Key Facts

Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease in Western countries. It predominantly affects elderly individuals and carries significant morbidity and mortality due to age-related comorbidities and treatment-related complications.

Epidemiology

• Incidence: ~6–7 per 100,000/year in UK; rising
• Median age at onset: ~80 years
• M:F ~equal or slight male predominance
• Strong association with neurological disease: dementia, stroke, Parkinson's disease, multiple sclerosis

Aetiology

• Autoimmune: IgG autoantibodies against BP180 (type XVII collagen, also called BPAG2) and BP230 (BPAG1) — hemidesmosomes at the dermal-epidermal junction
• Drug-induced: DPP-4 inhibitors (vildagliptin, sitagliptin), PD-1 checkpoint inhibitors, furosemide, spironolactone, NSAIDs
• Neurological association: strong epidemiological link — shared neural isoforms of BP180/BP230
• UV exposure: may trigger or exacerbate

Pathophysiology

• IgG autoantibodies bind BP180/BP230 at hemidesmosomes → complement activation → recruitment of eosinophils and neutrophils → release of proteases → disruption of dermal-epidermal junction → subepidermal blister formation
• Tense blisters because the full-thickness epidermis forms the blister roof

Pre-Bullous Phase

• Pruritus (may be severe) — often precedes blisters by weeks to months
• Urticarial plaques or eczematous eruption without blisters
• Frequently misdiagnosed as eczema or urticaria

Bullous Phase

• Tense blisters (1–3 cm) on erythematous or urticarial base
• Blisters do not rupture easily — subepidermal with full-thickness epidermal roof
• Often on flexural surfaces: inner thighs, forearms, axillae, abdomen
• May involve limbs and trunk; face/oral mucosa rarely affected (<20%)
• Blisters contain clear or haemorrhagic fluid
• Healing without scarring (unless secondary infection)

Nikolsky Sign

• NEGATIVE — lateral pressure on normal skin does NOT cause epidermal separation (distinguishes from pemphigus)

Red Flags

• Widespread blistering with systemic upset — may need hospitalisation
• Secondary infection of blisters (impetiginisation)
• Drug-induced BP — review medication list (especially DPP-4 inhibitors)
• Oral mucosal involvement — consider mucous membrane pemphigoid

Bedside

• Clinical assessment: distribution of blisters, Nikolsky sign, mucosal examination

Bloods

• FBC: eosinophilia (common in BP)
• BP180 and BP230 ELISA antibodies: serum — useful for diagnosis and monitoring; BP180 titre correlates with disease activity
• U&Es, glucose: baseline before immunosuppressive treatment

Biopsy

• Skin biopsy (perilesional): subepidermal blister with eosinophil-rich infiltrate
• Direct immunofluorescence (DIF): perilesional skin — linear IgG and C3 at the basement membrane zone — gold standard diagnostic test
• Indirect immunofluorescence: serum — circulating IgG binding to epidermal side of salt-split skin

Special Tests

• Salt-split skin test: IgG binds to EPIDERMAL side (roof) — distinguishes from epidermolysis bullosa acquisita (dermal side)
• Drug review: exclude drug-induced BP (DPP-4 inhibitors, checkpoint inhibitors)

Non-Pharmacological

• Wound care: non-adherent dressings for ruptured blisters, aseptic technique
• Blister management: large blisters can be aspirated with sterile needle (leave roof intact)
• Nutritional support: important in elderly with widespread disease

Pharmacological

First-line:

• Potent topical corticosteroid: clobetasol propionate 0.05% cream — apply to entire body surface BD; taper over months
• Superior to systemic prednisolone with fewer adverse effects (Burton et al. NEJM trial)
• Typical regimen: 30–40 g/day initially, taper based on new blister count

Second-line (moderate-severe or unable to apply topical):

• Prednisolone 0.5 mg/kg/day — taper over months as disease controlled
• Plus PPI (omeprazole 20 mg OD) and bone protection (alendronate 70 mg weekly + calcium/vitamin D)

Steroid-sparing agents:

• Doxycycline 200 mg OD: non-inferiority to prednisolone shown in BLISTER trial (NEJM 2017); fewer serious adverse events in elderly
• Azathioprine 1–3 mg/kg/day: check TPMT before starting
• Mycophenolate mofetil 1–1.5 g BD: alternative steroid-sparing agent
• Dapsone 50–150 mg OD: check G6PD before starting
• Rituximab: refractory cases — anti-CD20 monoclonal antibody

Referral Criteria

• All suspected BP: dermatology referral for biopsy and DIF
• Widespread or refractory disease: specialist immunobullous clinic
• Drug-induced BP: withdrawal of causative agent with dermatology input

• 1-year mortality: ~25–30% (largely driven by comorbidities and treatment complications in elderly)
• Disease is usually self-limiting: median duration 3–5 years
• Relapse rate: ~30–50% on treatment withdrawal
• Topical clobetasol: associated with lower mortality than systemic prednisolone (Burton trial)
• BLISTER trial: doxycycline non-inferior to prednisolone with fewer serious adverse events at 6 weeks
• Drug-induced BP: usually resolves after drug withdrawal (may take weeks–months)

Autoimmune Blistering Disease Comparison

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