Bullous Pemphigoid

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease of the skin, driven by circulating and tissue-bound autoantibodies against BP180 (type XVII collagen) and/or BP230 - 2 structural proteins of the hemidesmosome that anchor the epidermis to the underlying dermis at the dermal-epidermal junction (DEJ).^[1] Autoantibody binding activates complement (primarily through IgG1, generating C3 and a downstream membrane attack complex) alongside a parallel Th2-cytokine response (IL-4, IL-13, IL-31) that recruits eosinophils and mast cells to the DEJ. The combined effect strips the epidermis away from the dermis as a single intact sheet - a subepidermal split - which is why the resulting bullae are tense and do not extend or rupture with lateral pressure (a negative Nikolsky sign).^[2]

This is the key feature distinguishing BP from pemphigus vulgaris, an entirely different disease in which autoantibodies against desmoglein 1 and 3 attack the connections between keratinocytes themselves, producing an intraepidermal split, flaccid and easily ruptured blisters, a positive Nikolsky sign, and prominent early mucosal (often oral) involvement - in contrast to BP, where mucosal disease is rare.^[1]

BP is the most common autoimmune subepidermal blistering disease and predominantly affects the elderly: incidence in the general population is roughly 2.4-23 cases per million per year, rising about 10-fold to 190-232 cases per million per year in people 80 years and older, and overall incidence has increased approximately 2- to 4-fold over the past 2 decades as the population ages.^[2] BP meaningfully reduces quality of life through severe, often relentless pruritus, and carries genuine mortality risk - a meta-analysis found a nearly 3-fold increase in 1-year standardized mortality compared with the general population.^[3][2] A panel of 9 Canadian dermatologists published consensus recommendations for the diagnosis and management of BP specifically for the Canadian context in 2025, and this chapter follows that consensus closely, supplemented by the primary trial evidence it draws on.^[2]

Tense bullae on an erythematous base on the back of an 88-year-old man with bullous pemphigoid - the classic morphology described below. (Hansmuller, Wikimedia Commons, CC BY-SA 4.0)

The pre-bullous (prodromal) phase - easy to misdiagnose

BP often announces itself weeks to months before any blister appears, as intense, sometimes disabling pruritus accompanied by urticarial or eczematous-looking plaques, or excoriated papules - the itch is frequently out of proportion to how little the skin actually looks affected. This pre-bullous phase is very often mistaken for eczema, urticaria, a drug rash, or simply "itchy skin of old age," and the true diagnosis is only made once tense bullae appear, sometimes considerably later. Consider BP specifically whenever an older patient presents with new-onset pruritus, eczema-like change, or urticaria that does not behave like a typical case, especially with a plausible medication trigger (see Risk Factors).^[2]

The classic bullous phase

The hallmark presentation is intensely pruritic, tense bullae, filled with clear or occasionally hemorrhagic fluid, arising on both inflamed (erythematous or urticarial) and entirely normal-appearing skin, typically in a symmetric distribution favouring the flexural surfaces - inner thighs, groin, axillae, forearms, and lower abdomen. The trunk and limbs are affected far more often than the face, which (along with the scalp) is frequently spared.^[2] Older, ruptured bullae leave shallow erosions that, unlike pemphigus, tend to heal without significant scarring. Mucosal involvement is rare in classic BP - if mucosal disease is prominent, reconsider the diagnosis (see Assessment and Diagnosis).^[2]

Non-classical presentations

A meaningful minority of patients never develop the classic picture above. Recognized non-classical patterns include:^[2]

• Pauci-bullous or localized eczema-like disease - persistent, itchy, eczematous patches with few or no visible bullae.
• Localized disease, including pretibial BP confined to the lower legs.
• Dyshidrosiform (pompholyx-like) BP - small, deep-seated vesicles on the palms and soles.
• Prurigo nodularis-like BP - firm, intensely itchy nodules rather than blisters.

Because of this polymorphous presentation, maintain a genuinely wide differential (see Assessment and Diagnosis) rather than anchoring on "no blisters, so it can't be BP."

• Age over 70 years is the single most important risk factor, and incidence rises roughly 10-fold again after age 80 - BP should be an active consideration for any older patient with new pruritus, eczema, or urticaria.^[2]
• A personal history of a neurologic disorder - dementia, Parkinson disease, stroke, multiple sclerosis, or epilepsy - each shows an epidemiologic association with BP, though the underlying mechanism is not fully understood.^[2]
• Active BP is itself pro-inflammatory and prothrombotic, raising the risk of venous thromboembolism compared with age-matched controls - relevant when weighing immobility, hospitalization, or additional VTE risk factors in an affected patient.^[2]
• A number of medications are associated with an increased incidence of BP (medication-associated, or drug-induced, BP) - a thorough medication review is an essential part of the work-up in every newly diagnosed patient.^[2]

Medications associated with bullous pemphigoid

The table below reflects medication classes with at least moderate-strength evidence of association, from the 2025 Canadian consensus.^[2] A large UK case-control study and a separate systematic review/meta-analysis are the main sources of the odds ratios (ORs) cited.^[4][5]

The DPP-4 inhibitor signal is particularly relevant to pharmacists reviewing a diabetes regimen: it is consistent, replicated across multiple pharmacovigilance and case-control studies, and directly actionable (see Choose Initial Treatment and Special Populations for what to do once identified). For ICIs, roughly 30% of patients experience a cutaneous immune-related adverse event, and BP specifically develops in an estimated 3.5% of ICI-treated patients, with a median time to onset of about 22-29 weeks after starting therapy - though BP can also emerge after the ICI has already been stopped.^[6][2] Even with a 2- to 3-fold increase in relative risk, BP linked to any of these medication classes remains rare in absolute terms, and there is no recommendation to avoid these drugs pre-emptively in a patient with no personal history of BP.^[2]

Diagnostic approach

Diagnosis of classic BP rests on the combination of clinical morphology, compatible histopathology, and confirmatory immunofluorescence and/or serology - no single test is used in isolation.^[2]

^[2]

Biopsy technique

Take 2 separate biopsies. For routine histopathology (hematoxylin and eosin), biopsy the edge of a fresh, intact bulla - this typically shows a subepidermal split with an eosinophil-predominant inflammatory infiltrate. For direct immunofluorescence (DIF), biopsy perilesional skin (erythematous skin adjacent to a lesion is acceptable, but never a bulla itself) and place it in Michel's medium or saline - never formalin or another aldehyde-based fixative, which causes false-negative DIF results.^[2] DIF classically shows linear deposits of IgG and/or C3 along the DEJ; the precise location and serration pattern of these deposits can help distinguish BP from other subepidermal immunobullous diseases. If BP is strongly suspected clinically but the initial DIF is negative or equivocal, repeat the biopsy for DIF rather than abandoning the diagnosis.^[2]

Serology and its diagnostic performance

Circulating autoantibodies can be detected by indirect immunofluorescence on salt-split skin (IIF), which localizes IgG binding to the epidermal (roof) side of the artificially separated DEJ in BP - a key distinguishing feature from epidermolysis bullosa acquisita, in which binding localizes to the dermal (floor) side instead - or by ELISA for anti-BP180 (NC16A domain) or anti-BP230 IgG.^[2] A single-centre study of 1,125 patients reported the following diagnostic performance:^[2]

DIF has the best combined sensitivity and specificity and remains essential to a correct diagnosis in almost every case; serology is a valuable adjunct, particularly when DIF is unavailable, negative, or equivocal.^[2]

Differential diagnosis

Given how polymorphous BP can look, keep a genuinely wide differential:^[2]

• Pemphigus vulgaris - intraepidermal (not subepidermal) split, flaccid blisters, a positive Nikolsky sign, and prominent early mucosal (often oral) involvement - the single most important condition to distinguish from BP, since both the pathophysiology and the first-line topical approach differ.
• Pemphigus herpetiformis, dermatitis herpetiformis, linear IgA bullous dermatosis, bullous lichen planus, epidermolysis bullosa acquisita, bullous lupus erythematosus, and pemphigus foliaceus.
• For non-classic (pauci-bullous, eczema-like, or urticarial) presentations specifically: ordinary eczema, urticaria, prurigo nodularis, impetigo, erythema multiforme, Sweet syndrome, and Stevens-Johnson syndrome/toxic epidermal necrolysis (see that chapter) - and, in pregnancy, pemphigoid gestationis, a distinct disease (see Special Populations).

Associated work-up

A thorough medication review is essential at diagnosis, given the medication associations in Risk Factors. The association between BP and malignancy remains unclear in the literature; routine, extensive malignancy screening beyond age-appropriate cancer screening is not warranted unless prompted by specific symptoms.^[2]

• Prevent the development of new bullae and lesions.
• Heal existing lesions and erosions.
• Alleviate patient-reported symptoms - pruritus and pain - which may not correlate closely with the visible extent or number of blisters, so ask about them directly rather than relying on inspection alone.^[2]
• Minimize treatment-related morbidity and mortality - a goal in its own right, since BP predominantly affects elderly and often frail patients in whom the treatment (particularly high-dose systemic corticosteroids) can carry real risk.^[2]
• Reach control of disease activity (CDA) - the point at which new lesions and pruritic symptoms stop forming and existing lesions begin to heal - as the working treatment milestone, since no single validated severity scale has proven practical for routine clinical use.^[2]

Jointly decide with the patient (and caregiver, where relevant) what counts as "limited" disease that can realistically be managed with topical treatment alone, versus "extensive" disease warranting systemic therapy - this depends as much on the extent/location of disease and the practical time and effort of daily topical application (and whether a capable care partner is available) as on body-surface-area alone.^[2]

Skin and wound care

• Handle fragile, blistered, or eroded skin gently - avoid friction and shearing forces during transfers, dressing changes, and routine care, particularly in a bedridden or low-mobility patient.
• Use non-adherent dressings over eroded areas; large, tense bullae may be drained (leaving the blister roof intact as a natural biological dressing) at the discretion of the treating clinician, though this is not itself a treatment for the underlying disease.
• Monitor closely for signs of secondary bacterial infection in denuded skin (see Red Flags) - extensive erosions carry real fluid, protein, and thermoregulatory losses, conceptually similar to a partial-thickness burn.

Itch management

Pruritus is often the most distressing symptom and, notably, does not reliably correlate with the number or activity of visible blisters - ask about it directly rather than judging severity from the skin alone.^[2] Simple non-drug measures - lukewarm (not hot) bathing, fragrance-free emollients, loose, breathable clothing, and avoiding known individual triggers - provide modest but genuine relief alongside definitive treatment of the underlying disease.

Monitoring tools

No single validated severity scale has proven practical for routine clinical use. Consider the Itch Numeric Rating Scale (Itch NRS) for tracking pruritus in individual patients; the Bullous Pemphigoid Disease Area Index (BPDAI) and the Autoimmune Bullous Skin Disorder Intensity Score are more useful in research settings. A simple daily blister count has also been suggested as a practical activity measure some patients and caregivers can track at home.^[2]

Supporting adherence

Non-adherence to topical treatment is more common than with other routes of administration and is linked to worse clinical outcomes - a combination of patient, treatment, and disease factors drives this, and rates are often highest in elderly patients who have physical difficulty applying medication over a large body-surface area.^[2] Involve a caregiver early wherever one is available, keep the regimen as simple as realistically possible, and revisit whether a topical-only plan is still practical at each visit rather than assuming it remains so (see Choose Initial Treatment).

Patient and caregiver education

• Set expectations early: BP is a chronic, relapsing-remitting disease, and treatment courses commonly run for many months to over a year - this is not a "quick course of cream" condition.
• Explain that stopping topical or systemic treatment abruptly, rather than following the planned taper, risks a disease flare.
• Review the specific signs that should prompt the patient or caregiver to seek care promptly (see Red Flags).
• Coordinate explicitly with the patient's primary care or geriatric care team for monitoring items that fall outside dermatologic scope - bone health, glucose, blood pressure, and general frailty assessment are genuinely shared responsibilities.^[2]

Elderly and frail patients

Because BP itself is predominantly a disease of older, often multi-morbid patients, minimize systemic corticosteroid exposure as early as is clinically reasonable.^[2] Preferred dupilumab as first-choice therapy where available, given its favourable safety profile and lack of clinically significant drug-drug interactions; consider omalizumab if dupilumab is not effective or accessible, and methotrexate if not contraindicated. Avoid azathioprine in this population given hepatotoxicity risk - mycophenolate mofetil may be considered instead in appropriate scenarios. Rituximab and IVIG remain later-line options, with added caution for volume overload and other infusion-related adverse effects in frail patients.^[2]

Active malignancy, including immune-checkpoint-inhibitor-associated BP

Manage BP in a patient with active malignancy in close collaboration with the treating oncology team, though dermatology will often have more direct experience with both BP itself and with biologic therapy, and should generally lead these treatment discussions.^[2] Preferred dupilumab as first-line therapy here too, since systemic corticosteroids are frequently undesirable in a patient on active immunotherapy. Use with extreme caution rituximab in this group - though current data do not suggest it increases the risk of a second primary malignancy.^[2] Specifically consider medication-induced BP in any patient on an ICI (anti-PD-1, anti-PD-L1, or anti-CTLA-4 - see Risk Factors). If the ICI is withheld because of BP, re-challenge can be considered once control of disease activity is achieved, ideally continuing a steroid-sparing agent such as dupilumab through the re-challenge to maintain control; even so, BP results in permanent ICI discontinuation in over half of cases.^[2]

Pregnancy

Evaluate any pregnant patient with new blistering carefully for pemphigoid gestationis, a distinct, pregnancy-specific autoimmune blistering disease that must be distinguished from true BP occurring coincidentally during pregnancy.^[2] Many standard BP therapies can be used in pregnancy, but agents with known fetal risk - specifically methotrexate and mycophenolate mofetil - should be avoided.^[2] Discuss the risk-benefit profile of the remaining options with the patient and their obstetric team.

Children and adolescents

Childhood BP is rare, with 1 incidence peak in the first year of life and a second at a median age of about 8 years; mucosal involvement is more likely in early adolescence (roughly 10-13 years).^[2] Infantile BP commonly affects acral sites (hands and feet), while older children are more likely to have external genital involvement and less likely to have hand/foot involvement. Histopathology is similar to adult disease. Evidence supporting treatment is limited to case reports, but systemic corticosteroids are effective in most reported cases and may be supplemented with methotrexate, dapsone, doxycycline, or mycophenolate, dosed by weight and/or age; isolated case reports support dupilumab in adolescents and cyclosporine in infants. Reserve azathioprine, IVIG, and rituximab for resistant pediatric cases. Use topical corticosteroids with the usual pediatric precautions.^[2]

Renal impairment

Avoid methotrexate when eGFR is under 50 mL/min/1.73 m², per current Canadian product labelling; some data suggest careful use with dose reduction (as low as 5-10 mg/week) may be reasonable down to an eGFR of about 45 mL/min/1.73 m² in appropriately monitored patients, but the labelled threshold should guide routine practice.^[2] Rituximab and IVIG carry their own renal considerations (IVIG in particular can cause renal dysfunction) - dose and monitor per specialist direction.

Hepatic impairment

Azathioprine and methotrexate both carry hepatotoxicity risk and need closer monitoring, or an alternative agent, in significant hepatic impairment; mycophenolate mofetil's lower liver-toxicity profile may make it the more suitable choice in this situation.^[2]

Monitoring systemic corticosteroid therapy

Patients with BP are frequently at high risk for corticosteroid-related adverse events - including osteoporotic fracture and serious infection - and these can occur at doses of 5 mg/day or less.^[2] For any patient beginning long-term systemic corticosteroids:

• Consider vitamin D supplementation, adequate calcium intake (ideally from dietary sources), and bisphosphonate therapy for fracture prevention, alongside usual bone-density monitoring.^[2]
• Monitor blood pressure and blood glucose regularly.^[2]
• Manage predictable adverse effects per routine practice - for example, a proton pump inhibitor for corticosteroid-related gastroesophageal reflux.^[2]
• Coordinate this monitoring explicitly with the patient's primary care team, since much of it falls outside dermatologic scope.^[2]

Monitoring steroid-sparing agents

• Methotrexate: routine toxicity monitoring (CBC, liver enzymes, renal function) per usual practice; confirm eGFR before each dose adjustment.
• Azathioprine: dose according to TPMT activity where available; monitor CBC and liver enzymes regularly.
• Mycophenolate mofetil: monitor CBC and for signs of infection.
• Dapsone: screen before initiation and monitor hematologically throughout - watch specifically for hemolysis and methemoglobinemia.
• Rituximab/IVIG: monitor per specialist-directed infusion protocol, with particular attention to infusion reactions and, for IVIG, fluid status and renal function.

Disease-activity follow-up

Track patient-reported pruritus and pain alongside the visible extent of skin disease at every visit - these do not always move together.^[2] A daily blister count, kept by the patient or caregiver, is a simple, practical activity measure between visits. Reassess whether a topical-only regimen is still realistic at each visit, rather than assuming it remains so once initially agreed upon.^[2] If a steroid-sparing agent is being tapered or discontinued, do so only once the patient has been completely disease-free, with no new symptoms or flares, for at least 6 months.^[2]

1. Confirm genuine adherence to topical treatment before labelling it a failure - non-adherence is common, especially in elderly patients with reduced dexterity, mobility, or a large area to treat.^[2]
2. Lack of control after 2 weeks of appropriately dosed topical clobetasol (or an equivalent superpotent topical corticosteroid): escalate to systemic corticosteroid therapy - do not simply switch to a different topical agent.^[2]
3. Inadequate control on prednisone 0.5 mg/kg/day after 1-3 weeks: escalate toward 0.75-1.0 mg/kg/day rather than persisting at the starting dose.^[2]
4. Disease not adequately controlled by combined topical-plus-systemic corticosteroid therapy, or disease recurring during a corticosteroid taper: add a steroid-sparing agent - dupilumab first-choice, or methotrexate/azathioprine/mycophenolate mofetil/omalizumab as alternatives (see Choose Initial Treatment).^[2]
5. Failure of, or a contraindication to, first-choice and alternative steroid-sparing agents: consider dapsone for neutrophil-rich disease or heavy immunosuppression, with doxycycline as an ongoing adjunct throughout.^[2]
6. Multiple prior treatments have genuinely failed: this is the appropriate point to consider rituximab or IVIG, given their real efficacy balanced against a higher risk of serious adverse events, particularly in older patients.^[2]
7. Still refractory after the above: a JAK inhibitor (baricitinib, tofacitinib, or upadacitinib) may be considered on a case-by-case basis, recognizing the evidence is limited to case reports and the Canadian panel did not reach consensus recommending them.^[2]
8. At any point where a temporally plausible culprit medication is identified (see Risk Factors): withdraw it (outside of immune checkpoint inhibitors, which require oncology collaboration) and find an alternative agent alongside standard BP treatment - this does not replace the treatment ladder above, but should be pursued in parallel.^[2]

• Dismissing an older patient's new, severe pruritus with urticarial or eczematous plaques as "just eczema" or "senile pruritus" without considering the pre-bullous phase of BP, especially when a plausible culprit medication is present.
• Continuing to treat with topical corticosteroid alone for more than 2 weeks without disease control, rather than escalating to systemic therapy at that point.
• Treating a patient's stated pruritus or pain as adequately controlled based on the visible extent of blistering alone - the 2 do not reliably correlate.
• Choosing azathioprine over mycophenolate mofetil by default in an elderly or frail patient without weighing azathioprine's greater hepatotoxicity risk in this population.
• Prescribing methotrexate without checking eGFR, or continuing it despite eGFR falling under 50 mL/min/1.73 m².
• Missing a medication-associated cause - particularly a DPP-4 inhibitor - during medication reconciliation, and treating BP purely as "idiopathic" without a structured review.
• Stopping an immune checkpoint inhibitor unilaterally for suspected ICI-associated BP without involving the treating oncology team.
• Starting long-term systemic corticosteroids without arranging bone, gastrointestinal, glucose, and blood-pressure monitoring, on the assumption that "low-dose" steroids are risk-free - clinically significant adverse events, including fracture, occur even at 5 mg/day or less.
• Assuming a topical-only regimen agreed at diagnosis remains practical indefinitely, rather than reassessing feasibility (dexterity, mobility, caregiver support) at each visit.
• Reaching for rituximab, IVIG, or a JAK inhibitor before a genuine trial of first-line and alternative steroid-sparing agents, rather than reserving these for truly refractory disease.
• Missing mucosal involvement, atrophic scarring, or facial/scalp-predominant bullous lesions and continuing to diagnose "classic BP" rather than reconsidering pemphigus vulgaris or another blistering disease.

How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Topical Corticosteroid (First-Line)

First-line whenever practical, and an ongoing adjunct to systemic therapy. Lack of control after 2 weeks is the signal to escalate to systemic therapy, not to switch topical agents.

Systemic Corticosteroid

First-line when a topical-only regimen is not practical (extensive disease, or insufficient caregiver/nursing time for large-area topical application).

Steroid-Sparing Biologics

Dupilumab is the first-choice steroid-sparing agent given its favourable safety profile and minimal drug interactions; omalizumab is an alternative after 1st-line treatment failure.

Conventional Immunosuppressants (Steroid-Sparing)

Consider starting concomitantly with systemic corticosteroids to facilitate a safe taper.

Adjunctive Antibiotic Therapy

Not recommended as first-line monotherapy by the Canadian panel, but supported as an ongoing adjunct throughout the treatment course.

Reserved for Refractory Disease

Given the risk of serious adverse events, particularly in older patients, reserve these agents for after multiple prior treatments (steroid-sparing agents above) have failed.