Bullous Pemphigoid

Slide 1 · Bullous Pemphigoid

Clinical presentation • Immune pathogenesis • Morphology • Diagnosis

Autoimmune subepidermal blistering disease

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Localize bullous pemphigoid within the spectrum of blistering diseases.

Connect hemidesmosomal autoantibodies to subepidermal cleavage.

Recognize characteristic clinical, histologic and immunofluorescence patterns.

Differentiate pemphigoid from pemphigus and dermatitis herpetiformis.

Construct a rational confirmatory diagnostic approach.

Slide 3 · A characteristic clinicopathologic pattern

Clinical findings

Older individual with severe pruritus

Tense, clear-fluid blisters

Flexural or truncal involvement

Pathology findings

Subepidermal, nonacantholytic bulla

Eosinophil-rich inflammation

Linear immunoreactants at the junction

Slide 4 · Blistering diseases are classified by split level

Subcorneal

Very superficial

Pemphigus foliaceus

Roof includes superficial keratin

Suprabasal

Inside epidermis

Pemphigus vulgaris

Basal cells still attach to dermis

Subepidermal

Below epidermis

Bullous pemphigoid

Full epidermal thickness is lifted

Slide 5 · Desmosomes and hemidesmosomes have different roles

Desmosomes

Attach adjacent keratinocytes

Maintain cell-to-cell cohesion

Disrupted in pemphigus

Hemidesmosomes

Anchor basal keratinocytes

Connect epidermis to basement membrane

Targeted in bullous pemphigoid

Slide 6 · Normal epidermis is anchored to the dermis

DERMIS

EPIDERMIS

Basement membrane zone

Morphologic interpretation

Basal keratinocytes attach to the basement membrane zone.

Hemidesmosomal complexes resist separation under mechanical stress.

Schematic (not a histologic image)

Slide 7 · The level of cleavage determines blister robustness

Intraepidermal cleft

Part of the epidermis remains below the blister.

Thin roof tears more readily.

Typical of pemphigus.

Subepidermal cleft

The entire epidermis forms the roof.

Relatively robust roof produces tense bullae.

Typical of bullous pemphigoid.

Slide 8 · Bullous pemphigoid is an acquired autoimmune disease

Autoantibodies recognize proteins required for epidermal attachment.

The target structure is the hemidesmosome–basement membrane interface.

Inflammation progressively weakens dermoepidermal adhesion.

Cleavage develops beneath an otherwise cohesive epidermis.

Slide 9 · Bullous pemphigoid predominantly affects older adults

An older age distribution.

The disease may be clinically variable rather than uniformly bullous.

Age is an important clue, not a sufficient diagnostic criterion.

Slide 10 · The distribution favors flexural and truncal sites

Upper limb flexures

Flexor forearms, axillae

Trunk

Lower abdomen

Lower limb flexures

Inner thighs, groin

Slide 11 · Severe pruritus may dominate the presentation

Marked itching is a clinically important component.

Pruritic lesions may be noticed before unequivocal blisters.

Excoriations can obscure the primary eruption.

Absence of a visible tense bulla does not exclude pemphigoid.

Slide 12 · Urticarial plaques are a recognized presentation

Before blistering

Pruritic, urticarial plaques

Variable erythema

No obvious epidermal separation

As blistering develops

Tense fluid-filled bullae

Normal-looking or erythematous surrounding skin

Subepidermal cleft on tissue examination

Slide 13 · Nonbullous pemphigoid requires diagnostic suspicion

The contemporary guideline recognizes nonbullous presentations.

Histology of early lesions can be nonspecific.

Direct immunofluorescence and antibody studies are especially useful.

A negative routine section alone is insufficient to dismiss the diagnosis.

Slide 14 · The transition from inflammation to blistering

Pruritic / urticarial inflammation

Basal-layer injury and edema

Loss of epidermal attachment

Tense subepidermal bulla

Inflammatory change can precede a fully developed blister.

Slide 15 · A typical bulla is tense and filled with clear fluid

Blisters arise on erythematous or normal-appearing skin.

Intact epidermis constitutes the full blister roof.

Bullae tend to remain intact longer than in pemphigus.

Slide 16 · Bulla size varies considerably

Most bullae are described as less than 2 cm in diameter.

Robbins also describes occasional lesions measuring 4–8 cm.

Size alone does not identify the disease; Cleavage level is decisive.

Slide 17 · Blisters may occur without marked surrounding erythema

Erythematous background

Visible inflammatory skin change

Pruritus and urticarial plaques may coexist

Normal-appearing background

Tense clear-fluid bulla

Underlying immune injury may not be obvious clinically

Slide 18 · Rupture produces erosions and possible secondary injury

Intact tense bulla

Epidermal roof ruptures

Surface erosion / ulceration

Risk of secondary infection

Secondary infection can alter the expected pattern of healing.

Slide 19 · Healing is usually noncicatricial

Uncomplicated lesions generally heal without scarring.

Secondary infection can produce tissue damage and scars.

Significant scarring should prompt reconsideration of the differential.

Slide 20 · Mucosal involvement is less common than in pemphigus

Oral lesions in approximately 10–15% of affected individuals.

Oral lesions usually appear after cutaneous lesions.

Extensive mucosal disease invites evaluation for other pemphigoid phenotypes.

Slide 21 · Clinical manifestations form a continuum

Itch / urticarial plaques

Erythema and excoriation

Tense blister formation

Erosion followed by repair

Not all patients show every stage, and lesions can coexist.

Slide 22 · The autoantibody targets lie in hemidesmosomes

Basal keratinocytes

DERMIS

Red sites: Hemidesmosomal anchoring complexes

Bullous pemphigoid antigens (BPAGs) are junctional proteins.

Disrupted attachment occurs beneath basal keratinocytes.

Structural schematic

Slide 23 · BPAG2 is a demonstrated pathogenic antigen

Basal keratinocytes

DERMIS

Red sites: BP180 / BPAG2 in hemidesmosomes

Pathogenic antibodies directed against BPAG2.

BPAG2 is termed BP180 / type XVII collagen in the EADV guideline.

Structural schematic

Slide 24 · BP230 is another recognized autoantigen

BP180 / BPAG2

Transmembrane component of attachment machinery

Pathogenic autoantibodies demonstrably induce blistering

BP230 / BPAG1e

Hemidesmosomal plaque-associated antigen

Serologic marker included in contemporary investigations

Slide 25 · Immune targeting occurs at the basal cell interface

DERMIS

EPIDERMIS

Antibody binding at basement membrane zone

Basement membrane zone

Morphologic interpretation

Immunoglobulin binds proteins at the hemidesmosomal zone.

The immune signal localizes along the dermoepidermal interface.

Schematic (not a histologic image)

Slide 26 · Complement activation amplifies tissue inflammation

Autoantibodies bind BP antigens

Complement is activated

Inflammatory cells are recruited

Epidermal attachments are disrupted

Robbins explicitly describes complement-mediated inflammatory recruitment.

Slide 27 · Eosinophils are a central morphologic clue

Inflammatory recruitment

Eosinophils accumulate near basal keratinocytes

Neutrophils may be present

Lymphocytes populate perivascular sites

Morphologic consequence

Subepidermal inflammation

Basal-cell vacuolization

Progressive cleft formation

Slide 28 · Inflammation translates antibody binding into cleavage

Autoimmune recognition

Complement and leukocyte activity

Basal interface injury

Fluid-filled subepidermal space

The pathway connects the immune lesion to the clinical tense bulla.

Slide 29 · The plane of separation is subepidermal

DERMIS

EPIDERMIS

Subepidermal fluid-filled cleft

Basement membrane zone

Morphologic interpretation

The entire epidermis remains on the blister roof.

The separation occurs at the dermoepidermal interface.

Schematic (not a histologic image)

Slide 30 · Bullous pemphigoid contrasts with pemphigus mechanistically

Bullous pemphigoid

Hemidesmosomal / basement membrane targets

Basal anchoring failure

Subepidermal nonacantholytic cleft

Pemphigus

Desmoglein targets in desmosomes

Keratinocyte-to-keratinocyte failure

Intraepidermal acantholytic cleft

Slide 31 · Early lesions may be largely inflammatory

Superficial and sometimes deeper perivascular lymphocytes are seen.

Eosinophil numbers vary; Occasional neutrophils may be present.

Dermal edema may precede an overt split.

Basal-cell vacuolization is an important early change.

Slide 32 · Perivascular inflammation is not disease-specific

What it establishes

A superficial or deeper inflammatory process

Compatibility with an early inflammatory blistering lesion

What it does not establish

The exact autoantibody specificity

A confirmed bullous pemphigoid diagnosis

An unequivocal split if no bulla is present

Slide 33 · Eosinophils preferentially approach the basal layer

DERMIS

EPIDERMIS

Basement membrane zone

Morphologic interpretation

Eosinophils frequently cluster beneath basal keratinocytes.

The location connects inflammation to future epidermal detachment.

Schematic (not a histologic image)

Slide 34 · Basal vacuolization is a precursor to separation

DERMIS

EPIDERMIS

Basement membrane zone

Morphologic interpretation

The basal-cell layer develops vacuolar change.

Injury permits lifting of the epidermis and formation of a cleft.

Schematic (not a histologic image)

Slide 35 · A mature blister preserves the epidermal roof

DERMIS

EPIDERMIS

Subepidermal fluid-filled cleft

Basement membrane zone

Morphologic interpretation

An intact, full-thickness epidermis roofs the bulla.

Fluid accumulates in the subepidermal compartment.

Schematic (not a histologic image)

Slide 36 · Routine histology shows a nonacantholytic blister

The principal cleavage is beneath the epidermis.

Keratinocytes retain their intercellular attachment.

Inflammatory cells, particularly eosinophils, can accompany the bulla.

This differs from suprabasal acantholysis in pemphigus.

Slide 37 · Acantholysis is the pivotal negative finding

Acantholysis present

Loss of intercellular bridges

Rounded, dyscohesive keratinocytes

Characteristic mechanism of pemphigus

Acantholysis absent

Keratinocytes remain coherent

Whole epidermis can lift as one roof

Characteristic of bullous pemphigoid

Slide 38 · Eosinophils are informative but not pathognomonic

Eosinophils commonly appear in the dermis and blister cavity.

Their presence supports an immune-inflammatory process.

Interpret them with cleavage level and immunofluorescence.

A cell type alone cannot confirm antibody specificity.

Slide 39 · Light microscopy may be equivocal in nonbullous disease

Typical developed bulla

Clear subepidermal cleavage

Supportive eosinophil-rich infiltrate

Early or nonbullous eruption

Possible eosinophilic spongiosis

Nonspecific dermal inflammation

Confirm with immunopathology

Slide 40 · Direct immunofluorescence localizes bound antibodies

Schematic epidermis–dermis interface

Continuous linear junctional signal

IgG and/or C3 outline the basement membrane zone.

Slide 41 · The hallmark pattern is continuous and linear

Schematic epidermis–dermis interface

Continuous linear junctional signal

A continuous junctional ribbon differs from intercellular staining.

Slide 42 · Complement deposits also line the junction

Schematic epidermis–dermis interface

Linear complement deposition

Linear complement deposition in bullous pemphigoid.

Slide 43 · Pemphigus shows an intercellular fishnet pattern

Schematic epidermis–dermis interface

Intercellular keratinocyte signal

Intercellular IgG reflects desmosomal rather than basal-junction targeting.

Slide 44 · Biopsy location matters for direct immunofluorescence

Routine H&E

Choose a recent intact bulla.

Identify the level of cleavage and inflammatory cells.

Direct immunofluorescence

Sample perilesional nonbullous skin.

Place tissue in a suitable IF transport medium.

Avoid interpreting a poorly sampled negative test as exclusion.

Slide 45 · Histology and immunofluorescence are complementary

Compatible clinical eruption

Histology: Subepidermal split

DIF: Linear IgG and/or C3

Integrate findings for diagnosis

The 2022 guideline prioritizes DIF as a critical confirmation test.

Slide 46 · Circulating autoantibodies refine classification

Anti-BP180 and anti-BP230 serum antibodies can be measured.

EADV describes ELISA and indirect immunofluorescence as complementary tests.

A result requires interpretation in the clinical and tissue context.

Slide 47 · Salt-split skin helps localize serum binding

Epidermal (roof) side

Dermal (floor) side

Experimentally created split

For typical bullous pemphigoid, IgG binds the epidermal side of salt-split skin.

The roof-versus-floor pattern helps distinguish some subepidermal blistering disorders.

Schematic; Not a patient photomicrograph

Slide 48 · Integrated diagnostic evidence is more reliable

1 · Clinical phenotype

Age, itch, distribution, tense bullae

2 · Histologic evidence

Subepidermal cleavage ± eosinophils

3 · Tissue immune pattern

Linear IgG and/or C3 on direct IF

4 · Circulating antibodies

BP180/BP230 and salt-split assays when indicated

Slide 49 · Negative immunofluorescence warrants critical review

Verify sampling site, transport, and tissue adequacy.

Consider repeat biopsy if clinical suspicion remains high.

Correlate with routine histology and circulating antibodies.

Do not overrule consistent clinicopathologic evidence with an isolated technical failure.

Slide 50 · Pemphigus typically differs in blister behavior

Feature

Bullous pemphigoid

Pemphigus vulgaris

Roof

Full-thickness epidermis

Partial epidermal roof

Blister

Typically tense

Often fragile / eroded

Mucosa

Less frequent

Common

Split

Subepidermal

Suprabasal

Slide 51 · Pemphigus and pemphigoid differ microscopically

Feature

Bullous pemphigoid

Pemphigus

Cleft

Below epidermis

Within epidermis

Acantholysis

Absent

Present

Inflammation

Often eosinophil-rich

Variable

DIF

Linear junctional

Intercellular fishnet

Slide 52 · Antibody targets explain both morphology and DIF

Pemphigoid

Hemidesmosomal proteins at basal interface

Linear immune deposits

Whole-epidermis separation

Pemphigus

Intercellular desmogleins

Fishnet-pattern IgG

Acantholytic intraepidermal blister

Slide 53 · Dermatitis herpetiformis has a different clinical pattern

Bullous pemphigoid

Often older individuals

Tense bullae at flexural / truncal sites

IgG / complement at basal junction

Dermatitis herpetiformis

Grouped, intensely pruritic vesicles

Extensor surfaces and buttocks

Associated with gluten-sensitive enteropathy

Slide 54 · Dermatitis herpetiformis is neutrophilic and IgA-rich

Schematic epidermis–dermis interface

Granular signal at papillary tips

Granular IgA at dermal papillae, not continuous linear junctional deposition.

Slide 55 · The blistering differential requires multiple dimensions

Disorder

Cleft / lesion

Characteristic immune pattern

Bullous pemphigoid

Subepidermal, often eosinophils

Linear IgG/C3

Pemphigus vulgaris

Suprabasal acantholysis

Fishnet IgG

Dermatitis herpetiformis

Papillary neutrophil microabscesses

Granular papillary IgA

Epidermolysis bullosa

Inherited structural fragility

Not defined by BP antibodies

Slide 56 · Inherited epidermolysis bullosa is a distinct mechanism

Bullous pemphigoid

Acquired autoimmune injury

Usually older age

Inflammation and antibody deposition

Epidermolysis bullosa

Inherited defects in structural skin proteins

Often begins early in life

Trauma-associated mechanical blistering

Slide 57 · A rational diagnostic sequence begins with morphology

Examine age, pruritus, bullae

Identify cleft on H&E

Perform direct IF

Use circulating antibodies for classification

Exclude key mimics when morphology or antibody patterns do not agree.

Slide 58 · Clinical context must remain part of interpretation

Review how the eruption began and evolved.

Record distribution, lesion integrity, mucosal symptoms and excoriations.

Assess medication exposure and relevant comorbidities.

Choose and interpret investigations in context.

Slide 59 · Treatment focuses on controlling immune inflammation

Contemporary EADV guidance emphasizes high-potency topical corticosteroids.

Systemic approaches depend on extent, severity and treatment feasibility.

Management must be adapted to frailty, comorbidity and treatment risks.

Specific regimens require clinical judgment beyond this pathology lecture.

Slide 60 · Follow-up tracks formation of new lesions

Successful control means that new lesions or pruritic symptoms cease.

Existing lesions should begin to heal.

Disease activity and treatment toxicity both require monitoring.

Slide 61 · Case study: Tense bullae in an older adult

An older patient reports weeks of pruritus followed by tense, clear bullae on the lower abdomen and inner thighs. Histology reveals a subepidermal blister with eosinophils.

Which direct immunofluorescence pattern would best support the diagnosis?

Slide 62 · Case interpretation: Junctional immune deposition

Expected: Continuous linear IgG and/or C3 along the dermoepidermal junction.

Tense roof corresponds to full-thickness epidermal separation.

Eosinophils support the inflammatory phenotype.

A fishnet IgG pattern would suggest pemphigus instead.

Slide 63 · Case study: Pruritus without intact bullae

An older individual has persistent urticarial plaques and marked itch. A routine biopsy demonstrates eosinophilic inflammation but no definite cleft.

What important next step should be considered?

Slide 64 · Case interpretation: Biopsy for direct IF

Consider properly sampled perilesional direct immunofluorescence, integrated with serologic studies.

Nonbullous pemphigoid can precede typical blistering.

Routine H&E may be nonspecific early.

The clinical and immunopathologic evidence must be combined.

Slide 65 · Case study: Granular papillary IgA

A patient has intensely itchy grouped vesicles on elbows and buttocks. Microscopy shows neutrophils near dermal papillae; DIF demonstrates granular papillary IgA.

Which disease is more likely than bullous pemphigoid?

Slide 66 · Case interpretation: Dermatitis herpetiformis

Dermatitis herpetiformis.

Grouped extensor lesions and papillary neutrophils favor DH.

Granular papillary IgA contrasts with linear IgG/C3 in BP.

The distribution and IF pattern outweigh the shared subepidermal split.

Slide 67 · Core diagnostic synthesis

Clinical pattern

Older person • intense itch • tense blisters

Target and mechanism

BP antigens • complement • inflammatory recruitment

Morphology

Subepidermal, nonacantholytic bulla • eosinophils

Immunopathology

Linear basement membrane IgG/C3

Important differentials

Pemphigus • dermatitis herpetiformis • inherited blistering

Slide 68 · Selected references

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition. Elsevier; 2026.

Borradori L et al. Updated S2k guidelines for the management of bullous pemphigoid initiated by the EADV. J Eur Acad Dermatol Venereol. 2022. doi:10.1111/jdv.18220.