Pemphigus Vulgaris & Bullous Pemphigoid

Overview & Definition

The pemphigus and pemphigoid group together constitute the archetype autoimmune blistering diseases of the skin and mucous membranes. They are unified by a single pathogenic mechanism — autoantibodies directed against structural proteins of the skin, producing a clinically visible blister — and they are distinguished from one another by two axes that the candidate must master: the anatomical level of the split (intraepidermal vs subepidermal) and the target antigen (desmogleins in pemphigus; hemidesmosomal antigens BP180 and BP230 in pemphigoid). These two axes in turn dictate the clinical picture, immunofluorescence pattern, natural history, and the treatment ladder.^[20][21]

Pemphigus (from the Greek pemphix, "blister") is defined by intraepidermal split caused by IgG autoantibodies against the cadherin-family desmosomal proteins desmoglein 1 and desmoglein 3, producing acantholysis (loss of keratinocyte-to-keratinocyte adhesion). The blisters are flaccid, lie high in the epidermis (so the roof is thin and ruptures easily), and the resulting raw erosions are extensive. Mucosal involvement is prominent, because mucosal epithelium expresses desmoglein 3 but not desmoglein 1 (see Pathophysiology). Untreated pemphigus was almost always fatal before the era of immunosuppressive treatment — historically a death sentence, now treatable but still carrying excess mortality (threefold risk of death vs matched controls in UK data) from complications of the disease and its treatment.^[14][23]

Pemphigoid ("resembling pemphigus") is defined by a subepidermal split — the blister floor is the intact basal lamina and the roof is the full-thickness epidermis, producing a thick-walled, tense, long-lasting bulla. The autoantibodies target the hemidesmosomal proteins BP180 (BPAG2, a transmembrane collagen) and BP230 (BPAG1, a cytoplasmic plakin) of the dermoepidermal junction. Because the split is beneath the entire epidermis, mucosa is typically spared and the clinical course is more indolent. Bullous pemphigoid is the single commonest autoimmune blistering disease overall, and is the dominant blistering disorder of the elderly.^[2][5]

The clinical skill, the viva answer, and the MCQ discriminator all reduce to a single pivot — recognising the blister type and confirming it with biopsy and immunofluorescence, then treating promptly with an immunosuppressive ladder in which rituximab has moved from salvage to first-line for moderate-severe pemphigus vulgaris (PEMPHIX, 2017) and is now widely used in refractory pemphigoid. The single highest-yield laboratory pearl of the entire chapter: on salt-split skin, BP antibodies bind the epidermal roof while epidermolysis bullosa acquisita antibodies bind the dermal floor.^[3][4][13]

^[1]

Classification

The two broad families subdivide into clinically important variants. Both axes must be remembered because they shift the differential, the immunofluorescence pattern, and the treatment ladder. ^[1]

The pemphigus group

1. Pemphigus vulgaris (PV) — the commonest and most severe form; IgG against Dsg3 (mucosal-dominant type) or Dsg3 + Dsg1 (mucocutaneous type). Accounts for approximately 70 percent of all pemphigus. Includes the variant pemphigus vegetans, in which vegetating, fungoid masses form in intertriginous areas (Hallopeau and Neumann subtypes).
2. Pemphigus foliaceus (PF) — superficial, IgG against Dsg1 only; subcorneal split; spares mucosa entirely (Dsg3 is intact and compensates in mucosa); presents with scaly, crusted erosions on seborrhoeic areas (face, scalp, upper trunk). Includes the endemic fogo selvagem (Brazilian PF, linked to black fly exposure and a putative environmental antigen).
3. Pemphigus erythematosus (Senear-Usher) — localised PF with lupus-like features; anti-Dsg1 plus ANA; centromedial facial seborrhoeic rash.
4. Paraneoplastic pemphigus (PNP) — IgG against desmoplakin, envoplakin, periplakin, BP230, and Dsg3; non-healing painful mucositis, polymorphous cutaneous lesions, and underlying non-Hodgkin lymphoma, chronic lymphocytic leukaemia, Castleman disease, or other neoplasms. Stormy course, high mortality.
5. Drug-induced pemphigus — thiol drugs (captopril, penicillamine) are the classic cause (direct biochemical disruption of desmogleins); non-thiol drugs (rifampicin, NSAIDs, cephalosporins, carbamazepine, penicillins) cause immune-mediated pemphigus, usually foliaceus-like.
6. IgA pemphigus — IgA against desmocollin 1/2; subcorneal pustular or intraepidermal neutrophilic pattern; responds dramatically to dapsone. ^[1]

The pemphigoid group

1. Bullous pemphigoid (BP) — the prototype; elderly; tense pruritic flexural bullae; anti-BP180/BP230; subepidermal with eosinophils.
2. Mucous membrane pemphigoid (MMP, formerly cicatricial pemphigoid) — predominantly mucosal (oral, ocular, laryngeal, genital); scarring is the hallmark; conjunctival scarring causes symblepharon, synechiae, and blindness; anti-BP180 (especially the C-terminal domain), laminin-332, or β4 integrin; urgent ophthalmology referral is non-negotiable.
3. Pemphigoid gestationis (PG, herpes gestationis) — pregnancy or immediate postpartum; intensely pruritic urticarial plaques starting periumbilically, progressing to vesicles and bullae; anti-BP180 NC16A (same target as BP, but the IgG is complement-fixing and the inflammatory response is amplified in pregnancy).
4. Linear IgA bullous dermatosis (LABD) — linear IgA along the BMZ; string-of-pearls or cluster-of-jewels annular pattern; both childhood (chronic bullous disease of childhood) and adult forms; vancomycin is the classic drug trigger; responds to dapsone.
5. Epidermolysis bullosa acquisita (EBA) — IgG against type VII collagen (anchoring fibrils); trauma-prone sites (hands, feet, elbows, knees), milia and scarring are hallmarks; salt-split binding to the dermal floor is the discriminator from BP.
6. Anti-p200 pemphigoid — IgG against the laminin β4 epitope of the p200 antigen (classically detected as anti-laminin γ1 reactivity); clinical overlap with BP and EBA; salt-split binding to the dermal floor. ^[20][18]

Epidemiology & Risk Factors

^[1]

Pemphigus vulgaris is rare (annual incidence 0.1 to 0.5 per 100,000 in most populations, up to 3 per 100,000 in endemic regions) but has striking ethnic and geographic predilection: it is markedly more common in Mediterranean, Ashkenazi Jewish, and Indian/South Asian populations, and in endemic Brazil (fogo selvagem). PV mainly affects adults in their 4th to 6th decades.^[19] The PV-associated HLA alleles DRB1*0402 and DQB1*0503 are strongly associated, supporting a T-cell-driven, MHC-II-restricted autoimmune mechanism.^[8]

Bullous pemphigoid is the commonest autoimmune subepidermal blistering disease, mainly affecting the elderly in their 8th decade without gender predilection.^[24] The UK population incidence is 4.3 per 100,000 person-years (PV 0.7 per 100,000), rising about 17 per cent per year; European rates range from 2.5 to 42.8 per million per year, highest in the oldest old — UK median age at presentation is 80 years (61 per cent female).^[23][24] A striking and exam-relevant association is with neurological disease: patients with dementia, Parkinson disease, multiple sclerosis, stroke, and epilepsy have a significantly elevated risk of BP — thought to reflect cross-reactivity between BP180 isoforms expressed in brain and skin. Other associations include psoriasis, chronic lymphocytic leukaemia, UV radiation, radiotherapy, and certain drugs (loop diuretics, PD-1/PD-L1 checkpoint inhibitors, spironolactone).^[5]

Mucous membrane pemphigoid is a rare disease, reported more often in women, and is dominated by its ocular complications. Pemphigoid gestationis is a rare complication of pregnancy (classically beginning in the second or third trimester or immediately postpartum), recurs in subsequent pregnancies, and can occur with molar pregnancy or choriocarcinoma.^[9]

Drug-induced pemphigus risk: captopril, penicillamine (thiol drugs — direct biochemical effect, may remit on withdrawal), rifampicin, NSAIDs, cephalosporins, penicillins, carbamazepine (non-thiol, immune-mediated). Drug-induced BP has been linked to loop diuretics, aldosterone antagonists, DPP-4 inhibitors, and PD-1/PD-L1 checkpoint inhibitors. ^[1]

Pathophysiology

Pemphigus vulgaris — the desmoglein compensation hypothesis

The molecular mechanism of PV is the textbook exemplar of how an autoantibody causes disease by direct loss of cell adhesion. Pathogenic IgG (predominantly IgG4 subclass, with IgG1 contributing) binds the extracellular domain of desmoglein 3 and/or desmoglein 1 — transmembrane cadherins that mediate adhesion at desmosomes. Binding has at least three downstream consequences: (1) steric hindrance — the antibody physically blocks desmoglein trans-interaction; (2) intracellular signalling — p38MAPK, Rho-GTPase, c-Myc, and EGFR cascades are activated, causing basal cell shrinkage and reorganisation; (3) complement activation and plasminogen-plasmin cascade amplifies the split. The result is suprabasal acantholysis: the keratinocytes of the lower spinous layer detach from one another but remain tethered to the basement membrane, producing the pathognomonic "row of tombstones" appearance with a single layer of basal cells lining the blister floor.^[20][8]

The desmoglein compensation hypothesis explains why Dsg3 antibodies alone cause mucosal disease but Dsg3 + Dsg1 antibodies cause mucocutaneous disease. Dsg3 is expressed in the basal and immediate suprabasal layers of both skin and mucosa; Dsg1 is expressed throughout the upper epidermis in skin but only superficially in mucosa. A patient with anti-Dsg3 alone has lost adhesion in the lower layer of mucosa (Dsg1 cannot compensate in mucosa because it is not expressed there in sufficient quantity), but in skin the upper Dsg1 holds the epidermis together — hence mucosal-dominant PV. Adding anti-Dsg1 strips compensation and produces mucocutaneous PV. A fidelity assessment of the DCH found that roughly half of published pemphigus cases contradict the simple compensation story — the hypothesis is a useful framework, not an absolute law.^[8] Pemphigus foliaceus (anti-Dsg1 only) spares mucosa because Dsg3 compensates there, and produces only superficial (subcorneal) skin lesions because the upper epidermis depends on Dsg1 alone.^[8]

Bullous pemphigoid — the subepidermal split

BP autoantibodies target two hemidesmosomal proteins: BP180 (BPAG2, type XVII collagen) — a transmembrane collagen whose non-collagenous NC16A ectodomain is the dominant antibody target — and BP230 (BPAG1) — a cytoplasmic plakin that anchors keratin intermediate filaments to the hemidesmosome. Binding triggers complement activation (C5a → eosinophil and neutrophil chemotaxis), mast-cell degranulation, and release of matrix metalloproteinases (MMP-9, MMP-2) and elastase that cleave BP180, severing the hemidesmosome and producing a subepidermal blister filled with eosinophils. The split lies beneath the entire epidermis, so the roof is thick (the full viable epidermis), producing a tense, durable bulla that lasts for days — and the oral mucosa is spared because the split is beneath, not within, the mucosa.^[5]

The tense bulla of BP and the flaccid blister of PV are the direct mechanical consequence of the split level: an intraepidermal split has a thin, friable roof that ruptures at minor trauma (PV), whereas a subepidermal split has a thick, robust roof (BP). The Nikolsky sign follows the same logic — only when the split is high in the epidermis does lateral pressure on apparently normal skin shear off the superficial layer. ^[1]

Pemphigoid gestationis

In PG the antibody targets the same NC16A domain of BP180 as in BP, but is typically an IgG1 subclass that fixes complement robustly, and the hormonal-immune milieu of pregnancy amplifies inflammation. Placental expression of MHC-II molecules (shared with the BP180 ectodomain) is thought to be the trigger; the disease frequently flares at delivery and recurs, often earlier and more severely, in subsequent pregnancies.^[9]

Clinical Presentation

Pemphigus vulgaris

The classical PV patient is a middle-aged Mediterranean/Jewish/Indian individual presenting with oral erosions that precede cutaneous blisters by weeks to months. About 80 to 90 percent of PV patients exhibit oral manifestations at some stage, and in 60 percent or more the oral lesions are the sole presenting symptom, making isolated oral disease a common first presentation — often misattributed to aphthous ulcers, oral candidiasis, or poorly fitting dentures.^[1][2]

• Mucosal lesions: painful, shallow, irregular erosions of the buccal mucosa, palate, gingiva (desquamative gingivitis), lips, tongue, oropharynx, larynx (hoarseness), conjunctiva, oesophagus (dysphagia), and genital mucosa. They rarely form intact blisters because the thin intraepidermal roof is destroyed by minor friction. Desquamative gingivitis — diffuse erythema and sloughing of the attached gingiva — is a common and easily missed pattern.
• Cutaneous lesions: flaccid, flabby blisters arising on normal or erythematous skin, rupturing within hours to leave large, raw, weeping erosions that crust and extend. The blisters spread laterally with pressure (Asboe-Hansen sign). Any site may be involved but the scalp, face, chest, axillae, and groins predominate. Nikolsky sign positive.
• Atypical presentations: isolated oral disease; vulvar or penile erosions mistaken for sexually transmitted infection; nail involvement (onychodystrophy, paronychia); ocular PV mimicking conjunctivitis. ^[1]

Bullous pemphigoid

The BP patient is elderly (typically over 70), often with comorbid neurological disease, presenting with intense pruritus weeks to months before blisters appear. A prodromal phase of eczematous, urticarial, or excoriated plaques is common and frequently misdiagnosed as eczema or scabies. ^[1]

• Cutaneous lesions: tense bullae (1 to 3 cm) on normal or erythematous skin, symmetrically distributed on flexural surfaces — inner thighs, groins, axillae, lower abdomen, flexor forearms, and lower legs. The blisters do not rupture easily and may contain clear, haemorrhagic, or purulent fluid. Pruritus is intense. Crusts and erosions follow rupture, but milia are uncommon (unlike EBA). Nikolsky sign negative.
• Mucosal involvement is uncommon (10 to 30 percent — oral, oesophageal, genital; mild, transient, non-scarring), distinguishing BP from MMP.^[24] The oral mucosa is typically spared — a high-yield discriminator.
• Atypical variants: localised BP (lower legs in women, pretibial), vesicular BP (mimicking DH), nodular/prurigo-like BP, paediatric BP, mucosal-dominant BP (overlap with MMP). ^[1]

Mucous membrane pemphigoid

MMP presents predominantly with mucosal lesions, with scarring as the defining feature. Oral involvement (90 percent) is most common — desquamative gingivitis is the single most frequent sign, with blistering and erosions of the palate and buccal mucosa. Ocular involvement (50 to 70 percent) is the feared complication: chronic conjunctivitis, subepithelial fibrosis, shortening of the fornices, symblepharon (adhesion of lid to globe), synechiae, trichiasis, corneal abrasion, and progressive blindness — often bilateral and irreversible. Laryngeal and oesophageal involvement can cause stridor, stenosis, and dysphagia. Cutaneous lesions (25 percent) are scattered tense bullae that heal with scarring and milia. Skin Nikolsky is negative. ^[1]

Pemphigoid gestationis

PG classically begins in the second or third trimester (less often immediately postpartum) with intense pruritus and urticarial plaques classically beginning in the periumbilical area, often with periumbilical targetoid lesions. The eruption spreads to the trunk, buttocks, and proximal extremities, evolving into tense vesicles and bullae. Mucosa is spared. It typically remits spontaneously weeks to months postpartum, but flares at delivery are common and it recurs earlier and more severely in subsequent pregnancies. The neonate may develop transient blistering from transplacental antibody.^[9]

Pemphigus foliaceus

PF produces superficial, scaly, crusted erosions on seborrhoeic areas (scalp, face, upper chest, back) with "cornflake" scale and no mucosal involvement. Patients rarely demonstrate intact blisters because the split is subcorneal and the roof is the thin stratum corneum. ^[1]

Exam application bank (NEET-PG / INICET)

One-line answer

Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are the two archetype autoimmune blistering diseases of the skin and mucosa, distinguished by the level of the split and the target antigen. PV: pathogenic IgG against desmoglein 3 (Dsg3, mucosal) ± desmoglein 1 (Dsg1, cutaneous) → suprabasal intraepidermal acantholysis → flaccid blisters, raw erosions, oral ulceration, positive Nikolsky sign; affects middle-aged adults (40 to 60), Mediterranean/Jewish/Indian predilection; potentially fatal without immunosuppression. BP (commonest autoimmune blistering disease overall, and especially in the elderly): IgG against BP180 (BPAG2) and BP230 (BPAG1) of the hemidesmosome → subepidermal split → tense bullae on flexural skin, pruritic, oral mucosa spared, Nikolsky negative. Diagnosis rests on a triad: skin biopsy H&E + peri-lesional direct immunofluorescence + serum ELISA. DIF: PV = intercellula

Worked stems (answer without another resource)

Stem 1 — Classic presentation. Map symptoms to mechanism; name the first investigation and first treatment step with dose/route if drug therapy is standard. ^[1]

Stem 2 — Unstable / complicated. List red flags that force immediate resuscitation, theatre, ICU, antidote, or reperfusion — and what you do in the first 15 minutes. ^[1]

Stem 3 — Atypical group. Elderly, pregnancy, child, or immunocompromised: how presentation and thresholds change. ^[1]

Stem 4 — Differential trap. Name the three closest mimics and one discriminator for each. ^[1]

Stem 5 — Disposition. Who goes home with safety-netting, who is admitted, who needs HDU/ICU/theatre, and what follow-up is mandatory. ^[1]

Rapid viva checklist

1. Definition + classification
2. Pathophysiology chain
3. Bedside signs / criteria
4. Score with exact components (if any)
5. Emergency bundle
6. Definitive therapy with doses
7. Complications of disease and of treatment
8. Special populations
9. Guideline/trial name if classic
10. Three exam traps

Coverage self-check

If you cannot answer any stem above from this page alone, re-read the matching section — the page is intended to be self-sufficient for final-prof and NEET-PG/INICET questions on Pemphigus Vulgaris & Bullous Pemphigoid.

Differential Diagnosis

The differential of an autoimmune blistering disease is wide, because blistering is a final common pathway for many insults. The high-yield strategy is to triage by blister type (flaccid vs tense), by mucosal involvement, and by Nikolsky sign, then to confirm with DIF and salt-split IIF. ^[1]

^[1]

The complete differential also includes aphthous ulcers, erythema multiforme, oral lichen planus, oral candidiasis, herpes simplex, acute contact dermatitis, porphyria cutanea tarda, bullous diabeticorum, bullous tinea, and insect bites. In any blistering disorder, the single diagnostic step is skin biopsy for H&E plus peri-lesional biopsy for DIF; serology (ELISA, IIF) confirms. ^[1]

Clinical & Bedside Assessment

A structured bedside examination of a patient with suspected autoimmune blistering disease serves two purposes — to recognise the blister type and its distribution, and to triage severity (extensive skin loss, mucosal involvement, airway compromise). ^[1]

Step 1 — recognise the blister. Document the morphology (flaccid vs tense; intact vs ruptured; vesicle, bulla, pustule, erosion, crust, scale), distribution (flexural, seborrhoeic, acral, mucosal, photo-distributed), and the number and size of lesions. Examine the scalp, postauricular skin, axillae, groins, and the entire oral mucosa (buccal, palate, gingiva, tongue, oropharynx). Evert the eyelids to inspect the conjunctiva (MMP). Photograph with a ruler in frame. ^[1]

Step 2 — elicit the Nikolsky sign. Apply firm lateral (sliding) pressure with a thumb or cotton-tipped applicator to apparently normal skin 1 to 2 cm from an active lesion. Positive Nikolsky = the superficial epidermis shears off, leaving a moist, glistening erosion. A positive Nikolsky indicates an intraepidermal split and is the single most useful bedside discriminator for pemphigus vulgaris (also positive in TEN, staphylococcal scalded skin syndrome, and severe contact dermatitis — never diagnostic alone). ^[1]

Step 3 — elicit the Asboe-Hansen sign (Nikolsky's indirect sign). Apply vertical pressure to the intact roof of an existing blister. Positive Asboe-Hansen = the blister extends laterally onto adjacent, previously unblistered skin. Specific for pemphigus; negative in BP. ^[1]

Step 4 — Tzanck smear. Gently scrape the floor of a fresh blister with a scalpel blade, smear on a glass slide, fix, and stain with Giemsa, Wright, or H&E. Acantholytic Tzanck cells — large, rounded keratinocytes with enlarged hyperchromatic nuclei and a perinuclear halo — are characteristic of pemphigus, herpesvirus infection, and Darier disease. The Tzanck smear is rapid and cheap but does NOT distinguish pemphigus from HSV (hence the dictum "Tzanck is a cytology, not a diagnosis"). It has been largely supplanted by biopsy + DIF but remains a viva favourite. ^[1]

Step 5 — screen for systemic associations and paraneoplastic disease. Examine lymph nodes, liver, spleen (for paraneoplastic pemphigus with lymphoma/CLL/Castleman); examine for neurological disease in suspected BP (dementia, Parkinson, stroke); assess nutritional status (extensive oral erosions cause malnutrition); check temperature, pulse, BP, and urine output for systemic deterioration. ^[1]

Step 6 — grade severity. The Pemphigus Disease Area Index (PDAI) grades activity in skin, scalp, mucosa, and damage; the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) incorporates body surface area and oral involvement. These scores guide treatment intensity and are research endpoints in the pemphigus trials.^[3]

Investigations

The diagnosis rests on a triad of tests performed together — never on a single test alone: ^[1]

1. Skin biopsy for H&E — from the edge of a fresh blister (including intact blister and adjacent perilesional skin). 4 mm punch, in formalin.
2. Peri-lesional biopsy for direct immunofluorescence (DIF) — 4 mm punch from normal-appearing skin immediately adjacent to an active lesion (the perilesional skin, not the blister itself, which is often false-negative due to degradation of immunoreactants), in Michel's medium or Zeus transport (NOT formalin).
3. Serum ELISA and/or indirect immunofluorescence (IIF) — to detect circulating antibody and quantify titre. ^[1]

Histology (H&E)

• PV: suprabasal intraepidermal split with a single row of basal keratinocytes adherent to the basement membrane — the "row of tombstones" — and free-floating rounded acantholytic cells (Tzanck cells) within the blister cavity. The split is high in the epidermis.
• BP: subepidermal blister with no acantholysis, typically filled with eosinophils (and neutrophils). The intact epidermis forms the roof.
• MMP: subepidermal split with mixed inflammatory infiltrate; subepithelial fibrosis in chronic lesions.
• PF: subcorneal split (very superficial) with neutrophilic or eosinophilic infiltrate.
• DH: neutrophilic microabscesses at the tips of dermal papillae. ^[1]

Direct immunofluorescence (DIF) — the diagnostic centrepiece

DIF on perilesional skin is the single highest-yield test and the most commonly examined. ^[1]

^[1]

• PV: intercellular fishnet (honeycomb) IgG ± C3 throughout the epidermis and mucosal epithelium.
• BP: continuous linear IgG and/or C3 along the basement membrane zone (BMZ).
• MMP: identical to BP — linear IgG/C3 along the BMZ (BP180 is the dominant target; laminin-332 and β4 integrin in some subtypes).
• PG: identical to BP — linear C3 (and often IgG) along the BMZ.
• LABD: linear IgA along the BMZ.
• DH: granular IgA at the tips of dermal papillae.
• EBA: linear IgG along the BMZ — only distinguished from BP by salt-split binding pattern. ^[1]

Indirect immunofluorescence (IIF) and salt-split skin

IIF detects circulating antibody in the patient's serum applied to a substrate. PV is best detected on monkey oesophagus or guinea pig oesophagus (intercellular staining); BP is best detected on human skin split through the lamina lucida (salt-split skin), where IgG binds the epidermal roof. EBA antibody binds the dermal floor — the highest-yield laboratory pearl in the chapter. MMP may show binding to both roof and floor or to the floor alone (laminin-332 MMP).^[20][18]

ELISA — quantification and monitoring

• PV: anti-Dsg3 and anti-Dsg1 ELISA — titres correlate with disease activity and predict relapse. A rising anti-Dsg3 titre heralds a flare, prompting escalation before clinical deterioration.
• BP: anti-BP180 NC16A ELISA — titres correlate with disease activity and survival; anti-BP230 ELISA is supportive.
• PG: anti-BP180 NC16A, identical antigen to BP.
• MMP: anti-BP180 (often C-terminal), anti-laminin-332, anti-α6β4 integrin. ^[1]

Adjunct investigations

• FBC, ESR, CRP, U&E, LFTs, albumin — baseline before immunosuppression; track eosinophilia (BP).
• TPMT activity before azathioprine (low activity → myelosuppression).
• G6PD level before dapsone (risk of haemolysis).
• Hepatitis B, hepatitis C, HIV, QuantiFERON-TB before rituximab (reactivation risk).
• Serum IgG and immunoglobulins before and during rituximab (hypogammaglobulinaemia risk).
• DEXA scan, HbA1c, lipid profile, BP, weight — steroid safety baseline.
• Swab of any secondarily infected erosion for bacterial culture. ^[1]

Management — Resuscitation

Autoimmune blistering disease becomes a medical emergency when skin loss is extensive — extensive pemphigus behaves like a partial-thickness burn, with the same threats of fluid and electrolyte loss, hypoproteinaemia, secondary infection, and sepsis. Before the era of immunosuppressive treatment pemphigus was almost always fatal, and even today the chronic disease and the systemic effects of treatment carry significant morbidity and mortality.^[2][14]

Supportive bundle for severe/widespread pemphigus — manage with multidisciplinary input (dermatology, otolaryngology, oral surgery), as multimodality treatment is often required:^[2]

1. Admit severe disease — extensive cutaneous and mucosal erosions, fluid and electrolyte derangement, suspected sepsis, or airway compromise; in upper aerodigestive tract disease, surgical intervention may be required to protect the airway.^[2]
2. Fluid, electrolyte and nutritional support — replace cutaneous losses, monitor electrolytes and albumin, and support intake when painful oral disease limits feeding.
3. Wound and oral care — non-adherent dressings, aseptic technique, antiseptic mouth rinses and topical anaesthesia for painful oral erosions; the skin is fragile, so handle it gently and never surgically debride.
4. Infection surveillance — daily clinical review, inflammatory markers, and swabs of suspicious lesions; treat identified Staphylococcus aureus and Gram-negative infection promptly.
5. Pain control — paracetamol-based analgesia with judicious opioids.
6. Ophthalmology review for any conjunctival involvement. ^[1]

Management — Definitive & Stepwise

Definitive management differs sharply between PV and BP because of differences in natural history, age, and severity. The pivotal trials — Ritux 3 and PEMPHIX for PV, BLISTER for BP — together with the updated European guidelines have shifted first-line therapy: rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the United States.^[14]

Pemphigus vulgaris — first-line is now rituximab + short-course prednisone (Ritux 3, PEMPHIX)

The Ritux 3 trial (Joly et al, Lancet 2017) randomly assigned 90 patients with newly diagnosed pemphigus to rituximab 1000 mg IV on days 0 and 14, plus 500 mg at months 12 and 18, combined with a short-term prednisone regimen (0.5 or 1.0 mg/kg/day tapered over 3 or 6 months) versus prednisone alone (1.0 or 1.5 mg/kg/day tapered over 12 or 18 months). At month 24, 89 percent (41 of 46) of the rituximab group versus 34 percent (15 of 44) of the prednisone-alone group were in complete remission off-therapy (absolute difference 55 percentage points; p under 0.0001), and grade 3–4 severe adverse events were fewer with rituximab (27 events in 16 patients versus 53 events in 29 patients; p = 0.0021); no patient died during the study.^[3]

The PEMPHIX trial (Werth et al, N Engl J Med 2021) compared rituximab 1000 mg IV on days 1, 15, 168 and 182 with oral mycophenolate mofetil 2 g/day, both given on the same oral glucocorticoid tapering schedule: at week 52, sustained complete remission in 40 percent versus 10 percent, a lower mean cumulative glucocorticoid dose (3545 mg versus 5140 mg), and far fewer disease flares (6 versus 44).^[15]

Stepwise ladder for PV: ^[1]

^{[3] [14] [15] [11]}

Adjunctive measures: ^[2]

• Topical and systemic corticosteroids are the mainstay of management in both PV and BP of the upper aerodigestive tract, with immunomodulating and non-steroidal anti-inflammatory drugs as adjunct or alternative therapies; multidisciplinary involvement is the rule.^[2]
• Oral disease — the oral cavity or oropharynx may be the initial site of presentation or the only site involved, so involve oral medicine and dental services early.^[2]
• Serial antibody titres — autoantibodies to Dsg3 in PV (and to BP180 in BP) correlate with disease activity, so repeat ELISA can guide treatment decisions over time.^[21]

Escalation in PV: international consensus now includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus — escalate to rituximab rather than persisting with corticosteroid monotherapy — and a rising anti-Dsg3 ELISA titre reflects increasing disease activity and can prompt treatment escalation before clinical deterioration.^[16][21]

Bullous pemphigoid — first-line is doxycycline + topical clobetasol (BLISTER)

The BLISTER trial (Williams et al, Lancet 2017) randomly assigned 253 adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement-membrane IgG or C3; mean age 77.7 years) to doxycycline 200 mg/day or prednisolone 0.5 mg/kg/day. At 6 weeks, 74 percent (83 of 112) of the doxycycline group versus 91 percent (92 of 101) of the prednisolone group had three or fewer blisters — the upper limit of the 90 percent confidence interval (26.1 percent) lay within the predefined 37 percent non-inferiority margin — and at 52 weeks related severe, life-threatening and fatal events were 18 percent (22 of 121) versus 36 percent (41 of 113) (p = 0.001). Starting with doxycycline is therefore non-inferior to oral prednisolone for short-term blister control and significantly safer in the long term.^[4]

The updated European S2K guideline (Borradori 2022) tailors treatment to severity and comorbidities: high-potency topical corticosteroids are the mainstay of treatment whenever possible, with oral prednisone 0.5 mg/kg/day as a recommended alternative; methotrexate, azathioprine or mycophenolate when corticosteroids are contraindicated or resisted; doxycycline and dapsone are controversial but may be recommended, particularly in patients with contraindications to oral corticosteroids; B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases; and omalizumab and dupilumab have recently shown promising results.^[5]

Stepwise ladder for BP: ^[1]

^{[4] [5]}

Why doxycycline? It is anti-inflammatory (inhibits matrix metalloproteinases, including those that cleave BP180), has a favourable safety profile in the elderly (compared with high-dose steroids), is cheap and oral, and provides anti-staphylococcal cover for secondarily infected lesions. Photosensitivity and oesophageal irritation are practical concerns — advise sun protection and taking with water while upright. ^[1]

Adjunctive measures in BP: antihistamines for pruritus (sedating at night — chlorphenamine, hydroxyzine; non-sedating by day — cetirizine, loratadine); bland emollients; compression bandaging for associated venous disease; frailty assessment, fall prevention, osteoporosis prophylaxis, glycaemic and BP monitoring for the elderly. ^[1]

Mucous membrane pemphigoid — early aggressive therapy to prevent scarring

MMP demands early, aggressive immunosuppression because the scarring is irreversible. The European S3 guideline (Schmidt 2021) stratifies therapy by severity.^[6]

• Mild to moderate disease: dapsone, methotrexate or tetracyclines and/or topical corticosteroids are the recommended first-line options (European S3, Schmidt 2021).^[6]
• Severe disease: dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens; recommendations are limited by the complete lack of high-quality randomised trials in MMP.^[6]
• Malignancy link — the major target antigen in MMP is type XVII collagen (BP180), but laminin 332 is recognised in 10 to 25 percent of patients, and in 25 to 30 percent of those with anti-laminin 332 reactivity a malignancy has been associated — keep this in mind at diagnosis.^[6]
• Laryngeal involvement: urgent ENT assessment — in upper aerodigestive tract blistering, surgical intervention may be required to protect the airway.^[2]

Specific Subtypes & Scenarios

Pemphigus foliaceus (PF) is managed within the same EADV S2K pemphigus guideline as PV, with systemic corticosteroids and adjunctive immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide, cyclosporine, methotrexate — none of which has led to long-term remissions) and with new targeted therapies emerging alongside them.^[14][11] Serologically, desmoglein 1 is the target antigen in PF and anti-Dsg1 levels correlate with disease activity, so titres can guide treatment decisions.^[21]

Paraneoplastic pemphigus (PNP) demands treatment of the underlying neoplasm (lymphoma, CLL, Castleman) plus systemic steroids and rituximab or cyclophosphamide; the mucositis is characteristically refractory, the lung involvement (bronchiolitis obliterans) is often fatal, and overall mortality is high. ^[1]

Drug-induced pemphigus — withdraw the offending drug (captopril, penicillamine, rifampicin, NSAIDs); thiol-drug cases may resolve without immunosuppression, while non-thiol-drug cases behave like idiopathic PV and require standard therapy. ^[1]

IgA pemphigus presents with vesicles (80.8 percent), pustules (75.0 percent) and circinate plaques (63.6 percent), is often pruritic, and shows intercellular IgA deposition on direct immunofluorescence in 97 percent of patients; IgA gammopathy (9.5 percent) and ulcerative colitis (6.6 percent) are associated. Oral dapsone and corticosteroids are the most commonly used treatments.^[17]

Linear IgA bullous dermatosis — dapsone is first-line; withdraw the offending drug (vancomycin); colchicine, sulfasalazine, IVIG for refractory. ^[1]

Pemphigoid gestationis (PG) — a pregnancy-specific pemphigoid driven by autoantibodies against BP180 and BP230 that damage the basement membrane of the skin, producing marked pruritus and blisters on the abdomen and extremities. Diagnosis is made from the characteristic clinical picture, confirmed by immunofluorescence studies and histopathology of a skin biopsy. Treatment is with corticosteroids, with a risk of relapses in subsequent pregnancies; fetal growth restriction and pre-maturity are potential fetal complications — hence the recommended combined antenatal care by a dermatologist and an obstetrician; the disease is unlikely to be a source of significant maternal morbidity or mortality.^[18]

Complications & Pitfalls

Disease-related complications of PV include secondary bacterial infection (Staphylococcus aureus, Streptococcus, Gram-negative), sepsis, fluid and electrolyte loss, hypoalbuminaemia, malnutrition (from oral disease and dysphagia), laryngeal and oesophageal strictures, ocular scarring (in ocular PV), anaemia of chronic disease, and venous thromboembolism. Untreated PV is uniformly fatal within years. ^[1]

Treatment-related complications dominate modern mortality. Corticosteroids: infection (including reactivation of TB, HBV, herpes), hyperglycaemia and new-onset diabetes, hypertension, osteoporosis and vertebral fracture, avascular necrosis of the femoral head, peptic ulcer disease, cataract and glaucoma, psychiatric disturbance (steroid psychosis, mood elevation), adrenal suppression, skin atrophy and striae, growth retardation in children. Azathioprine: hepatotoxicity, myelosuppression (especially if TPMT-deficient), pancreatitis. Mycophenolate: myelosuppression, GI upset, teratogenicity. Cyclophosphamide: haemorrhagic cystitis (mesna), bladder cancer, myelosuppression. Rituximab: infusion reactions, late-onset neutropenia, hypogammaglobulinaemia (cumulative infection risk), HBV reactivation, PML (rare), vaccine impairment (live vaccines contraindicated; non-live vaccines should ideally be given before infusion or 4 weeks before next cycle). Dapsone: haemolysis (especially G6PD-deficient), methaemoglobinaemia, agranulocytosis, dapsone hypersensitivity syndrome (DRESS — at 4–8 weeks). ^[1]

BP-specific complications in the elderly: delirium from systemic steroids, falls and fragility fractures, opportunistic pneumonia, opportunist infections, cardiovascular decompensation — all driving the pooled 23.5 per cent one-year mortality of BP (Europe 26.7, Asia 20.5, US 15.1 per cent), largely iatrogenic.^[5][24]

Pitfalls: ^[1]

• Nikolsky sign is not pathognomonic — positive in PV, TEN, SSSS, and severe contact dermatitis; never diagnostic alone.
• Tzanck smear is not a diagnosis — acantholytic cells also occur in HSV, zoster, and Darier disease.
• Missing MMP — desquamative gingivitis labelled as "oral lichen planus" for months; by the time symblepharon develops, sight is permanently threatened.
• Treating PV like a burn with surgical debridement — the skin is fragile and debridement extends the wound; pathergy is not a feature of PV, but secondary infection risk is high.
• Stopping rituximab abruptly — relapse is common; titrate to B-cell count and anti-Dsg3 titre.
• Inadequate steroid-safety bundle — every patient on long-term steroids needs bone, gastric, glycaemic, and infection prophylaxis.
• Inadequate pre-rituximab screening — HBV, HCV, HIV, TB, immunoglobulins.
• Misattributing PG to polymorphic eruption of pregnancy (PEP) — PEP spares the periumbilicus (starts in striae), PG starts periumbilically; PEP is more common and milder; PG is intensely pruritic and bullous.^[9]

Prognosis & Disposition

PV: before the era of immunosuppressive treatment, pemphigus was almost always fatal.^[14] Treated, the risk of death remains three times that of matched controls (UK adjusted hazard ratio 3.3), predominantly from steroid complications and infection.^[23] The Ritux 3 trial reported 89 percent complete remission off-therapy at month 24 with first-line rituximab plus short-term prednisone. Long-term control is now achievable for most patients.^[3]

BP: typically self-limiting over 3 to 6 years (treatment can be tapered and stopped), but 1-year mortality is high — 23.5 per cent pooled across 25 studies (Europe 26.7, Asia 20.5, US 15.1 per cent), and death risk is twice that of matched controls (adjusted hazard ratio 2.3) — driven by steroid complications, comorbidity, and neurological disease.^[24][23]. The BLISTER trial demonstrated that doxycycline-first strategies halve serious adverse events without compromising blister control.^[4][5]

MMP: chronic, relapsing; prognosis dominated by ocular scarring (irreversible) — early aggressive therapy is essential. ^[1]

PG: typically resolves weeks to months postpartum; recurs, often earlier and more severely, in subsequent pregnancies; neonatal risk of transient blistering.^[9]

Dispositions: severe/widespread PV — burn unit or ICU; ocular involvement — urgent ophthalmology; laryngeal involvement — ENT; suspected PNP — haematology-oncology; rituximab therapy — day-case infusion unit; long-term management — specialist dermatology with shared-care GP. ^[1]

Long-term monitoring: serial anti-Dsg3/Dsg1 ELISA in PV (rising titre heralds relapse, prompting escalation before clinical deterioration); PDAI/ABSIS scoring; B-cell counts and immunoglobulins on rituximab; DEXA, HbA1c, lipids, BP on steroids; FBC, LFTs on azathioprine/MMF. ^[1]

Special Populations

The elderly (BP): treatment is tailored to severity and comorbidities — high-potency topical corticosteroids are the mainstay whenever possible, and doxycycline 200 mg/day is a significantly safer initial strategy than prednisolone 0.5 mg/kg/day in this age group (BLISTER: 18 percent versus 36 percent related severe, life-threatening and fatal events at 52 weeks). Remember the strong association of BP with neurological disorders when reviewing comorbidity.^[5][4]

Pregnancy:

• Pemphigoid gestationis: corticosteroids are the treatment, with relapse risk in subsequent pregnancies; fetal growth restriction and prematurity are potential fetal complications — combined dermatology–obstetrics antenatal care is recommended.^[18]
• PV in pregnancy: treat as a high-risk pregnancy with frequent maternal and fetal monitoring. Systemic corticosteroids remain the mainstay of treatment; topical therapy should be encouraged since it may decrease the need for higher corticosteroid doses; azathioprine appears to be the safest immunosuppressive agent; intravenous immunoglobulin can provide significant benefits when available and affordable. In a critical analysis of 90 studies involving 111 pregnant PV patients, neonatal pemphigus occurred in 38 percent, fetal mortality in 9.8 percent, and post-partum flares in 37 percent — outcomes that correlated with lack of control of maternal disease — so advise conceiving during remission.^[10]

Children: juvenile PV is a rare paediatric variant with unusual features that may mimic other mucosal lesions, so diagnosis and treatment are often delayed. Primary treatment consists of systemic corticosteroids and immunosuppressive agents, with rituximab emerging as a potential alternative — a recent literature review (2014 to 2024) identified only 37 cases of juvenile PV across 16 studies, so evidence remains scarce and controlled studies are lacking for this age group.^[19]

HIV and immunocompromised: PV may be more severe and refractory; rituximab is effective but requires careful screening (HBV reactivation risk); watch for opportunistic infection. ^[1]

Transplant patients and concurrent immunosuppression: check drug interactions — azathioprine and calcineurin inhibitors share CYP/hypoxanthine pathways; TPMT testing is mandatory before azathioprine; monitor for cumulative immunosuppression (infection, lymphoma). ^[1]

Anticoagulated patients: extensive skin loss and immobility raise VTE risk — LMWH prophylaxis; warfarin/DOACs continue, but beware drug interactions with azathioprine (steroid-sparing agents rarely interact) and antibiotics used for secondary infection. ^[1]

Evidence, Guidelines & Regional Differences

^{[5] [6] [14] [16] [4] [2]}

Landmark trials: ^[3]

• Ritux 3 (Joly 2017, Lancet) — first-line rituximab 1000 mg on days 0 and 14 (plus 500 mg at months 12 and 18) with short-term prednisone versus prednisone alone: 89 percent versus 34 percent complete remission off-therapy at 24 months, with fewer grade 3–4 adverse events.^[3]
• PEMPHIX (Werth 2021, N Engl J Med) — rituximab 1000 mg on days 1, 15, 168 and 182 versus mycophenolate mofetil 2 g/day, both with the same oral glucocorticoid taper: 40 percent versus 10 percent sustained complete remission at week 52, fewer flares (6 versus 44) and a lower cumulative glucocorticoid dose.^[15]
• BLISTER (Williams 2017, Lancet) — doxycycline 200 mg/day versus prednisolone 0.5 mg/kg/day as initial therapy for BP: non-inferior for blister control at 6 weeks (74 percent versus 91 percent with three or fewer blisters, within the predefined 37 percent margin) and significantly safer at 52 weeks (18 percent versus 36 percent related severe, life-threatening and fatal events).^[4]
• European S2K BP (Borradori 2022), S3 MMP (Schmidt 2021) and S2K pemphigus (Joly 2020) — the current European guidelines standardising BP, MMP and pemphigus management; the pemphigus guideline records that rituximab is now approved as first-line treatment for moderate and severe PV in Europe and the United States.^[5][6][14]

Controversies and emerging therapies: ^[11]

• Doxycycline and dapsone in BP — their use remains controversial in the European S2K guideline, though they may be recommended, particularly in patients with contraindications to oral corticosteroids.^[5]
• BP biologics — omalizumab and dupilumab have recently shown promising results, and B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases.^[5]
• PV targeted therapies — intravenous immunoglobulin, anti-CD20 monoclonal antibodies, Bruton tyrosine kinase inhibitors, neonatal Fc receptor inhibitors and adoptive cellular transfer are in development, aiming at lasting control without long-term corticosteroids.^[11]

Exam Pearls

^{[12] [21] [13] [22] [3] [15] [4] [5] [6] [17] [18] [10]}

References24ShowHide

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2. [2]Hussain MH, Tanweer F, Sakagiannis G. Pemphigus Vulgaris and Bullous Pemphigoid of the Upper Aerodigestive Tract: A Review Article and Novel Approaches to Management ORL J Otorhinolaryngol Relat Spec, 2021.PMID 33902048
3. [3]Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial Lancet, 2017.PMID 28342637
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