidermis lies the basement membrane
zone, which is a specialised area of cell-extracellular
matrix adhesion .
• The Basement membrane zone is particularly vulnerable
to damage or malformation and is a common site of
blister formation.

8. BULLOUS PEMPHIGOID
• The term Bullous pemphigoid was coined in 1953 by
Lever.
• It is an acquired autoimmune blistering disorder
characterised by subepidermal bullae and deposition of
complement and antibodies along the basement
membrane zone.
• Typically affects people aged 70 years and older.
• However , the condition can occur in the younger age
and cases can also occur in infancy and childhood .

9. ETIOLOGY
• Genetic susceptibility as well as certain environmental
factors can contribute to triggering Bullous Pemphigoid.
• Many studies show an association between HLA-
DQβ1*0301 and Bullous Pemphigoid.
• A recognizable precipitating factor is observed in 15% of
patients.

10. • Precipitating factors :
• Influenza vaccination
• Ultraviolet light
• Radiation therapy
• Thermal and electrical burns
• Surgical procedures
• Infections :
• Cytomegalovirus , Hepatitis B and C viruses , Ebstein
Barr virus , HHV-6 , HHV-8 , Helicobacter Pylori and
Toxoplasma Gondii.

11. • DRUGS :
• Furosemide
• Spironolactone
• Phenacetin
• Sulfinpyrazone
• Phenacetin
• Penicillin
• Penicillamine
• Fluoxetine
• Etanercept
• Patients with drug induced Bullous Pemphigoid have a
younger age than usual patients of Bullous Pemphigoid .

12. PATHOGENESIS
• The central role in pathogenesis of Bullous Pemphigoid
is played by autoantibodies to proteins of 180kD and
230kD that are normally present in the skin.
• The 230kD protein called BP230 or BPAG1 was
originally identified as the major antigen of Bullous
Pemphigoid.
• It is a cytoplasmic protein, a member of plakin family ,
involved in the anchorage of Keratin Intermediate
Filaments to the hemidesmosome .

13. • The 180KD Protein, also known as BP180 or BPAG2 is a
transmembrane hemidesmosomal component Collagen
type XVII .
• The major pathogenic epitope for Bullous Pemphigoid is
the non-collagenous 16A (NC16A),located at the
membrane –proximal region of COL17.
• The anti- BP180 antibodies belong to the IgG class
(IgG1 and IgG4 subclasses) as well as the IgE class.

15. Autoantibodies bind to Bullous Pemphigoid antigens
activate complement
Mast cell degranulation
Release inflammatory mediators
Recruitment of Eosinophils and Neutrophils

16. • Neutrophils Eosinophils
• Elastase Elastase
• Cathepsin G Gelatinase
• Collagenase MMP ‘s
• Matrix metalloproteinases
Breakdown of Dermoepidermal Junction leading to tissue damage

20. CLINICAL FEATURES
• Non bullous phase :
• Commonly starts with itching and a nonspecific rash on
the limbs that may be urticaria like or ocassionally
dermatitic.
• The pruritus may persist for several months .
• The possibility of Bullous Pemphigoid should be
considered in all elderly patients who presents with a
chronic relapsing pruritus ,even without frank blistering.

21. • Bullous phase :
• Few to hundreds of vesicles and bullae arise on
apparently normal or erythematous skin along with
urticarial and infiltrated papules and plaques or
dermatitic lesions.
• Blisters are usually tense ,1-3 cm in size or larger and
usually contain clear exudate , but at times can be
hemorrhagic.
• Blisters rupture to leave erosions that heal rapidly with
mild post-inflammatory changes.

23. • Lesions are distributed symmetrically and predominate
on the lower abdomen, inner or anterior thighs, and
flexor forearms.
• Oral cavity involvement is rare and is seen in 30% of
patients.
• Involvement of other mucosa is rare.
• Nikolsky sign is negative.
• Bulla spread sign(Asboe Hansen sign) may be positive
and the advanced border is rounded.

24. • Umbilical area , lower extremities-Pretibial Pemphigoid .
• Palmoplantar region – Dyshydrosiform Pemphigoid
• Vulva – localised vulvar Pemphigoid.

25. MORPHOLOGICAL VARIANTS
• Pemphigoid Vegetans –intertriginous vegetating lesions .
• Pigmented BP –Precursor lesions are hyperpigmented
macules and bullous lesions develop later.
• Pemphigoid nodularis – excoriated nodules and papules
are seen, predominantly over arms, legs and shoulders
in elderly patients.
• Papular Pemphigoid
• Lymphomatoid papulosis like pemphigoid .

26. • Vesicular Pemphigoid
• Erythrodermic BP – Characterised by erythroderma with
or without accompanying blistering.
• TEN like Bullous pemphigoid
• Ecthyma like Bullous Pemphigoid

27. CHILDHOOD BULLOUS PEMPHIGOID
• Rarely affects children .
• Urticarial plaques in annular or polycyclic patterns are
common.
• Groin , Axilla, abdomen and inner thigh involvement are
more common.
• Palmoplantar involvement is characteristic of infantile
BP.
• Facial involvement is more common in childhood BP.
• Mucous membrane involvement is more frequent than in
adult BP .

28. DRUG INDUCED BP
• BP like bullous lesions with characteristic
immunoflorescence findings can develop following
systemic therapy with certain drugs.
• Drugs such as Penicillin, ampicillin, Penicillamine,
Ibuprofen are more commonly implicated.
• Precipitation of pre-existing subclinical BP or provocation
of an immunologic response following basement
membrane destruction and release of BP antigen has
been implicated in pathogenesis.

29. ASSOCIATIONS
• Neurological diseases : Epilepsy , stroke , Parkinsonism
and Multiple Sclerosis .
• Psoriasis
• Lichen planus
• Malignancy

30. DIFFERENTIAL DIAGNOSIS
• Non bullous stage : drug reactions , contact dermatitis ,
prurigo, urticaria, urticarial vasculitis , arthropod
reactions , Scabies , Ecthyma .
• Bullous stage: Pemphigus group
Linear IgA bullous dermatosis
Epidermolysis bullosa acquisita
anti –p200 Pemphigoid

31. INVESTIGATIONS
• Light microscopy : (Non bullous lesion)
• Sub epidermal clefts
• Eosinophilic spongiosis
• Infiltrate of eosinophils in upper dermis .
• Bullous lesion :
• Subepidermal blister
• Dermal inflammatory infiltrate predominantly of
eosinophils and neutrophils.
• Blister cavity –eosinophils , neutrophils and fibrin.

33. Subepidermal blister
Eosinophilic
infiltration

35. • Tzanck smear – Eosinophils and Neutrophils
No acantholytic cells .
Direct Immunoflorescence :Linear IgG and complement
deposits along the Basement membrane zone with IgG in
90-95% and C3 in 100% of cases .
Less frequently , there may be deposits of IgA, IgE and
IgM .

36. Linear IgG and C3
deposition

37. • Indirect Immunoflorescence:
• Shows pressence of circulating IgG autoantibodies that
bind to epidermal side of salt-split normal human skin.
• Circulating autoantibodies of IgA, IgE, and IgM classes
can also be found.
• Autoantibodies can be detected by indirect
immunoflorescence in blister fluid and urine .
• ELISA :BP180 ELISA is found to be specific and
sensitive .

38. • Other tests :
• Immunoblotting
• Immunoprecipitation
• Immunoelectron Microscopy

40. DIAGNOSTIC CRITERIA
• Linear IgG and /or C3 deposits along the
dermoepidermal junction along with three of these four
clinical criteria :
• Age > 70 years
• Absence of atrophic scars
• Absence of mucosal lesions
• Absence of predominant bullous lesions on the head and
neck .

41. TREATMENT
• Localised or mild disease :
• Very potent topical steroids alone
• Systemic corticosteroids 0.3mg/kg daily ,weaning once
control achieved ± very potent topical steroids for
lesional skin.
• Anti-inflammatory antibiotics (Doxycycline 200mg /day ,
Oxytetracycline 1 g/day , Minocycline 100 mg/day ,
Erythromycin 1-2 g/day )± very potent topical steroids for
lesional skin.

42. • Moderate-severe disease :
• Systemic corticosteroids 0.5-1mg /kg daily , weaning
once control achieved ± very potent topical steroids .
• Very potent topical steroids 5-15 g twice daily to whole
skin surface .
• Anti-inflammatory antibiotics ±very potent topical steroids
applied to lesional skin .

43. • Relapse cases or patients not responding to existing treatment :s
• Systemic corticosteroids 0.5-1 mg/kg daily ±very potent topical
steroids .
• Anti-inflammatory antibiotics ±nicotinamide 500-2500 mg daily
• Azathioprine 1-2.5 mg/kg daily
• Methotrexate 5-15 mg weekly
• Dapsone 50-200 mg daily
• MMF 0.5-1g twice daily
• Chlorambucil 0.05-0.1mg /kg daily
• Refractory cases :
• IVIG
• Cyclophosphamide
• Plasmapheresis

45. DERMATITIS HERPETIFORMIS
• Also known as Duhring Brocq disease .
• It is a chronic ,polymorphic ,pruritic skin disease that
develops in patients with gluten-sensitive enteropathy ,
which is generally mild or latent .
• Positive family history is seen in 10.5% of patients.
• All patients carry either HLA DQ2 or HLA DQ8
haplotypes .
• M/c age group affected is 30-40 years.
• M:F=1.5-2:1.

46. HISTORY
• Louis A Duhring first described this dermatosis in 1884.
• 1950- Pierard first described the pressence of clusters of
neutrophils and eosinophils in the dermal papillae.
• 1969 – Van der Meer , in turn revealed the occurrence of
granular IgA deposits.
• 1978- Strober and Katz elucidated the association
between HLA B8/DR3 with coeliac disease and
Dermatitis Herpetiformis .
• 1987- Kumar et al first noticed the pressence of anti-
endomysial antibodies in both diseases.

47. ETIOPATHOGENESIS
• Complex interplay between autoimmune factors such as HLA
predisposition, genetics and environment .
• Genetic :
• One gene found to be linked to Coeliac disease and weakly to
Dermatitis Herpetiformis is myosinIXB(MYO9B) on
chromosome 9 .
• MYO9B functions in cell signalling and regulation of actin
cytoskeleton dynamics ,thereby regulating cell integrity and
gut barrier permeability.
• It is proposed that increased intestinal permeability may allow
more gluten penetration ,and that a subsequent
immunological triggering .

48. TRIGGERING FACTORS
• Major environmental factor involved in triggering the
disease is exposure to gluten .
• Gluten –made up of two peptides , Gliadin and Glutenin.
• It can be classified according to its electrophoretic
mobility into 4 groups α,β,γ and δ.
• The pathogenesis is linked to α-gliadin group, and its
immunoreactivity is due to N- terminal group.

50. IMMUNOLOGICAL RESPONSE
1. Transglutaminase family and IgA deposits :
• The transglutaminase family consists of nine different
types of proteins expressed in various cell types.
• Two of them are relevant in Dermatitis Herpetiformis.
a. Tissue transglutaminase (coeliac disease ,
Huntington’s disease ,Alzheimer’s disease).
b. Epidermal transglutaminase –present in Keratinocytes,
also known as Transglutaminase-3 , it performs its
function by connecting the various epidermal structural
proteins .

51. • Normally, Epidermal transglutaminase is found in more
superficial keratinocytes.
• After trauma, keratinocytes might release epidermal
transglutaminase , deposit in the basement membrane .
• Circulating antibodies would bind to these auto antigens
forming the disease characteristic deposits in that site.
• Another mechanism – keratinocytes would release
epidermal transglutaminase into blood stream where it
would form immune complexes with IgA which would
deposit in the dermal papillae.

52. • Anti-tissue transglutaminase antibodies cross react with
epidermal transglutaminase leading to the onset of
cutaneous IgA deposits.
2. Role of IL-8 :
• Intestinal intolerance to gluten activation of CD4 cells
increased IL-8 levels neutophilic infiltration
Microabscess .
• Macrophages also produce enzymes , such as
metalloproteinases, Collagenase-3, Stromelysin -1 which
destruct the extracellular matrix.

55. CLINICAL FEATURES
• Onset may be acute or gradual , and pruritus is usually
the first and predominant symptom.
• Primary lesions are erythematous papules or urticarial
wheals surrounded by groups of small vesicles.
• Eczematous or lichenified changes may be seen.
• Lesions are characteristically distributed symmetrically
on the extensor aspects of the limbs, especially knees
,elbows and shoulders.
• Lesions usually heal without scarring .
• Oral lesions are common but asymptomatic.

58. • Atypical manifestations include – Palmoplantar purpura,
palmoplantar keratoses, chronic-urticaria like lesions and
lesions mimicking prurigo pigmentosa.
• The majority (75-90%) of DH patients have an
associated mild or latent CD.
• Gastrointestinal manifestations:
• Diarrhoea, constipation, bloating , pain abdomen ,weight
loss .

59. • Associations :
• Thyroiditis
• Type 1 DM
• SLE
• Sjogren syndrome
• Vitiligo
• Primary Biliary Cirrhosis
• Pernicious anaemia
• Alopecia areata
• DH predispose to enteropathy associated T-cell
Lymphomas that have poor prognosis.

60. DIFFERENTIAL DIAGNOSIS
• Urticaria
• Atopic eczema
• Contact dermatitis
• Scabies
• Linear IgA dermatosis
• Chronic prurigo

61. INVESTIGATIONS
• Histopathology :
• Subepidermal cleft with neutrophils and eosinophils
forming microabscesses at the tips of dermal papillae.
• Perivascular mixed inflammatory infiltrate .

64. • Immunoflorescence :
• DIF of perilesional skin is the diagnostic gold standard
for DH .
• Granular deposits of IgA at the tips of dermal papillae are
pathognomonic.
• Ocassionally linear granular deposits along the BMZ
may be seen.
• In about 2% of cases , there is a fibrillar pattern of IgA
deposition along BMZ.
• There may also be C3 and IgG deposits.

65. Granular IgA deposits

66. • Indirect immunoflorescence:
• IgA endomysial antibodies can be detected by using
monkey esophagus.
• Other tests:
• ELISA
• Genetic testing .
• Upper duodenoscopy
• Small bowel histology

67. DUODENAL BIOPSY

69. TREATMENT
• Gluten free diet
• Dapsone (100-200mg/day)
• Sulfapyridine (3g/day)
• Cyclosporine
• Colchicine
• Tetracycline
• Nicotinamide

70. CHRONIC BULLOUS DISEASE OF
CHILDHOOD
• Linear IgA dermatosis or chronic bullous disease of
childhood is a rare, non-hereditary , autoimmune
disease.
• Most common chronic bullous disease during the first
decade of life.
• Was first described by Bowen in 1901.
• It is an autoimmune disease with the targeted antigens
localised in the basement membrane of squamous
epithelium.

71. PATHOGENESIS
• LABD 97 and LAD-1 antigen which represent fragments
of the extracellular domain of collagenXVII (BP180), a
transmembrane protein playing a role in epidermal
adhesion.
• Targeted dermal-epidermal antigen have been identified
in Lamina lucida and sublamina densa.
• The variety of target antigen in CBDC is caused by
epitope spreading by which primary autoimmune
process is extended to neighbouring molecules,
generating new autoantigenic epitopes.

72. • Production of IgA against the antigens and linear pattern
of deposition is along the basement membrane.
• Plasminogen activation by keratinocytes activation
of matrix metalloproteinase 9 activation of
neutrophils neutrophil elastase
epithelial –dermal detatchment
blister formation

73. • Drug induced: Amoxycillin-clavulunic acid
Vancomycin
NSAID s
• Infections: Salmonella enteritis
EBV
• Onset of CBDC usually occurs between 6 months and
10 years.

74. CLINICAL FEATURES
• Characterised by tense pruritic blisters of variable sizes
with small clear fluid filled vesicles on normal appearing
skin or at periphery of annular erythema,along with
crusts, excoriations and erosions.
• Called as “Cluster of Jewels” appearance .
• Lower limbs are more commonly involved.
• Lesions heal without scarring
• Mucous membranes may also be involved with painful
erosions.

77. • Ocular- subconjunctival fibrosis
symblepharon
cicatrical entropion
D/d- Bullous pemphigoid
Dermatitis herpetiformis
Erythema Multiforme

78. • H/P – Subepidermal blister
eosinophils and neutrophils
DIF – Linear pattern of IgA deposition along the basement
membrane with IgG , IgM and C3.

81. TREATMENT
• Dapsone is used as first line therapy .
• Oral steroids
• Erythromycin
• Colchicine
• Mycophenolate mofetil
• IVIgs

83. ALGORITHM FOR SUBEPIDERMAL
BLISTERING DISORDERS
• SUBEPIDERMAL BULLAE
•
Cellular Acellular
Congenital –EBA
Acquired-
EBA/BP/BSLE
PAS positive –PCT
Lymphocytes- EMF
Mast cell mastocytosis
Neutrophils –DH/CBDC
Mixed- BP/IgABD
Eosinophils- BP/HG

84. REFERENCES
• IADVL TEXTBOOK OF DERMATOLOGY ; 4TH EDITION
• FITZPATRICK’S DERMATOLOGY IN GENERAL
MEDICINE; 8TH EDITION
• ROOK’S TEXTBOOK OF DERMATOLOGY ;9TH
EDITION
• LEVER’S HISTOPATHOLOGY OF THE SKIN-10TH
EDITION
• MEDSCAPE ARTICLES
• PUBMED ARTICLES .

85. MCQ’S
1. “Cluster of Jewels” appearance is seen in
a. Epidermolysis bullosa
b. Chronic bullous disease of childhood
c. Bullous Pemphigoid
d. Bullous SLE

86. Ans –b. Chronic bullous disease of childhood
2. Transglutaminase -3 is found in
a.Epidermis
b. Gastrointestinal tract
c. Brain
d. Peripheral nerves

87. • a. Epidermis
3. Antibodies against BP180Ag is involved in pathogenesis
of
a. Bullous Pemphigoid
b. Lichen Planus Pemphigoides
c. Cicatrical Pemphigoid
d. All of the above

88. d. All of the above .
4. Eosinophilic infiltrate on H/P examination is found in
a. Bullous Pemphigoid
b. Dermatitis Herpetiformis
c. Pemphigus Vulgaris
d. Linear IgA Dermatosis

89. a. Bullous Pemphigoid
5. Drug of choice for Dermatitis Herpetiformis is
a. Corticosteroids
b. Azathioprine
c. Dapsone
d. Cyclosporine

90. Ans – C. Dapsone
6. Subepidermal bullae with PAS positivity is seen in
a. Epidermolysis bullosa acquisita
b. Bullous SLE
c. Erythema Multiforme
d. Porphyria Cutanea Tarda

91. Ans – Porphyria Cutanea Tarda
7. Acqired Hemophilia is associated with
a. Dermatitis Herpetiformis
b. Cicatrical Pemphigoid
c. Bullous Pemphigoid
d. Epidermolysis Bullosa

92. Ans c. Bullous Pemphigoid