Bullous pemphigoid

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Bullous pemphigoid is the commonest autoimmune blistering disease in older adults. The earliest clue may be new relentless pruritus with urticarial or eczematous plaques and no visible blister. Once subepidermal separation develops, clear or haemorrhagic tense bullae appear, often on trunk and flexural limbs. In deeply pigmented skin, the inflammatory base may look violaceous, grey or dark brown rather than bright red; tension, itch, erosions and distribution remain reliable. A negative Nikolsky sign can support a deep split but is not a stand-alone test.

Autoantibodies against hemidesmosomal proteins recruit complement and eosinophilic inflammation at the dermal–epidermal junction. Neurological disease, frailty and polypharmacy are frequent in the affected population and substantially shape care. DPP-4 inhibitors have a recognised association, while checkpoint inhibition can produce persistent disease after cancer treatment. Association is not proof for one individual, so the medicine timeline and consequence of withdrawal belong in a multidisciplinary decision.

Treatment aims to stop new blisters, heal erosions, control itch and avoid treatment mortality. Superpotent topical corticosteroid can control even extensive disease with less systemic toxicity, but application over a large area may be impossible without carers or nursing. Doxycycline-based treatment trades some early blister control for lower serious-harm risk in selected patients. Systemic corticosteroid remains important for severe disease but creates infection, delirium, diabetes, osteoporosis and muscle-loss hazards in exactly the population most vulnerable to them.

Key points

Bullous pemphigoid usually affects older adults and may begin with weeks or months of intense itch, urticarial plaques or excoriated eczema before any blister is visible.
Established blisters are tense because the split is subepidermal; they arise on normal or inflamed skin and are less easily ruptured than pemphigus bullae.
Mucosal disease can occur but is less dominant than in pemphigus vulgaris; extensive oral, ocular or genital involvement should widen the differential and increase referral urgency.
Biopsy a fresh blister edge for routine histology and take a separate normal-appearing perilesional specimen for direct immunofluorescence in the receiving laboratory's transport medium.
Linear IgG and C3 along the basement membrane on direct immunofluorescence supports pemphigoid; serum BP180 or BP230 antibodies add evidence and may help follow difficult disease.
Review DPP-4 inhibitors, checkpoint inhibitors, diuretics and other temporal medicines, but do not stop essential treatment without coordinating the prescribing clinician and diabetes or oncology consequences.
Superpotent topical corticosteroid is the preferred disease-directed treatment when nursing support and treated area make whole-body application feasible; quantity and taper need specialist supervision.
Doxycycline 100 mg twice daily can be a safer initial systemic strategy for selected patients in whom long-term corticosteroid toxicity is a major concern, although blister control may be slower or less complete.
Oral prednisolone is used for rapidly progressive or extensive disease when topical treatment is impractical, with an explicit response-led taper and early plan to minimise cumulative exposure.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Autoimmune basement-membrane disease

Loss of tolerance generates antibodies against BP180 and BP230 components that anchor basal keratinocytes to the underlying dermis.

Neurological association

Dementia, stroke, Parkinson disease and other neurological conditions occur frequently, possibly reflecting age and shared neural and cutaneous antigens.

Medicine-associated disease

DPP-4 inhibitors, checkpoint inhibitors and selected other medicines can precede pemphigoid, with latency and persistence varying substantially.

Age-related susceptibility

Immune regulation, barrier change and multimorbidity make disease most common in later life and magnify both blister and treatment consequences.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Antibodies bind hemidesmosomes
IgG targets junctional adhesion proteins beneath basal keratinocytes, marking the basement-membrane zone for complement-driven inflammatory tissue injury.
2
Complement recruits eosinophils
Complement activation and eosinophil proteases damage anchoring structures, often producing urticarial inflammation and intense itch before separation.
3
The epidermis separates intact
Cleavage below the epidermis preserves a thick roof, creating tense blisters that resist rupture and heal without primary scarring.
4
Barrier loss drives systemic risk
When multiple bullae erode, exposed dermis loses fluid and heat and permits bacterial invasion, especially in frail or immunosuppressed patients.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Pre-bullous pruritus

New severe itch with urticarial plaques, excoriations or an eczematous eruption may precede diagnostic blisters by weeks or months.

Tense intact bullae

Firm clear or blood-stained blisters resist gentle lateral pressure because their roofs contain the full epidermal thickness.

Flexural trunk distribution

Lower abdomen, groins, axillae and limb flexures are common, although generalised and localised forms can occur.

Mucosal involvement

Oral or genital erosions occur in a minority; prominent multi-mucosal disease raises pemphigus, mucous-membrane pemphigoid or severe drug reaction.

Secondary infectionRed flag

Increasing pain, purulence, odour, spreading warmth, fever or confusion around erosions suggests bacterial complication and requires urgent reassessment.

Atypical non-bullous disease

Persistent itch, nodules or urticarial plaques in an older adult can represent non-bullous pemphigoid and warrants specialist testing when ordinary therapy fails.

Red flags requiring action

Fever, hypotension, confusion, rapidly spreading erythema, purulence, severe skin pain, extensive denudation, eye symptoms, dysphagia, inability to maintain intake or a recently started high-risk medicine requires urgent assessment for infection or another severe blistering disorder.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Routine histology from a fresh blister edgeFirst step
Why
Demonstrate the anatomical split and inflammatory pattern while preserving blister roof and adjacent skin.
Interpretation and limitations
A subepidermal blister with eosinophils supports pemphigoid but overlaps with other junctional blistering diseases, so histology is paired with immunofluorescence.
02
Direct immunofluorescence of perilesional skin
Why
Detect tissue-bound immunoglobulin and complement at an intact basement membrane.
Interpretation and limitations
A smooth linear IgG and C3 pattern supports pemphigoid; erosion, old blister centre, formalin or prolonged treatment can produce a falsely negative specimen.
03
Serum BP180 and BP230 antibodies
Why
Add non-invasive evidence and provide a quantitative trend in selected cases.
Interpretation and limitations
BP180 is more closely associated with activity, but titres are not perfectly sensitive or specific and never rescue a mismatched clinical and biopsy picture alone.
04
Indirect immunofluorescence with salt-split skin
Why
Distinguish epidermal-roof binding from floor-binding junctional disorders when routine findings are uncertain.
Interpretation and limitations
Pemphigoid antibodies usually bind the epidermal side, while epidermolysis bullosa acquisita more often binds the dermal floor; exceptions require specialist interpretation.
05
Bacterial swab and sepsis assessment
Why
Identify infection in purulent, increasingly painful or systemically complicated erosions.
Interpretation and limitations
Colonisation is common, so culture is interpreted with clinical invasion; cultures should not delay sepsis treatment when the patient is unstable.
06
Baseline treatment-safety profile
Why
Prepare for corticosteroid, doxycycline or steroid-sparing systemic treatment.
Interpretation and limitations
Record FBC, renal and liver function, glucose, blood pressure, bone and infection risk, vaccination, pregnancy relevance and interacting medicines before the selected regimen.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Pemphigus vulgaris

Fragile flaccid bullae, widespread erosions and prominent oral disease suggest an intraepidermal split with intercellular rather than linear fluorescence.

Linear IgA bullous dermatosis

Annular strings of vesicles and linear IgA along basement membrane require immunopathological distinction and a medicine trigger review.

Epidermolysis bullosa acquisita

Trauma-site blisters, scarring and milia with dermal-floor binding on salt-split testing suggest antibodies to type VII collagen.

Bullous drug eruption

A tight temporal medicine relationship, atypical target lesions, mucosal injury, skin pain or systemic features can indicate a different urgent drug reaction.

Bullous eczema or arthropod reaction

More local exposure-shaped inflammation may blister, but persistent generalised itch in an older adult warrants immune testing when treatment fails.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First diagnostic sequencePair morphology with two correctly handled biopsiesFirst stepTense blisters or otherwise unexplained severe pruritic plaques suggest autoimmune subepidermal disease.

1Examine the entire skin and mouth, eyes and genital symptoms, photograph representative fresh lesions with consent and review medicines, neurological disease and infection risk.
2Take a blister-edge specimen into formalin for routine histology and a separate normal-appearing perilesional specimen into the laboratory-specified immunofluorescence medium.
3Request BP180 and BP230 serology and specialist salt-split testing when needed, then reconcile every result with lesion age, biopsy site and treatment exposure before assigning the diagnosis.

02Preferred topical controlUse superpotent corticosteroid when delivery is feasiblePreferredPemphigoid is confirmed or strongly supported and topical application can be performed safely over all active skin.

1Dermatology defines the clobetasol quantity from disease extent, age and frailty and teaches thin application to active and recently active areas rather than individual intact blisters alone.
2Arrange carers, district nurses or admission when self-application is impossible, and protect erosions with non-adherent dressings and infection-aware washing.
3Once new blister formation stops, taper application and cumulative quantity gradually against objective activity while checking skin atrophy and systemic steroid absorption.

03Safer systemic alternativeConsider doxycycline where steroid harm dominatesAlternativeTopical delivery is impractical and immediate life-threatening blister control is not required in a patient vulnerable to oral corticosteroid toxicity.

1Confirm diagnosis and review swallowing, photosensitivity, oesophageal, pregnancy and medicine-interaction risks before prescribing doxycycline 100 mg twice daily.
2Explain that control may be less rapid than prednisolone, add local corticosteroid to limited active areas when useful and arrange early review for continuing new blisters.
3EscalationEscalate promptly if disease progresses, intake fails or infection develops, rather than extending an ineffective safer regimen merely to avoid corticosteroid.

04Extensive or refractory diseaseControl quickly then reduce systemic exposureRapid new blister formation, widespread erosions, failed topical delivery or refractory disease threatens health or function.

1Admit when needed for skin-failure care, cultures, analgesia, nutrition, glucose and fluid management and start specialist oral prednisolone, often around 0.5 mg/kg daily.
2Measure new blister count and healing and taper once control is achieved, introducing an appropriate steroid-sparing drug or biologic through specialist governance when repeated relapse prevents reduction.
3EscalationAt every escalation recheck diagnosis, adherence, application support, infection and a culprit medicine rather than assuming immune resistance automatically.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Preferred potent local immune suppression when full-area application can be delivered safely and reliably.

Clobetasol propionate 0.05% topical treatment

Apply once daily in the dermatologist-calculated whole-body quantity, often within a supervised 10–30 g daily induction range for extensive disease, then taper according to cessation of new blisters.

This extensive regimen requires specialist oversight and can exceed ordinary localised-dermatosis product limits. Monitor skin atrophy, infection, adrenal suppression, hyperglycaemia and total weekly exposure; avoid eyes and untreated infected skin.

A lower-harm systemic anti-inflammatory alternative for selected bullous pemphigoid patients at high risk from oral corticosteroid.

Doxycycline

Take 100 mg by mouth twice daily as the selected initial systemic strategy, with an early review of new-blister control and tolerability.

Swallow with ample water while upright, follow product food instructions and review oesophagitis, photosensitivity, pregnancy, severe liver disease and interactions with antacids, iron, retinoids and warfarin.

Provides rapid systemic suppression when topical delivery or doxycycline is insufficient for severe disease.

Prednisolone

Specialist induction commonly begins near 0.5 mg/kg by mouth each morning for extensive active disease, then tapers as soon as new blister formation is controlled.

Screen infection, monitor glucose, pressure, mood, delirium, muscle and bone risk and provide gastric or bone protection when indicated. Do not stop abruptly after sustained exposure and minimise cumulative dose.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Skin failure and dehydration

Widespread erosions cause fluid, protein and heat loss and can make eating, washing and movement difficult in a frail person.

Bacterial infection and sepsis

Open skin and corticosteroid exposure permit cellulitis and bloodstream infection, sometimes presenting as delirium rather than fever in later life.

Glucocorticoid morbidity

Diabetes, infection, osteoporosis, delirium, cataract and proximal weakness can exceed disease harm when oral or absorbed topical exposure accumulates.

Functional and care breakdown

Itch, dressings and whole-body treatment can overwhelm self-care, family support or residential staffing and precipitate avoidable admission.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Count new blisters over a defined interval and document healing erosions, itch, sleep and function; old blisters alone do not measure ongoing activity.
Check wounds for pain, warmth, purulence and odour and assess temperature, hydration and cognition promptly in a frail person.
During extensive topical or systemic corticosteroid use monitor skin atrophy, glucose, blood pressure, infection, mood, muscle strength, bone protection and adrenal suppression risk.
For doxycycline review swallowing technique, gastrointestinal injury, photosensitivity, interactions and whether blister control is adequate at early follow-up.
Revisit DPP-4 inhibitor or checkpoint-treatment timing with the relevant specialist and document why a medicine was continued, changed or stopped.
Repeat antibody titres only when they answer a difficult activity or relapse question; clinical control and steroid exposure remain primary outcomes.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Itch can be the blister

A non-bullous phase may last months, so new treatment-resistant pruritus in an older adult can justify pemphigoid serology and specialist review.

Tension reveals depth

A subepidermal split leaves the whole epidermis as a strong roof, explaining why pemphigoid blisters are usually firmer than pemphigus bullae.

Biopsy sites answer different questions

The blister edge shows split anatomy on histology, while nearby intact skin preserves the immune deposits required for direct fluorescence.

Topical treatment can be systemic in scale

Whole-body clobetasol reduces oral steroid harm but still absorbs systemically and succeeds only when sufficient application support exists.

Safer is not always strong enough

Doxycycline reduces major treatment harm for selected patients, yet rapidly progressive blistering still requires timely escalation when control is inadequate.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for a tense blister before considering pemphigoid in an older adult with unexplained severe pruritus.
02
Putting the direct-immunofluorescence biopsy into formalin or sampling the eroded blister centre.
03
Prescribing whole-body clobetasol without checking who can physically apply the correct quantity.
04
Continuing a safer doxycycline strategy despite ongoing rapid blister formation or inability to drink.
05
Starting systemic corticosteroid before assessing infection, diabetes, delirium and bone risk.
06
Stopping a DPP-4 inhibitor or checkpoint treatment without coordinating the disease it was prescribed to control.