bullous pemphigoid

1. Dermatology
Case Presentation
Presenter: FM R2盧敬文
Supervisor: VS 邱健群
2020.07.29

2. Patient profile
Gender: male
Age: 58-year-old

3. Patient history
2020-07-14 黃鴻怡醫師會診
• S+O:
Multiple itchy red plaques over the
trunk and limbs for 3-4 months.
Post topical Tx at 台中榮總:
Clobetasol oint
Rinderon-V
Fusidic Acid Cream
Ruptured bullae over bil. legs for
1-2 months after burn.
• A: r/o Bullous pemphigoid
• P:
1. Check intercellular and basement
menbrane Ab
2. Clobestasol oint bid over skin rash
3. Silvadene cream bid over wounds
4. Prednisolone 1# bid po
5. Doxycycline 1# qd po
6. OPD F/U

7. • Past History
Type 2 diabetes mellitus at CSMUH followed-up for 3-4 years
Hypertension at CSMUH followed-up for 3-4 years
Chronic kidney disease at CSMUH followed-up for 3-4 years
• Personal History:
Occupation/personal description：服務業
Travel History：無
吸菸：+ 喝酒：+ 吃檳榔：-
• Family History: nil.

8. Lab
2020-07-14

9. Pathology
• Microscopic Finding
The sections show fragments of skin tissues with
hyperkeratosis, mild epithelial hyperplasia, and mild
spongiosis.
No interface dermatitis between dermo-epidermal junction is
seen.
The dermis is edematous with perivascular lymphocytic and
eosinophilic infiltration, especially over the superficial dermis.
No granulomatous inflammation nor septic thrombus is
found.
The direct immunofluorescence on this specimen of skin
tissue reveals negative deposit for IgA, IgM, IgG, C3, C4, C1q,
Fibrinogen.
Note : The differential diagnoses include drug reactions,
urticarial reactions, insect bites, infestations, and virus
related dermatoses.
2020-07-17
• Diagnosis
Skin, body, biopsy :
Perivascular inflammation with
lymphoeosinophilic infiltration.
• Gross Finding
The specimen submitted consists of two pieces
of skin tissue fragments measuring up to
0.3x0.3x0.2 cm in size.
Grossly, they are tannish and soft.
All for sections, one for routine stain and the
other for direct immunofluorescence.

12. Bullous pemphigoid
Topic review

13. Pathophysiology
Epidemiology
Clinical manifestations
Associated disorders
Diagnosis
Differential diagnosis
Treatment

14. Pathophysiology
• autoantibody-mediated damage to epithelial basement
membrane zone
a complex structure that mediates adhesion, permeability, and
cellular organization and differentiation
• autoantibodies against two principal hemidesmosomal
proteins are strongly linked to clinical disease:
bullous pemphigoid antigen 180 (BP180)
a 180 kilodalton protein also known as bullous pemphigoid antigen 2 (BPAg2)
and type XVII collagen
bullous pemphigoid antigen 230 (BP230)
a 230 kilodalton protein also referred to as bullous pemphigoid antigen 1
(BPAg1).

15. Copyrights apply

16. Epidemiology
Uncommon
incidence rates of 4 to 22 cases per million individuals per year
most common autoimmune blistering disorder in Europe
primarily a disease of older adults
over the age of 60 years
Multiple studies reported a slight female predominance

17. Clinical manifestations
• prodromal phase
weeks to months
pruritic eczematous,
papular,
or urticaria-like skin lesions

18. • Blister(+)
• classical lesion is a 1 to 3 cm tense
bulla on an erythematous, urticarial,
or noninflammatory base,
• numerous and widespread
• pruritus
• tense quality
• rupture, leaving moist erosions and crusts
that resolve without scarring

19. • trunk, extremity flexures, and axillary and inguinal folds
common sites for cutaneous involvement
• 10 to 30 %: Mucosal lesions; oral mucosa
• 30 % : Localized forms
• 20 % : nonbullous presentations
• pruritic papules or nodules
• pruritus without primary skin lesions

20. Rare variants
pemphigoid vegetans
verruciform plaques
in intertriginous areas
dyshidrosiform pemphigoid
on palmar and/or plantar skin
(resembling dyshidrotic eczema
汗皰疹)
often hemorrhagic
Lichen planus pemphigoides
Postulated
cellular inflammatory process that
occurs at the basement
membrane zone in lichen planus

21. Associated disorders
• often have multiple comorbidities
• Neurologic disorders
dementia, Parkinson's disease, and unipolar or bipolar disorder
Stroke
multiple sclerosis
bullous pemphigoid antigens in the skin and neuronal antigens in the
central nervous system has been proposed as a cause for the
observed link
Bastuji-Garin S, Joly P, Lemordant P, et al. Risk factors for bullous pemphigoid in the elderly: a
prospective case-control study. J Invest Dermatol. 2011;131(3):637. Epub 2010 Oct 14.
Langan SM, Groves RW, West J, The relationship between neurological disease and bullous
pemphigoid: a population-based case-control study. J Invest Dermatol. 2011;131(3):631. Epub
2010 Nov 18.
Langer-Gould A, Albers KB, Van Den Eeden SK, et al. Autoimmune diseases prior to the
diagnosis of multiple sclerosis: a population-based case-control study. Mult Scler. 2010
Jul;16(7):855-61. Epub 2010 May 12.

22. • Malignancy
Mucous membrane pemphigoid: laminin 332 antibodies
solid organ malignancies
non-Hodgkin lymphoma and cutaneous T cell lymphoma
relationship between bullous pemphigoid and malignancy is less
clear.
Egan CA, Lazarova Z, Darling TN, et al. Anti-epiligrin cicatricial pemphigoid and relative risk for
cancer. Lancet. 2001;357(9271):1850.
Sadler E, Lazarova Z, Sarasombath P, Yancey KB, A widening perspective regarding the
relationship between anti-epiligrin cicatricial pemphigoid and cancer. J Dermatol Sci.
2007;47(1):1.

23. Diagnosis
• A lesional skin biopsy from the edge of an intact blister
(or other inflamed/affected tissue, urticarial or eczematous)
for H&E staining
• a skin biopsy from a perilesional area
for direct immunofluorescence (DIF)
• A serum specimen for indirect immunofluorescence (IIF) and
enzyme-linked immunosorbent assay (ELISA) testing
detect circulating basement membrane zone antibodies

24. Test
Specim
en
Site Procedure Transport
Histopatho
logy (H&E)
Skin or
mucous
membr
ane
Lesional or part lesional
•At least 4 mm punch
biopsy*Specimen should contain
intact epidermis/epithelium,
basement membrane zone, and
upper dermis/subepithelium
•Avoid torsion and crushing to
prevent separation artifact
In formalin to a
dermatopathology
laboratory
Direct
immunoflu
orescence
Skin or
mucous
membr
ane
•Perilesional For cutaneous lesions,
an erythematous or urticarial area
next to a blister from a proximal
anatomical location is ideal
•For mucous membrane lesions,
avoid areas of scarring; normal-
appearing epithelium since
perilesional tissue may be friable
•At least 4 mm punch
biopsy*Specimen should contain
intact epidermis/epithelium,
basement membrane zone, and
upper dermis/subepithelium
•Avoid torsion and crushing to
prevent separation artifact
In Michel's or Zeus
medium to an
immunodermatology
laboratory
¶
Indirect
immunoflu
orescence
and ELISA
Serum Peripheral blood
Serum separated from at least 5 mL
of blood obtained by venipuncture
(red top, no anticoagulant); send
serum separated from clot
Δ
In serum tube to an
immunodermatology
laboratory
Diagnostic pemphigoid testing

26. Clinical
Dermatology: A
Color Guide to
Diagnosis and
Therapy, 4th Ed.

28. Differential diagnosis of mucocutaneous
lesions in pemphigoid disorders

29. • Pemphigoid gestationis
an autoimmune subepidermal blistering disorder
develops during pregnancy and the postpartum period.
• Anti-p200 (laminin gamma-1) pemphigoid
a variant of pemphigoid
characterized by antibodies to a 200 kilodalton component of the
dermal-epidermal junction.
• Brunsting-Perry pemphigoid
a cicatricial (scarring) form of pemphigoid
most commonly occurs in older men.

30. Clinical
Dermatology: A
Color Guide to
Diagnosis and
Therapy, 4th Ed.

31. Clinical
Dermatology: A
Color Guide to
Diagnosis and
Therapy, 4th Ed.

32. Treatment
• First-line therapy: Topical Corticosteroids
clobetasol 0.05% cream.
• extensive bullous pemphigoid treated with topical corticosteroids
 better clinical outcomes than with systemic glucocorticoid therapy
1. One-year survival rates significantly higher
(76 versus 58 percent)
2. treated with clobetasol responded significantly more quickly
(By day 21, disease control was achieved in 99 versus 91 percent of
patients.)
3. Severe complications significantly less common
(29 versus 54 percent) Joly P, Roujeau JC, Benichou J, et al. A comparison of oral and topical corticosteroids in patients
with bullous pemphigoid. N Engl J Med. 2002;346(5):321.

33. • Administration
Same effective for attaining control
relapses more likely to occur during the one-year trial
in patients in the less aggressive treatment group
10 to 20 g per day for moderate disease and 20
to 30 g per day for extensive disease until 15
days after disease control, then tapered to
discontinuation over 4 months
vs. 40 g per day tapered slowly over
12 months
Joly P, Roujeau JC, Benichou J, et al. A comparison of two regimens of topical corticosteroids in
the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest
Dermatol. 2009;129(7):1681. Epub 2009 Jan 29.

34. • Systemic glucocorticoids
as effective treatments for BP
the response to prednisone is usually rapid
• The optimum regimen to be determined.
• typically treat patients with prednisolone with starting doses:
from 0.5 to 0.75 mg/kg per day
• continue the effective dose until active inflammation
 new blister formation, pruritus ceased for at least 2 weeks
80 percent of existing blisters have healed.
followed by a slow tapering
Joly P, Roujeau JC, Benichou J, et al. A comparison of oral
and topical corticosteroids in patients with bullous
pemphigoid. N Engl J Med. 2002;346(5):321.

35. • Glucocorticoid-sparing agents
Azathioprine (Imuran)
Data are limited on the efficacy
Mycophenolate mofetil (MMF)
methylprednisolone (0.5 mg/kg per day) + mycophenolate mofetil (2 g per day)
to methylprednisolone (0.5 mg/kg per day) + azathioprine (2 mg/kg per day)
 two regimens appeared similarly effective.
Methotrexate
• Anti-inflammatory agents
Antibiotics and nicotinamide
Dapsone
Beissert S, Werfel T, Frieling U, et al. A comparison of oral methylprednisolone plus azathioprine
or mycophenolate mofetil for the treatment of bullous pemphigoid. Arch Dermatol.
2007;143(12):1536.

36. • Refractory disease
• Intravenous immunoglobulin
2 g/kg per cycle, with cycles repeated every 4 weeks.
86 percent attained clinical improvement within three months.
serum levels of BP180 and BP230 antibodies decline
• Rituximab
targets and destroys CD20+ B and pre-B cells.
Czernik A, Toosi S, Bystryn JC, et al. Intravenous immunoglobulin in the treatment of
autoimmune bullous dermatoses: an update. Autoimmunity. 2012 Feb;45(1):111-8. Epub 2011
Sep 19.
Sami N, Ali S, Bhol KC, et al. Influence of intravenous immunoglobulin therapy on autoantibody
titres to BP Ag1 and BP Ag2 in patients with bullous pemphigoid. J Eur Acad Dermatol Venereol.
2003 Nov;17(6):641-5.

37. Back to our patient
• 2020/07/28 黃鴻怡醫師門診
S:
still skin rash over the trunk and limbs
O:
Multiple itchy red nodules with
excoriated wounds over the trunk and
legs for 6 months
Intercellular Ab (-)
Anti-BMZ (-)
Patho：
DIF：negative deposit for IgA, IgM,
IgG, C3, C4, C1q, Fibrinogen.
A:
1. Uremic pruritus
2. Aquired perforating dermatitis
3. Prurigo nodularis
P：
Sinquart cream BIDE TOPI
C.B. oint PRN TOPI
ClariTyne 10mg tab 1# HS PO