Autoimmune blistering Flashcards
Associations of EBA
IBD (esp crohns), myeloma, SLE, RA, thyroiditis, dermatomyositis, amyloidosis, lymphoma, carcinoma, drug induced.
Types of EBA
1) classic - acral with alopecia and nail dystrophy
2) BP like (no milia or scarring): widespread with accentuation in skin folds
3) mucous membrane including bursting-perry with scarring alopecia. oesophageal strictures, laryngeal stenosis, ocular scarring, blindness.
DIF of EBA
SSS
Continuous, linear, IgG at BMZ, can have C3, IgA or M
SSS: dermal side.
EBA can occur at any age
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EBA is more common in asians
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Antibodies in EBA
alpha-chain 290kDa NC1 domain (collagen VII) 145kDa
Where is the blister in EBA
sublamina densa
PMN predominant
BP antigens
BPAg1 230kDa
BPag2 NC16A 180kDa
BP IF
Linear C3 and IgG at BMZ
IgG4>G1
Drugs associated with BP
Fluid Sores Caused by Prescription
Frusemide, Spironolactone/sulphasalazine, Captopril, Betablockers, PCN, penicillamine.
Potential associations with BP
Psoriasis, LP, parkinsons, dementia, stroke, MS
Triggers for BP
trauma, burns, radiotherapy, UV irradiation
BP oral cavity in %
30%
Eosinophilia in BP %
50%
Gender predominance in BP
M>F
BP in children - where
acral and vulvar
EM in BP where is the blister
Lamina lucida blister
Variants of BP
Localised variants: pretibial, vulva, peristomal, umbilical, distal end of amputated limb, sites of radiotherapy, burns
Unusual: palmo/plantar, vegetans, nodularis, vesicular TEN like, papular, eczematous, erythrodermic, LP pemphigoides
Drugs associated with MMP
penicillamine, clonidine
Antibodies and MMP
Group 1 = laminin332=5, laminin 6
Group 2= just ocular: integrin beta4
Group 3: mucosa + skin BPAG2/BP/collagen XVII/BP230
Group 4: heterogenous. variable mucosa, no skin
% of oral mucosa in MMP
85%
skin involvement in MMP
25-30%
Associations with MMP
Anti-laminin 5 (332) and adenocarcinoma,
autoimmune disease: LS
DIF MMP
linear deposits of immunoglobulins and/or complement along epithelial BMZ. Linear IgG and C3 at BMZ
Mucosa 50-90% > skin 20-50%
SSS MMP
epidermal roof mostly
but anti-laminin 5 (332): dermal
histo MMP
blister in lamina lucida with mixed infiltrate: may have plasma cells, Eos, PMNs
Ddx of cicatricial pemphigoid
PV, erosive LP, ocular pseudopemphigoid, SJS/TEN, BP, EBA, linear IgA
Herpes gestationis DIF
linear C3 at BMZ
Associations with pemphigus gestationis
Graves, hydatidiform mole, choriocarcinoma.
Pemphigus gestationis antigens
BPAg2 NC16A
Pemphigus gestationis DIF
linear C3 at BMZ
Pemphigus gestationis - mucosal involvement?
No
Pemphigus gestationis - when
4 weeks to 5 weeks post part
Pemphigus gestationis who
father more often HLA-DR2
50% 1st pregnancy, 8% of subsequent pregnancies are spared.
Pemphigus gestationis flares
post partum, menstruation, OCP
Pemphigus gestationis more likely to be prolonged if:
older age, multiparity, mucosal involvement
Pemphigus gestationis fetal prognosis
worse when early onset. Risk of low birth weight and premature
neonatal PG in 3%
SSS MMP
Epidermal (roof) except anti-laminin 5 (332): floor
MMP antigens
BPAg2 - NC16A, BPAg1, Laminin 5, type VII collagen, alpha 6integrin beta 4
MMP M>F
F
DIF MMP
Linear IgG +/- complement along epithelial BMZ (mucosa >skin). Less commonly IgA and IgM
%+ve IIF MMP
20-30% usually IgG +/-IgA
What gives a worse prognosis in children with MMP
IgA
Associations with MMP
LS
antiliminin 5 - adenoca
Drugs: penicillamine, clonidine, NSAIDS
Which HLA is MMP associated with
HLA DQ7, DQB1*0301
MMP H&E vs BP
MMP: subepidermal blister with usually fewer eosinophils in the cutaneous lymphochistiocytic infiltrate than in bullous pemphigoid. Later stage: fibrosis
All patients with MMP will have +ve DIF
false
Most commonly +ve DIF site for MMP
Conjunctiva
T/F in mmp SSS increases sensitivity of autoantibodies and is more likely to detect IgA
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MMP - genitals involved in half of female patients
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2 types of skin lesions in MMP `
Generalised blistering (looks like BP) or localised blisters on an erythematous plaque
% sites involved in MMP
85% oral
Skin 25-30%
Genitals of females in 50%
Conjunctiva
Pemphigoid gestationis occurs when
Pregnancy, hydatidiform mole, choriocarcinoma. Male more likely HLA-DR2
Pemphigoid gestationis - target antigens
BP180 >BP230
IgG and C3 (as IgG1 avidly binds C3, C3 is sometimes more often detected than the IgG themselves)
Pemphigoid gestationis - other associations
14% other autoimmune disease
Graves 10%
Hypothyroidism
vitiligo, alopecia, autoimmune thrombocytopenia
Linear IgA antigens
BP180 (shed ectodomain LAD1) , BP230, LAD285 Collagen VII
Least satisfactory DIF site for linear IgA
forearm
t/f mucosal biopsies but not necessarily the conjunctiva are positive in linear IgA
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SSS with linear IgA usually shows the binding to the dermal side
F epidermal> dermal (dermal more likely collagen VII)
IIF in linear IgA is more commonly +ve in adults than children t/f
F children 80% vs 30% adults
Linear IgA - how to do IIF
Can use blister fluid, or serum
T/F in linear IgA, IIF can use urine
F
In chronic bullous disease of childhood, the mucosa is rarely involved
F - common. However if conjunctiva scarring - consider this to be MMP
What age does chronic bullous disease of childhood usually occur?
Less than 5
Associations with linear IgA
Drugs: vancomycin, frusemide, penicillin, diclofenac, lithium
Infection, IBD
Presence of building work in home, (50% adults and 75% children)
Increase in lymphoproliferative disease in adults. Case reports of increased risk of bladder and renal cancer
Prognosis of linear IgA
Spontaneous remission after 3-6 years. Often improvement in pregnancy, but relapse post partum. No fetal problems
Treatment of linear IgA
Dapsone
Which type of EBA has the best prognosis
BP like
Bullous SLE - target antigen
Collagen VII
H&E bullous SLE
subepidermal blister with neutrophlic infiltrate, occasionally resulting in microabscesses resembling DH.
DIF bullous SLE
Linear bands of IgG, IgA, IgM and C3
T/F bullous SLE occurs when SLE flares
F
SSS bullous SLE
Floor
Tx of bullous SLE
Capstone, MTX, rituxumab
DH: family hx of coeliac disease or DH in what %
10%
DH: HLA associations
HLA DQ2, HLADR3, DQw2, HLAB8
DIF DH
Granular IgA in papillary dermis
IIF in DH
Negative for BMZ or dermal autoantibodies. But if monkey oesophagus used - IgA endomysial abs may be detected.
Usual onset of DH
20-55
T/F oral lesions do not occur in DH
F - common but asymptomatic
Associations with DH
Gluten
Thyroid disease in 30%
Lymphoma (GI)
DM, SLE, vitiligo, sjogrens
Prognosis of DH
10% remission
Do not have a reduced life expectancy, despite increased risk of lymphoma, likely due to reduced IHYD
Tx of DH
dapsone sulfapyridine Topical steroids Heparin +/-tetracyclines + nicotinamide Gluten free diet Avoid iodine products Gluten free after 2 years, maybe be able to reduce dapsone and diet after 5-10 years, protects from lymphoma.
% of PNP with an existing neoplasm
2/3
PNP IIF is +ve in what sort of epithelial
Simple, transitional and stratifying.
Associations with PNP
40% NHL, 30% CLL, 10% castlemans, 6% thymomas, 6% sarcomas, 6% waldenstroms macroglobulinaemia
Clinical features of PNP
Intractable stomatitis, pseudomembranous conjunctivitis, oesophageal, nasopharyngeal, vaginal, labia, penile, mucosal lesions. EM like lesions palms and soles.
H&E of PNP
Suprabasal acantholysis and individual keratinocytes necrosis with lymphocytes in the epidermis. Basal cell liquefactive degeneration.
PNP DIF
Intercellular and subepidermal IgG + C3.
PNP target antigens
Plains (desmoplakin, envoplakin, BP230, periplakin. ) and desmogleins
Complications of PNP
bronchiolitis obliterans - RFTs and CXray or CT
T/F the intracellular location of plakin proteins makes it unlikely that antiplakin autoabs initiate pathology in PNP because IgG cannot penetrate cell membranes.
T
After castlemans or thymoma removed, how long will it take to clear completely (PNP)
6-18/12
Drug induced pemphigus - mechanism
thiol: provoke acantholysis by increasing the activity of plasminogen activators.
Non thiol: active amide group
% of drug induced pemphigus that remits
40-50% thiols when drug withdrawn, only 15% non thiol group
Thiol drugs (sulfhydryl group)
Captopril, penicillamine
Non thiol causes of pemphigus
angiotensin II blockers, enalapril, ramapril, nifedipine, penicillin, cephalosporin, rifampicin, montelukast, hydroxychloroquine.
Susceptibility allele to drug induced pemphigus
HLADR4
Non drug triggers of pemphigus
allium family of veggies (onion, garlic, shallot, leek)
Radiotherapy, thermal burns and electrical injury
Where does fogo selvagem occur?
Brazil, Columbia, el Salvador, Paraguay and Peru, Tunisia and Libya
bg prevalence of antidesmoglein 1 abs in general population of endemic pemphigus
20% antidesmoglein 1 with non pathogenic subclasses or a non pathogenic domain of dsg1
43% have antidesmoglein 3 but significance is unknown
Risk factor for endemic PF
Black flies at the end of the rainy season. Simuliidae bites
Age group affected by endemic PF
Children and young adults.
Endemic PF - sites affected and clinical features
head and neck first. Burning sensation (wild fire), spreads aurally and may become generalised.
Endemic PF is often transferred via the placenta T/F
F - although the abs transfer, rarely does the disease occur in neonates. Desmoglein3 is more highly expressed in neonatal than adult skin and this may be protective.
World wide PV is more common than PF
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Areas of the world where PF is more common than PV
Mali, Libya, south Africa.
DIF PF
Intercellular IgG and C3, may be restricted to upper epidermis.
IIF in PF = %
85%
Areas which PF tends to occur
seborrhoeic areas - scalp, face, chest, upper back.
Clinical variants of PF
Pemphigus resembling DH (pemphigus herptiformis) Pemphigus erythematosus(senear usher)
senear usher DIF
Granular IGG and C3 at BMZ, intercellular IGG and C3 in epidermis
Tx of PF
Potent or IL steroids Prod 20-40mg/day aza, cyclophosphamide HCQ as adjuvant IVIg MTX Dapsone MMF Nicotinamide 1.5mg + minocycline 100mg daily Rituximab.
H&E PF
Dyskeratotic cells in the granular layer of older lesions with a mixed inflammatory infiltrate of eosinophils and Neutrophils in the superficial dermis.
T/F people with PV in India tend to be older than those elsewhere
F younger
Types of pemphigus
PV - variant: veterans PF - vary: PH, PE Drug induced Intercellular IGA PNP
% of pemphigus that is PV
70%
Races that more susceptible to PV
Ashkenazi Jews, Indians, eastern countries
HLA and PV
DRB10402 and DRB11401
IN Iranian pemphigus, epidemiology
Increase in OCP, pesticides, protective effect from smoking
In PV patients, Indian patients are more likely to have what
Dsg 1
Clinical features PB
Oral lesions 50-70%
Scalp, face, axillae, groins and pressure points.
Nail dystrophy and paronychia
PV - poor prognostic factors
Jews, older patients
PV, most relapse occur when
First 2 years after Dx.
2 subtypes of pemphigus vegetans
Neumann (severe) and hallopeau (mild)
Pemphigus veterans antigens
desmocollins 1 and 2 and dig 3
2 types of IgA pemphigus
1) subcorneal pustular (desmocollin 1) - associated with monoclonal IgA gammopathy
2) intraepidermal neutrophilic type (sometimes desmocollin1)
Associations with IgA pemphigus
IgA monoclonal gammopathy, HIV, IBD, gluten sensitive enteropathy, RA, thiol drugs