Bullous Pemphigoid

Bullous pemphigoid (BP) is the commonest autoimmune subepidermal blistering disease, classically seen in the elderly, characterised by large tense bullae on a normal or urticarial/erythematous base. The autoantibodies are directed against components of the hemidesmosome (BP180 and BP230) at the dermo-epidermal junction. It is a perennial NEET PG favourite because it offers crisp contrasts with pemphigus vulgaris on almost every parameter — depth of split, Nikolsky sign, antigen, DIF pattern, and drug of choice.

High-yield: BP = subepidermal split, elderly, tense bullae, Nikolsky negative, target antigens BP180 (BPAG2) and BP230 (BPAG1), DIF shows linear IgG and C3 along the basement membrane zone (BMZ).

Definition & Classification

Bullous pemphigoid belongs to the pemphigoid group of subepidermal autoimmune bullous diseases, distinct from the pemphigus group (intraepidermal). The unifying feature of the pemphigoid family is autoimmunity against the hemidesmosome / lamina lucida anchoring complex, producing a split below the epidermis.

The subepidermal blistering / pemphigoid spectrum includes:

Disease	Target antigen	Distinctive clue
Bullous pemphigoid	BP180 (collagen XVII), BP230	Elderly, tense bullae, pruritus, eosinophilia
Pemphigoid gestationis (herpes gestationis)	BP180 (NC16A domain)	2nd–3rd trimester pregnancy, periumbilical onset
Mucous membrane (cicatricial) pemphigoid	BP180, laminin-332 (epiligrin), β4 integrin	Scarring, ocular symblepharon, oral mucosa
Linear IgA disease	LAD-1 (cleaved BP180), 97/120 kDa	"String of pearls", drug-induced (vancomycin), children = chronic bullous disease of childhood
Epidermolysis bullosa acquisita (EBA)	Type VII collagen (anchoring fibrils, sub-lamina densa)	Trauma-prone sites, scarring, milia; salt-split = dermal/floor
Dermatitis herpetiformis	Epidermal transglutaminase (tTG3)	Coeliac association, intensely pruritic, granular IgA in dermal papillae

High-yield: Among all of these, BP and EBA both bind to the BMZ but the salt-split skin test separates them — BP binds the epidermal side (roof), EBA binds the dermal side (floor).

Etiology & Pathophysiology

The hemidesmosome target

The dermo-epidermal junction is held together by the hemidesmosome–anchoring filament complex. Two hemidesmosomal antigens are attacked in BP:

• BP180 (BPAG2 / type XVII collagen) — a transmembrane protein. Its extracellular NC16A domain is the immunodominant, pathogenic epitope. Anti-BP180 NC16A titres correlate with disease activity.
• BP230 (BPAG1) — an intracellular plakin protein linking the hemidesmosome to keratin intermediate filaments. Antibodies to it are thought to be a secondary, less pathogenic phenomenon.

Sequence of blister formation

IgG (mainly IgG4 and IgG1) binds BP180 NC16A → complement activation (classical pathway, C3) → mast cell degranulation → chemotaxis of eosinophils and neutrophils → release of proteases (eosinophil-derived, MMP-9, neutrophil elastase) → degradation of BP180 and the lamina lucida → subepidermal split with tense blister.

High-yield: Eosinophils are central to BP. There is peripheral blood eosinophilia, tissue eosinophilia, and raised serum IgE in a large proportion of patients. A subepidermal blister packed with eosinophils on histology strongly favours BP.

Triggers and associations

• Drug-induced BP: loop diuretics (furosemide), gliptins (DPP-4 inhibitors — vildagliptin, sitagliptin), penicillamine, spironolactone, some antibiotics, and immune checkpoint inhibitors (anti-PD-1). Gliptin-associated BP is increasingly tested.
• Neurological disease: strong, repeatedly demonstrated association with stroke, dementia, Parkinson's disease and multiple sclerosis (shared BP230/BP180 neuronal isoforms).
• Physical triggers: trauma, radiotherapy, UV/PUVA, burns.
• Rarely paraneoplastic, but BP is not as strongly malignancy-linked as paraneoplastic pemphigus; routine occult-malignancy hunting is age-appropriate, not BP-specific.

Clinical Features

BP is typically a disease of patients over 60–70 years. The eruption often passes through phases:

1. Prodromal / non-bullous phase — intense pruritus, with eczematous or urticarial (annular, polycyclic) plaques. Can last weeks to months and be misdiagnosed as eczema, urticaria or scabies.
2. Bullous phase — large, tense, dome-shaped bullae filled with clear (sometimes haemorrhagic) fluid, arising on normal-looking or erythematous/urticarial skin.

Key descriptive points:

• Tense bullae (because the roof is the full-thickness epidermis) — they do not rupture easily, unlike the flaccid bullae of pemphigus.
• Distribution: flexural — lower abdomen, inner/anterior thighs, groin, axillae, flexor forearms and lower legs.
• Mucosal involvement is uncommon and mild (10–30%), and when present is usually oral and non-scarring — a major contrast to pemphigus vulgaris where mucosa is the first and dominant site.
• Nikolsky sign — NEGATIVE. Lateral pressure does not extend the blister because the split is subepidermal with an intact epidermal roof.
• Bulla spread (Asboe-Hansen / "bulla-spread") sign — usually negative.
• Healing is without scarring and without milia (unlike EBA and cicatricial pemphigoid).

High-yield: A pruritic urticarial/eczematous eruption in an elderly patient that won't settle = think pre-bullous BP; ask for DIF before bullae even appear.

Diagnosis & Investigation of Choice

A confident diagnosis rests on a triad: histopathology + direct immunofluorescence (DIF) + serology.

Histopathology (lesional, fresh blister)

• Subepidermal blister with the intact epidermis forming the roof.
• Dermal infiltrate rich in eosinophils (± neutrophils); "eosinophilic spongiosis" may be seen in the urticarial phase.

Direct immunofluorescence — the GOLD STANDARD

• Take a biopsy of perilesional skin (not the blister itself).
• Shows linear deposition of IgG and C3 along the basement membrane zone in an n-serrated pattern (vs u-serrated in EBA).

High-yield (most-tested): DIF = linear IgG and C3 at the BMZ is the single best confirmatory test for BP. Contrast with pemphigus vulgaris where DIF shows intercellular ("fish-net" / chicken-wire) IgG and C3 in the epidermis.

Indirect immunofluorescence & salt-split skin

• IIF on monkey oesophagus / human skin detects circulating anti-BMZ IgG.
• Salt-split skin (SSS) technique: normal human skin is incubated in 1 M NaCl, which cleaves the skin through the lamina lucida. Patient serum is then applied:
  • BP → fluorescence on the EPIDERMAL side (roof / "blister roof"), because BP180/BP230 sit in the upper lamina lucida.
  • EBA → fluorescence on the DERMAL side (floor), because type VII collagen sits below the lamina densa.

High-yield: Salt-split skin separates roof (BP) from floor (EBA) — a classic single-best-answer item.

Serology (ELISA)

• Anti-BP180 NC16A ELISA is the most useful — high sensitivity/specificity and titres track disease activity (useful for monitoring and tapering therapy).
• Anti-BP230 ELISA is supportive.

Parameter	Bullous pemphigoid	Pemphigus vulgaris
Age	Elderly (>60)	Middle age (40–60)
Blister	Tense, subepidermal	Flaccid, intraepidermal
Nikolsky sign	Negative	Positive
Mucosa	Spared/mild, late	First & dominant, painful erosions
Antigen	BP180, BP230 (hemidesmosome)	Desmoglein 3 (± Dsg1), desmosome
Acantholysis (Tzanck)	Absent	Present (acantholytic cells)
DIF	Linear IgG/C3 at BMZ	Intercellular IgG/C3 (fish-net)
Prognosis	Better, self-limiting over years	Was fatal pre-steroids; more aggressive
Drug of choice	Topical clobetasol / oral prednisolone	Systemic steroids + rituximab

Management / Drug of Choice

Goals: heal blisters, control pruritus, minimise steroid toxicity in an elderly, comorbid population.

Stepwise approach:

1. Localised / mild–moderate BP → potent topical corticosteroid (clobetasol propionate 0.05%) applied to the whole body. Landmark trials (Joly et al.) showed whole-body superpotent topical steroid is at least as effective as, and safer than, oral prednisolone, especially in extensive disease in the elderly.
2. Moderate–severe / generalised BP → oral prednisolone 0.5 mg/kg/day, tapered as blistering controls and anti-BP180 falls.
3. Steroid-sparing / adjuvant agents: tetracyclines (doxycycline) ± nicotinamide (good evidence, used as first-line steroid-sparing), dapsone, azathioprine, mycophenolate mofetil, methotrexate.
4. Refractory disease: rituximab, omalizumab (anti-IgE — exploits the IgE/eosinophil axis), IVIG, dupilumab (emerging).

High-yield: First-line in most exam answers = potent topical steroid (clobetasol) for limited disease and oral prednisolone for widespread disease. Doxycycline ± nicotinamide is the favoured steroid-sparing combo. Dapsone is especially useful when neutrophils predominate. High-yield: Dapsone is the drug of choice for Linear IgA disease and Dermatitis herpetiformis — a common distractor. For BP, dapsone is adjuvant, not first-line.

Before starting dapsone, check G6PD levels (risk of haemolysis); watch for methaemoglobinaemia and dapsone hypersensitivity syndrome.

Complications

• Secondary bacterial infection of eroded skin → sepsis (a leading cause of death).
• Fluid, electrolyte and protein loss from extensive denudation.
• Iatrogenic — corticosteroid and immunosuppressant toxicity: infections, osteoporosis, hyperglycaemia, GI bleed — particularly hazardous in elderly comorbid patients (this drives the preference for topical steroids).
• Increased mortality: 1-year mortality is significant (often quoted ~20–40%), largely due to age, comorbidity and treatment complications rather than the skin disease itself.
• Post-inflammatory dyspigmentation (heals without scarring, unlike cicatricial pemphigoid/EBA).

Key Differentials

• Pemphigus vulgaris — flaccid blisters, Nikolsky positive, mucosa-first, intraepidermal split, fish-net DIF. (See table above.)
• Epidermolysis bullosa acquisita — subepidermal too, but trauma-prone sites, scarring, milia, dermal (floor) binding on salt-split, anti-type VII collagen.
• Linear IgA bullous dermatosis — "string of pearls / cluster of jewels" annular blisters, linear IgA (not IgG) on DIF, vancomycin-induced, commonest autoimmune bullous disease of childhood.
• Dermatitis herpetiformis — grouped intensely pruritic vesicles on extensors (elbows, knees, buttocks), granular IgA in dermal papillae, coeliac disease, responds dramatically to dapsone + gluten-free diet.
• Pemphigoid gestationis — BP180-driven, but in pregnancy, starts periumbilically.
• Bullous drug eruptions / SJS-TEN / bullous insect bites / bullous impetigo — clinical and DIF distinction.

Recently asked / exam angle

• Single-best image/clinical vignette: elderly patient, tense bullae, Nikolsky negative → answer bullous pemphigoid; then a follow-on asks for DIF (linear IgG + C3 at BMZ) or antigen (BP180/BP230).
• "Salt-split skin shows antibodies on the roof / epidermal side" → BP (floor = EBA). Recurrent assertion-reason and match-the-following item.
• Blood finding in BP → eosinophilia (and raised IgE). Histology image of subepidermal blister full of eosinophils.
• Drug of choice / steroid-sparing: topical clobetasol vs prednisolone; doxycycline + nicotinamide; and the dapsone = DH/linear IgA distractor.
• Drug triggers: gliptins (DPP-4 inhibitors) and furosemide; neurological associations (stroke/dementia/Parkinson's).
• Compare-and-contrast with pemphigus vulgaris — depth of split, Nikolsky, mucosa, Tzanck/acantholysis, DIF pattern.

Rapid revision

• BP = subepidermal, tense bullae, elderly, Nikolsky negative, pruritus.
• Antigens: BP180 (BPAG2 / collagen XVII, NC16A domain) and BP230 (BPAG1, intracellular plakin) — at the hemidesmosome.
• DIF (gold standard): linear IgG and C3 along the BMZ. Pemphigus = intercellular fish-net pattern.
• Salt-split skin: BP binds the EPIDERMAL roof; EBA binds the DERMAL floor.
• Histology: subepidermal blister rich in EOSINOPHILS; blood shows eosinophilia + ↑IgE.
• Anti-BP180 NC16A ELISA titre correlates with disease activity — best for monitoring.
• Mucosa usually spared in BP (contrast pemphigus vulgaris = mucosa first).
• First-line: potent topical steroid clobetasol (limited) / oral prednisolone (widespread); steroid-sparing = doxycycline + nicotinamide.
• Dapsone is DOC for Linear IgA disease & Dermatitis herpetiformis, only adjuvant in BP.
• Drug triggers: gliptins, furosemide, checkpoint inhibitors; strong link with neurological disease.
• Healing in BP is without scarring or milia; scarring/milia point to EBA or cicatricial pemphigoid.
• Linear IgA = "string of pearls", vancomycin, childhood (chronic bullous disease of childhood).