Download Bullous Pemphigoid - UCLA Oral Medicine

PEMPHIGOID
Jun Flores #130
Alina Tiraspolskaya
#183
Joshua Cardwell #108
Jared Martin #147
Cicatricial Pemphigoid
•Chronic, autoimmune, subepidermal, blistering of the
oral mucous membrane
•Immunoglobulin G (IgG) autoantibodies specific for
the hemidesmosomal antigens
•No racial predilection is apparent
•Incidence of pemphigoid appears to be equal in men
and women
•BP primarily affects elderly individuals in the fifth
through seventh decades of life, with an average age
at onset of 65 years
Pathophysiology
• IgG autoantibodies bind to the basement
membrane
•  complement and inflammatory mediators
•  inflammatory cells to the basement
membrane
•  release proteases
•  degrade hemidesmosomal proteins 
blister formation
Causes/Relevant factors:
• Immunogenetics
– Increased of specific HLA  presentation of the target antigen by
antigen-presenting cells in the initial development of the autoimmune
response
• Age
– Intrinsic changes in the immune system with aging are factors in the
initiation of an autoimmune response
• Epitope spreading
– Reports of bullous pemphigoid arising in patients with inflammatory skin
diseases (psoriasis, lichen planus), or post- trauma (drug reactions) 
inflammation exposes sequestered skin basement membrane proteins
and antigens leading to the development of an autoimmune response
• Complement activation
– Autoantibodies bind hemidesmosome/upper lamina lucida area of the
skin basement membrane  complement activation  inflammatory
cells release enzymes  blister formation.
• Chemokines
– The histologic hallmark for bullous pemphigoid is the prominent
eosinophil infiltration at the skin basement membrane area likely
induced by chemokines
Pathogenesis (con’t)
• Involves the mucosa in 10-25% of patients
• Limited oral intake secondary to dysphagia
• Erosions secondary to rupture of the blisters,
pain, functional limitations (palms, soles)
• Bullous pemphigoid can be fatal in debilitated
patients, mostly due to sepsis and adverse
effects to treatment
• Patients on high dose corticosteroids –
increased risk for PUD, GI bleed,
agranulocytosis, diabetes
Clinical Presentations
•
The gingival epithelium is peeling off revealing a
raw red connective tissue surface. In benign
mucous membrane the basement membrane is
destroyed allowing the epithelium to peel off.
•generalized bullous form is the most common presentation.
•vesicular form
•vegetative form
•generalized erythroderma form
•urticarial form
•nodular form
•acral form
•
Whitish area of gingiva
represents broken
blister, with surrounding
hemorrhage
•
•
•
Benign mucous membrane
pemphigoid.
Exposed connective tissue
appear as red areas;
epithelium about to slough
appears as white areas
Red inflamed gingiva is
the typical clinical
appearance of benign
mucous membrane
pemphigoid. These raw
surfaces were covered
with bullae.
•
Conjunctival
involvement can be
severe, resulting in loss
of hair, of the lid itself,
bulbar conjunctivitis and
scar formation
•
•
Ulcer bed of huge
buccal mucosa bulla
Bullae on external
skin surfaces
Diagnostic Tests
Positive Nikolsky Sign
• With a blunt instrument (back of a mouth mirror), the
investigator firmly places and pushes against the
mucous membrane and twists. A positive Nikolsky sign
presents as blister formation within a matter of minutes
– Note: many other vesicular/bullous diseases have a positive nikolsky
sign
Diagnostic Tests Continued
• Light microscopy and direct immunofluorescense are
necessary to differentiate pemphigoid from other
diseases with a positive Nikolsky sign
• The immunopathologic hallmark of pemphigoid is a
linear deposition along the basement membrane as
detected by direct immunofluorescense microscopy
Histopathology
• A separation of the epithelial and
connective tissue layer at the level of the
basement membrane
• Immunofluorescence reveals a linear
striation of IgG and C3 at the level of the
basement membrane (Chan and Cooper, 1994)
Histologic Appearance
•
Subepithelial blister has intact
overlying epithelium, without
liquefactive degeneration
(separation at the basement
membrane)
•
Immunofluorescence shows green
line along the basement membrane
of the epithelium (this shows the
lineal IgG and C3 striations)
•
In this photomicrograph of benign mucous membrane
pemphigoid the peeling away of the epithelium from connective
tissue is obvious. This change results in what pathologists call
"sub-basalar clefting."
Recent Histological Findings
• Recent research
have suggested that
there is an affinity of
anti-bodies against
BP180 antigen at the
lamina lucida level.
Calabresi et. al, 2007
BP180 is a
transmembrane
complex involved in
adhesion at the dermalepidermal layer
Image from
2002 Br J Obstet Gynaecol 109
Treatment
Goal – decrease blister formation
- promote healing of blisters and
erosions
- reduce inflammatory response and
autoantibody production
Treatment (con’t)
Medications
-Anti-inflammatory agents – inhibit specific
cytokine production and vascular
permeability
-Prednisone (1mg/kg/d)
-Tetracycline (500mg qid)
-Clobetasol – topical steroid (bid for up
to 2 wk)
Treatment (con’t)
-A recent article from Europe provided evidence
that strong topical corticosteriods can achieve
disease control while avoiding systemic adverse
effects from systemic corticosteroids
-Immunosuppressive agents – if antiinflammatory agents cause no response
-Azathioprine (1mg/kg/d bid, increase by
0.5mg/kg q4wk until response, do not exceed
2.5mg/kg/d)
Treatment (con’t)
-For patients treated with systemic corticosteroid for
longer than 1 month, a combined supplement of calcium
and vitamin D should be instituted to prevent
osteoporosis.
 -In addition to calcium and vitamin D supplementation,
patients on long-term treatment with systemic
corticosteroids should be taking bisphosphonate, a
specific inhibitor for osteoclast-mediated bone resorption
(eg, alendronate).
Before
The remaining images are of the same patient. •
Here the mucous membrane inside the lower
lip shows the red and white desquamative
areas so typical of benign mucous membrane
pemphigoid.
•
After
Within a week after starting systemic
corticosteroid therapy, the patient showed
significant improvement. Here the lesion on lip
mucosa have resolved completely.
•
•
In the same patient, the raw and sloughing
process has affected the buccal mucosa.
The improvement in the buccal mucous lesion
after corticosteroid therapy is remarkable.
References
•
•
•
•
Calabresi V, Carrozzo M, Cozzani E, Arduino P, Bertolusso G, Tirone F, Parodi A,
Zambruno G, Di Zenzo G. Oral pemphigoid autoantibodies preferentially target
BP180 ectodomain. Clin Immunol. 2007 Feb;122(2):207-13. Epub 2006 Dec 1.
Chan LS, Cooper . A novel immune-mediated subepidermal bullous dermatosis
characterized by IgG autoantibodies to a lower lamina lucida component.
Arch Dermatol. 1994 Mar;130(3):343-7.
Chan LS, Yancey KB, Hammerberg C. Immune-mediated subepithelial blistering
diseases of mucous membranes. Arch Dermatol. 1993 Apr; 129(4): 448-55.
Sapp, J.P., Eversole, L.R., Wysocki, G.P. Contemproary Oral and Maxillofacial
Pathology. Mosby 2004, p. 262-265.
2 m/c Test Questions
1)
What is the immunoflorescence pattern for pemphigoid
A Linear IgA and C3
B Linear IgG and C3
C Fishnet patter of C3
D Fishnet patter of IgA
E Shaggy pattern
ANS: B
2)
Which one is true?
A BP tends to occur in men more than in women
B BP is one of few bullous diseases negative for Nikolsky sign
C Anti-inflammatory agents inhibit specific cytokine production and
increase vascular permeability
D Complement activation is an important factor in BP pathogenesis
E BP frequently involves mucous membranes
ANS: D