DermatologyTier 2Disease (DEADMAN)

Autoimmune bullous disease - bullous pemphigoid

Description

Subepidermal autoimmune blistering disease - autoantibodies against hemidesmosomal antigens of the dermo-epidermal junction
Commonest autoimmune blistering disease of adults
Tense blisters on erythematous or urticarial base; mucosal involvement uncommon (<20%) and mild
Prodrome of intense pruritus +/- urticarial/eczematous plaques for weeks-months before any blister
- "Pre-bullous" phase is where the diagnosis is missed

Variants

Non-bullous/prurigo-like - itch only, no blisters (especially in the very old)
Drug-induced - gliptins, PD-1 inhibitors
Pemphigoid gestationis - pregnancy, periumbilical, anti-BP180
Mucous membrane (cicatricial) pemphigoid - mucosa-dominant, scarring, risk of blindness
Linear IgA disease - vancomycin-induced, "string of pearls"
Epidermolysis bullosa acquisita - trauma sites, scarring, milia

Contrast with pemphigus vulgaris

	Bullous pemphigoid	Pemphigus vulgaris
Plane	Subepidermal	Intraepidermal (suprabasal)
Blister	Tense, intact	Flaccid, erodes
Mucosa	Uncommon, mild	Almost always, often first
Nikolsky	Negative	Positive
Target	BP180 (BPAG2/collagen XVII), BP230	Desmoglein 3 +/- 1
DIF	Linear IgG + C3 at BMZ	Intercellular "chicken-wire" IgG
Age	70s-80s	40-60
Untreated mortality	Low	High

Elderly - peak 70-80 yrs; incidence rises steeply after 70
~10-40 per million/yr, rising (ageing population + drug-induced cases)
M=F, slight M predominance in the very old
Blistering disease in a young adult is much more likely to be pemphigus, linear IgA or EBA

IgG (and IgE) autoantibodies vs BP180 (collagen XVII, NC16A domain) and BP230
- Anti-BP180-NC16A titre correlates with disease activity - BP230 does not
Antibody binding -> complement activation (C3) -> mast cell degranulation -> eosinophil recruitment
- Eosinophil proteases + MMP-9 + neutrophil elastase -> cleavage of collagen XVII
- -> separation at the lamina lucida -> tense subepidermal blister with intact roof
IgE anti-BP180 and Th2/eosinophil biology -> rationale for anti-IL-4R (dupilumab) and omalizumab

Triggers

Drugs - gliptins (DPP-4 inhibitors: vildagliptin, linagliptin), PD-1/PD-L1 inhibitors, loop diuretics (furosemide), spironolactone, penicillins, gliflozins
- Gliptin-associated BP: check the diabetes list in every new case; HLA-DQB103:01 association*
Neurological disease - stroke, dementia, Parkinson disease, MS (shared BP230 isoform in CNS)
Trauma, burns, radiotherapy, UV

Clinical

A. Biopsy - lesional, for histology

Subepidermal split with eosinophil-rich infiltrate; eosinophilic spongiosis in pre-bullous phase

B. Direct immunofluorescence - the diagnostic test

Perilesional normal-appearing skin (NOT the blister - the roof is lost and the antigen is destroyed)
Linear IgG and/or C3 along the basement membrane zone
- vs pemphigus: intercellular net-like/chicken-wire IgG within the epidermis

C. Serology

Indirect IF on salt-split skin - BP binds the epidermal (roof) side; EBA binds the dermal (floor) side
ELISA anti-BP180-NC16A (sensitive, correlates with activity) and anti-BP230
Peripheral eosinophilia in ~50%; total IgE often raised

Practical

Review every drug, especially gliptins and checkpoint inhibitors
Baseline: FBE, UEC, LFT, glucose/HbA1c, TPMT if azathioprine planned, bone density, hepatitis/TB screening if immunosuppression

Severity-stratified. Endpoint: control of new blistering + itch at the lowest steroid exposure.

Assess severity

A. Localised or mild

Superpotent topical corticosteroid (clobetasol propionate 0.05%) applied to the WHOLE body, ~10-40 g/day
- *Whole-body application is at least as effective as oral prednisolone and has lower mortality* - the single most important management point
- Taper by frequency once no new blisters for 2 weeks
Adjunct: doxycycline 100 mg bd (anti-inflammatory, steroid-sparing; non-inferior on 6-week blister control with better safety)
Potent topical steroid + emollient for itch; sedating antihistamine at night

B. Moderate-severe or refractory

Prednisolone 0.5 mg/kg/day, taper once controlled (>0.75 mg/kg confers no extra benefit, more harm)
Steroid-sparing immunosuppressant: methotrexate (well tolerated in the elderly), azathioprine, mycophenolate
Dupilumab - anti-IL-4Rα; RCT-proven (ADEPT/LIBERTY-BP) and now the first targeted approval for BP in the US and Japan; off-label and non-PBS in Australia - individual access required
Rituximab, omalizumab, IVIg for refractory disease

C. Drug-induced

Stop the culprit - gliptins, checkpoint inhibitors (may take months to settle; often still needs treatment)

D. Supportive - the real determinants of outcome in the elderly

Wound care: do not deroof; aspirate large tense blisters leaving the roof as a biological dressing
Non-adherent dressings, pressure area care, nutrition, analgesia
Infection is the leading cause of death - low threshold for swabs and antibiotics
Osteoporosis prophylaxis, PJP prophylaxis with prolonged high-dose steroid, glycaemic monitoring
Deprescribe; involve aged care and carers - applying whole-body clobetasol daily is not achievable alone

Neurological disease - stroke, dementia, Parkinson disease, multiple sclerosis (strong, well replicated)
DPP-4 inhibitors (gliptins) and immune checkpoint inhibitors
Psoriasis (especially after phototherapy)
Other autoimmune disease - RA, Hashimoto, pernicious anaemia
Malignancy - weak and inconsistent; routine cancer screening is NOT indicated (unlike paraneoplastic pemphigus)
Frailty and polypharmacy

Self-limiting over 1-5 years in most; relapse on withdrawal is common
1-year mortality 20-40% - far higher than the disease severity suggests
- Driven by age, comorbidity, frailty and treatment complications (sepsis, steroid harms), not by blistering
Poor prognostic markers: age >80, low Karnofsky/functional status, high-dose oral steroid requirement, cardiac disease, dementia
Relapse predictors: persistently high anti-BP180-NC16A titre and positive DIF at the end of treatment
Complications: secondary infection and sepsis, fluid/protein loss, steroid osteoporosis, diabetes, GI bleed, delirium
Aim for topical-first, steroid-sparing therapy - the treatment kills more often than the disease

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